Complex Hereditary Spastic Paraplegia

Mendelian MONDO:0015150 Pathograph 62 Show in embeddings browser

Complex (also "complicated") hereditary spastic paraplegia (HSP) is the clinical-genetic category of HSP in which the core corticospinal-tract syndrome of progressive lower-limb spasticity and weakness is accompanied by additional neurologic or systemic abnormalities — such as thin corpus callosum, cognitive impairment or intellectual disability, peripheral neuropathy, cerebellar ataxia, distal amyotrophy, epilepsy, optic atrophy, pigmentary retinopathy, or dysarthria. It is defined in contrast to "pure" (uncomplicated) HSP, in which lower-limb spasticity with subtle dorsal-column impairment and urinary urgency are the only features. Complex HSP is not a single disease but a syndromic grouping (MONDO:0015150) spanning many spastic paraplegia (SPG) genetic loci, and it is stratified by inheritance into autosomal dominant (MONDO:0015087), autosomal recessive, and X-linked complex forms. The shared substrate is the same length-dependent, distal-predominant degeneration of the longest corticospinal-tract upper motor neuron axons (maximal in the thoracic spinal cord) and dorsal-column sensory fibers seen in pure HSP; the "complex" features arise because many of the mutated SPG proteins have pleiotropic housekeeping roles (endoplasmic reticulum morphogenesis, axonal transport, mitochondrial quality control, myelination, endolysosomal and autophagic trafficking, lipid metabolism) whose loss injures additional neuronal and glial populations beyond the corticospinal tract. Correlation between the clinical pure-versus-complex split and the underlying genetic type is imperfect: several loci can present as either form. Autosomal recessive complex forms (e.g., SPG11/spatacsin, SPG15/ZFYVE26/spastizin) are classically associated with thin corpus callosum and cognitive decline; X-linked complex forms include SPG1 (L1CAM) and SPG2 (PLP1). Individual gene-defined complex forms are carried as `has_subtypes` rows bound to their own MONDO classes beneath the three inheritance-stratified rows; see `notes` for the rule that routes a given SPG form here rather than to the pure HSP entry.

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Classifications

Harrison's Part

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Inheritance

Autosomal Dominant HP:0000006

Autosomal dominant complex HSP (MONDO:0015087) includes loci such as SPG10 (KIF5A) and complicated presentations of SPG3A/SPG4. Penetrance is age-dependent.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"Genetic penetrance in autosomal dominant HSP is age-dependent"

Autosomal dominant HSP shows age-dependent penetrance.

Autosomal Recessive HP:0000007

Autosomal recessive complex HSP includes SPG11 (spatacsin), SPG15 (ZFYVE26/spastizin), and SPG7 (paraplegin); these require biallelic pathogenic variants and are the forms most associated with thin corpus callosum and cognitive decline.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:20301389 SUPPORT Human Clinical

"SPG11 is inherited in an autosomal recessive manner."

Establishes autosomal recessive inheritance for the common complex form SPG11.

X-Linked HP:0001417

X-linked complex HSP includes SPG1 (L1CAM/L1 syndrome) and SPG2 (PLP1-related disorders).

X-linked inheritance

Show evidence (1 reference)

PMID:20301361 SUPPORT Human Clinical

"PLP1-related disorders are inherited in an X-linked manner"

PLP1-related disorders (including SPG2) are X-linked.

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Subtypes

Autosomal Dominant Complex Hereditary Spastic Paraplegia

KIF5A hgnc:6323 ALDH18A1 hgnc:9722 Autosomal dominant inheritance

Autosomal dominant forms of complex HSP (MONDO:0015087), in which dominantly transmitted spastic paraplegia is accompanied by additional neurologic features. Representative loci include SPG10 (KIF5A, with peripheral neuropathy and distal amyotrophy), SPG9 (ALDH18A1, with cataracts and other systemic features), SPG17/Silver syndrome (BSCL2, with amyotrophy of the hands), and complicated presentations of otherwise "pure" dominant loci such as SPG3A (ATL1) and SPG4 (SPAST). Penetrance is age-dependent.

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"cause both autosomal dominant HSP (SPG17), Charcot-Marie-Tooth type 2, and distal hereditary motor neuropathy type V"

SPG17 (Silver syndrome), caused by heterozygous BSCL2/seipin variants, is a representative autosomal dominant complex HSP (spastic paraplegia with distal amyotrophy), evidencing the autosomal-dominant complex-HSP subtype.

Autosomal Recessive Complex Hereditary Spastic Paraplegia

SPG11 hgnc:11226 ZFYVE26 hgnc:20761 SPG7 hgnc:11237 FA2H hgnc:21197 SPART hgnc:18514 AP4B1 hgnc:572 Autosomal recessive inheritance

Autosomal recessive forms of complex HSP, the group most strongly associated with thin corpus callosum and progressive cognitive decline. SPG11 (spatacsin) is the most common form and is characteristically associated with thin corpus callosum, intellectual disability/cognitive decline, peripheral neuropathy, and pseudobulbar involvement. SPG15 (ZFYVE26/spastizin) causes complicated autosomal-recessive spastic paraplegia including Kjellin syndrome (with pigmentary maculopathy). SPG7 (paraplegin) frequently presents with cerebellar ataxia and optic atrophy reflecting mitochondrial dysfunction. Additional characteristic autosomal recessive complex forms include SPG35 (FA2H, with leukodystrophy, seizures, and intellectual disability), SPG20/Troyer syndrome (SPART/spartin, with distal amyotrophy, dysarthria, and short stature), and the AP-4-associated HSP disorders (AP4B1/AP4M1/AP4E1/AP4S1; SPG47/50/51/52), a childhood-onset complex form with severe developmental delay and microcephaly.

Show evidence (2 references)

PMID:23897027 SUPPORT Human Clinical

"such as SPG11 HSP, a common autosomal recessive form of HSP frequently associated with mental retardation and thin corpus callosum"

Establishes SPG11 as a common autosomal recessive complex HSP defined by cognitive impairment and thin corpus callosum.

PMID:18394578 SUPPORT Human Clinical

"the identification of ZFYVE26, which encodes a zinc-finger protein with a FYVE domain that we named spastizin, as the cause of SPG15"

Identifies ZFYVE26/spastizin as the cause of SPG15, a complicated autosomal-recessive spastic paraplegia including Kjellin syndrome. Requoted from the abstract: the previous quote was taken from the paper's title and did not verify against the abstract text.

X-Linked Complex Hereditary Spastic Paraplegia

L1CAM hgnc:6470 PLP1 hgnc:9086 X-linked inheritance

X-linked forms of complex HSP. SPG1 is part of the L1CAM (L1) syndrome spectrum — X-linked complicated hereditary spastic paraplegia type 1, within a spectrum that also includes MASA syndrome (intellectual disability, aphasia, spastic paraplegia, adducted thumbs), X-linked hydrocephalus, and corpus callosum agenesis. SPG2 lies within the PLP1-related disorder spectrum, which ranges from Pelizaeus-Merzbacher disease to spastic paraplegia 2, reflecting a CNS myelin-formation defect.

Show evidence (2 references)

PMID:20301657 SUPPORT Human Clinical

"complicated hereditary spastic paraplegia type 1"

L1CAM (L1 syndrome) explicitly includes X-linked complicated hereditary spastic paraplegia type 1 (SPG1).

PMID:20301361 SUPPORT Human Clinical

"to spastic paraplegia 2 (SPG2)"

PLP1-related disorders span a phenotypic range extending to X-linked spastic paraplegia 2 (SPG2).

Troyer syndrome (SPG20, SPART) MONDO:0010156

SPART hgnc:18514 Autosomal recessive inheritance

Troyer syndrome (SPG20), caused by biallelic SPART (spartin) variants. The disease-defining report describes it as an autosomal recessive complicated hereditary spastic paraplegia occurring with high frequency in the Old Order Amish, mapped to chromosome 13q12.3, with a frameshift mutation in SPG20 (now SPART). ClinGen classifies the SPART-Troyer syndrome relationship as Definitive under autosomal recessive inheritance. The SPART record in `genetic` points at this row.

Show evidence (2 references)

PMID:12134148 SUPPORT Human Clinical

"Troyer syndrome (TRS) is an autosomal recessive complicated hereditary spastic paraplegia (HSP) that occurs with high frequency in the Old Order Amish."

Establishes Troyer syndrome as an autosomal recessive complicated (complex) HSP, which is why it is a subtype row on this entry rather than a separate entry.

CGGV:assertion_5f0c5bcd-68a3-46f2-b632-82feb28381d4-2022-12-19T170000.000Z SUPPORT Other

ClinGen gene-disease validity: SPART-Troyer syndrome is Definitive under autosomal recessive inheritance, against the same MONDO class bound here.

Autosomal recessive spastic paraplegia type 70 (MARS1) MONDO:0018422

MARS1 hgnc:6898 Autosomal recessive inheritance

SPG70, attributed to MARS1 (methionyl-tRNA synthetase 1). This is the most thinly evidenced row on the entry: a PubMed search for the SPG70 designation and for MARS1/MARS together with spastic paraplegia returned no dedicated SPG70 report, and the human evidence cited here is a childhood-onset HSP case series in which MARS was the confirmed genetic etiology in two of sixteen patients. ClinGen has not curated MARS1 against any HSP entity; its only MARS1 record is Charcot-Marie-Tooth disease (Limited, autosomal dominant). The autosomal recessive designation follows the bound MONDO class label.

Show evidence (1 reference)

PMID:35303589 SUPPORT Human Clinical

"Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1)."

MARS (now MARS1) was the confirmed genetic etiology in two patients of a childhood-onset hereditary spastic paraplegia cohort, which is the human evidence available for this gene-disease pair.

Autosomal recessive spastic paraplegia type 76 (CAPN1) MONDO:0014827

CAPN1 hgnc:1476 Autosomal recessive inheritance

SPG76, caused by biallelic CAPN1 (calpain 1) variants. Rare homozygous and compound heterozygous nonsense, missense, frameshift and splice-site CAPN1 variants were identified in nine affected individuals from three autosomal recessive HSP families and segregated with disease. Calpain 1 is a CNS protease implicated in synaptic plasticity and in axon maturation and maintenance, which is why CAPN1 is also bound on the corticospinal-tract axonal degeneration node.

Show evidence (1 reference)

PMID:27153400 SUPPORT Human Clinical

"mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76])"

Identifies biallelic CAPN1 variants as the cause of SPG76 in three autosomal recessive HSP families, with segregation confirmed.

Autosomal recessive spastic paraplegia type 78 (ATP13A2) MONDO:0014975

ATP13A2 hgnc:30213 Autosomal recessive inheritance

SPG78, caused by biallelic ATP13A2 variants. ATP13A2 is allelic with Kufor-Rakeb syndrome, which dismech curates as its own entry (Kufor-Rakeb_syndrome, MONDO:0011706); the SPG78 presentation is recorded here because the defining report frames it as complicated hereditary spastic paraplegia added to the clinical continuum of ATP13A2-associated disorders, dominated by adult-onset lower-limb predominant spastic paraparesis. ClinGen's only ATP13A2 record is Kufor-Rakeb syndrome (Definitive), not SPG78.

Show evidence (2 references)

PMID:28137957 SUPPORT Human Clinical

"In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2."

Identifies a homozygous ATP13A2 variant in a family with complicated HSP, the observation on which the SPG78 designation rests.

PMID:28137957 SUPPORT BACKGROUND Human Clinical

"Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome"

Records the allelic relationship that makes the lump/split ruling necessary: the same gene underlies Kufor-Rakeb syndrome, which is a separate dismech entry.

Glutamate pyruvate transaminase 2 deficiency MONDO:0014567

GPT2 hgnc:18062 Autosomal recessive inheritance

GPT2 deficiency, caused by biallelic loss-of-function GPT2 variants. Affected individuals in the defining kindreds were ascertained for intellectual and developmental disability, showed postnatal microcephaly, and most of those followed over time developed a progressive spastic paraplegia, which is why the disease is recorded on this entry. ClinGen classifies the GPT2-GPT2 deficiency relationship as Definitive under autosomal recessive inheritance against the same MONDO class bound here.

Show evidence (3 references)

PMID:27601654 SUPPORT Human Clinical

"We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD)."

Establishes autosomal recessive GPT2 variants as the cause of this disease in the defining kindreds.

PMID:27601654 SUPPORT Human Clinical

"all affected individuals show postnatal microcephaly"

Records the postnatal microcephaly that accompanies the spastic paraplegia, the complicating feature that places this disease under complex HSP.

CGGV:assertion_42a70a83-40da-4acc-b6a3-9ef3942abd14-2021-10-05T115427.845Z SUPPORT Other

ClinGen gene-disease validity: GPT2-glutamate pyruvate transaminase 2 deficiency is Definitive under autosomal recessive inheritance, against the same MONDO class bound here.

Hereditary sensory and autonomic neuropathy with spastic paraplegia (CCT5) MONDO:0009748

CCT5 hgnc:1618 Autosomal recessive inheritance

Mutilating sensory neuropathy with spastic paraplegia, caused by a CCT5 missense variant in a consanguineous Moroccan family with four affected members. CCT5 encodes the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1. ClinGen has no CCT5 gene-disease validity record.

Show evidence (2 references)

PMID:16399879 SUPPORT Human Clinical

"A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated."

Defines the clinical entity - mutilating sensory neuropathy with spastic paraplegia - in the family in which the causal gene was found.

PMID:16399879 SUPPORT Human Clinical

"Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4"

Identifies the CCT5 missense variant segregating in that family, the basis for binding CCT5 to this subtype.

Hereditary spastic paraplegia 15 (ZFYVE26, Kjellin syndrome) MONDO:0010044

ZFYVE26 hgnc:20761 Autosomal recessive inheritance

SPG15, caused by biallelic truncating ZFYVE26 (spastizin) variants; six different truncating mutations segregated with disease in eight families whose phenotype included variable features of Kjellin syndrome. Spastizin colocalizes partially with endoplasmic reticulum and endosomal markers, which is why ZFYVE26 is also bound on the endolysosomal and ESCRT membrane-traffic node. The ZFYVE26 record in `genetic` points at this row. ClinGen has no ZFYVE26 gene-disease validity record.

Show evidence (1 reference)

PMID:18394578 SUPPORT Human Clinical

"Six different truncating mutations were found to segregate with the disease in eight families with a phenotype that included variable clinical features of Kjellin syndrome."

Establishes biallelic truncating ZFYVE26 variants as the cause of SPG15 across eight families, including the Kjellin-syndrome presentation.

Hereditary spastic paraplegia 18 (ERLIN2) MONDO:0012639

ERLIN2 hgnc:1356 Autosomal recessive inheritance

SPG18, caused by ERLIN2 variants. ClinGen holds two ERLIN2 records against this same MONDO class: autosomal recessive is Definitive and autosomal dominant is Limited, so the recessive form is the one this row treats as established. ERLIN2 acts in inositol 1,4,5-trisphosphate receptor degradation, which is why it is bound on the endoplasmic reticulum calcium-release node alongside RNF170.

Show evidence (2 references)

CGGV:assertion_9599fa0e-da62-437d-8f6f-2f2ef0297c8c-2025-06-18T190000.000Z SUPPORT Other

ClinGen gene-disease validity: ERLIN2-hereditary spastic paraplegia 18 is Definitive under autosomal recessive inheritance, against the same MONDO class bound here.

CGGV:assertion_1467b8b6-6295-4fa8-bafc-86478e6ffd19-2025-06-18T190000.000Z SUPPORT Other

ClinGen's separate autosomal dominant ERLIN2 record for the same disease is only Limited, which is why this row records recessive inheritance.

Hereditary spastic paraplegia 23 (DSTYK, Lison syndrome) MONDO:0010046

DSTYK hgnc:29043 Autosomal recessive inheritance

SPG23, attributed to biallelic DSTYK variants. ClinGen curates DSTYK against complex hereditary spastic paraplegia - this entry's own bound class - at Moderate strength under autosomal recessive inheritance, so the gene-disease relationship is supported but not definitive.

Show evidence (1 reference)

CGGV:assertion_bbac4423-e313-4694-a7ac-2005164ea832-2023-09-29T023000.000Z SUPPORT Other

ClinGen gene-disease validity: DSTYK-complex hereditary spastic paraplegia is Moderate under autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is anchored on.

Hereditary spastic paraplegia 26 (B4GALNT1) MONDO:0012213

B4GALNT1 hgnc:4117 Autosomal recessive inheritance

SPG26, caused by biallelic B4GALNT1 variants. Functional studies in patient-derived fibroblasts and in cell models of GM2 synthase deficiency confirmed loss of B4GALNT1 function with no synthesis of GM2 or downstream gangliosides, which is why B4GALNT1 is bound on the membrane-lipid and ganglioside node. ClinGen classifies B4GALNT1-complex hereditary spastic paraplegia as Definitive under autosomal recessive inheritance.

Show evidence (2 references)

PMID:35775650 SUPPORT Human Clinical

"Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26)."

Establishes the SPG26 diagnosis in a patient with biallelic B4GALNT1 variants after functional confirmation.

CGGV:assertion_4cabf677-8fa5-4455-831c-1d06dd48c780-2023-06-01T060000.000Z SUPPORT Other

ClinGen gene-disease validity: B4GALNT1-complex hereditary spastic paraplegia is Definitive under autosomal recessive inheritance, curated against MONDO:0015150.

Hereditary spastic paraplegia 39 (PNPLA6) MONDO:0012787

PNPLA6 hgnc:16268 Autosomal recessive inheritance

SPG39, the spastic-paraplegia presentation of the PNPLA6 disorder spectrum, which also includes Gordon-Holmes, Boucher-Neuhauser, Oliver-McFarlane and Laurence-Moon syndromes. dismech curates the ataxia-hypogonadism-choroidal dystrophy end of that spectrum separately as Boucher-Neuhauser_Syndrome; this row carries the spastic-paraplegia end. ClinGen's Definitive PNPLA6 record for spastic paraplegia is filed against its own entity (PNPLA6-related spastic paraplegia with or without ataxia, MONDO:0100149) rather than against the SPG39 class bound here.

Show evidence (2 references)

PMID:35069422 SUPPORT Human Clinical

"A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon-Holmes, Boucher-Neuhauser, Oliver-Mc Farlane, and Laurence-Moon syndromes."

Places spastic paraplegia type 39 inside the PNPLA6 allelic spectrum, which is the basis for binding PNPLA6 to this row and for keeping the Boucher-Neuhauser presentation in its own entry.

CGGV:assertion_f05d3811-d318-4d8e-be25-8b9da90e6d23-2022-11-02T040000.000Z SUPPORT Other

ClinGen gene-disease validity: PNPLA6 is Definitive for a spastic paraplegia entity under autosomal recessive inheritance, although against MONDO:0100149 rather than the SPG39 class.

Hereditary spastic paraplegia 43 (C19orf12) MONDO:0014024

C19orf12 hgnc:25443 Autosomal recessive inheritance

SPG43, caused by a homozygous C19orf12 missense variant first reported in two Malian sisters. C19orf12 is allelic with neurodegeneration with brain iron accumulation, which dismech curates in Neurodegeneration_With_Brain_Iron_Accumulation; the two presentations are distinguished in the defining report by brain imaging, which showed no iron deposition in the SPG43 subjects. ClinGen's only C19orf12 records are for neurodegeneration with brain iron accumulation 4.

Show evidence (2 references)

PMID:23857908 SUPPORT Human Clinical

"We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12"

Identifies the homozygous C19orf12 variant causing SPG43.

PMID:23857908 SUPPORT Human Clinical

"MRI scans showed no brain iron deposition in the Malian SPG43 subjects"

Distinguishes SPG43 from the NBIA presentation of the same gene, which is why SPG43 is recorded here and NBIA in its own entry.

Hereditary spastic paraplegia 53 (VPS37A) MONDO:0013962

VPS37A hgnc:24928 Autosomal recessive inheritance

SPG53, caused by a homozygous VPS37A missense founder mutation in two kindreds of Arab Moslem origin presenting with early-onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. VPS37A is a component of the ESCRT system, which is why it is bound on the endolysosomal and ESCRT membrane-traffic node. ClinGen classifies VPS37A-complex hereditary spastic paraplegia as Limited, so the gene-disease relationship is not yet established at ClinGen even though the founder mutation segregated fully in both families.

Show evidence (3 references)

PMID:22717650 SUPPORT Human Clinical

"the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families"

Identifies the fully penetrant homozygous VPS37A founder mutation segregating in both kindreds.

PMID:22717650 SUPPORT Human Clinical

"Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis."

Records the complicating features - intellectual disability and skeletal involvement - that make this a complex rather than pure HSP.

CGGV:assertion_14dcdd9d-bd32-49ff-ab29-fa7b79baf463-2025-03-06T170000.000Z SUPPORT Other

ClinGen gene-disease validity: VPS37A-complex hereditary spastic paraplegia is only Limited, which this row records rather than overstating.

Hereditary spastic paraplegia 54 (DDHD2) MONDO:0014018

DDHD2 hgnc:29106 Autosomal recessive inheritance

SPG54, caused by recessive DDHD2 variants in four families. The defining report gives the core phenotype as very early-onset spastic paraplegia with intellectual disability and a specific pattern of brain abnormalities on imaging, and reports an abnormal lipid peak on cerebral magnetic resonance spectroscopy as a distinguishing biomarker. DDHD2 encodes an intracellular phospholipase A1, which is why it is bound on the membrane-lipid node. ClinGen has no DDHD2 gene-disease validity record.

Show evidence (2 references)

PMID:23176823 SUPPORT Human Clinical

"The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging."

Gives the core complex-HSP phenotype of recessive DDHD2 disease.

PMID:23176823 SUPPORT Human Clinical

"We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking a member of the PLA(1) family to human neurologic disease."

Establishes recessive DDHD2 variants as the cause of SPG54.

Hereditary spastic paraplegia 57 (TFG) MONDO:0014295

TFG hgnc:11758 Autosomal recessive inheritance

SPG57, caused by homozygous TFG variants. Two consanguineous Iranian families carrying homozygous TFG missense variants were reported with early-onset progressive muscle weakness, spasticity and further neurological features. ClinGen has no TFG gene-disease validity record.

Show evidence (2 references)

PMID:33767317 SUPPORT BACKGROUND Human Clinical

"the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia, named spastic paraplegia type 57 (SPG57)"

States the TFG-SPG57 relationship and that SPG57 is a complex HSP; quoted from the report's framing of prior work rather than from its own result.

PMID:33767317 SUPPORT Human Clinical

"Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys) have been found in the related families."

Reports the homozygous TFG variants found in the two consanguineous families, the study's own contribution to this gene-disease pair.

Hereditary spastic paraplegia 63 (AMPD2) MONDO:0014305

AMPD2 hgnc:469 Autosomal recessive inheritance

SPG63, attributed to a homozygous AMPD2 frameshift variant reported in two family members. AMPD2 is allelic with pontocerebellar hypoplasia type 9, which is the presentation most AMPD2 cohorts describe; the SPG63 designation rests on that single family. ClinGen has no AMPD2 gene-disease validity record.

Show evidence (1 reference)

PMID:29463858 SUPPORT BACKGROUND Human Clinical

"a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63)"

Records the AMPD2-SPG63 relationship and its narrow evidence base; the sentence restates an earlier report rather than this cohort's own finding.

Hereditary spastic paraplegia 64 (ENTPD1) MONDO:0014303

ENTPD1 hgnc:3363 Autosomal recessive inheritance

SPG64, caused by biallelic ENTPD1 variants. ClinGen classifies ENTPD1-complex hereditary spastic paraplegia as Definitive under autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is anchored on.

Show evidence (1 reference)

CGGV:assertion_8634ea9c-3fce-4d72-94e9-2ac6756e5cb6-2023-05-06T023000.000Z SUPPORT Other

ClinGen gene-disease validity: ENTPD1-complex hereditary spastic paraplegia is Definitive under autosomal recessive inheritance, curated against MONDO:0015150.

Hereditary spastic paraplegia 74 (IBA57) MONDO:0014644

IBA57 hgnc:27302 Autosomal recessive inheritance

SPG74, caused by a homozygous IBA57 donor splice-site mutation in a highly consanguineous family whose ten affected members had a childhood-onset SPOAN-like phenotype - spastic paraplegia with optic atrophy and peripheral neuropathy - progressing slowly into late adulthood. IBA57 is a mitochondrial iron-sulfur protein assembly factor, which is why it is bound on the mitochondrial iron-sulfur cluster assembly node. ClinGen curates IBA57 against mitochondrial disease (Definitive) rather than against an HSP entity.

Show evidence (1 reference)

PMID:25609768 SUPPORT Human Clinical

"We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene"

Identifies the homozygous IBA57 splice-site mutation in the family that defines this subtype.

Hereditary spastic paraplegia 75 (MAG) MONDO:0014729

MAG hgnc:6783 Autosomal recessive inheritance

SPG75, caused by biallelic MAG (myelin associated glycoprotein) variants. ClinGen classifies MAG-complex hereditary spastic paraplegia as Definitive under autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is anchored on.

Show evidence (1 reference)

CGGV:assertion_27976cb3-605a-4f56-a262-64dfd9793559-2023-11-20T190000.000Z SUPPORT Other

ClinGen gene-disease validity: MAG-complex hereditary spastic paraplegia is Definitive under autosomal recessive inheritance, curated against MONDO:0015150.

Spastic ataxia 2 (KIF1C, SPG58) MONDO:0012651

KIF1C hgnc:6317 Autosomal recessive inheritance

Spastic ataxia 2, caused by homozygous KIF1C variants in two consanguineous families of Palestinian and Moroccan ancestry with spastic paraparesis and cerebellar dysfunction; the linked locus on chromosome 17 had previously been associated with spastic ataxia type 2. KIF1C is a kinesin, which is why it is bound on the kinesin-dependent axonal cargo transport node. ClinGen has no KIF1C gene-disease validity record.

Show evidence (2 references)

PMID:24319291 SUPPORT Human Clinical

"Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls"

Identifies the homozygous KIF1C mutations in the two families with spastic paraparesis and cerebellar dysfunction.

PMID:24319291 SUPPORT Human Clinical

"found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM %611302)"

Ties the KIF1C locus to the spastic ataxia 2 concept bound on this row.

Spastic paraplegia 85, autosomal recessive (RNF170) MONDO:0030512

RNF170 hgnc:25358 Autosomal recessive inheritance

SPG85, caused by bi-allelic RNF170 variants in four unrelated families. RNF170 is the ubiquitin E3 ligase that targets inositol 1,4,5-trisphosphate receptors for degradation, which is why it is bound on the endoplasmic reticulum calcium-release node alongside ERLIN2. The dominant RNF170 disease at the other end of the same allelic series, autosomal dominant sensory ataxia 1, is curated separately as Autosomal_Dominant_Sensory_Ataxia_1, which already records SPG85 as a differential diagnosis. ClinGen has no RNF170 gene-disease validity record.

Show evidence (1 reference)

PMID:31636353 SUPPORT Human Clinical

"We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families"

Establishes bi-allelic RNF170 variants as the cause of autosomal recessive HSP in four families and names the molecular role on which the mechanism node rests.

Spastic paraplegia 86, autosomal recessive (ABHD16A) MONDO:0030673

ABHD16A hgnc:13921 Autosomal recessive inheritance

SPG86, caused by biallelic ABHD16A variants. Two homozygous ABHD16A variants segregated with a phenotype of spasticity, psychomotor developmental delay or regression and intellectual impairment in two unrelated consanguineous Sudanese families. ABHD16A is the main brain phosphatidylserine hydrolase, which is why it is bound on the membrane-lipid node. ClinGen has no ABHD16A gene-disease validity record.

Show evidence (1 reference)

PMID:34489854 SUPPORT Human Clinical

"Two homozygous variants in ABHD16A segregated with the disease in the two studied families."

Establishes biallelic ABHD16A variants as the cause of this complex spastic-paraplegia phenotype in the two families reported.

Spastic paraplegia, intellectual disability, nystagmus and obesity (KIDINS220) MONDO:0015007

KIDINS220 hgnc:29508 Autosomal dominant inheritance

SINO syndrome, attributed to KIDINS220. It is the only autosomal dominant gene-defined row on this entry: ClinGen curates KIDINS220 against this MONDO class under autosomal dominant inheritance, at Moderate strength. ClinGen's other KIDINS220 record is a recessive entity (ventriculomegaly and arthrogryposis) and is not this disease.

Show evidence (1 reference)

CGGV:assertion_22271df6-f033-4ecc-9aa7-2b5cdd8f060e-2024-10-29T160000.000Z SUPPORT Other

ClinGen gene-disease validity: KIDINS220 is curated against this exact MONDO class under autosomal dominant inheritance at Moderate strength, which is the basis for both the gene binding and the dominant inheritance on this row.

Spastic paraplegia, optic atrophy and neuropathy (KLC2) MONDO:0012297

KLC2 hgnc:20716 Autosomal recessive inheritance

SPOAN syndrome, caused by a homozygous 216-bp deletion in the non-coding region upstream of KLC2 that leads to KLC2 overexpression - a recessive disease mechanism acting through increased rather than lost gene product. KLC2 is a kinesin light chain, which is why it is bound on the kinesin-dependent axonal cargo transport node. ClinGen has no KLC2 gene-disease validity record. Note that the bound MONDO label carries the misspelling 'optic atropy'; it is copied here as the ontology's canonical label.

Show evidence (2 references)

PMID:26385635 SUPPORT Human Clinical

"SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN)."

Defines the SPOAN clinical triad bound on this row.

PMID:26385635 SUPPORT Human Clinical

"whole-genome sequencing allowed to detect a homozygous 216-bp deletion (chr11.hg19:g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2 gene"

Identifies the homozygous non-coding deletion upstream of KLC2 as the causal lesion.

Spastic paraplegia and psychomotor retardation with or without seizures (HACE1) MONDO:0014764

HACE1 hgnc:21033 Autosomal recessive inheritance

SPPRS, caused by biallelic loss-of-function HACE1 variants. ClinGen has no HACE1 gene-disease validity record.

Show evidence (1 reference)

PMID:36553453 SUPPORT BACKGROUND Human Clinical

"Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756) is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene."

States the HACE1-SPPRS gene-disease relationship and its recessive mode; quoted from the report's opening framing of established knowledge rather than from its own new deletions.

AP-4-associated hereditary spastic paraplegia (AP-4 deficiency syndrome) MONDO:0100176

AP4B1 hgnc:572 AP4E1 hgnc:573 AP4M1 hgnc:574 AP4S1 hgnc:575 Autosomal recessive inheritance

AP-4-associated HSP (SPG47/50/51/52), caused by biallelic variants in any of the four AP-4 adaptor complex subunit genes. This is curated as ONE row with four genes rather than four gene-defined rows: GeneReviews has a single AP-4-HSP chapter whose diagnostic criterion is biallelic variants in AP4B1, AP4E1, AP4M1 or AP4S1; ClinGen curates all four genes as Definitive against one entity, AP-4 deficiency syndrome (MONDO:0100176); and MONDO supplies that same integrated class alongside its four gene-generated SPG classes (MONDO:0013551 SPG47/AP4B1, MONDO:0013048 SPG50/AP4M1, MONDO:0013401 SPG51/AP4E1, MONDO:0013552 SPG52/AP4S1). All four subunit genes are bound on this row and each has its own `genetic` record pointing back at it.

Show evidence (6 references)

PMID:30543385 SUPPORT Human Clinical

"The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing."

GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4 subunit genes, which is the primary basis for curating this as a single four-gene subtype row.

PMID:30543385 SUPPORT Human Clinical

"AP-4-HSP is inherited in an autosomal recessive manner."

Establishes autosomal recessive inheritance for this subtype.

CGGV:assertion_4436344a-e0da-4c42-b06a-cdf8a2581ce5-2021-07-25T220000.000Z SUPPORT Other

ClinGen curates AP4B1 as Definitive against AP-4 deficiency syndrome, the single entity bound on this row.

+ 3 more references

Hereditary spastic paraplegia 45 (NT5C2) MONDO:0013165

NT5C2 hgnc:8022 Autosomal recessive inheritance

SPG45, caused by biallelic NT5C2 variants. Onset is in infancy or early childhood with lower-limb spasticity and delayed motor development, variably accompanied by learning difficulty or intellectual disability, dysarthria, ataxia, nystagmus and strabismus; a consanguineous Saudi family homozygous for a splice-donor variant was reported as spastic diplegic cerebral palsy with developmental delay and microcephaly. NT5C2 is the cytosolic 5'-nucleotidase II, which is why it is bound on the purine nucleotide node rather than on the pleiotropic node. MONDO:0013165 carries both SPG45 and SPG65 as synonyms, and the exome study that identified the gene listed NT5C2 under the newly assigned locus number SPG65 while noting that NT5C2 lies within the previously mapped SPG45 locus; HGNC likewise records SPG45 as a previous symbol and SPG65 as an alias of NT5C2 (read from rest.genenames.org 2026-09-30).

Show evidence (3 references)

PMID:39119448 SUPPORT BACKGROUND Human Clinical

"SPG45 is the AR inherited type of complicated SPG, which is due to a mutation in the NT5C2 gene."

States the identity this row binds: SPG45 is the autosomal recessive, complicated form of spastic paraplegia attributed to NT5C2, which is the placement of the row on this entry rather than on the pure HSP entry.

PMID:39119448 SUPPORT Human Clinical

"Whole-exome sequencing identified a previously unidentified homozygous mutation in the NT5C2 gene, leading to the diagnosis of SPG45 in both siblings."

A homozygous NT5C2 variant established the SPG45 diagnosis in two affected siblings, which is the gene-disease relationship this row records.

PMID:39119448 SUPPORT Human Clinical

"They also experienced learning difficulties, dysarthric speech, ataxia, nystagmus, strabismus, and spasticity in their extremities."

Records the features accompanying the spasticity in this sibling pair, which are the complicating features placing SPG45 in the complex category.

Hereditary spastic paraplegia 61 (ARL6IP1) MONDO:0014304

ARL6IP1 hgnc:697 Autosomal recessive inheritance

SPG61, caused by biallelic ARL6IP1 variants; both alleles cited on this row are truncating, a homozygous frameshift in one reported patient and a homozygous nonsense variant predicted to abolish the protein in a second kindred. Onset is in infancy with spastic paraplegia accompanied by a sensory neuropathy; congenital insensitivity to pain with acromutilation has also been reported. That combination is not unique on this entry: the CCT5 row is hereditary sensory and autonomic neuropathy with spastic paraplegia, whose cited source describes a mutilating sensory neuropathy. The severe end of the range is lethal: a Saudi kindred homozygous for the nonsense allele lost both affected siblings in the neonatal period, with developmental delay, microcephaly, cerebral atrophy, seizures and respiratory distress. ARL6IP1 shapes high-curvature endoplasmic reticulum tubules and binds atlastin, which is why it is bound on the ER membrane shaping node rather than on the IP3-receptor calcium-release node.

Show evidence (3 references)

PMID:31272422 SUPPORT BACKGROUND Human Clinical

"Mutations in ARL6IP1, which encodes a tetraspan membrane protein localized to the endoplasmic reticulum (ER), have been recently described in a large family with a complicated form of hereditary spastic paraplegia (HSP)."

Restates the founding human observation behind this row, that ARL6IP1 variants cause a complicated form of hereditary spastic paraplegia; the sentence is this paper's framing of work reported elsewhere rather than its own result.

PMID:28471035 SUPPORT Human Clinical

"Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia."

Records the clinical combination reported for this gene: pain insensitivity and acromutilation alongside the spastic paraplegia.

PMID:31272422 SUPPORT Human Clinical

"Clinical features encompassed not only spastic paraplegia but also developmental delay, microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures, spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and respiratory distress."

Documents the severe end of the ARL6IP1 phenotypic range quoted in this row's description.

⚙

Pathophysiology

Length-Dependent Corticospinal-Tract Axonal Degeneration

The core lesion shared with pure HSP: distal-predominant degeneration of the longest corticospinal-tract upper motor neuron axons (maximal in the thoracic spinal cord) together with degeneration of the dorsal-column fasciculus gracilis sensory fibers. This length-dependent, dying-back axonopathy of the longest CNS motor-sensory tracts produces the progressive lower-limb spasticity, weakness, hyperreflexia, and extensor plantar responses common to all HSP.

Corticospinal-tract upper motor neuron CL:0008048

CAPN1 hgnc:1476

Axonal transport GO:0098930 ↓ DECREASED

Downstream

Lower-Limb Spastic Paraplegia

Lower-Limb Weakness

Show evidence (1 reference)

PMID:27153400 SUPPORT BACKGROUND Other

"CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance."

Assigns calpain 1 a role in axon maturation and maintenance, the process whose failure this node describes, which is why CAPN1 is bound here.

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

In complex HSP the mutated SPG proteins have diverse housekeeping functions — axonal transport, endoplasmic reticulum tubular network morphogenesis, mitochondrial quality control, myelin formation, and endolysosomal/autophagic membrane trafficking. Loss of these functions injures neuronal and glial populations beyond the corticospinal tract (cortical neurons, cerebellar neurons, peripheral nerve, retina, and oligodendrocyte myelin), producing the additional "complicating" features (thin corpus callosum, cognitive decline, ataxia, neuropathy, retinopathy) that distinguish complex from pure HSP. This pleiotropy explains why complex forms cluster among loci with broad subcellular roles (e.g., SPG11/SPG15 endolysosomal-autophagy, SPG7 mitochondrial, SPG2/PLP1 myelin).

Pyramidal neuron CL:0000598

SPG11 hgnc:11226 SPG7 hgnc:11237 PLP1 hgnc:9086 MARS1 hgnc:6898 CCT5 hgnc:1618 DSTYK hgnc:29043 TFG hgnc:11758 C19orf12 hgnc:25443 MAG hgnc:6783 HACE1 hgnc:21033 KIDINS220 hgnc:29508 L1CAM hgnc:6470

Endoplasmic reticulum tubular network morphogenesis GO:0071786 Mitochondrion organization GO:0007005 ⚠ ABNORMAL Myelination GO:0042552 ⚠ ABNORMAL

Downstream

Length-Dependent Corticospinal-Tract Axonal Degeneration

Thin Corpus Callosum

Cognitive Impairment

Peripheral Neuropathy

Cerebellar Ataxia

Distal Amyotrophy

Pigmentary Maculopathy

Dysarthria

Leukodystrophy

Show evidence (2 references)

PMID:23897027 SUPPORT Human Clinical

"proteins encoded by HSP genes have diverse functions including (1) axon"

The node's own claim: the proteins encoded by HSP genes have diverse cellular functions, which is why genes with no mechanism-specific node in this entry are bound here.

PMID:20301657 SUPPORT Human Clinical

"Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity; intellectual disability is severe."

L1CAM disease involves CNS structures well beyond the corticospinal tract - hydrocephalus and intellectual disability alongside the spasticity - which is the pleiotropy this node describes and the basis for binding L1CAM here.

Endolysosomal and ESCRT Membrane-Traffic Failure

A mechanism class shared by complex-HSP genes whose products act in endosomal sorting, endosome maturation and lysosomal transport. Spastizin (ZFYVE26) localizes partly to endoplasmic reticulum and endosomal compartments; spartin (SPART) resembles molecules of endosomal trafficking; VPS37A is a subunit of the ESCRT system that matures multivesicular bodies; and ATP13A2 is a lysosomal transport ATPase. The AP-4 adaptor complex is curated as its own node because its characterised defect is autophagosome formation rather than endosomal transport. Every gene bound here causes a complex HSP recorded on this entry, and the node's downstream edge records that failure feeding the pleiotropic SPG-protein dysfunction the entry models.

ZFYVE26 hgnc:20761 SPART hgnc:18514 VPS37A hgnc:24928 ATP13A2 hgnc:30213

Endosomal transport GO:0016197 ⚠ ABNORMAL

Downstream

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

Show evidence (4 references)

PMID:18394578 SUPPORT In Vitro

"spastizin colocalized partially with markers of endoplasmic reticulum and endosomes, suggesting a role in intracellular trafficking"

Places spastizin, the SPG15 protein, in the endoplasmic reticulum and endosomal compartments this node describes.

PMID:12134148 SUPPORT Computational

"spartin shares similarity with molecules involved in endosomal trafficking"

Comparative sequence analysis assigns spartin, the Troyer syndrome protein, to the endosomal trafficking machinery.

PMID:22717650 SUPPORT Human Clinical

"The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease."

Links VPS37A, an ESCRT-I subunit, to upper motor neuron disease, which is the claim this node makes for that gene.

+ 1 more reference

AP-4-Dependent ATG9A Export and Autophagosome Formation Failure

The AP-4 adaptor complex associates with the trans-Golgi network and exports ATG9A from it; in AP-4-deficient cells that export fails, reducing ATG9A delivery to pre-autophagosomal structures and impairing autophagosome formation. All four AP-4 subunit genes are curated on this node because biallelic variants in any of them cause the same disease, AP-4-associated HSP, which this entry carries as a single subtype row. The node is kept separate from the endolysosomal membrane-traffic node because the characterised AP-4 defect is autophagosome biogenesis rather than endosomal transport.

AP4B1 hgnc:572 AP4E1 hgnc:573 AP4M1 hgnc:574 AP4S1 hgnc:575

Autophagosome assembly GO:0000045 ↓ DECREASED

Downstream

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

Show evidence (1 reference)

PMID:33084855 SUPPORT REVIEW SYNTHESIS In Vitro

"Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A delivery to pre-autophagosomal structures, impairing autophagosome formation and/or maturation."

Gives the autophagy defect that follows AP-4 loss in cells, which is the mechanism this node names.

Neuronal Membrane-Lipid and Ganglioside Metabolic Failure

A second recurrent mechanism class among complex-HSP genes, whose products are lipid-modifying enzymes. DDHD2 is an intracellular phospholipase A1 and its loss produces an abnormal cerebral lipid peak detectable by magnetic resonance spectroscopy; PNPLA6 encodes neuropathy target esterase, which maintains phospholipid homeostasis in the nervous system; ABHD16A is the main brain phosphatidylserine hydrolase; and B4GALNT1 loss abolishes synthesis of GM2 and the downstream complex gangliosides. Each of these genes causes a complex HSP recorded on this entry, and the DDHD2 report shows the lipid disturbance directly in patients by cerebral magnetic resonance spectroscopy.

DDHD2 hgnc:29106 PNPLA6 hgnc:16268 ABHD16A hgnc:13921 B4GALNT1 hgnc:4117 FA2H hgnc:21197

Lipid metabolic process GO:0006629 ⚠ ABNORMAL Ganglioside biosynthetic process GO:0001574 ↓ DECREASED

Downstream

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

Show evidence (5 references)

PMID:23176823 SUPPORT Human Clinical

"In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance spectroscopy"

Demonstrates disturbed brain lipid metabolism in patients with recessive DDHD2 disease, the direct clinical evidence for this node.

PMID:37732399 SUPPORT REVIEW SYNTHESIS Human Clinical

"PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking in the nervous system."

Assigns PNPLA6 to nervous-system phospholipid homeostasis, the basis for placing SPG39 on this node.

PMID:34489854 SUPPORT BACKGROUND Other

"ABHD16A encodes the main brain phosphatidylserine hydrolase."

Identifies ABHD16A as a brain phospholipid-hydrolysing enzyme, the basis for placing SPG86 on this node.

+ 2 more references

Mitochondrial Iron-Sulfur Cluster Assembly Failure

IBA57 is the mitochondrial iron-sulfur protein assembly factor. The SPG74 splice-site variant leaves ten-fold lower levels of wild-type IBA57 protein and reduces the levels and activities of several mitochondrial 4Fe-4S proteins including respiratory complexes I and II, while 2Fe-2S proteins remain normal. This node is one of two mitochondrial mechanisms on the entry - the other, impaired anaplerosis, is a separate node because GPT2 takes no part in iron-sulfur cluster assembly - and both are counterparts of the SPG7/paraplegin mitochondrial mechanism already recorded here.

IBA57 hgnc:27302

Iron-sulfur cluster assembly GO:0016226 ↓ DECREASED

Downstream

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

Show evidence (2 references)

PMID:25609768 SUPPORT BACKGROUND Other

"This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57."

Identifies IBA57 as the mitochondrial iron-sulfur cluster assembly factor named by this node.

PMID:25609768 SUPPORT In Vitro

"Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated IBA57 protein."

Measures the loss of IBA57 protein in patient-derived cells, the molecular lesion behind the assembly defect this node describes.

Impaired Mitochondrial Anaplerosis

GPT2 is a mitochondrial transaminase. Its biallelic variants are biochemically loss-of-function, and loss of Gpt2 produces defects in anaplerosis, the process that replenishes tricarboxylic-acid-cycle intermediates. This is a separate node from the iron-sulfur cluster assembly mechanism because IBA57 takes no part in transamination or anaplerosis, and GPT2 takes no part in iron-sulfur cluster assembly.

GPT2 hgnc:18062

Tricarboxylic acid cycle GO:0006099 ⚠ ABNORMAL

Downstream

Microcephaly Postnatal microcephaly was present in every affected individual of the kindreds that defined GPT2 deficiency, alongside the progressive spastic paraplegia.

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract

Show evidence (2 references)

PMID:27601654 SUPPORT Model Organism

"we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates"

Identifies the anaplerotic defect, measured by metabolomics and isotope tracing in Gpt2-null mice, that this node names.

PMID:27601654 SUPPORT In Vitro

"Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function."

Establishes that the disease-associated GPT2 variants abolish enzyme function, which is the lesion upstream of the anaplerotic defect.

Kinesin-Dependent Axonal Cargo Transport Failure

Kinesins are cargo/motor proteins whose mutation is an established cause of hereditary spastic paraplegia. Three complex forms on this entry act through this machinery: spastic ataxia 2 is caused by homozygous KIF1C variants, SPOAN syndrome by a non-coding deletion upstream of KLC2 that raises KLC2 expression in patient fibroblasts and patient-derived motor neurons - a gain, not a loss, of gene product - and SPG10 by heterozygous missense variants in the motor domain of KIF5A, the neuronal heavy chain of conventional kinesin-I, which carries membranous organelles anterogradely to the distal axon. SPAX2 and SPOAN are recorded as subtype rows on this entry and SPG10 under the autosomal dominant complex HSP row, so this node's downstream consequence is the length-dependent corticospinal-tract axonopathy of the entry's core node.

KIF1C hgnc:6317 KLC2 hgnc:20716 KIF5A hgnc:6323

Microtubule motor activity GO:0003777 ⚠ ABNORMAL

Downstream

Length-Dependent Corticospinal-Tract Axonal Degeneration

Show evidence (3 references)

PMID:24319291 SUPPORT BACKGROUND Other

"Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated."

States the kinesin cargo/motor role and its established link to HSP, which is what this node asserts.

PMID:26385635 SUPPORT In Vitro

"Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN patients showed KLC2 overexpression."

Measures raised KLC2 in patient cells and patient-derived motor neurons, the molecular lesion by which SPOAN reaches this node.

PMID:12355402 SUPPORT Human Clinical

"We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia."

The founding SPG10 report places the KIF5A lesion in the kinesin motor domain, which is how SPG10 reaches this node.

Pyrroline-5-Carboxylate Synthase Dysfunction

ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), which catalyzes the reduction of glutamate to pyrroline-5-carboxylate, a shared step in proline, ornithine and arginine biosynthesis. Monoallelic ALDH18A1 variants cause autosomal dominant pure or complex spastic paraplegia (SPG9A), the reason the gene is listed on this entry's autosomal dominant complex HSP row. The ALDH18A1 allelic series, including the variable plasma amino-acid changes and the cutis laxa branches, is curated in full in ALDH18A1_De_Barsy_Spectrum; this node records only the enzyme lesion so that the gene reaches this entry's corticospinal-tract node. It is kept separate from the purine and anaplerosis nodes because P5CS acts in neither pathway.

ALDH18A1 hgnc:9722

delta1-pyrroline-5-carboxylate synthetase (NADP+) activity GO:0017084 ↓ DECREASED

Downstream

Length-Dependent Corticospinal-Tract Axonal Degeneration Heterozygous ALDH18A1 variants segregate with spastic paraplegia, but the step from reduced P5CS activity to corticospinal axon degeneration has not been established.

Show evidence (2 references)

PMID:11092761 SUPPORT BACKGROUND Other

"catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine."

Defines the P5CS reaction whose loss this node records.

PMID:26026163 SUPPORT Human Clinical

"Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from two families suggested P5CS deficiency."

Reduced plasma products of the P5CS reaction in some ALDH18A1 spastic paraplegia families point to a P5CS functional defect; the same study notes this is not seen in every family, which is why the node asserts reduced enzyme activity rather than systemic depletion.

IP3-Receptor-Dependent Endoplasmic Reticulum Calcium Release Dysregulation

Calcium efflux from the endoplasmic reticulum into the cytoplasm is controlled by inositol 1,4,5-trisphosphate binding to its receptor, and activated receptors are then degraded by the endoplasmic-reticulum-associated degradation pathway. Two complex-HSP genes on this entry act in that degradation step: ERLIN2, whose biallelic variants cause SPG18, and RNF170, the ubiquitin E3 ligase that targets the receptors and whose bi-allelic variants cause SPG85. The RNF170 report names inositol 1,4,5-trisphosphate signalling as a candidate key pathway for the hereditary spastic paraplegias, which is the claim this node records.

ERLIN2 hgnc:1356 RNF170 hgnc:25358

Release of sequestered calcium ion into cytosol GO:0051209 ↕ DYSREGULATED ERAD pathway GO:0036503 ⚠ ABNORMAL

Downstream

Length-Dependent Corticospinal-Tract Axonal Degeneration

Show evidence (3 references)

PMID:31636353 SUPPORT BACKGROUND Other

"Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway."

States the calcium-release and receptor-degradation steps that this node names.

PMID:31636353 SUPPORT BACKGROUND Human Clinical

"genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia"

Places ERLIN2 in the receptor-degradation step and links it to HSP.

PMID:31636353 SUPPORT Human Clinical

Places RNF170 in the same step and establishes its bi-allelic variants as a cause of recessive HSP.

Purine Nucleotide Metabolic Imbalance

Three complex-HSP genes on this entry act in purine nucleotide metabolism rather than in membrane traffic, lipid metabolism, mitochondrial assembly or axonal transport: NT5C2, the cytosolic 5'-nucleotidase II that hydrolyses nucleoside monophosphates and whose biallelic variants cause SPG45; AMPD2, an AMP deaminase, mutated in SPG63; and ENTPD1, described by the same study as an extracellular enzyme that hydrolyses adenosine nucleotides in the synaptic cleft, mutated in SPG64. The exome study that identified all three placed them in one purine-metabolism module, which is why they are bound together here rather than on the pleiotropic node that holds the genes with diverse housekeeping roles. The node records the pathway the lesions fall in rather than a measured metabolite change; the sources cited here establish the genetic lesions and the enzymes' assigned pathway, and the modifier is therefore ABNORMAL rather than a direction.

NT5C2 hgnc:8022 AMPD2 hgnc:469 ENTPD1 hgnc:3363

Purine nucleotide metabolic process GO:0006163 ⚠ ABNORMAL

5'-nucleotidase activity (NT5C2) GO:0008253 ↓ DECREASED

Downstream

Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract Loss of NT5C2 produces features outside the corticospinal tract, which is the involvement the target node describes. No source cited at this node reports the same for AMPD2 or ENTPD1.

Microcephaly Reduced head circumference accompanies the spastic motor picture in the NT5C2 family reported with a splice-donor variant.

Show evidence (3 references)

PMID:24482476 SUPPORT BACKGROUND Other

"AMPD2, ENTPD1, and NT5C2 are involved in purine nucleotide metabolism"

Assigns the three genes bound on this node to one pathway, which is the grouping the node asserts; the sentence classifies the enzymes rather than reporting a measurement.

PMID:32153630 SUPPORT BACKGROUND Other

"NT5C2 gene (OMIM: 600417) encode a hydrolase enzyme 5'-nucleotidase, cytosolic II play an important role in maintaining the balance of purine nucleotides and free nucleobases in the spinal cord and brain."

States the enzyme activity of NT5C2 and the purine balance it maintains in the central nervous system, which is why the SPG45 gene is bound at this node.

PMID:24482476 SUPPORT Human Clinical

"Three of these genes, ERLIN1, KIF1C, and NT5C2, were found independently mutated in more than one family, and all mutations were predicted to be highly deleterious."

NT5C2 was mutated independently in more than one family of this autosomal recessive HSP cohort, which is the human genetic support for treating loss of this enzyme as a mechanism.

Tubular Endoplasmic Reticulum Membrane Shaping Failure

ARL6IP1, the gene mutated in SPG61, is a tetraspan endoplasmic reticulum membrane protein whose reticulon-like short hairpin transmembrane domains shape high-curvature ER tubules; it binds atlastin, the GTPase that mediates formation of the tubular ER network and is itself mutated in SPG3A. The SPG61 allele cited at this node is a nonsense variant predicted to abolish the protein, so the lesion recorded here is loss of ER tubule shaping. It is kept separate from the IP3-receptor calcium-release node because ERLIN2 and RNF170 act on receptor degradation and ER calcium handling rather than on ER membrane geometry, and separate from the pleiotropic node because the mechanism here is a single named biophysical function rather than a diverse housekeeping role.

ARL6IP1 hgnc:697

Endoplasmic reticulum tubular network organization GO:0071786 ↓ DECREASED

Downstream

Length-Dependent Corticospinal-Tract Axonal Degeneration Loss of ARL6IP1 produces the spastic paraplegia that the corticospinal-tract node describes.

Peripheral Neuropathy A sensory neuropathy accompanied the spastic paraplegia in the ARL6IP1 patient reported with pain insensitivity.

Pain Insensitivity Congenital insensitivity to pain with acromutilation is reported with biallelic ARL6IP1 loss, and ARL6IP1 binds the same atlastin-1 that is mutated in hereditary sensory and autonomic neuropathy type ID.

Microcephaly Reduced head circumference was present in the kindred homozygous for the ARL6IP1 nonsense allele.

Show evidence (3 references)

PMID:24262037 SUPPORT In Vitro

"The results of the present study indicate that Arl6IP1 has the ability to shape high-curvature ER tubules in a reticulon-like fashion."

Establishes the ER tubule shaping activity this node names, measured in mammalian cells and in liposomes.

PMID:24262037 SUPPORT In Vitro

"Arl6IP1, which does not share an overall primary sequence homology with reticulons, harbours reticulon-like short hairpin transmembrane domains and binds to atlastin, a GTPase that mediates the formation of the tubular ER network."

Records the hairpin transmembrane architecture and the atlastin interaction that place ARL6IP1 in the tubular ER network machinery.

PMID:31272422 SUPPORT Human Clinical

"WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein."

The disease allele is predicted to abolish the protein, so the human lesion is loss of this ER shaping function rather than an altered activity.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Eye 1

Pigmentary Maculopathy Pigmentary retinopathy HP:0000580

Show evidence (1 reference)

PMID:18394578 SUPPORT Human Clinical

"pigmented maculopathy"

Pigmentary maculopathy is a feature of SPG15/Kjellin syndrome.

Head and Neck 1

Microcephaly HP:0000252

Show evidence (2 references)

PMID:32153630 SUPPORT Human Clinical

"In this study we have identified a large consanguineous Saudi family segregating a novel homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral palsy, developmental delay and microcephaly."

Records microcephaly in the NT5C2 family homozygous for the splice-donor variant.

PMID:31272422 SUPPORT Human Clinical

Records microcephaly in the kindred homozygous for the ARL6IP1 nonsense allele.

Limbs 1

Lower-Limb Weakness Lower limb muscle weakness HP:0007340

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"bilateral lower extremity weakness and spasticity"

Lower-limb weakness is a predominant HSP manifestation.

Musculoskeletal 2

Lower-Limb Spastic Paraplegia HP:0001258

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"in which bilateral lower extremity weakness and spasticity (each of variable degree) are the predominant"

Establishes lower-limb spasticity and weakness as the predominant HSP feature.

Distal Amyotrophy HP:0003693

Show evidence (1 reference)

PMID:18394578 SUPPORT Human Clinical

"distal amyotrophy"

Distal amyotrophy is part of the SPG15/Kjellin complex HSP phenotype.

Nervous System 7

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"such as SPG11 HSP, a common autosomal recessive form of HSP frequently associated with mental retardation and thin corpus callosum"

Thin corpus callosum is characteristic of SPG11 complex HSP.

Cognitive Impairment HP:0100543

Show evidence (1 reference)

PMID:20301389 SUPPORT Human Clinical

"mild intellectual disability with learning difficulties in"

SPG11 is associated with intellectual disability and cognitive decline.

Peripheral Neuropathy HP:0009830

Show evidence (1 reference)

PMID:20301389 SUPPORT Human Clinical

"peripheral neuropathy"

Peripheral neuropathy is a recognized complicating feature of SPG11.

Cerebellar Ataxia HP:0001251

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"paraplegin gene mutation, in which spastic paraparesis is often associated with ataxia"

SPG7 (paraplegin) complex HSP is often associated with ataxia.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:18394578 SUPPORT Human Clinical

"dysarthria"

Dysarthria is part of the SPG15 complex HSP spectrum.

Leukodystrophy HP:0002415

Show evidence (1 reference)

PMID:20104589 SUPPORT Human Clinical

"white matter abnormalities suggestive of a leukodystrophy"

SPG35 (FA2H) complex HSP shows white-matter abnormalities suggestive of a leukodystrophy on MRI.

Pain Insensitivity HP:0007021

Show evidence (1 reference)

PMID:28471035 SUPPORT Human Clinical

"Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia."

Reports congenital insensitivity to pain with acromutilation in a patient with biallelic ARL6IP1 loss, which is the phenotype this row names.

🧬

Genetic Associations

SPG11

Gene: SPG11 hgnc:11226 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:20301389 SUPPORT Human Clinical

"Spastic paraplegia 11 (SPG11) is characterized by"

Biallelic SPG11 (spatacsin) variants cause the most common autosomal recessive complex HSP, with thin corpus callosum and cognitive decline.

ZFYVE26

Gene: ZFYVE26 hgnc:20761

Autosomal Recessive

Show evidence (1 reference)

PMID:18394578 SUPPORT Human Clinical

"the identification of ZFYVE26, which encodes a zinc-finger"

Truncating ZFYVE26 (spastizin) mutations cause SPG15 complicated autosomal-recessive spastic paraplegia including Kjellin syndrome.

SPG7

Gene: SPG7 hgnc:11237 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:9635427 SUPPORT Human Clinical

"Two additional Paraplegin mutations, both resulting in a frameshift, were found in a complicated and in a pure form of HSP"

SPG7/paraplegin mutations cause both complicated and pure recessive HSP, with mitochondrial OXPHOS impairment.

FA2H

Gene: FA2H hgnc:21197

Autosomal Recessive

Show evidence (1 reference)

PMID:20104589 SUPPORT Human Clinical

"Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del)."

Biallelic FA2H (fatty acid 2-hydroxylase) mutations cause SPG35, a complicated recessive HSP. Requoted from the abstract: the previous quote was the paper's title and did not verify against the abstract text.

SPART

Gene: SPART hgnc:18514

Autosomal Recessive

Show evidence (1 reference)

PMID:12134148 SUPPORT Human Clinical

"We report mapping of the TRS locus to chromosome 13q12.3 and identify a frameshift mutation in SPG20, encoding spartin."

A frameshift mutation in SPG20 (now SPART, encoding spartin) causes Troyer syndrome, a complex recessive HSP. Requoted from the abstract: the previous quote was the paper's title and did not verify against the abstract text.

AP4B1

Gene: AP4B1 hgnc:572

Autosomal Recessive

Show evidence (1 reference)

PMID:30543385 SUPPORT Human Clinical

"is a childhood-onset and complex form of hereditary spastic paraplegia"

Biallelic variants in the AP-4 complex genes (AP4B1/AP4E1/AP4M1/AP4S1) cause AP-4-associated HSP (SPG47/50/51/52), a childhood-onset complex HSP.

L1CAM

Gene: L1CAM hgnc:6470 gene page

X-Linked

Show evidence (1 reference)

PMID:20301657 SUPPORT Human Clinical

"complicated hereditary spastic paraplegia type 1"

L1CAM variants cause X-linked complicated HSP type 1 (SPG1) within the L1 syndrome spectrum.

PLP1

Gene: PLP1 hgnc:9086 gene page

X-Linked

Show evidence (1 reference)

PMID:20301361 SUPPORT Human Clinical

"to spastic paraplegia 2 (SPG2)"

PLP1 CNS-myelin defects span a spectrum extending to X-linked spastic paraplegia 2 (SPG2).

MARS1

Gene: MARS1 hgnc:6898 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:35303589 SUPPORT Human Clinical

"Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1), SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1)."

MARS (now MARS1) was the confirmed genetic etiology in two patients of a childhood-onset hereditary spastic paraplegia cohort, which is the human evidence available for this gene-disease pair.

CAPN1

Gene: CAPN1 hgnc:1476

Autosomal Recessive

Show evidence (1 reference)

PMID:27153400 SUPPORT Human Clinical

Identifies biallelic CAPN1 variants as the cause of SPG76 in three autosomal recessive HSP families, with segregation confirmed.

ATP13A2

Gene: ATP13A2 hgnc:30213 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:28137957 SUPPORT Human Clinical

Identifies a homozygous ATP13A2 variant in a family with complicated HSP, the observation on which the SPG78 designation rests.

GPT2

Gene: GPT2 hgnc:18062

Autosomal Recessive

Show evidence (1 reference)

PMID:27601654 SUPPORT Human Clinical

"We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD)."

Establishes autosomal recessive GPT2 variants as the cause of this disease in the defining kindreds.

CCT5

Gene: CCT5 hgnc:1618

Autosomal Recessive

Show evidence (1 reference)

PMID:16399879 SUPPORT Human Clinical

"A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy associated with spastic paraplegia was investigated."

Defines the clinical entity - mutilating sensory neuropathy with spastic paraplegia - in the family in which the causal gene was found.

ERLIN2

Gene: ERLIN2 hgnc:1356 gene page

Autosomal Recessive

Show evidence (1 reference)

CGGV:assertion_9599fa0e-da62-437d-8f6f-2f2ef0297c8c-2025-06-18T190000.000Z SUPPORT Other

ClinGen gene-disease validity: ERLIN2-hereditary spastic paraplegia 18 is Definitive under autosomal recessive inheritance, against the same MONDO class bound here.

DSTYK

Gene: DSTYK hgnc:29043

Autosomal Recessive

Show evidence (1 reference)

CGGV:assertion_bbac4423-e313-4694-a7ac-2005164ea832-2023-09-29T023000.000Z SUPPORT Other

ClinGen gene-disease validity: DSTYK-complex hereditary spastic paraplegia is Moderate under autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is anchored on.

B4GALNT1

Gene: B4GALNT1 hgnc:4117

Autosomal Recessive

Show evidence (1 reference)

PMID:35775650 SUPPORT Human Clinical

"Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26)."

Establishes the SPG26 diagnosis in a patient with biallelic B4GALNT1 variants after functional confirmation.

PNPLA6

Gene: PNPLA6 hgnc:16268 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:35069422 SUPPORT Human Clinical

Places spastic paraplegia type 39 inside the PNPLA6 allelic spectrum, which is the basis for binding PNPLA6 to this row and for keeping the Boucher-Neuhauser presentation in its own entry.

C19orf12

Gene: C19orf12 hgnc:25443 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:23857908 SUPPORT Human Clinical

Identifies the homozygous C19orf12 variant causing SPG43.

VPS37A

Gene: VPS37A hgnc:24928

Autosomal Recessive

Show evidence (1 reference)

PMID:22717650 SUPPORT Human Clinical

Identifies the fully penetrant homozygous VPS37A founder mutation segregating in both kindreds.

DDHD2

Gene: DDHD2 hgnc:29106

Autosomal Recessive

Show evidence (1 reference)

PMID:23176823 SUPPORT Human Clinical

"The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral imaging."

Gives the core complex-HSP phenotype of recessive DDHD2 disease.

TFG

Gene: TFG hgnc:11758

Autosomal Recessive

Show evidence (1 reference)

PMID:33767317 SUPPORT BACKGROUND Human Clinical

States the TFG-SPG57 relationship and that SPG57 is a complex HSP; quoted from the report's framing of prior work rather than from its own result.

AMPD2

Gene: AMPD2 hgnc:469 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:29463858 SUPPORT BACKGROUND Human Clinical

"a homozygous AMPD2 frameshift variant has recently been reported in two family members with spastic paraplegia type 63 (SPG63)"

Records the AMPD2-SPG63 relationship and its narrow evidence base; the sentence restates an earlier report rather than this cohort's own finding.

ENTPD1

Gene: ENTPD1 hgnc:3363

Autosomal Recessive

Show evidence (1 reference)

CGGV:assertion_8634ea9c-3fce-4d72-94e9-2ac6756e5cb6-2023-05-06T023000.000Z SUPPORT Other

ClinGen gene-disease validity: ENTPD1-complex hereditary spastic paraplegia is Definitive under autosomal recessive inheritance, curated against MONDO:0015150.

IBA57

Gene: IBA57 hgnc:27302

Autosomal Recessive

Show evidence (1 reference)

PMID:25609768 SUPPORT Human Clinical

"We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor splice-site mutation in the IBA57 gene"

Identifies the homozygous IBA57 splice-site mutation in the family that defines this subtype.

MAG

Gene: MAG hgnc:6783

Autosomal Recessive

Show evidence (1 reference)

CGGV:assertion_27976cb3-605a-4f56-a262-64dfd9793559-2023-11-20T190000.000Z SUPPORT Other

ClinGen gene-disease validity: MAG-complex hereditary spastic paraplegia is Definitive under autosomal recessive inheritance, curated against MONDO:0015150.

KIF1C

Gene: KIF1C hgnc:6317

Autosomal Recessive

Show evidence (1 reference)

PMID:24319291 SUPPORT Human Clinical

"Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls"

Identifies the homozygous KIF1C mutations in the two families with spastic paraparesis and cerebellar dysfunction.

RNF170

Gene: RNF170 hgnc:25358 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:31636353 SUPPORT Human Clinical

Establishes bi-allelic RNF170 variants as the cause of autosomal recessive HSP in four families and names the molecular role on which the mechanism node rests.

ABHD16A

Gene: ABHD16A hgnc:13921

Autosomal Recessive

Show evidence (1 reference)

PMID:34489854 SUPPORT Human Clinical

"Two homozygous variants in ABHD16A segregated with the disease in the two studied families."

Establishes biallelic ABHD16A variants as the cause of this complex spastic-paraplegia phenotype in the two families reported.

KIDINS220

Gene: KIDINS220 hgnc:29508

Autosomal Dominant

Show evidence (1 reference)

CGGV:assertion_22271df6-f033-4ecc-9aa7-2b5cdd8f060e-2024-10-29T160000.000Z SUPPORT Other

KLC2

Gene: KLC2 hgnc:20716

Autosomal Recessive

Show evidence (1 reference)

PMID:26385635 SUPPORT Human Clinical

"SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia, optic atrophy and neuropathy (SPOAN)."

Defines the SPOAN clinical triad bound on this row.

HACE1

Gene: HACE1 hgnc:21033

Autosomal Recessive

Show evidence (1 reference)

PMID:36553453 SUPPORT BACKGROUND Human Clinical

"Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756) is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene."

States the HACE1-SPPRS gene-disease relationship and its recessive mode; quoted from the report's opening framing of established knowledge rather than from its own new deletions.

AP4E1

Gene: AP4E1 hgnc:573 gene page

Autosomal Recessive

Show evidence (1 reference)

PMID:30543385 SUPPORT Human Clinical

"The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing."

GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4 subunit genes, which is the primary basis for curating this as a single four-gene subtype row.

AP4M1

Gene: AP4M1 hgnc:574

Autosomal Recessive

Show evidence (1 reference)

PMID:30543385 SUPPORT Human Clinical

"The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing."

GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4 subunit genes, which is the primary basis for curating this as a single four-gene subtype row.

AP4S1

Gene: AP4S1 hgnc:575

Autosomal Recessive

Show evidence (1 reference)

PMID:30543385 SUPPORT Human Clinical

"The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing."

GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4 subunit genes, which is the primary basis for curating this as a single four-gene subtype row.

NT5C2

Gene: NT5C2 hgnc:8022

Autosomal Recessive

Show evidence (2 references)

PMID:39119448 SUPPORT Human Clinical

"Whole-exome sequencing identified a previously unidentified homozygous mutation in the NT5C2 gene, leading to the diagnosis of SPG45 in both siblings."

A homozygous NT5C2 variant segregating in two affected siblings is the human genetic basis for this record and for its autosomal recessive mode.

PMID:24482476 SUPPORT Human Clinical

"Three of these genes, ERLIN1, KIF1C, and NT5C2, were found independently mutated in more than one family, and all mutations were predicted to be highly deleterious."

Independent recurrence across more than one family in an autosomal recessive HSP cohort is the replication behind the NT5C2 gene-disease relationship.

ARL6IP1

Gene: ARL6IP1 hgnc:697

Autosomal Recessive

Show evidence (2 references)

PMID:31272422 SUPPORT Human Clinical

"WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein."

A homozygous nonsense ARL6IP1 allele segregating with the phenotype, and predicted to abolish the protein, is the human genetic basis for this record and its recessive mode.

PMID:28471035 SUPPORT Human Clinical

"Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy, acromutilation, and spastic paraplegia."

A second, independently reported patient with biallelic ARL6IP1 loss, widening the phenotype this gene record covers to pain insensitivity and acromutilation.

KIF5A

Gene: KIF5A hgnc:6323 gene page

Autosomal Dominant

Show evidence (2 references)

PMID:18853458 SUPPORT Human Clinical

"SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France."

Places heterozygous KIF5A variants among the autosomal dominant complicated HSPs, the subtype row this record points at.

PMID:12355402 SUPPORT Human Clinical

"We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia."

The founding identification of KIF5A as the SPG10 gene.

ALDH18A1

Gene: ALDH18A1 hgnc:9722 gene page

Autosomal Dominant

Show evidence (1 reference)

PMID:26026163 SUPPORT Human Clinical

"identified monoallelic ALDH18A1 mutations segregating in three independent families with autosomal dominant pure or complex hereditary spastic paraplegia,"

Heterozygous ALDH18A1 variants segregate with autosomal dominant complex spastic paraplegia, the basis for this record and its dominant mode.

💊

Medical Actions

Antispasticity Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972 tizanidine CHEBI:63629

Platform: Small molecule

Symptomatic reduction of lower-limb spasticity with agents such as baclofen (oral or intrathecal), tizanidine, and dantrolene, plus selective botulinum toxin injection. Treatment is symptomatic — no disease-modifying therapy exists for HSP.

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"intrathecal Lioresal or oral Dantrolene or Tizanidine and selective injection of botulinum toxin (Botox)"

Antispasticity agents (Lioresal is the baclofen brand, plus dantrolene, tizanidine, and botulinum toxin) are used for symptomatic spasticity in HSP.

Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Regular physiotherapy to maintain range of motion, reduce contractures, and preserve ambulation, a mainstay of supportive HSP management.

Show evidence (1 reference)

PMID:23897027 SUPPORT Human Clinical

"Physical therapy is generally recommended to improve range of motion, maintain and increase lower extremity strength"

Physical therapy is a core supportive intervention recommended in HSP.

Genetic Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic counseling addressing the relevant inheritance mode (autosomal dominant, autosomal recessive, or X-linked) for the specific SPG subtype.

Show evidence (1 reference)

PMID:20301682 SUPPORT Human Clinical

"Inform genetic counseling of family members"

Genetic counseling of at-risk family members is a recommended component of HSP management.

{ }

Source YAML

click to show

name: Complex Hereditary Spastic Paraplegia
creation_date: "2026-07-01T00:00:00Z"
category: Mendelian
description: >
  Complex (also "complicated") hereditary spastic paraplegia (HSP) is the
  clinical-genetic category of HSP in which the core corticospinal-tract
  syndrome of progressive lower-limb spasticity and weakness is accompanied by
  additional neurologic or systemic abnormalities — such as thin corpus
  callosum, cognitive impairment or intellectual disability, peripheral
  neuropathy, cerebellar ataxia, distal amyotrophy, epilepsy, optic atrophy,
  pigmentary retinopathy, or dysarthria. It is defined in contrast to "pure"
  (uncomplicated) HSP, in which lower-limb spasticity with subtle dorsal-column
  impairment and urinary urgency are the only features. Complex HSP is not a
  single disease but a syndromic grouping (MONDO:0015150) spanning many spastic
  paraplegia (SPG) genetic loci, and it is stratified by inheritance into
  autosomal dominant (MONDO:0015087), autosomal recessive, and X-linked complex
  forms. The shared substrate is the same length-dependent, distal-predominant
  degeneration of the longest corticospinal-tract upper motor neuron axons
  (maximal in the thoracic spinal cord) and dorsal-column sensory fibers seen in
  pure HSP; the "complex" features arise because many of the mutated SPG
  proteins have pleiotropic housekeeping roles (endoplasmic reticulum
  morphogenesis, axonal transport, mitochondrial quality control, myelination,
  endolysosomal and autophagic trafficking, lipid metabolism) whose loss injures
  additional neuronal and glial populations beyond the corticospinal tract.
  Correlation between the clinical pure-versus-complex split and the underlying
  genetic type is imperfect: several loci can present as either form. Autosomal
  recessive complex forms (e.g., SPG11/spatacsin, SPG15/ZFYVE26/spastizin) are
  classically associated with thin corpus callosum and cognitive decline;
  X-linked complex forms include SPG1 (L1CAM) and SPG2 (PLP1). Individual
  gene-defined complex forms are carried as `has_subtypes` rows bound to their own
  MONDO classes beneath the three inheritance-stratified rows; see `notes` for the
  rule that routes a given SPG form here rather than to the pure HSP entry.
disease_term:
  preferred_term: complex hereditary spastic paraplegia
  term:
    id: MONDO:0015150
    label: complex hereditary spastic paraplegia
references:
- reference: PMID:30543385
  title: "AP-4-Associated Hereditary Spastic Paraplegia."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301682
  title: "Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview."
  tags:
  - GeneReviews
- reference: PMID:20301389
  title: "Spastic Paraplegia 11."
  tags:
  - GeneReviews
- reference: PMID:20301657
  title: "L1 Syndrome."
  tags:
  - GeneReviews
- reference: PMID:20301361
  title: "PLP1-Related Disorders."
  tags:
  - GeneReviews
- reference: PMID:23897027
  title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."

has_subtypes:
- name: AD Complex HSP
  display_name: Autosomal Dominant Complex Hereditary Spastic Paraplegia
  description: >
    Autosomal dominant forms of complex HSP (MONDO:0015087), in which
    dominantly transmitted spastic paraplegia is accompanied by additional
    neurologic features. Representative loci include SPG10 (KIF5A, with
    peripheral neuropathy and distal amyotrophy), SPG9 (ALDH18A1, with
    cataracts and other systemic features), SPG17/Silver syndrome (BSCL2, with
    amyotrophy of the hands), and complicated presentations of otherwise
    "pure" dominant loci such as SPG3A (ATL1) and SPG4 (SPAST). Penetrance is
    age-dependent.
  genes:
  - preferred_term: KIF5A
    term:
      id: hgnc:6323
      label: KIF5A
  - preferred_term: ALDH18A1
    term:
      id: hgnc:9722
      label: ALDH18A1
  inheritance:
  - name: Autosomal Dominant (Complex)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cause both autosomal dominant HSP (SPG17), Charcot-Marie-Tooth type 2, and distal hereditary motor neuropathy type V"
    explanation: >
      SPG17 (Silver syndrome), caused by heterozygous BSCL2/seipin variants, is
      a representative autosomal dominant complex HSP (spastic paraplegia with
      distal amyotrophy), evidencing the autosomal-dominant complex-HSP subtype.
- name: AR Complex HSP
  display_name: Autosomal Recessive Complex Hereditary Spastic Paraplegia
  description: >
    Autosomal recessive forms of complex HSP, the group most strongly
    associated with thin corpus callosum and progressive cognitive decline.
    SPG11 (spatacsin) is the most common form and is characteristically
    associated with thin corpus callosum, intellectual disability/cognitive
    decline, peripheral neuropathy, and pseudobulbar involvement. SPG15
    (ZFYVE26/spastizin) causes complicated autosomal-recessive spastic
    paraplegia including Kjellin syndrome (with pigmentary maculopathy). SPG7
    (paraplegin) frequently presents with cerebellar ataxia and optic atrophy
    reflecting mitochondrial dysfunction. Additional characteristic autosomal
    recessive complex forms include SPG35 (FA2H, with leukodystrophy, seizures,
    and intellectual disability), SPG20/Troyer syndrome (SPART/spartin, with
    distal amyotrophy, dysarthria, and short stature), and the AP-4-associated
    HSP disorders (AP4B1/AP4M1/AP4E1/AP4S1; SPG47/50/51/52), a childhood-onset
    complex form with severe developmental delay and microcephaly.
  genes:
  - preferred_term: SPG11
    term:
      id: hgnc:11226
      label: SPG11
  - preferred_term: ZFYVE26
    term:
      id: hgnc:20761
      label: ZFYVE26
  - preferred_term: SPG7
    term:
      id: hgnc:11237
      label: SPG7
  - preferred_term: FA2H
    term:
      id: hgnc:21197
      label: FA2H
  - preferred_term: SPART
    term:
      id: hgnc:18514
      label: SPART
  - preferred_term: AP4B1
    term:
      id: hgnc:572
      label: AP4B1
  inheritance:
  - name: Autosomal Recessive (Complex)
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as SPG11 HSP, a common autosomal recessive form of HSP frequently associated with mental retardation and thin corpus callosum"
    explanation: >
      Establishes SPG11 as a common autosomal recessive complex HSP defined by
      cognitive impairment and thin corpus callosum.
  - reference: PMID:18394578
    reference_title: "Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the identification of ZFYVE26, which encodes a zinc-finger protein with a FYVE domain
      that we named spastizin, as the cause of SPG15
    explanation: >
      Identifies ZFYVE26/spastizin as the cause of SPG15, a complicated
      autosomal-recessive spastic paraplegia including Kjellin syndrome. Requoted
      from the abstract: the previous quote was taken from the paper's title and
      did not verify against the abstract text.
- name: XL Complex HSP
  display_name: X-Linked Complex Hereditary Spastic Paraplegia
  description: >
    X-linked forms of complex HSP. SPG1 is part of the L1CAM (L1) syndrome
    spectrum — X-linked complicated hereditary spastic paraplegia type 1,
    within a spectrum that also includes MASA syndrome (intellectual
    disability, aphasia, spastic paraplegia, adducted thumbs), X-linked
    hydrocephalus, and corpus callosum agenesis. SPG2 lies within the
    PLP1-related disorder spectrum, which ranges from Pelizaeus-Merzbacher
    disease to spastic paraplegia 2, reflecting a CNS myelin-formation defect.
  genes:
  - preferred_term: L1CAM
    term:
      id: hgnc:6470
      label: L1CAM
  - preferred_term: PLP1
    term:
      id: hgnc:9086
      label: PLP1
  inheritance:
  - name: X-Linked (Complex)
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
  evidence:
  - reference: PMID:20301657
    reference_title: "L1 Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complicated hereditary spastic paraplegia type 1"
    explanation: >
      L1CAM (L1 syndrome) explicitly includes X-linked complicated hereditary
      spastic paraplegia type 1 (SPG1).
  - reference: PMID:20301361
    reference_title: "PLP1-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to spastic paraplegia 2 (SPG2)"
    explanation: >
      PLP1-related disorders span a phenotypic range extending to X-linked
      spastic paraplegia 2 (SPG2).

- name: Troyer Syndrome
  display_name: Troyer syndrome (SPG20, SPART)
  subtype_term:
    preferred_term: Troyer syndrome
    term:
      id: MONDO:0010156
      label: Troyer syndrome
  genes:
  - preferred_term: SPART
    term:
      id: hgnc:18514
      label: SPART
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Troyer syndrome (SPG20), caused by biallelic SPART (spartin) variants. The disease-defining
    report describes it as an autosomal recessive complicated hereditary spastic paraplegia
    occurring with high frequency in the Old Order Amish, mapped to chromosome 13q12.3, with a
    frameshift mutation in SPG20 (now SPART). ClinGen classifies the SPART-Troyer syndrome
    relationship as Definitive under autosomal recessive inheritance. The SPART record in
    `genetic` points at this row.
  evidence:
  - reference: PMID:12134148
    reference_title: 'SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Troyer syndrome (TRS) is an autosomal recessive complicated hereditary spastic paraplegia
      (HSP) that occurs with high frequency in the Old Order Amish.
    explanation: >-
      Establishes Troyer syndrome as an autosomal recessive complicated (complex) HSP, which is why
      it is a subtype row on this entry rather than a separate entry.
  - reference: CGGV:assertion_5f0c5bcd-68a3-46f2-b632-82feb28381d4-2022-12-19T170000.000Z
    reference_title: 'SPART / Troyer syndrome (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SPART | HGNC:18514 | Troyer syndrome | MONDO:0010156 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: SPART-Troyer syndrome is Definitive under autosomal recessive
      inheritance, against the same MONDO class bound here.
- name: SPG70
  display_name: Autosomal recessive spastic paraplegia type 70 (MARS1)
  subtype_term:
    preferred_term: autosomal recessive spastic paraplegia type 70
    term:
      id: MONDO:0018422
      label: autosomal recessive spastic paraplegia type 70
  genes:
  - preferred_term: MARS1
    term:
      id: hgnc:6898
      label: MARS1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG70, attributed to MARS1 (methionyl-tRNA synthetase 1). This is the most thinly evidenced
    row on the entry: a PubMed search for the SPG70 designation and for MARS1/MARS together with
    spastic paraplegia returned no dedicated SPG70 report, and the human evidence cited here is a
    childhood-onset HSP case series in which MARS was the confirmed genetic etiology in two of
    sixteen patients. ClinGen has not curated MARS1 against any HSP entity; its only MARS1 record
    is Charcot-Marie-Tooth disease (Limited, autosomal dominant). The autosomal recessive
    designation follows the bound MONDO class label.
  evidence:
  - reference: PMID:35303589
    reference_title: 'Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1),
      SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1).
    explanation: >-
      MARS (now MARS1) was the confirmed genetic etiology in two patients of a childhood-onset
      hereditary spastic paraplegia cohort, which is the human evidence available for this
      gene-disease pair.
- name: SPG76
  display_name: Autosomal recessive spastic paraplegia type 76 (CAPN1)
  subtype_term:
    preferred_term: autosomal recessive spastic paraplegia type 76
    term:
      id: MONDO:0014827
      label: autosomal recessive spastic paraplegia type 76
  genes:
  - preferred_term: CAPN1
    term:
      id: hgnc:1476
      label: CAPN1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG76, caused by biallelic CAPN1 (calpain 1) variants. Rare homozygous and compound
    heterozygous nonsense, missense, frameshift and splice-site CAPN1 variants were identified in
    nine affected individuals from three autosomal recessive HSP families and segregated with
    disease. Calpain 1 is a CNS protease implicated in synaptic plasticity and in axon maturation
    and maintenance, which is why CAPN1 is also bound on the corticospinal-tract axonal
    degeneration node.
  evidence:
  - reference: PMID:27153400
    reference_title: 'Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in CAPN1 were identified in all affected individuals, and sequencing in additional
      family members confirmed the segregation of these mutations with the disease (spastic
      paraplegia 76 [SPG76])
    explanation: >-
      Identifies biallelic CAPN1 variants as the cause of SPG76 in three autosomal recessive HSP
      families, with segregation confirmed.
- name: SPG78
  display_name: Autosomal recessive spastic paraplegia type 78 (ATP13A2)
  subtype_term:
    preferred_term: autosomal recessive spastic paraplegia type 78
    term:
      id: MONDO:0014975
      label: autosomal recessive spastic paraplegia type 78
  genes:
  - preferred_term: ATP13A2
    term:
      id: hgnc:30213
      label: ATP13A2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG78, caused by biallelic ATP13A2 variants. ATP13A2 is allelic with Kufor-Rakeb syndrome,
    which dismech curates as its own entry (Kufor-Rakeb_syndrome, MONDO:0011706); the SPG78
    presentation is recorded here because the defining report frames it as complicated hereditary
    spastic paraplegia added to the clinical continuum of ATP13A2-associated disorders, dominated
    by adult-onset lower-limb predominant spastic paraparesis. ClinGen's only ATP13A2 record is
    Kufor-Rakeb syndrome (Definitive), not SPG78.
  evidence:
  - reference: PMID:28137957
    reference_title: 'Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a Bulgarian family with three siblings affected by complicated hereditary spastic
      paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a
      homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2.
    explanation: >-
      Identifies a homozygous ATP13A2 variant in a family with complicated HSP, the observation on
      which the SPG78 designation rests.
  - reference: PMID:28137957
    reference_title: 'Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome
    explanation: >-
      Records the allelic relationship that makes the lump/split ruling necessary: the same gene
      underlies Kufor-Rakeb syndrome, which is a separate dismech entry.
- name: GPT2 Deficiency
  display_name: Glutamate pyruvate transaminase 2 deficiency
  subtype_term:
    preferred_term: glutamate pyruvate transaminase 2 deficiency
    term:
      id: MONDO:0014567
      label: glutamate pyruvate transaminase 2 deficiency
  genes:
  - preferred_term: GPT2
    term:
      id: hgnc:18062
      label: GPT2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    GPT2 deficiency, caused by biallelic loss-of-function GPT2 variants. Affected individuals in
    the defining kindreds were ascertained for intellectual and developmental disability, showed
    postnatal microcephaly, and most of those followed over time developed a progressive spastic
    paraplegia, which is why the disease is recorded on this entry. ClinGen classifies the
    GPT2-GPT2 deficiency relationship as Definitive under autosomal recessive inheritance against
    the same MONDO class bound here.
  evidence:
  - reference: PMID:27601654
    reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2)
      in large kindreds initially ascertained for intellectual and developmental disability (IDD).
    explanation: >-
      Establishes autosomal recessive GPT2 variants as the cause of this disease in the defining
      kindreds.
  - reference: PMID:27601654
    reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all affected individuals show postnatal microcephaly
    explanation: >-
      Records the postnatal microcephaly that accompanies the spastic paraplegia, the complicating
      feature that places this disease under complex HSP.
  - reference: CGGV:assertion_42a70a83-40da-4acc-b6a3-9ef3942abd14-2021-10-05T115427.845Z
    reference_title: 'GPT2 / glutamate pyruvate transaminase 2 deficiency (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      GPT2 | HGNC:18062 | glutamate pyruvate transaminase 2 deficiency | MONDO:0014567 | AR |
      Definitive
    explanation: >-
      ClinGen gene-disease validity: GPT2-glutamate pyruvate transaminase 2 deficiency is Definitive
      under autosomal recessive inheritance, against the same MONDO class bound here.
- name: HSAN-SP
  display_name: Hereditary sensory and autonomic neuropathy with spastic paraplegia (CCT5)
  subtype_term:
    preferred_term: hereditary sensory and autonomic neuropathy with spastic paraplegia
    term:
      id: MONDO:0009748
      label: hereditary sensory and autonomic neuropathy with spastic paraplegia
  genes:
  - preferred_term: CCT5
    term:
      id: hgnc:1618
      label: CCT5
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Mutilating sensory neuropathy with spastic paraplegia, caused by a CCT5 missense variant in a
    consanguineous Moroccan family with four affected members. CCT5 encodes the epsilon subunit of
    the cytosolic chaperonin-containing t-complex peptide-1. ClinGen has no CCT5 gene-disease
    validity record.
  evidence:
  - reference: PMID:16399879
    reference_title: 'Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy
      associated with spastic paraplegia was investigated.
    explanation: >-
      Defines the clinical entity - mutilating sensory neuropathy with spastic paraplegia - in the
      family in which the causal gene was found.
  - reference: PMID:16399879
    reference_title: 'Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequence analysis of the Cct5 gene revealed a missense A492G mutation in exon 4
    explanation: >-
      Identifies the CCT5 missense variant segregating in that family, the basis for binding CCT5 to
      this subtype.
- name: SPG15
  display_name: Hereditary spastic paraplegia 15 (ZFYVE26, Kjellin syndrome)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 15
    term:
      id: MONDO:0010044
      label: hereditary spastic paraplegia 15
  genes:
  - preferred_term: ZFYVE26
    term:
      id: hgnc:20761
      label: ZFYVE26
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG15, caused by biallelic truncating ZFYVE26 (spastizin) variants; six different truncating
    mutations segregated with disease in eight families whose phenotype included variable features
    of Kjellin syndrome. Spastizin colocalizes partially with endoplasmic reticulum and endosomal
    markers, which is why ZFYVE26 is also bound on the endolysosomal and ESCRT membrane-traffic node. The
    ZFYVE26 record in `genetic` points at this row. ClinGen has no ZFYVE26 gene-disease validity
    record.
  evidence:
  - reference: PMID:18394578
    reference_title: 'Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Six different truncating mutations were found to segregate with the disease in eight families
      with a phenotype that included variable clinical features of Kjellin syndrome.
    explanation: >-
      Establishes biallelic truncating ZFYVE26 variants as the cause of SPG15 across eight families,
      including the Kjellin-syndrome presentation.
- name: SPG18
  display_name: Hereditary spastic paraplegia 18 (ERLIN2)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 18
    term:
      id: MONDO:0012639
      label: hereditary spastic paraplegia 18
  genes:
  - preferred_term: ERLIN2
    term:
      id: hgnc:1356
      label: ERLIN2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG18, caused by ERLIN2 variants. ClinGen holds two ERLIN2 records against this same MONDO
    class: autosomal recessive is Definitive and autosomal dominant is Limited, so the recessive
    form is the one this row treats as established. ERLIN2 acts in inositol 1,4,5-trisphosphate
    receptor degradation, which is why it is bound on the endoplasmic reticulum calcium-release
    node alongside RNF170.
  evidence:
  - reference: CGGV:assertion_9599fa0e-da62-437d-8f6f-2f2ef0297c8c-2025-06-18T190000.000Z
    reference_title: 'ERLIN2 / hereditary spastic paraplegia 18 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ERLIN2 | HGNC:1356 | hereditary spastic paraplegia 18 | MONDO:0012639 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: ERLIN2-hereditary spastic paraplegia 18 is Definitive under
      autosomal recessive inheritance, against the same MONDO class bound here.
  - reference: CGGV:assertion_1467b8b6-6295-4fa8-bafc-86478e6ffd19-2025-06-18T190000.000Z
    reference_title: 'ERLIN2 / hereditary spastic paraplegia 18 (Limited)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ERLIN2 | HGNC:1356 | hereditary spastic paraplegia 18 | MONDO:0012639 | AD | Limited
    explanation: >-
      ClinGen's separate autosomal dominant ERLIN2 record for the same disease is only Limited,
      which is why this row records recessive inheritance.
- name: SPG23
  display_name: Hereditary spastic paraplegia 23 (DSTYK, Lison syndrome)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 23
    term:
      id: MONDO:0010046
      label: hereditary spastic paraplegia 23
  genes:
  - preferred_term: DSTYK
    term:
      id: hgnc:29043
      label: DSTYK
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG23, attributed to biallelic DSTYK variants. ClinGen curates DSTYK against complex
    hereditary spastic paraplegia - this entry's own bound class - at Moderate strength under
    autosomal recessive inheritance, so the gene-disease relationship is supported but not
    definitive.
  evidence:
  - reference: CGGV:assertion_bbac4423-e313-4694-a7ac-2005164ea832-2023-09-29T023000.000Z
    reference_title: 'DSTYK / complex hereditary spastic paraplegia (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DSTYK | HGNC:29043 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Moderate
    explanation: >-
      ClinGen gene-disease validity: DSTYK-complex hereditary spastic paraplegia is Moderate under
      autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is
      anchored on.
- name: SPG26
  display_name: Hereditary spastic paraplegia 26 (B4GALNT1)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 26
    term:
      id: MONDO:0012213
      label: hereditary spastic paraplegia 26
  genes:
  - preferred_term: B4GALNT1
    term:
      id: hgnc:4117
      label: B4GALNT1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG26, caused by biallelic B4GALNT1 variants. Functional studies in patient-derived
    fibroblasts and in cell models of GM2 synthase deficiency confirmed loss of B4GALNT1 function
    with no synthesis of GM2 or downstream gangliosides, which is why B4GALNT1 is bound on the
    membrane-lipid and ganglioside node. ClinGen classifies B4GALNT1-complex hereditary spastic
    paraplegia as Definitive under autosomal recessive inheritance.
  evidence:
  - reference: PMID:35775650
    reference_title: 'Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26).
    explanation: >-
      Establishes the SPG26 diagnosis in a patient with biallelic B4GALNT1 variants after functional
      confirmation.
  - reference: CGGV:assertion_4cabf677-8fa5-4455-831c-1d06dd48c780-2023-06-01T060000.000Z
    reference_title: 'B4GALNT1 / complex hereditary spastic paraplegia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      B4GALNT1 | HGNC:4117 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: B4GALNT1-complex hereditary spastic paraplegia is Definitive
      under autosomal recessive inheritance, curated against MONDO:0015150.
- name: SPG39
  display_name: Hereditary spastic paraplegia 39 (PNPLA6)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 39
    term:
      id: MONDO:0012787
      label: hereditary spastic paraplegia 39
  genes:
  - preferred_term: PNPLA6
    term:
      id: hgnc:16268
      label: PNPLA6
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG39, the spastic-paraplegia presentation of the PNPLA6 disorder spectrum, which also
    includes Gordon-Holmes, Boucher-Neuhauser, Oliver-McFarlane and Laurence-Moon syndromes.
    dismech curates the ataxia-hypogonadism-choroidal dystrophy end of that spectrum separately as
    Boucher-Neuhauser_Syndrome; this row carries the spastic-paraplegia end. ClinGen's Definitive
    PNPLA6 record for spastic paraplegia is filed against its own entity (PNPLA6-related spastic
    paraplegia with or without ataxia, MONDO:0100149) rather than against the SPG39 class bound
    here.
  evidence:
  - reference: PMID:35069422
    reference_title: 'Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in
      the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic
      paraplegia type 39, Gordon-Holmes, Boucher-Neuhauser, Oliver-Mc Farlane, and Laurence-Moon
      syndromes.
    explanation: >-
      Places spastic paraplegia type 39 inside the PNPLA6 allelic spectrum, which is the basis for
      binding PNPLA6 to this row and for keeping the Boucher-Neuhauser presentation in its own
      entry.
  - reference: CGGV:assertion_f05d3811-d318-4d8e-be25-8b9da90e6d23-2022-11-02T040000.000Z
    reference_title: 'PNPLA6 / PNPLA6-related spastic paraplegia with or without ataxia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PNPLA6 | HGNC:16268 | PNPLA6-related spastic paraplegia with or without ataxia | MONDO:0100149
      | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: PNPLA6 is Definitive for a spastic paraplegia entity under
      autosomal recessive inheritance, although against MONDO:0100149 rather than the SPG39 class.
- name: SPG43
  display_name: Hereditary spastic paraplegia 43 (C19orf12)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 43
    term:
      id: MONDO:0014024
      label: hereditary spastic paraplegia 43
  genes:
  - preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG43, caused by a homozygous C19orf12 missense variant first reported in two Malian sisters.
    C19orf12 is allelic with neurodegeneration with brain iron accumulation, which dismech curates
    in Neurodegeneration_With_Brain_Iron_Accumulation; the two presentations are distinguished in
    the defining report by brain imaging, which showed no iron deposition in the SPG43 subjects.
    ClinGen's only C19orf12 records are for neurodegeneration with brain iron accumulation 4.
  evidence:
  - reference: PMID:23857908
    reference_title: 'Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the genetic basis for a form of progressive hereditary spastic paraplegia
      (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous
      missense variant (c.187G>C; p.Ala63Pro) in C19orf12
    explanation: >-
      Identifies the homozygous C19orf12 variant causing SPG43.
  - reference: PMID:23857908
    reference_title: 'Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MRI scans showed no brain iron deposition in the Malian SPG43 subjects
    explanation: >-
      Distinguishes SPG43 from the NBIA presentation of the same gene, which is why SPG43 is
      recorded here and NBIA in its own entry.
- name: SPG53
  display_name: Hereditary spastic paraplegia 53 (VPS37A)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 53
    term:
      id: MONDO:0013962
      label: hereditary spastic paraplegia 53
  genes:
  - preferred_term: VPS37A
    term:
      id: hgnc:24928
      label: VPS37A
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG53, caused by a homozygous VPS37A missense founder mutation in two kindreds of Arab Moslem
    origin presenting with early-onset spastic paraparesis of upper and lower limbs, mild
    intellectual disability, kyphosis, pectus carinatum and hypertrichosis. VPS37A is a component
    of the ESCRT system, which is why it is bound on the endolysosomal and ESCRT
    membrane-traffic node.
    ClinGen classifies VPS37A-complex hereditary spastic paraplegia as Limited, so the
    gene-disease relationship is not yet established at ClinGen even though the founder mutation
    segregated fully in both families.
  evidence:
  - reference: PMID:22717650
    reference_title: 'A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the
      vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease
      in both families
    explanation: >-
      Identifies the fully penetrant homozygous VPS37A founder mutation segregating in both
      kindreds.
  - reference: PMID:22717650
    reference_title: 'A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced
      early onset spastic paraparesis of upper and lower limbs, mild intellectual disability,
      kyphosis, pectus carinatum and hypertrichosis.
    explanation: >-
      Records the complicating features - intellectual disability and skeletal involvement - that
      make this a complex rather than pure HSP.
  - reference: CGGV:assertion_14dcdd9d-bd32-49ff-ab29-fa7b79baf463-2025-03-06T170000.000Z
    reference_title: 'VPS37A / complex hereditary spastic paraplegia (Limited)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      VPS37A | HGNC:24928 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Limited
    explanation: >-
      ClinGen gene-disease validity: VPS37A-complex hereditary spastic paraplegia is only Limited,
      which this row records rather than overstating.
- name: SPG54
  display_name: Hereditary spastic paraplegia 54 (DDHD2)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 54
    term:
      id: MONDO:0014018
      label: hereditary spastic paraplegia 54
  genes:
  - preferred_term: DDHD2
    term:
      id: hgnc:29106
      label: DDHD2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG54, caused by recessive DDHD2 variants in four families. The defining report gives the core
    phenotype as very early-onset spastic paraplegia with intellectual disability and a specific
    pattern of brain abnormalities on imaging, and reports an abnormal lipid peak on cerebral
    magnetic resonance spectroscopy as a distinguishing biomarker. DDHD2 encodes an intracellular
    phospholipase A1, which is why it is bound on the membrane-lipid node. ClinGen has no DDHD2
    gene-disease validity record.
  evidence:
  - reference: PMID:23176823
    reference_title: 'Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic
      paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral
      imaging.
    explanation: >-
      Gives the core complex-HSP phenotype of recessive DDHD2 disease.
  - reference: PMID:23176823
    reference_title: 'Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking
      a member of the PLA(1) family to human neurologic disease.
    explanation: >-
      Establishes recessive DDHD2 variants as the cause of SPG54.
- name: SPG57
  display_name: Hereditary spastic paraplegia 57 (TFG)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 57
    term:
      id: MONDO:0014295
      label: hereditary spastic paraplegia 57
  genes:
  - preferred_term: TFG
    term:
      id: hgnc:11758
      label: TFG
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG57, caused by homozygous TFG variants. Two consanguineous Iranian families carrying
    homozygous TFG missense variants were reported with early-onset progressive muscle weakness,
    spasticity and further neurological features. ClinGen has no TFG gene-disease validity record.
  evidence:
  - reference: PMID:33767317
    reference_title: 'Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary
      neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia,
      named spastic paraplegia type 57 (SPG57)
    explanation: >-
      States the TFG-SPG57 relationship and that SPG57 is a complex HSP; quoted from the report's
      framing of prior work rather than from its own result.
  - reference: PMID:33767317
    reference_title: 'Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous missense variants including c.41A>G (p.Lys14Arg) and c.316C>T (p.Arg106Cys)
      have been found in the related families.
    explanation: >-
      Reports the homozygous TFG variants found in the two consanguineous families, the study's own
      contribution to this gene-disease pair.
- name: SPG63
  display_name: Hereditary spastic paraplegia 63 (AMPD2)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 63
    term:
      id: MONDO:0014305
      label: hereditary spastic paraplegia 63
  genes:
  - preferred_term: AMPD2
    term:
      id: hgnc:469
      label: AMPD2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG63, attributed to a homozygous AMPD2 frameshift variant reported in two family members.
    AMPD2 is allelic with pontocerebellar hypoplasia type 9, which is the presentation most AMPD2
    cohorts describe; the SPG63 designation rests on that single family. ClinGen has no AMPD2
    gene-disease validity record.
  evidence:
  - reference: PMID:29463858
    reference_title: 'Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous AMPD2 frameshift variant has recently been reported in two family members with
      spastic paraplegia type 63 (SPG63)
    explanation: >-
      Records the AMPD2-SPG63 relationship and its narrow evidence base; the sentence restates an
      earlier report rather than this cohort's own finding.
- name: SPG64
  display_name: Hereditary spastic paraplegia 64 (ENTPD1)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 64
    term:
      id: MONDO:0014303
      label: hereditary spastic paraplegia 64
  genes:
  - preferred_term: ENTPD1
    term:
      id: hgnc:3363
      label: ENTPD1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG64, caused by biallelic ENTPD1 variants. ClinGen classifies ENTPD1-complex hereditary
    spastic paraplegia as Definitive under autosomal recessive inheritance, curated against
    MONDO:0015150, the class this entry is anchored on.
  evidence:
  - reference: CGGV:assertion_8634ea9c-3fce-4d72-94e9-2ac6756e5cb6-2023-05-06T023000.000Z
    reference_title: 'ENTPD1 / complex hereditary spastic paraplegia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ENTPD1 | HGNC:3363 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: ENTPD1-complex hereditary spastic paraplegia is Definitive
      under autosomal recessive inheritance, curated against MONDO:0015150.
- name: SPG74
  display_name: Hereditary spastic paraplegia 74 (IBA57)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 74
    term:
      id: MONDO:0014644
      label: hereditary spastic paraplegia 74
  genes:
  - preferred_term: IBA57
    term:
      id: hgnc:27302
      label: IBA57
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG74, caused by a homozygous IBA57 donor splice-site mutation in a highly consanguineous
    family whose ten affected members had a childhood-onset SPOAN-like phenotype - spastic
    paraplegia with optic atrophy and peripheral neuropathy - progressing slowly into late
    adulthood. IBA57 is a mitochondrial iron-sulfur protein assembly factor, which is why it is
    bound on the mitochondrial iron-sulfur cluster assembly node. ClinGen curates IBA57 against mitochondrial disease
    (Definitive) rather than against an HSP entity.
  evidence:
  - reference: PMID:25609768
    reference_title: 'Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor
      splice-site mutation in the IBA57 gene
    explanation: >-
      Identifies the homozygous IBA57 splice-site mutation in the family that defines this subtype.
- name: SPG75
  display_name: Hereditary spastic paraplegia 75 (MAG)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 75
    term:
      id: MONDO:0014729
      label: hereditary spastic paraplegia 75
  genes:
  - preferred_term: MAG
    term:
      id: hgnc:6783
      label: MAG
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG75, caused by biallelic MAG (myelin associated glycoprotein) variants. ClinGen classifies
    MAG-complex hereditary spastic paraplegia as Definitive under autosomal recessive inheritance,
    curated against MONDO:0015150, the class this entry is anchored on.
  evidence:
  - reference: CGGV:assertion_27976cb3-605a-4f56-a262-64dfd9793559-2023-11-20T190000.000Z
    reference_title: 'MAG / complex hereditary spastic paraplegia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MAG | HGNC:6783 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: MAG-complex hereditary spastic paraplegia is Definitive under
      autosomal recessive inheritance, curated against MONDO:0015150.
- name: SPAX2
  display_name: Spastic ataxia 2 (KIF1C, SPG58)
  subtype_term:
    preferred_term: spastic ataxia 2
    term:
      id: MONDO:0012651
      label: spastic ataxia 2
  genes:
  - preferred_term: KIF1C
    term:
      id: hgnc:6317
      label: KIF1C
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    Spastic ataxia 2, caused by homozygous KIF1C variants in two consanguineous families of
    Palestinian and Moroccan ancestry with spastic paraparesis and cerebellar dysfunction; the
    linked locus on chromosome 17 had previously been associated with spastic ataxia type 2. KIF1C
    is a kinesin, which is why it is bound on the kinesin-dependent axonal cargo transport node.
    ClinGen has no KIF1C gene-disease validity record.
  evidence:
  - reference: PMID:24319291
    reference_title: 'KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among
      controls
    explanation: >-
      Identifies the homozygous KIF1C mutations in the two families with spastic paraparesis and
      cerebellar dysfunction.
  - reference: PMID:24319291
    reference_title: 'KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2
      (SPAX2, OMIM %611302)
    explanation: >-
      Ties the KIF1C locus to the spastic ataxia 2 concept bound on this row.
- name: SPG85
  display_name: Spastic paraplegia 85, autosomal recessive (RNF170)
  subtype_term:
    preferred_term: spastic paraplegia 85, autosomal recessive
    term:
      id: MONDO:0030512
      label: spastic paraplegia 85, autosomal recessive
  genes:
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG85, caused by bi-allelic RNF170 variants in four unrelated families. RNF170 is the
    ubiquitin E3 ligase that targets inositol 1,4,5-trisphosphate receptors for degradation, which
    is why it is bound on the endoplasmic reticulum calcium-release node alongside ERLIN2. The
    dominant RNF170 disease at the other end of the same allelic series, autosomal dominant
    sensory ataxia 1, is curated separately as Autosomal_Dominant_Sensory_Ataxia_1, which already
    records SPG85 as a differential diagnosis. ClinGen has no RNF170 gene-disease validity record.
  evidence:
  - reference: PMID:31636353
    reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets
      inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal
      recessive HSP in four unrelated families
    explanation: >-
      Establishes bi-allelic RNF170 variants as the cause of autosomal recessive HSP in four
      families and names the molecular role on which the mechanism node rests.
- name: SPG86
  display_name: Spastic paraplegia 86, autosomal recessive (ABHD16A)
  subtype_term:
    preferred_term: spastic paraplegia 86, autosomal recessive
    term:
      id: MONDO:0030673
      label: spastic paraplegia 86, autosomal recessive
  genes:
  - preferred_term: ABHD16A
    term:
      id: hgnc:13921
      label: ABHD16A
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG86, caused by biallelic ABHD16A variants. Two homozygous ABHD16A variants segregated with a
    phenotype of spasticity, psychomotor developmental delay or regression and intellectual
    impairment in two unrelated consanguineous Sudanese families. ABHD16A is the main brain
    phosphatidylserine hydrolase, which is why it is bound on the membrane-lipid node. ClinGen has
    no ABHD16A gene-disease validity record.
  evidence:
  - reference: PMID:34489854
    reference_title: 'Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous variants in ABHD16A segregated with the disease in the two studied families.
    explanation: >-
      Establishes biallelic ABHD16A variants as the cause of this complex spastic-paraplegia
      phenotype in the two families reported.
- name: SINO
  display_name: Spastic paraplegia, intellectual disability, nystagmus and obesity (KIDINS220)
  subtype_term:
    preferred_term: spastic paraplegia, intellectual disability, nystagmus, and obesity
    term:
      id: MONDO:0015007
      label: spastic paraplegia, intellectual disability, nystagmus, and obesity
  genes:
  - preferred_term: KIDINS220
    term:
      id: hgnc:29508
      label: KIDINS220
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  description: >-
    SINO syndrome, attributed to KIDINS220. It is the only autosomal dominant gene-defined row on
    this entry: ClinGen curates KIDINS220 against this MONDO class under autosomal dominant
    inheritance, at Moderate strength. ClinGen's other KIDINS220 record
    is a recessive entity (ventriculomegaly and arthrogryposis) and is not this disease.
  evidence:
  - reference: CGGV:assertion_22271df6-f033-4ecc-9aa7-2b5cdd8f060e-2024-10-29T160000.000Z
    reference_title: 'KIDINS220 / spastic paraplegia, intellectual disability, nystagmus, and obesity (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      KIDINS220 | HGNC:29508 | spastic paraplegia, intellectual disability, nystagmus, and obesity |
      MONDO:0015007 | AD | Moderate
    explanation: >-
      ClinGen gene-disease validity: KIDINS220 is curated against this exact MONDO class under
      autosomal dominant inheritance at Moderate strength, which is the basis for both the gene
      binding and the dominant inheritance on this row.
- name: SPOAN
  display_name: Spastic paraplegia, optic atrophy and neuropathy (KLC2)
  subtype_term:
    preferred_term: spastic paraplegia, optic atropy, and neuropathy
    term:
      id: MONDO:0012297
      label: spastic paraplegia, optic atropy, and neuropathy
  genes:
  - preferred_term: KLC2
    term:
      id: hgnc:20716
      label: KLC2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPOAN syndrome, caused by a homozygous 216-bp deletion in the non-coding region upstream of
    KLC2 that leads to KLC2 overexpression - a recessive disease mechanism acting through
    increased rather than lost gene product. KLC2 is a kinesin light chain, which is why it is
    bound on the kinesin-dependent axonal cargo transport node. ClinGen has no KLC2 gene-disease
    validity record. Note that the bound MONDO label carries the misspelling 'optic atropy'; it is
    copied here as the ontology's canonical label.
  evidence:
  - reference: PMID:26385635
    reference_title: 'Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia,
      optic atrophy and neuropathy (SPOAN).
    explanation: >-
      Defines the SPOAN clinical triad bound on this row.
  - reference: PMID:26385635
    reference_title: 'Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whole-genome sequencing allowed to detect a homozygous 216-bp deletion
      (chr11.hg19:g.66,024,557_66,024,773del) located at the non-coding upstream region of the KLC2
      gene
    explanation: >-
      Identifies the homozygous non-coding deletion upstream of KLC2 as the causal lesion.
- name: SPPRS
  display_name: Spastic paraplegia and psychomotor retardation with or without seizures (HACE1)
  subtype_term:
    preferred_term: spastic paraplegia-severe developmental delay-epilepsy syndrome
    term:
      id: MONDO:0014764
      label: spastic paraplegia-severe developmental delay-epilepsy syndrome
  genes:
  - preferred_term: HACE1
    term:
      id: hgnc:21033
      label: HACE1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPPRS, caused by biallelic loss-of-function HACE1 variants. ClinGen has no HACE1 gene-disease
    validity record.
  evidence:
  - reference: PMID:36553453
    reference_title: 'Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756)
      is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene.
    explanation: >-
      States the HACE1-SPPRS gene-disease relationship and its recessive mode; quoted from the
      report's opening framing of established knowledge rather than from its own new deletions.
- name: AP-4-HSP
  display_name: AP-4-associated hereditary spastic paraplegia (AP-4 deficiency syndrome)
  subtype_term:
    preferred_term: AP-4 deficiency syndrome
    term:
      id: MONDO:0100176
      label: AP-4 deficiency syndrome
  genes:
  - preferred_term: AP4B1
    term:
      id: hgnc:572
      label: AP4B1
  - preferred_term: AP4E1
    term:
      id: hgnc:573
      label: AP4E1
  - preferred_term: AP4M1
    term:
      id: hgnc:574
      label: AP4M1
  - preferred_term: AP4S1
    term:
      id: hgnc:575
      label: AP4S1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    AP-4-associated HSP (SPG47/50/51/52), caused by biallelic variants in any of the four AP-4
    adaptor complex subunit genes. This is curated as ONE row with four genes rather than four
    gene-defined rows: GeneReviews has a single AP-4-HSP chapter whose diagnostic criterion is
    biallelic variants in AP4B1, AP4E1, AP4M1 or AP4S1; ClinGen curates all four genes as
    Definitive against one entity, AP-4 deficiency syndrome (MONDO:0100176); and MONDO supplies
    that same integrated class alongside its four gene-generated SPG classes (MONDO:0013551
    SPG47/AP4B1, MONDO:0013048 SPG50/AP4M1, MONDO:0013401 SPG51/AP4E1, MONDO:0013552 SPG52/AP4S1).
    All four subunit genes are bound on this row and each has its own `genetic` record pointing
    back at it.
  evidence:
  - reference: PMID:30543385
    reference_title: 'AP-4-Associated Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic
      pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.
    explanation: >-
      GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4
      subunit genes, which is the primary basis for curating this as a single four-gene subtype row.
  - reference: PMID:30543385
    reference_title: 'AP-4-Associated Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AP-4-HSP is inherited in an autosomal recessive manner.
    explanation: >-
      Establishes autosomal recessive inheritance for this subtype.
  - reference: CGGV:assertion_4436344a-e0da-4c42-b06a-cdf8a2581ce5-2021-07-25T220000.000Z
    reference_title: 'AP4B1 / AP-4 deficiency syndrome (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AP4B1 | HGNC:572 | AP-4 deficiency syndrome | MONDO:0100176 | AR | Definitive
    explanation: >-
      ClinGen curates AP4B1 as Definitive against AP-4 deficiency syndrome, the single entity bound
      on this row.
  - reference: CGGV:assertion_be93d2e7-f302-41a7-9675-032510e46ad2-2020-12-16T170000.000Z
    reference_title: 'AP4E1 / AP-4 deficiency syndrome (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AP4E1 | HGNC:573 | AP-4 deficiency syndrome | MONDO:0100176 | AR | Definitive
    explanation: >-
      ClinGen curates AP4E1 as Definitive against the same single entity.
  - reference: CGGV:assertion_f49be3e4-4e1f-478b-b4e0-f41623e5b548-2021-04-06T220000.000Z
    reference_title: 'AP4M1 / AP-4 deficiency syndrome (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AP4M1 | HGNC:574 | AP-4 deficiency syndrome | MONDO:0100176 | AR | Definitive
    explanation: >-
      ClinGen curates AP4M1 as Definitive against the same single entity; MONDO also has a
      gene-generated class for it (MONDO:0013048, SPG50).
  - reference: CGGV:assertion_652e2cbe-22aa-4cd4-ba41-5bacca69af13-2023-04-25T160000.000Z
    reference_title: 'AP4S1 / AP-4 deficiency syndrome (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      AP4S1 | HGNC:575 | AP-4 deficiency syndrome | MONDO:0100176 | AR | Definitive
    explanation: >-
      ClinGen curates AP4S1 as Definitive against the same single entity.

- name: SPG45
  display_name: Hereditary spastic paraplegia 45 (NT5C2)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 45
    term:
      id: MONDO:0013165
      label: hereditary spastic paraplegia 45
  genes:
  - preferred_term: NT5C2
    term:
      id: hgnc:8022
      label: NT5C2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG45, caused by biallelic NT5C2 variants. Onset is in infancy or early childhood with
    lower-limb spasticity and delayed motor development, variably accompanied by learning
    difficulty or intellectual disability, dysarthria, ataxia, nystagmus and strabismus; a
    consanguineous Saudi family homozygous for a splice-donor variant was reported as spastic
    diplegic cerebral palsy with developmental delay and microcephaly. NT5C2 is the
    cytosolic 5'-nucleotidase II, which is why it is bound on the purine nucleotide node rather
    than on the pleiotropic node. MONDO:0013165 carries both SPG45 and SPG65 as synonyms, and the
    exome study that identified the gene listed NT5C2 under the newly assigned locus number SPG65
    while noting that NT5C2 lies within the previously mapped SPG45 locus; HGNC likewise records
    SPG45 as a previous symbol and SPG65 as an alias of NT5C2 (read from rest.genenames.org
    2026-09-30).
  evidence:
  - reference: PMID:39119448
    reference_title: 'Two Sibling Cases of Spastic Paraplegia-45 with a Novel Pathogenic Variant in NT5C2 Gene: Concomitant RYR1 Gene in One Sibling.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG45 is the AR inherited type of complicated SPG, which is due to a mutation in the NT5C2
      gene.
    explanation: >-
      States the identity this row binds: SPG45 is the autosomal recessive, complicated form of
      spastic paraplegia attributed to NT5C2, which is the placement of the row on this entry
      rather than on the pure HSP entry.
  - reference: PMID:39119448
    reference_title: 'Two Sibling Cases of Spastic Paraplegia-45 with a Novel Pathogenic Variant in NT5C2 Gene: Concomitant RYR1 Gene in One Sibling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a previously unidentified homozygous mutation in the NT5C2
      gene, leading to the diagnosis of SPG45 in both siblings.
    explanation: >-
      A homozygous NT5C2 variant established the SPG45 diagnosis in two affected siblings, which
      is the gene-disease relationship this row records.
  - reference: PMID:39119448
    reference_title: 'Two Sibling Cases of Spastic Paraplegia-45 with a Novel Pathogenic Variant in NT5C2 Gene: Concomitant RYR1 Gene in One Sibling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They also experienced learning difficulties, dysarthric speech, ataxia, nystagmus,
      strabismus, and spasticity in their extremities.
    explanation: >-
      Records the features accompanying the spasticity in this sibling pair, which are the
      complicating features placing SPG45 in the complex category.
- name: SPG61
  display_name: Hereditary spastic paraplegia 61 (ARL6IP1)
  subtype_term:
    preferred_term: hereditary spastic paraplegia 61
    term:
      id: MONDO:0014304
      label: hereditary spastic paraplegia 61
  genes:
  - preferred_term: ARL6IP1
    term:
      id: hgnc:697
      label: ARL6IP1
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  description: >-
    SPG61, caused by biallelic ARL6IP1 variants; both alleles cited on this row are truncating, a
    homozygous frameshift in one reported patient and a homozygous nonsense variant predicted to
    abolish the protein in a second kindred. Onset is in infancy with spastic paraplegia
    accompanied by a sensory neuropathy; congenital insensitivity to pain with acromutilation has
    also been reported. That combination is not unique on this entry: the CCT5 row is hereditary
    sensory and autonomic neuropathy with spastic paraplegia, whose cited source describes a
    mutilating sensory neuropathy. The severe end of the range is lethal: a Saudi kindred homozygous for
    the nonsense allele lost both affected siblings in the neonatal period, with developmental
    delay, microcephaly, cerebral atrophy, seizures and respiratory distress. ARL6IP1 shapes
    high-curvature endoplasmic reticulum tubules and binds atlastin, which is why it is bound on
    the ER membrane shaping node rather than on the IP3-receptor calcium-release node.
  evidence:
  - reference: PMID:31272422
    reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in ARL6IP1, which encodes a tetraspan membrane protein localized to the
      endoplasmic reticulum (ER), have been recently described in a large family with a
      complicated form of hereditary spastic paraplegia (HSP).
    explanation: >-
      Restates the founding human observation behind this row, that ARL6IP1 variants cause a
      complicated form of hereditary spastic paraplegia; the sentence is this paper's framing of
      work reported elsewhere rather than its own result.
  - reference: PMID:28471035
    reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy,
      acromutilation, and spastic paraplegia.
    explanation: >-
      Records the clinical combination reported for this gene: pain insensitivity and
      acromutilation alongside the spastic paraplegia.
  - reference: PMID:31272422
    reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features encompassed not only spastic paraplegia but also developmental delay,
      microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures,
      spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and
      respiratory distress.
    explanation: >-
      Documents the severe end of the ARL6IP1 phenotypic range quoted in this row's description.

classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC

pathophysiology:
- name: Length-Dependent Corticospinal-Tract Axonal Degeneration
  conforms_to: "corticospinal_tract_axonopathy#Distal Length-Dependent Degeneration of Long CNS Axons"
  description: >
    The core lesion shared with pure HSP: distal-predominant degeneration of the
    longest corticospinal-tract upper motor neuron axons (maximal in the
    thoracic spinal cord) together with degeneration of the dorsal-column
    fasciculus gracilis sensory fibers. This length-dependent, dying-back
    axonopathy of the longest CNS motor-sensory tracts produces the progressive
    lower-limb spasticity, weakness, hyperreflexia, and extensor plantar
    responses common to all HSP.
  genes:
  - preferred_term: CAPN1
    term:
      id: hgnc:1476
      label: CAPN1
    description: >-
      Bound here because the cited report assigns calpain 1 a role in axon maturation and
      maintenance, which is the process this node describes; SPG76 is its disease row.
  evidence:
  - reference: PMID:27153400
    reference_title: 'Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved
      in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance.
    explanation: >-
      Assigns calpain 1 a role in axon maturation and maintenance, the process whose failure this
      node describes, which is why CAPN1 is bound here.
  cell_types:
  - preferred_term: Corticospinal-tract upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  biological_processes:
  - preferred_term: Axonal transport
    term:
      id: GO:0098930
      label: axonal transport
    modifier: DECREASED
  downstream:
  - target: Lower-Limb Spastic Paraplegia
    evidence:
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "in which bilateral lower extremity weakness and spasticity (each of variable degree) are the predominant"
      explanation: >
        The length-dependent corticospinal-tract axonal degeneration produces
        the predominant lower-limb spasticity and weakness of HSP.
  - target: Lower-Limb Weakness
    evidence:
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "degeneration of corticospinal tract \naxons (maximal in the thoracic spinal cord) and degeneration of fasciculus \ngracilis fibers"
      explanation: >
        Postmortem studies consistently show the length-dependent corticospinal
        and dorsal-column axonal degeneration underlying the HSP syndrome.
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "HSP syndromes thus \nappear to involve motor-sensory axon degeneration affecting predominantly (but \nnot exclusively) the distal ends of long central nervous system (CNS) axons"
      explanation: >
        Frames HSP as a distal, length-dependent motor-sensory axonopathy of the
        longest CNS axons.
- name: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
  description: >
    In complex HSP the mutated SPG proteins have diverse housekeeping functions
    — axonal transport, endoplasmic reticulum tubular network morphogenesis,
    mitochondrial quality control, myelin formation, and endolysosomal/autophagic
    membrane trafficking. Loss of these functions injures neuronal and glial
    populations beyond the corticospinal tract (cortical neurons, cerebellar
    neurons, peripheral nerve, retina, and oligodendrocyte myelin), producing
    the additional "complicating" features (thin corpus callosum, cognitive
    decline, ataxia, neuropathy, retinopathy) that distinguish complex from pure
    HSP. This pleiotropy explains why complex forms cluster among loci with
    broad subcellular roles (e.g., SPG11/SPG15 endolysosomal-autophagy,
    SPG7 mitochondrial, SPG2/PLP1 myelin).
  genes:
  - preferred_term: SPG11
    term:
      id: hgnc:11226
      label: SPG11
  - preferred_term: SPG7
    term:
      id: hgnc:11237
      label: SPG7
  - preferred_term: PLP1
    term:
      id: hgnc:9086
      label: PLP1
  - preferred_term: MARS1
    term:
      id: hgnc:6898
      label: MARS1
  - preferred_term: CCT5
    term:
      id: hgnc:1618
      label: CCT5
  - preferred_term: DSTYK
    term:
      id: hgnc:29043
      label: DSTYK
  - preferred_term: TFG
    term:
      id: hgnc:11758
      label: TFG
  - preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  - preferred_term: MAG
    term:
      id: hgnc:6783
      label: MAG
  - preferred_term: HACE1
    term:
      id: hgnc:21033
      label: HACE1
  - preferred_term: KIDINS220
    term:
      id: hgnc:29508
      label: KIDINS220
  - preferred_term: L1CAM
    term:
      id: hgnc:6470
      label: L1CAM
  cell_types:
  - preferred_term: Pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  biological_processes:
  - preferred_term: Endoplasmic reticulum tubular network morphogenesis
    term:
      id: GO:0071786
      label: endoplasmic reticulum tubular network organization
  - preferred_term: Mitochondrion organization
    term:
      id: GO:0007005
      label: mitochondrion organization
    modifier: ABNORMAL
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "proteins encoded by HSP genes have diverse functions including (1) axon"
    explanation: >-
      The node's own claim: the proteins encoded by HSP genes have diverse cellular
      functions, which is why genes with no mechanism-specific node in this entry are
      bound here.
  - reference: PMID:20301657
    reference_title: "L1 Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Males with HSAS are born with severe hydrocephalus, adducted thumbs, and spasticity;
      intellectual disability is severe.
    explanation: >-
      L1CAM disease involves CNS structures well beyond the corticospinal tract -
      hydrocephalus and intellectual disability alongside the spasticity - which is the
      pleiotropy this node describes and the basis for binding L1CAM here.
  downstream:
  - target: Length-Dependent Corticospinal-Tract Axonal Degeneration
    evidence:
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "proteins encoded by HSP genes have diverse functions including (1) axon"
      explanation: >
        The diverse housekeeping functions of SPG proteins converge on the
        shared corticospinal-tract axonopathy when disrupted.
  - target: Thin Corpus Callosum
    evidence:
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "such as SPG11 HSP, a common autosomal recessive form of HSP frequently associated with mental retardation and thin corpus callosum"
      explanation: >
        Pleiotropic SPG-protein dysfunction (e.g., SPG11) produces thin corpus
        callosum, a hallmark complicating feature.
  - target: Cognitive Impairment
    evidence:
    - reference: PMID:20301389
      reference_title: "Spastic Paraplegia 11."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "mild intellectual disability with learning difficulties in"
      explanation: >
        Pleiotropic SPG-protein dysfunction produces intellectual disability
        and cognitive decline in complex HSP.
  - target: Peripheral Neuropathy
  - target: Cerebellar Ataxia
  - target: Distal Amyotrophy
  - target: Pigmentary Maculopathy
  - target: Dysarthria
  - target: Leukodystrophy
    evidence:
    - reference: PMID:23897027
      reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "proteins encoded by HSP genes have diverse functions including (1) axon"
      explanation: >
        The diverse cellular functions of HSP-gene products underlie the
        multisystem features that define complex HSP.

- name: Endolysosomal and ESCRT Membrane-Traffic Failure
  description: >-
    A mechanism class shared by complex-HSP genes whose products act in endosomal sorting,
    endosome maturation and lysosomal transport. Spastizin (ZFYVE26) localizes partly to
    endoplasmic reticulum and endosomal compartments; spartin (SPART) resembles molecules of
    endosomal trafficking; VPS37A is a subunit of the ESCRT system that matures multivesicular
    bodies; and ATP13A2 is a lysosomal transport ATPase. The AP-4 adaptor complex is curated as
    its own node because its characterised defect is autophagosome formation rather than
    endosomal transport. Every gene bound here causes a complex HSP recorded on this entry, and
    the node's downstream edge records that failure feeding the pleiotropic SPG-protein
    dysfunction the entry models.
  genes:
  - preferred_term: ZFYVE26
    term:
      id: hgnc:20761
      label: ZFYVE26
  - preferred_term: SPART
    term:
      id: hgnc:18514
      label: SPART
  - preferred_term: VPS37A
    term:
      id: hgnc:24928
      label: VPS37A
  - preferred_term: ATP13A2
    term:
      id: hgnc:30213
      label: ATP13A2
  biological_processes:
  - preferred_term: Endosomal transport
    term:
      id: GO:0016197
      label: endosomal transport
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18394578
    reference_title: 'Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      spastizin colocalized partially with markers of endoplasmic reticulum and endosomes,
      suggesting a role in intracellular trafficking
    explanation: >-
      Places spastizin, the SPG15 protein, in the endoplasmic reticulum and endosomal compartments
      this node describes.
  - reference: PMID:12134148
    reference_title: 'SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      spartin shares similarity with molecules involved in endosomal trafficking
    explanation: >-
      Comparative sequence analysis assigns spartin, the Troyer syndrome protein, to the endosomal
      trafficking machinery.
  - reference: PMID:22717650
    reference_title: 'A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting
      complex required for transport (ESCRT) system, in upper motor neuron disease.
    explanation: >-
      Links VPS37A, an ESCRT-I subunit, to upper motor neuron disease, which is the claim this node
      makes for that gene.
  - reference: PMID:28137957
    reference_title: 'Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      ATP13A2 is a lysosomal P5-type transport ATPase
    explanation: >-
      Identifies ATP13A2 as a lysosomal transporter, the basis for placing SPG78 on this node.
  downstream:
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    evidence:
    - reference: PMID:22717650
      reference_title: 'A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced
        early onset spastic paraparesis of upper and lower limbs, mild intellectual disability,
        kyphosis, pectus carinatum and hypertrichosis.
      explanation: >-
        Failure of this trafficking machinery produces spastic paraparesis together with cognitive
        and skeletal involvement, which is the pleiotropy beyond the corticospinal tract that the
        target node describes.
- name: AP-4-Dependent ATG9A Export and Autophagosome Formation Failure
  description: >-
    The AP-4 adaptor complex associates with the trans-Golgi network and exports ATG9A from it;
    in AP-4-deficient cells that export fails, reducing ATG9A delivery to pre-autophagosomal
    structures and impairing autophagosome formation. All four AP-4 subunit genes are curated on
    this node because biallelic variants in any of them cause the same disease, AP-4-associated
    HSP, which this entry carries as a single subtype row. The node is kept separate from the
    endolysosomal membrane-traffic node because the characterised AP-4 defect is autophagosome
    biogenesis rather than endosomal transport.
  genes:
  - preferred_term: AP4B1
    term:
      id: hgnc:572
      label: AP4B1
  - preferred_term: AP4E1
    term:
      id: hgnc:573
      label: AP4E1
  - preferred_term: AP4M1
    term:
      id: hgnc:574
      label: AP4M1
  - preferred_term: AP4S1
    term:
      id: hgnc:575
      label: AP4S1
  biological_processes:
  - preferred_term: Autophagosome assembly
    term:
      id: GO:0000045
      label: autophagosome assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:33084855
    reference_title: 'The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia.'
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: IN_VITRO
    snippet: >-
      Defective export of ATG9A from the TGN in AP-4-deficient cells was shown to reduce ATG9A
      delivery to pre-autophagosomal structures, impairing autophagosome formation and/or
      maturation.
    explanation: >-
      Gives the autophagy defect that follows AP-4 loss in cells, which is the mechanism this node
      names.
  downstream:
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    evidence:
    - reference: PMID:33084855
      reference_title: 'The role of AP-4 in cargo export from the trans-Golgi network and hereditary spastic paraplegia.'
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        mutations in AP-4-subunit genes were found to cause neurological dysfunction in mice and a
        form of complicated hereditary spastic paraplegia referred to as 'AP-4-deficiency syndrome' in
        humans
      explanation: >-
        Connects AP-4 subunit loss to complicated (complex) hereditary spastic paraplegia in humans,
        which is the human half of the quoted sentence; the sentence also reports a mouse phenotype,
        which is not what this edge is cited for.
- name: Neuronal Membrane-Lipid and Ganglioside Metabolic Failure
  description: >-
    A second recurrent mechanism class among complex-HSP genes, whose products are lipid-modifying
    enzymes. DDHD2 is an intracellular phospholipase A1 and its loss produces an abnormal cerebral
    lipid peak detectable by magnetic resonance spectroscopy; PNPLA6 encodes neuropathy target
    esterase, which maintains phospholipid homeostasis in the nervous system; ABHD16A is the main
    brain phosphatidylserine hydrolase; and B4GALNT1 loss abolishes synthesis of GM2 and the
    downstream complex gangliosides. Each of these genes causes a complex HSP
    recorded on this entry, and the DDHD2 report shows the lipid disturbance directly in patients
    by cerebral magnetic resonance spectroscopy.
  genes:
  - preferred_term: DDHD2
    term:
      id: hgnc:29106
      label: DDHD2
  - preferred_term: PNPLA6
    term:
      id: hgnc:16268
      label: PNPLA6
  - preferred_term: ABHD16A
    term:
      id: hgnc:13921
      label: ABHD16A
  - preferred_term: B4GALNT1
    term:
      id: hgnc:4117
      label: B4GALNT1
  - preferred_term: FA2H
    term:
      id: hgnc:21197
      label: FA2H
  biological_processes:
  - preferred_term: Lipid metabolic process
    term:
      id: GO:0006629
      label: lipid metabolic process
    modifier: ABNORMAL
  - preferred_term: Ganglioside biosynthetic process
    term:
      id: GO:0001574
      label: ganglioside biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:23176823
    reference_title: 'Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In line with the function of DDHD2 in lipid metabolism and its role in the CNS, an abnormal
      lipid peak indicating accumulation of lipids was detected with cerebral magnetic resonance
      spectroscopy
    explanation: >-
      Demonstrates disturbed brain lipid metabolism in patients with recessive DDHD2 disease, the
      direct clinical evidence for this node.
  - reference: PMID:37732399
    reference_title: 'PNPLA6 disorders: what''s in a name?'
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PNPLA6 encodes NTE, an enzyme involved in maintaining phospholipid homeostasis and trafficking
      in the nervous system.
    explanation: >-
      Assigns PNPLA6 to nervous-system phospholipid homeostasis, the basis for placing SPG39 on this
      node.
  - reference: PMID:34489854
    reference_title: 'Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      ABHD16A encodes the main brain phosphatidylserine hydrolase.
    explanation: >-
      Identifies ABHD16A as a brain phospholipid-hydrolysing enzyme, the basis for placing SPG86 on
      this node.
  - reference: PMID:35775650
    reference_title: 'Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency
      confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream
      gangliosides.
    explanation: >-
      Shows that disease-associated B4GALNT1 variants abolish complex ganglioside synthesis, which
      is the ganglioside arm of this node.
  - reference: PMID:20104589
    reference_title: 'Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe
      progressive phenotype, with a clinical presentation of complicated HSP and radiological
      features of leukodystrophy
    explanation: >-
      Ties failure of a membrane-lipid hydroxylation step to complicated HSP with leukodystrophy,
      which is why FA2H (SPG35, recorded on the AR Complex HSP row) is bound on this node.
  downstream:
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    evidence:
    - reference: PMID:23176823
      reference_title: 'Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We show that mutations in DDHD2 cause a specific complex HSP subtype (SPG54), thereby linking
        a member of the PLA(1) family to human neurologic disease.
      explanation: >-
        Ties failure of this lipid-metabolic machinery to a complex HSP phenotype in humans.
- name: Mitochondrial Iron-Sulfur Cluster Assembly Failure
  description: >-
    IBA57 is the mitochondrial iron-sulfur protein assembly factor. The SPG74 splice-site variant
    leaves ten-fold lower levels of wild-type IBA57 protein and reduces the levels and activities
    of several mitochondrial 4Fe-4S proteins including respiratory complexes I and II, while
    2Fe-2S proteins remain normal. This node is one of two mitochondrial mechanisms on the entry -
    the other, impaired anaplerosis, is a separate node because GPT2 takes no part in iron-sulfur
    cluster assembly - and both are counterparts of the SPG7/paraplegin mitochondrial mechanism
    already recorded here.
  genes:
  - preferred_term: IBA57
    term:
      id: hgnc:27302
      label: IBA57
  biological_processes:
  - preferred_term: Iron-sulfur cluster assembly
    term:
      id: GO:0016226
      label: iron-sulfur cluster assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:25609768
    reference_title: 'Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      This gene encodes the mitochondrial iron-sulfur (Fe/S) protein assembly factor IBA57.
    explanation: >-
      Identifies IBA57 as the mitochondrial iron-sulfur cluster assembly factor named by this node.
  - reference: PMID:25609768
    reference_title: 'Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Lymphoblasts contained 10-fold-lower levels of wild-type, but no signs of truncated
      IBA57 protein.
    explanation: >-
      Measures the loss of IBA57 protein in patient-derived cells, the molecular lesion
      behind the assembly defect this node describes.
  downstream:
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    evidence:
    - reference: PMID:25609768
      reference_title: 'Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Ten members of a highly consanguineous family manifested a childhood-onset SPOAN-like
        phenotype with slow progression into late adulthood.
      explanation: >-
        IBA57 deficiency produces spastic paraplegia together with optic atrophy and peripheral
        neuropathy, which is the involvement beyond the corticospinal tract that the target node
        describes.
- name: Impaired Mitochondrial Anaplerosis
  description: >-
    GPT2 is a mitochondrial transaminase. Its biallelic variants are biochemically
    loss-of-function, and loss of Gpt2 produces defects in anaplerosis, the process that
    replenishes tricarboxylic-acid-cycle intermediates. This is a separate node from the
    iron-sulfur cluster assembly mechanism because IBA57 takes no part in transamination or
    anaplerosis, and GPT2 takes no part in iron-sulfur cluster assembly.
  genes:
  - preferred_term: GPT2
    term:
      id: hgnc:18062
      label: GPT2
  biological_processes:
  - preferred_term: Tricarboxylic acid cycle
    term:
      id: GO:0006099
      label: tricarboxylic acid cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27601654
    reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle
      intermediates
    explanation: >-
      Identifies the anaplerotic defect, measured by metabolomics and isotope tracing in Gpt2-null
      mice, that this node names.
  - reference: PMID:27601654
    reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to
      be loss of function.
    explanation: >-
      Establishes that the disease-associated GPT2 variants abolish enzyme function, which is the
      lesion upstream of the anaplerotic defect.
  downstream:
  - target: Microcephaly
    description: >-
      Postnatal microcephaly was present in every affected individual of the kindreds that defined
      GPT2 deficiency, alongside the progressive spastic paraplegia.
    evidence:
    - reference: PMID:27601654
      reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        all affected individuals show postnatal microcephaly
      explanation: >-
        Records the postnatal microcephaly in the GPT2 kindreds, which is why this mitochondrial
        node is a third source of the microcephaly phenotype rather than it being confined to the
        two forms curated with their own purine and ER nodes.
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    evidence:
    - reference: PMID:27601654
      reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism
        with relevance to developmental as well as potentially to neurodegenerative mechanisms.
      explanation: >-
        Connects the mitochondrial metabolic defect to developmental and neurodegenerative
        consequences beyond the corticospinal tract.
- name: Kinesin-Dependent Axonal Cargo Transport Failure
  description: >-
    Kinesins are cargo/motor proteins whose mutation is an established cause of hereditary spastic
    paraplegia. Three complex forms on this entry act through this machinery: spastic ataxia 2 is
    caused by homozygous KIF1C variants, SPOAN syndrome by a non-coding deletion upstream of
    KLC2 that raises KLC2 expression in patient fibroblasts and patient-derived motor neurons - a
    gain, not a loss, of gene product - and SPG10 by heterozygous missense variants in the motor
    domain of KIF5A, the neuronal heavy chain of conventional kinesin-I, which carries membranous
    organelles anterogradely to the distal axon. SPAX2 and SPOAN are recorded as subtype rows on
    this entry and SPG10 under the autosomal dominant complex HSP row, so this node's downstream
    consequence is the length-dependent corticospinal-tract axonopathy of the entry's core node.
  genes:
  - preferred_term: KIF1C
    term:
      id: hgnc:6317
      label: KIF1C
  - preferred_term: KLC2
    term:
      id: hgnc:20716
      label: KLC2
  - preferred_term: KIF5A
    term:
      id: hgnc:6323
      label: KIF5A
  molecular_functions:
  - preferred_term: Microtubule motor activity
    term:
      id: GO:0003777
      label: microtubule motor activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24319291
    reference_title: 'KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated.
    explanation: >-
      States the kinesin cargo/motor role and its established link to HSP, which is what this node
      asserts.
  - reference: PMID:26385635
    reference_title: 'Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Expression assays performed with patient's fibroblasts and motor neurons derived from SPOAN
      patients showed KLC2 overexpression.
    explanation: >-
      Measures raised KLC2 in patient cells and patient-derived motor neurons, the molecular lesion
      by which SPOAN reaches this node.
  - reference: PMID:12355402
    reference_title: 'A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a missense mutation in the motor domain of the neuronal kinesin heavy
      chain gene KIF5A, in a family with hereditary spastic paraplegia.
    explanation: >-
      The founding SPG10 report places the KIF5A lesion in the kinesin motor domain, which is how
      SPG10 reaches this node.
  downstream:
  - target: Length-Dependent Corticospinal-Tract Axonal Degeneration
    evidence:
    - reference: PMID:24319291
      reference_title: 'KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report a novel genetic defect in KIF1C of patients with spastic paraparesis and
        cerebellar dysfunction in two consanguineous families of Palestinian and Moroccan ancestry.
      explanation: >-
        A KIF1C-specific human observation: loss of this kinesin produces spastic paraparesis, the
        clinical expression of the corticospinal-tract axonopathy this edge targets.
    - reference: PMID:12355402
      reference_title: 'A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        This finding suggests that the underlying pathology of SPG10 and possibly of other forms
        of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or
        retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest
        axons of the central nervous system.
      explanation: >-
        The SPG10 authors propose exactly this edge - disturbed axonal transport leading to
        degeneration of the longest CNS axons - as an inference from the motor-domain lesion
        rather than a measurement of it.
- name: Pyrroline-5-Carboxylate Synthase Dysfunction
  description: >-
    ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthase (P5CS), which catalyzes the
    reduction of glutamate to pyrroline-5-carboxylate, a shared step in proline, ornithine and
    arginine biosynthesis. Monoallelic ALDH18A1 variants cause autosomal dominant pure or
    complex spastic paraplegia (SPG9A), the reason the gene is listed on this entry's autosomal
    dominant complex HSP row. The ALDH18A1 allelic series, including the variable plasma
    amino-acid changes and the cutis laxa branches, is curated in full in
    ALDH18A1_De_Barsy_Spectrum; this node records only the enzyme lesion so that the gene
    reaches this entry's corticospinal-tract node. It is kept separate from the purine and
    anaplerosis nodes because P5CS acts in neither pathway.
  genes:
  - preferred_term: ALDH18A1
    term:
      id: hgnc:9722
      label: ALDH18A1
  molecular_functions:
  - preferred_term: delta1-pyrroline-5-carboxylate synthetase (NADP+) activity
    term:
      id: GO:0017084
      label: delta1-pyrroline-5-carboxylate synthetase (NADP+) activity
    modifier: DECREASED
  evidence:
  - reference: PMID:11092761
    reference_title: 'Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step
      in the biosynthesis of proline, ornithine and arginine.
    explanation: >-
      Defines the P5CS reaction whose loss this node records.
  - reference: PMID:26026163
    reference_title: 'Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Low levels of plasma ornithine, citrulline, arginine and proline in four individuals from
      two families suggested P5CS deficiency.
    explanation: >-
      Reduced plasma products of the P5CS reaction in some ALDH18A1 spastic paraplegia families
      point to a P5CS functional defect; the same study notes this is not seen in every family,
      which is why the node asserts reduced enzyme activity rather than systemic depletion.
  downstream:
  - target: Length-Dependent Corticospinal-Tract Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Heterozygous ALDH18A1 variants segregate with spastic paraplegia, but the step from reduced
      P5CS activity to corticospinal axon degeneration has not been established.
    evidence:
    - reference: PMID:26026163
      reference_title: 'Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        identified monoallelic ALDH18A1 mutations segregating in three independent families with
        autosomal dominant pure or complex hereditary spastic paraplegia,
      explanation: >-
        Segregation of monoallelic ALDH18A1 variants with complex spastic paraplegia links the
        enzyme lesion to the corticospinal phenotype without identifying the intermediate steps.
- name: IP3-Receptor-Dependent Endoplasmic Reticulum Calcium Release Dysregulation
  description: >-
    Calcium efflux from the endoplasmic reticulum into the cytoplasm is controlled by inositol
    1,4,5-trisphosphate binding to its receptor, and activated receptors are then degraded by the
    endoplasmic-reticulum-associated degradation pathway. Two complex-HSP genes on this entry act
    in that degradation step: ERLIN2, whose biallelic variants cause SPG18, and RNF170, the
    ubiquitin E3 ligase that targets the receptors and whose bi-allelic variants cause SPG85. The RNF170
    report names inositol 1,4,5-trisphosphate signalling as a candidate key pathway for the
    hereditary spastic paraplegias, which is the claim this node records.
  genes:
  - preferred_term: ERLIN2
    term:
      id: hgnc:1356
      label: ERLIN2
  - preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  biological_processes:
  - preferred_term: Release of sequestered calcium ion into cytosol
    term:
      id: GO:0051209
      label: release of sequestered calcium ion into cytosol
    modifier: DYSREGULATED
  - preferred_term: ERAD pathway
    term:
      id: GO:0036503
      label: ERAD pathway
    modifier: ABNORMAL
  evidence:
  - reference: PMID:31636353
    reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of
      inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors
      are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway.
    explanation: >-
      States the calcium-release and receptor-degradation steps that this node names.
  - reference: PMID:31636353
    reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known
      to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia
    explanation: >-
      Places ERLIN2 in the receptor-degradation step and links it to HSP.
  - reference: PMID:31636353
    reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets
      inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal
      recessive HSP in four unrelated families
    explanation: >-
      Places RNF170 in the same step and establishes its bi-allelic variants as a cause of recessive
      HSP.
  downstream:
  - target: Length-Dependent Corticospinal-Tract Axonal Degeneration
    evidence:
    - reference: PMID:31636353
      reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets
        inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal
        recessive HSP in four unrelated families
      explanation: >-
        Disruption of this pathway produces hereditary spastic paraplegia, whose core lesion is the
        corticospinal-tract axonopathy.

- name: Purine Nucleotide Metabolic Imbalance
  description: >-
    Three complex-HSP genes on this entry act in purine nucleotide metabolism rather than in
    membrane traffic, lipid metabolism, mitochondrial assembly or axonal transport: NT5C2, the
    cytosolic 5'-nucleotidase II that hydrolyses nucleoside monophosphates and whose biallelic
    variants cause SPG45; AMPD2, an AMP deaminase, mutated in SPG63; and ENTPD1, described by the
    same study as an extracellular enzyme that hydrolyses adenosine nucleotides in the synaptic
    cleft, mutated in SPG64. The exome study that identified all three placed them in
    one purine-metabolism module, which is why they are bound together here rather than on the
    pleiotropic node that holds the genes with diverse housekeeping roles. The node records the
    pathway the lesions fall in rather than a measured metabolite change; the sources cited here
    establish the genetic lesions and the enzymes' assigned pathway, and the modifier is therefore
    ABNORMAL rather than a direction.
  genes:
  - preferred_term: NT5C2
    term:
      id: hgnc:8022
      label: NT5C2
  - preferred_term: AMPD2
    term:
      id: hgnc:469
      label: AMPD2
  - preferred_term: ENTPD1
    term:
      id: hgnc:3363
      label: ENTPD1
  molecular_functions:
  - preferred_term: 5'-nucleotidase activity (NT5C2)
    modifier: DECREASED
    term:
      id: GO:0008253
      label: 5'-nucleotidase activity
  biological_processes:
  - preferred_term: Purine nucleotide metabolic process
    term:
      id: GO:0006163
      label: purine nucleotide metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24482476
    reference_title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      AMPD2, ENTPD1, and NT5C2 are involved in purine nucleotide metabolism
    explanation: >-
      Assigns the three genes bound on this node to one pathway, which is the grouping the node
      asserts; the sentence classifies the enzymes rather than reporting a measurement.
  - reference: PMID:32153630
    reference_title: 'Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: >-
      NT5C2 gene (OMIM: 600417) encode a hydrolase enzyme 5'-nucleotidase, cytosolic II play an
      important role in maintaining the balance of purine nucleotides and free nucleobases in the
      spinal cord and brain.
    explanation: >-
      States the enzyme activity of NT5C2 and the purine balance it maintains in the central
      nervous system, which is why the SPG45 gene is bound at this node.
  - reference: PMID:24482476
    reference_title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these genes, ERLIN1, KIF1C, and NT5C2, were found independently mutated in more
      than one family, and all mutations were predicted to be highly deleterious.
    explanation: >-
      NT5C2 was mutated independently in more than one family of this autosomal recessive HSP
      cohort, which is the human genetic support for treating loss of this enzyme as a mechanism.
  downstream:
  - target: Pleiotropic SPG-Protein Dysfunction Beyond the Corticospinal Tract
    description: >-
      Loss of NT5C2 produces features outside the corticospinal tract, which is the involvement
      the target node describes. No source cited at this node reports the same for AMPD2 or
      ENTPD1.
    evidence:
    - reference: PMID:32153630
      reference_title: 'Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In this study we have identified a large consanguineous Saudi family segregating a novel
        homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral
        palsy, developmental delay and microcephaly.
      explanation: >-
        Loss of NT5C2 in this family produced developmental delay and microcephaly alongside the
        spastic motor picture, which is involvement beyond the corticospinal tract.
  - target: Microcephaly
    description: >-
      Reduced head circumference accompanies the spastic motor picture in the NT5C2 family
      reported with a splice-donor variant.
    evidence:
    - reference: PMID:32153630
      reference_title: 'Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In this study we have identified a large consanguineous Saudi family segregating a novel
        homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral
        palsy, developmental delay and microcephaly.
      explanation: >-
        Names microcephaly among the features caused by the homozygous NT5C2 splice-donor variant
        in this family.
- name: Tubular Endoplasmic Reticulum Membrane Shaping Failure
  description: >-
    ARL6IP1, the gene mutated in SPG61, is a tetraspan endoplasmic reticulum membrane protein
    whose reticulon-like short hairpin transmembrane domains shape high-curvature ER tubules; it
    binds atlastin, the GTPase that mediates formation of the tubular ER network and is itself
    mutated in SPG3A. The SPG61 allele cited at this node is a nonsense variant predicted to
    abolish the protein, so the lesion recorded here is loss of ER tubule shaping. It is kept
    separate from the
    IP3-receptor calcium-release node because ERLIN2 and RNF170 act on receptor degradation and ER
    calcium handling rather than on ER membrane geometry, and separate from the pleiotropic node
    because the mechanism here is a single named biophysical function rather than a diverse
    housekeeping role.
  genes:
  - preferred_term: ARL6IP1
    term:
      id: hgnc:697
      label: ARL6IP1
  biological_processes:
  - preferred_term: Endoplasmic reticulum tubular network organization
    term:
      id: GO:0071786
      label: endoplasmic reticulum tubular network organization
    modifier: DECREASED
  evidence:
  - reference: PMID:24262037
    reference_title: Arl6IP1 has the ability to shape the mammalian ER membrane in a reticulon-like fashion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The results of the present study indicate that Arl6IP1 has the ability to shape
      high-curvature ER tubules in a reticulon-like fashion.
    explanation: >-
      Establishes the ER tubule shaping activity this node names, measured in mammalian cells and
      in liposomes.
  - reference: PMID:24262037
    reference_title: Arl6IP1 has the ability to shape the mammalian ER membrane in a reticulon-like fashion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Arl6IP1, which does not share an overall primary sequence homology with reticulons, harbours
      reticulon-like short hairpin transmembrane domains and binds to atlastin, a GTPase that
      mediates the formation of the tubular ER network.
    explanation: >-
      Records the hairpin transmembrane architecture and the atlastin interaction that place
      ARL6IP1 in the tubular ER network machinery.
  - reference: PMID:31272422
    reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1
      that segregated with the phenotype and was predicted to result in loss of the protein.
    explanation: >-
      The disease allele is predicted to abolish the protein, so the human lesion is loss of this
      ER shaping function rather than an altered activity.
  downstream:
  - target: Length-Dependent Corticospinal-Tract Axonal Degeneration
    description: >-
      Loss of ARL6IP1 produces the spastic paraplegia that the corticospinal-tract node describes.
    evidence:
    - reference: PMID:28471035
      reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This report highlights the role of ARL6IP1 in the pathophysiology of insensitivity to pain
        and spastic paraplegia.
      explanation: >-
        Attributes the spastic paraplegia, the clinical expression of the target node, to loss of
        ARL6IP1.
  - target: Peripheral Neuropathy
    description: >-
      A sensory neuropathy accompanied the spastic paraplegia in the ARL6IP1 patient reported
      with pain insensitivity.
    evidence:
    - reference: PMID:28471035
      reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy,
        acromutilation, and spastic paraplegia.
      explanation: >-
        Records the sensory neuropathy in an ARL6IP1 patient, which is the peripheral nerve
        involvement the target phenotype names.
  - target: Pain Insensitivity
    description: >-
      Congenital insensitivity to pain with acromutilation is reported with biallelic ARL6IP1
      loss, and ARL6IP1 binds the same atlastin-1 that is mutated in hereditary sensory and
      autonomic neuropathy type ID.
    evidence:
    - reference: PMID:28471035
      reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy,
        acromutilation, and spastic paraplegia.
      explanation: >-
        Reports the pain insensitivity in a patient with a homozygous ARL6IP1 frameshift variant.
    - reference: PMID:28471035
      reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
      supports: SUPPORT
      quote_role: BACKGROUND
      evidence_source: OTHER
      snippet: >-
        ARL6IP1 interacts with atlastin-1 responsible for SPG3A and HSAN type ID.
      explanation: >-
        Places ARL6IP1 in a protein interaction whose partner causes both a spastic paraplegia and
        a hereditary sensory neuropathy, which is the shared-machinery argument in this edge's
        description.
  - target: Microcephaly
    description: >-
      Reduced head circumference was present in the kindred homozygous for the ARL6IP1 nonsense
      allele.
    evidence:
    - reference: PMID:31272422
      reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical features encompassed not only spastic paraplegia but also developmental delay,
        microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures,
        spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and
        respiratory distress.
      explanation: >-
        Names microcephaly among the features of this truncating ARL6IP1 kindred.

phenotypes:
- name: Lower-Limb Spastic Paraplegia
  description: >
    Progressive bilateral lower-limb spasticity and weakness with hyperreflexia
    and extensor plantar responses — the obligate core feature of all HSP,
    including complex forms.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in which bilateral lower extremity weakness and spasticity (each of variable degree) are the predominant"
    explanation: Establishes lower-limb spasticity and weakness as the predominant HSP feature.
- name: Lower-Limb Weakness
  description: >
    Weakness of the lower limbs accompanying spasticity, contributing to gait
    impairment and, in advanced disease, loss of ambulation.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral lower extremity weakness and spasticity"
    explanation: Lower-limb weakness is a predominant HSP manifestation.
- name: Thin Corpus Callosum
  description: >
    Thinning of the corpus callosum on neuroimaging is a hallmark of several
    autosomal recessive complex HSP forms, classically SPG11 and SPG15.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "such as SPG11 HSP, a common autosomal recessive form of HSP frequently associated with mental retardation and thin corpus callosum"
    explanation: Thin corpus callosum is characteristic of SPG11 complex HSP.
- name: Cognitive Impairment
  description: >
    Intellectual disability and/or progressive cognitive decline, a defining
    "complicating" feature seen in SPG11, SPG15, and other complex forms.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:20301389
    reference_title: "Spastic Paraplegia 11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mild intellectual disability with learning difficulties in"
    explanation: SPG11 is associated with intellectual disability and cognitive decline.
- name: Peripheral Neuropathy
  description: >
    Peripheral (usually axonal) neuropathy accompanying spastic paraplegia in
    complex forms such as SPG11.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:20301389
    reference_title: "Spastic Paraplegia 11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peripheral neuropathy"
    explanation: Peripheral neuropathy is a recognized complicating feature of SPG11.
- name: Cerebellar Ataxia
  description: >
    Cerebellar ataxia complicates several forms of complex HSP, most notably
    SPG7, reflecting cerebellar involvement beyond the corticospinal tract.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "paraplegin gene mutation, in which spastic paraparesis is often associated with ataxia"
    explanation: SPG7 (paraplegin) complex HSP is often associated with ataxia.
- name: Distal Amyotrophy
  description: >
    Distal muscle wasting, a complicating feature in forms such as Silver
    syndrome (SPG17) and SPG15/Kjellin syndrome.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:18394578
    reference_title: "Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "distal amyotrophy"
    explanation: Distal amyotrophy is part of the SPG15/Kjellin complex HSP phenotype.
- name: Pigmentary Maculopathy
  description: >
    Pigmentary maculopathy (retinal pigmentary change) is characteristic of
    Kjellin syndrome, the SPG15 (ZFYVE26) form of complex HSP.
  phenotype_term:
    preferred_term: Pigmentary maculopathy
    term:
      id: HP:0000580
      label: Pigmentary retinopathy
  evidence:
  - reference: PMID:18394578
    reference_title: "Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pigmented maculopathy"
    explanation: Pigmentary maculopathy is a feature of SPG15/Kjellin syndrome.
- name: Dysarthria
  description: >
    Dysarthria complicates several complex HSP forms, including SPG15/Kjellin
    syndrome.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:18394578
    reference_title: "Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysarthria"
    explanation: Dysarthria is part of the SPG15 complex HSP spectrum.
- name: Leukodystrophy
  description: >
    White-matter abnormalities/leukodystrophy on neuroimaging, characteristic of
    the SPG35 (FA2H) form of complex HSP.
  phenotype_term:
    preferred_term: Leukodystrophy
    term:
      id: HP:0002415
      label: Leukodystrophy
  evidence:
  - reference: PMID:20104589
    reference_title: "Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "white matter \nabnormalities suggestive of a leukodystrophy"
    explanation: >
      SPG35 (FA2H) complex HSP shows white-matter abnormalities suggestive of a
      leukodystrophy on MRI.

- name: Microcephaly
  description: >-
    Reduced head circumference. It recurs across unrelated complex forms on this entry rather than
    marking any one of them: the GPT2 Deficiency row records postnatal microcephaly in all affected
    individuals of the defining kindreds, the AR Complex HSP row names the AP-4-associated
    disorders as a childhood-onset complex form with severe developmental delay and microcephaly,
    and it was reported in both the NT5C2 family with a splice-donor variant and the kindred
    homozygous for the ARL6IP1 nonsense allele. Microcephaly is not part of the core corticospinal
    syndrome, which is why the incoming edges come from the gene-specific mechanism nodes rather
    than from the corticospinal-tract node.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:32153630
    reference_title: 'Exome Analysis Identified Novel Homozygous Splice Site Donor Alteration in NT5C2 Gene in a Saudi Family Associated With Spastic Diplegia Cerebral Palsy, Developmental Delay, and Intellectual Disability.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study we have identified a large consanguineous Saudi family segregating a novel
      homozygous splice site donor alteration in NT5C2 gene leading to spastic diplegia cerebral
      palsy, developmental delay and microcephaly.
    explanation: >-
      Records microcephaly in the NT5C2 family homozygous for the splice-donor variant.
  - reference: PMID:31272422
    reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical features encompassed not only spastic paraplegia but also developmental delay,
      microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures,
      spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and
      respiratory distress.
    explanation: >-
      Records microcephaly in the kindred homozygous for the ARL6IP1 nonsense allele.
- name: Pain Insensitivity
  description: >-
    Congenital insensitivity to pain, reported together with acromutilation in a patient with a
    homozygous ARL6IP1 frameshift variant, the only form on this entry for which a cited source
    states pain insensitivity. The row is deliberately not scoped to SPG61: the CCT5 row on this
    entry is hereditary sensory and autonomic neuropathy with spastic paraplegia, whose cited
    source describes a mutilating sensory neuropathy, so whether pain insensitivity is peculiar to
    SPG61 is not something this entry's sources settle. The entry's separate Peripheral Neuropathy
    phenotype carries the sensory nerve involvement that accompanies it.
  phenotype_term:
    preferred_term: Congenital insensitivity to pain
    term:
      id: HP:0007021
      label: Pain insensitivity
  evidence:
  - reference: PMID:28471035
    reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy,
      acromutilation, and spastic paraplegia.
    explanation: >-
      Reports congenital insensitivity to pain with acromutilation in a patient with biallelic
      ARL6IP1 loss, which is the phenotype this row names.

inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >
    Autosomal dominant complex HSP (MONDO:0015087) includes loci such as SPG10
    (KIF5A) and complicated presentations of SPG3A/SPG4. Penetrance is
    age-dependent.
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic penetrance in autosomal dominant HSP is age-dependent"
    explanation: Autosomal dominant HSP shows age-dependent penetrance.
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >
    Autosomal recessive complex HSP includes SPG11 (spatacsin), SPG15
    (ZFYVE26/spastizin), and SPG7 (paraplegin); these require biallelic
    pathogenic variants and are the forms most associated with thin corpus
    callosum and cognitive decline.
  evidence:
  - reference: PMID:20301389
    reference_title: "Spastic Paraplegia 11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPG11 is inherited in an autosomal recessive manner."
    explanation: Establishes autosomal recessive inheritance for the common complex form SPG11.
- name: X-Linked
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >
    X-linked complex HSP includes SPG1 (L1CAM/L1 syndrome) and SPG2
    (PLP1-related disorders).
  evidence:
  - reference: PMID:20301361
    reference_title: "PLP1-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLP1-related disorders are inherited in an X-linked manner"
    explanation: PLP1-related disorders (including SPG2) are X-linked.

genetic:
- name: SPG11
  gene_term:
    preferred_term: SPG11
    term:
      id: hgnc:11226
      label: SPG11
  subtype: AR Complex HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301389
    reference_title: "Spastic Paraplegia 11."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spastic paraplegia 11 (SPG11) is characterized by"
    explanation: >
      Biallelic SPG11 (spatacsin) variants cause the most common autosomal
      recessive complex HSP, with thin corpus callosum and cognitive decline.
- name: ZFYVE26
  gene_term:
    preferred_term: ZFYVE26
    term:
      id: hgnc:20761
      label: ZFYVE26
  subtype: SPG15
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:18394578
    reference_title: "Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the identification of ZFYVE26, which encodes a zinc-finger"
    explanation: >
      Truncating ZFYVE26 (spastizin) mutations cause SPG15 complicated
      autosomal-recessive spastic paraplegia including Kjellin syndrome.
- name: SPG7
  gene_term:
    preferred_term: SPG7
    term:
      id: hgnc:11237
      label: SPG7
  subtype: AR Complex HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:9635427
    reference_title: "Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two additional Paraplegin mutations, both resulting in a frameshift, \nwere found in a complicated and in a pure form of HSP"
    explanation: >
      SPG7/paraplegin mutations cause both complicated and pure recessive HSP,
      with mitochondrial OXPHOS impairment.
- name: FA2H
  gene_term:
    preferred_term: FA2H
    term:
      id: hgnc:21197
      label: FA2H
  subtype: AR Complex HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20104589
    reference_title: "Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report homozygous mutations in the fatty acid 2-hydroxylase gene (FA2H) in the
      original family used to define the SPG35 locus (p.Arg235Cys) as well as in a previously
      unreported Pakistani family with a similar phenotype (p.Arg53_Ile58del).
    explanation: >
      Biallelic FA2H (fatty acid 2-hydroxylase) mutations cause SPG35, a
      complicated recessive HSP. Requoted from the abstract: the previous quote was
      the paper's title and did not verify against the abstract text.
- name: SPART
  gene_term:
    preferred_term: SPART
    term:
      id: hgnc:18514
      label: SPART
  subtype: Troyer Syndrome
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:12134148
    reference_title: '"SPG20 is mutated in Troyer syndrome, an hereditary spastic paraplegia."'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report mapping of the TRS locus to chromosome 13q12.3 and identify a frameshift
      mutation in SPG20, encoding spartin.
    explanation: >
      A frameshift mutation in SPG20 (now SPART, encoding spartin) causes Troyer
      syndrome, a complex recessive HSP. Requoted from the abstract: the previous
      quote was the paper's title and did not verify against the abstract text.
- name: AP4B1
  gene_term:
    preferred_term: AP4B1
    term:
      id: hgnc:572
      label: AP4B1
  subtype: AP-4-HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30543385
    reference_title: "AP-4-Associated Hereditary Spastic Paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is a childhood-onset and complex form of hereditary spastic \nparaplegia"
    explanation: >
      Biallelic variants in the AP-4 complex genes (AP4B1/AP4E1/AP4M1/AP4S1)
      cause AP-4-associated HSP (SPG47/50/51/52), a childhood-onset complex HSP.
- name: L1CAM
  gene_term:
    preferred_term: L1CAM
    term:
      id: hgnc:6470
      label: L1CAM
  subtype: XL Complex HSP
  inheritance:
  - name: X-Linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
  evidence:
  - reference: PMID:20301657
    reference_title: "L1 Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "complicated hereditary spastic paraplegia type 1"
    explanation: >
      L1CAM variants cause X-linked complicated HSP type 1 (SPG1) within the L1
      syndrome spectrum.
- name: PLP1
  gene_term:
    preferred_term: PLP1
    term:
      id: hgnc:9086
      label: PLP1
  subtype: XL Complex HSP
  inheritance:
  - name: X-Linked
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
  evidence:
  - reference: PMID:20301361
    reference_title: "PLP1-Related Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to spastic paraplegia 2 (SPG2)"
    explanation: >
      PLP1 CNS-myelin defects span a spectrum extending to X-linked spastic
      paraplegia 2 (SPG2).

- name: MARS1
  gene_term:
    preferred_term: MARS1
    term:
      id: hgnc:6898
      label: MARS1
  subtype: SPG70
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35303589
    reference_title: 'Childhood-Onset Hereditary Spastic Paraplegia (HSP): A Case Series and Review of Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetically confirmed etiologies included SPAST (3 patients), MARS (2), KIF1A (2), KIF5A (1),
      SACS (1), SPG7 (1), REEP1 (1), PNPT1 (1), MT-ATP6 (1), and ATL1 (1).
    explanation: >-
      MARS (now MARS1) was the confirmed genetic etiology in two patients of a childhood-onset
      hereditary spastic paraplegia cohort, which is the human evidence available for this
      gene-disease pair.
  notes: >-
    PubMed searches run 2026-09-26 for the SPG70 designation ("spastic paraplegia 70", SPG70
    hereditary spastic paraplegia) and for MARS1 or MARS together with spastic paraplegia returned
    no dedicated SPG70 report, so the human evidence cited here is a childhood-onset HSP case
    series in which MARS was the confirmed genetic etiology in two of sixteen patients. The
    committed ClinGen gene-validity snapshot holds one MARS1 record, Charcot-Marie-Tooth disease
    (Limited, autosomal dominant), and none against an HSP entity. The autosomal recessive mode
    recorded here follows the bound MONDO class label rather than a cited study.
- name: CAPN1
  gene_term:
    preferred_term: CAPN1
    term:
      id: hgnc:1476
      label: CAPN1
  subtype: SPG76
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27153400
    reference_title: 'Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in CAPN1 were identified in all affected individuals, and sequencing in additional
      family members confirmed the segregation of these mutations with the disease (spastic
      paraplegia 76 [SPG76])
    explanation: >-
      Identifies biallelic CAPN1 variants as the cause of SPG76 in three autosomal recessive HSP
      families, with segregation confirmed.
- name: ATP13A2
  gene_term:
    preferred_term: ATP13A2
    term:
      id: hgnc:30213
      label: ATP13A2
  subtype: SPG78
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28137957
    reference_title: 'Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a Bulgarian family with three siblings affected by complicated hereditary spastic
      paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a
      homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2.
    explanation: >-
      Identifies a homozygous ATP13A2 variant in a family with complicated HSP, the observation on
      which the SPG78 designation rests.
  notes: >-
    Allelic with Kufor-Rakeb syndrome (MONDO:0011706), which dismech curates as its own entry; the
    committed ClinGen snapshot holds one ATP13A2 record, Kufor-Rakeb syndrome (Definitive,
    autosomal recessive), and none against SPG78.
- name: GPT2
  gene_term:
    preferred_term: GPT2
    term:
      id: hgnc:18062
      label: GPT2
  subtype: GPT2 Deficiency
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:27601654
    reference_title: 'Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2)
      in large kindreds initially ascertained for intellectual and developmental disability (IDD).
    explanation: >-
      Establishes autosomal recessive GPT2 variants as the cause of this disease in the defining
      kindreds.
- name: CCT5
  gene_term:
    preferred_term: CCT5
    term:
      id: hgnc:1618
      label: CCT5
  subtype: HSAN-SP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:16399879
    reference_title: 'Mutation in the epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5) gene causes autosomal recessive mutilating sensory neuropathy with spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A consanguineous Moroccan family with four patients displaying mutilating sensory neuropathy
      associated with spastic paraplegia was investigated.
    explanation: >-
      Defines the clinical entity - mutilating sensory neuropathy with spastic paraplegia - in the
      family in which the causal gene was found.
- name: ERLIN2
  gene_term:
    preferred_term: ERLIN2
    term:
      id: hgnc:1356
      label: ERLIN2
  subtype: SPG18
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_9599fa0e-da62-437d-8f6f-2f2ef0297c8c-2025-06-18T190000.000Z
    reference_title: 'ERLIN2 / hereditary spastic paraplegia 18 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ERLIN2 | HGNC:1356 | hereditary spastic paraplegia 18 | MONDO:0012639 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: ERLIN2-hereditary spastic paraplegia 18 is Definitive under
      autosomal recessive inheritance, against the same MONDO class bound here.
  notes: >-
    The committed ClinGen snapshot holds two ERLIN2 records against MONDO:0012639: autosomal
    recessive Definitive and autosomal dominant Limited.
- name: DSTYK
  gene_term:
    preferred_term: DSTYK
    term:
      id: hgnc:29043
      label: DSTYK
  subtype: SPG23
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_bbac4423-e313-4694-a7ac-2005164ea832-2023-09-29T023000.000Z
    reference_title: 'DSTYK / complex hereditary spastic paraplegia (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DSTYK | HGNC:29043 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Moderate
    explanation: >-
      ClinGen gene-disease validity: DSTYK-complex hereditary spastic paraplegia is Moderate under
      autosomal recessive inheritance, curated against MONDO:0015150, the class this entry is
      anchored on.
  notes: >-
    ClinGen curates DSTYK against complex hereditary spastic paraplegia (MONDO:0015150), the class
    this entry itself is anchored on, at Moderate strength.
- name: B4GALNT1
  gene_term:
    preferred_term: B4GALNT1
    term:
      id: hgnc:4117
      label: B4GALNT1
  subtype: SPG26
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35775650
    reference_title: 'Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26).
    explanation: >-
      Establishes the SPG26 diagnosis in a patient with biallelic B4GALNT1 variants after functional
      confirmation.
- name: PNPLA6
  gene_term:
    preferred_term: PNPLA6
    term:
      id: hgnc:16268
      label: PNPLA6
  subtype: SPG39
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35069422
    reference_title: 'Multifaceted and Age-Dependent Phenotypes Associated With Biallelic PNPLA6 Gene Variants: Eight Novel Cases and Review of the Literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in
      the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic
      paraplegia type 39, Gordon-Holmes, Boucher-Neuhauser, Oliver-Mc Farlane, and Laurence-Moon
      syndromes.
    explanation: >-
      Places spastic paraplegia type 39 inside the PNPLA6 allelic spectrum, which is the basis for
      binding PNPLA6 to this row and for keeping the Boucher-Neuhauser presentation in its own
      entry.
  notes: >-
    ClinGen files its Definitive PNPLA6 spastic-paraplegia record against its own entity,
    PNPLA6-related spastic paraplegia with or without ataxia (MONDO:0100149), rather than against
    the SPG39 class bound on this subtype; its second PNPLA6 record is the retinal
    dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome (MONDO:0100155), whose
    Boucher-Neuhauser presentation is a separate dismech entry.
- name: C19orf12
  gene_term:
    preferred_term: C19orf12
    term:
      id: hgnc:25443
      label: C19orf12
  subtype: SPG43
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23857908
    reference_title: 'Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report here the genetic basis for a form of progressive hereditary spastic paraplegia
      (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous
      missense variant (c.187G>C; p.Ala63Pro) in C19orf12
    explanation: >-
      Identifies the homozygous C19orf12 variant causing SPG43.
  notes: >-
    Allelic with neurodegeneration with brain iron accumulation, curated in dismech as
    Neurodegeneration_With_Brain_Iron_Accumulation; the committed ClinGen snapshot holds two
    C19orf12 records, both against neurodegeneration with brain iron accumulation 4
    (MONDO:0013674), and none against SPG43.
- name: VPS37A
  gene_term:
    preferred_term: VPS37A
    term:
      id: hgnc:24928
      label: VPS37A
  subtype: SPG53
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:22717650
    reference_title: 'A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the
      vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease
      in both families
    explanation: >-
      Identifies the fully penetrant homozygous VPS37A founder mutation segregating in both
      kindreds.
- name: DDHD2
  gene_term:
    preferred_term: DDHD2
    term:
      id: hgnc:29106
      label: DDHD2
  subtype: SPG54
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:23176823
    reference_title: 'Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The core phenotype of this HSP syndrome consists of very early-onset (<2 years) spastic
      paraplegia, intellectual disability, and a specific pattern of brain abnormalities on cerebral
      imaging.
    explanation: >-
      Gives the core complex-HSP phenotype of recessive DDHD2 disease.
- name: TFG
  gene_term:
    preferred_term: TFG
    term:
      id: hgnc:11758
      label: TFG
  subtype: SPG57
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33767317
    reference_title: 'Homozygous TFG gene variants expanding the mutational and clinical spectrum of hereditary spastic paraplegia 57 and a review of literature.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the tropomyosin-receptor kinase fused gene (TFG) has been linked to diverse hereditary
      neurodegenerative disorders, including a very rare complex hereditary spastic paraplegia,
      named spastic paraplegia type 57 (SPG57)
    explanation: >-
      States the TFG-SPG57 relationship and that SPG57 is a complex HSP; quoted from the report's
      framing of prior work rather than from its own result.
- name: AMPD2
  gene_term:
    preferred_term: AMPD2
    term:
      id: hgnc:469
      label: AMPD2
  subtype: SPG63
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29463858
    reference_title: 'Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous AMPD2 frameshift variant has recently been reported in two family members with
      spastic paraplegia type 63 (SPG63)
    explanation: >-
      Records the AMPD2-SPG63 relationship and its narrow evidence base; the sentence restates an
      earlier report rather than this cohort's own finding.
  notes: >-
    Allelic with pontocerebellar hypoplasia type 9, which is the presentation the AMPD2 cohorts
    describe; the SPG63 designation rests on the single family the cited cohort report mentions.
    The committed ClinGen snapshot holds no AMPD2 record.
- name: ENTPD1
  gene_term:
    preferred_term: ENTPD1
    term:
      id: hgnc:3363
      label: ENTPD1
  subtype: SPG64
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_8634ea9c-3fce-4d72-94e9-2ac6756e5cb6-2023-05-06T023000.000Z
    reference_title: 'ENTPD1 / complex hereditary spastic paraplegia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ENTPD1 | HGNC:3363 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: ENTPD1-complex hereditary spastic paraplegia is Definitive
      under autosomal recessive inheritance, curated against MONDO:0015150.
- name: IBA57
  gene_term:
    preferred_term: IBA57
    term:
      id: hgnc:27302
      label: IBA57
  subtype: SPG74
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25609768
    reference_title: 'Fe/S protein assembly gene IBA57 mutation causes hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We mapped this disorder to a locus on chromosome 1q and identified a homozygous donor
      splice-site mutation in the IBA57 gene
    explanation: >-
      Identifies the homozygous IBA57 splice-site mutation in the family that defines this subtype.
  notes: >-
    The committed ClinGen snapshot curates IBA57 against mitochondrial disease (MONDO:0044970,
    Definitive, autosomal recessive) rather than against an HSP entity.
- name: MAG
  gene_term:
    preferred_term: MAG
    term:
      id: hgnc:6783
      label: MAG
  subtype: SPG75
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_27976cb3-605a-4f56-a262-64dfd9793559-2023-11-20T190000.000Z
    reference_title: 'MAG / complex hereditary spastic paraplegia (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MAG | HGNC:6783 | complex hereditary spastic paraplegia | MONDO:0015150 | AR | Definitive
    explanation: >-
      ClinGen gene-disease validity: MAG-complex hereditary spastic paraplegia is Definitive under
      autosomal recessive inheritance, curated against MONDO:0015150.
- name: KIF1C
  gene_term:
    preferred_term: KIF1C
    term:
      id: hgnc:6317
      label: KIF1C
  subtype: SPAX2
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24319291
    reference_title: 'KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among
      controls
    explanation: >-
      Identifies the homozygous KIF1C mutations in the two families with spastic paraparesis and
      cerebellar dysfunction.
- name: RNF170
  gene_term:
    preferred_term: RNF170
    term:
      id: hgnc:25358
      label: RNF170
  subtype: SPG85
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31636353
    reference_title: 'Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets
      inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal
      recessive HSP in four unrelated families
    explanation: >-
      Establishes bi-allelic RNF170 variants as the cause of autosomal recessive HSP in four
      families and names the molecular role on which the mechanism node rests.
  notes: >-
    The dominant disease at the other end of the same RNF170 allelic series, autosomal dominant
    sensory ataxia 1 (MONDO:0012166), is a separate dismech entry which already records SPG85 as a
    differential diagnosis rather than as one of its own manifestations.
- name: ABHD16A
  gene_term:
    preferred_term: ABHD16A
    term:
      id: hgnc:13921
      label: ABHD16A
  subtype: SPG86
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34489854
    reference_title: 'Pathogenic Variants in ABHD16A Cause a Novel Psychomotor Developmental Disorder With Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous variants in ABHD16A segregated with the disease in the two studied families.
    explanation: >-
      Establishes biallelic ABHD16A variants as the cause of this complex spastic-paraplegia
      phenotype in the two families reported.
- name: KIDINS220
  gene_term:
    preferred_term: KIDINS220
    term:
      id: hgnc:29508
      label: KIDINS220
  subtype: SINO
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_22271df6-f033-4ecc-9aa7-2b5cdd8f060e-2024-10-29T160000.000Z
    reference_title: 'KIDINS220 / spastic paraplegia, intellectual disability, nystagmus, and obesity (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      KIDINS220 | HGNC:29508 | spastic paraplegia, intellectual disability, nystagmus, and obesity |
      MONDO:0015007 | AD | Moderate
    explanation: >-
      ClinGen gene-disease validity: KIDINS220 is curated against this exact MONDO class under
      autosomal dominant inheritance at Moderate strength, which is the basis for both the gene
      binding and the dominant inheritance on this row.
  notes: >-
    The committed ClinGen snapshot holds a second KIDINS220 record, ventriculomegaly and
    arthrogryposis (MONDO:0859184, Definitive, autosomal recessive); that is a different disease
    and is not curated here.
- name: KLC2
  gene_term:
    preferred_term: KLC2
    term:
      id: hgnc:20716
      label: KLC2
  subtype: SPOAN
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26385635
    reference_title: 'Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPOAN syndrome is a neurodegenerative disorder mainly characterized by spastic paraplegia,
      optic atrophy and neuropathy (SPOAN).
    explanation: >-
      Defines the SPOAN clinical triad bound on this row.
- name: HACE1
  gene_term:
    preferred_term: HACE1
    term:
      id: hgnc:21033
      label: HACE1
  subtype: SPPRS
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:36553453
    reference_title: 'Previously Undescribed Gross HACE1 Deletions as a Cause of Autosomal Recessive Spastic Paraplegia.'
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS, OMIM 616756)
      is a rare genetic disease caused by biallelic pathogenic variants in the HACE1 gene.
    explanation: >-
      States the HACE1-SPPRS gene-disease relationship and its recessive mode; quoted from the
      report's opening framing of established knowledge rather than from its own new deletions.
- name: AP4E1
  gene_term:
    preferred_term: AP4E1
    term:
      id: hgnc:573
      label: AP4E1
  subtype: AP-4-HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30543385
    reference_title: 'AP-4-Associated Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic
      pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.
    explanation: >-
      GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4
      subunit genes, which is the primary basis for curating this as a single four-gene subtype row.
- name: AP4M1
  gene_term:
    preferred_term: AP4M1
    term:
      id: hgnc:574
      label: AP4M1
  subtype: AP-4-HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30543385
    reference_title: 'AP-4-Associated Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic
      pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.
    explanation: >-
      GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4
      subunit genes, which is the primary basis for curating this as a single four-gene subtype row.
- name: AP4S1
  gene_term:
    preferred_term: AP4S1
    term:
      id: hgnc:575
      label: AP4S1
  subtype: AP-4-HSP
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30543385
    reference_title: 'AP-4-Associated Hereditary Spastic Paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic
      pathogenic variants in AP4B1, AP4E1, AP4M1, or AP4S1 identified on molecular genetic testing.
    explanation: >-
      GeneReviews defines one disease diagnosed by biallelic variants in any of the four AP-4
      subunit genes, which is the primary basis for curating this as a single four-gene subtype row.

- name: NT5C2
  gene_term:
    preferred_term: NT5C2
    term:
      id: hgnc:8022
      label: NT5C2
  subtype: SPG45
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    NT5C2 is bound on the purine nucleotide node together with AMPD2 and ENTPD1, the two other
    purine enzymes on this entry. HGNC records SPG45 as a previous symbol of NT5C2 and SPG65 as an
    alias (rest.genenames.org, read 2026-09-30), and MONDO:0013165 carries both designations as
    synonyms of one class. The committed ClinGen gene-disease validity cache in this repository
    holds no NT5C2 assertion; the full ClinGen CSV is gitignored and absent, so that is a
    statement about the committed snapshot and not about ClinGen as a whole. The Bookshelf index
    at cache/bookshelf/genereviews.csv has no chapter for NT5C2 or for spastic paraplegia 45
    (searched for both the gene symbol and the disease designation).
  evidence:
  - reference: PMID:39119448
    reference_title: 'Two Sibling Cases of Spastic Paraplegia-45 with a Novel Pathogenic Variant in NT5C2 Gene: Concomitant RYR1 Gene in One Sibling.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing identified a previously unidentified homozygous mutation in the NT5C2
      gene, leading to the diagnosis of SPG45 in both siblings.
    explanation: >-
      A homozygous NT5C2 variant segregating in two affected siblings is the human genetic basis
      for this record and for its autosomal recessive mode.
  - reference: PMID:24482476
    reference_title: Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three of these genes, ERLIN1, KIF1C, and NT5C2, were found independently mutated in more
      than one family, and all mutations were predicted to be highly deleterious.
    explanation: >-
      Independent recurrence across more than one family in an autosomal recessive HSP cohort is
      the replication behind the NT5C2 gene-disease relationship.
- name: ARL6IP1
  gene_term:
    preferred_term: ARL6IP1
    term:
      id: hgnc:697
      label: ARL6IP1
  subtype: SPG61
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    ARL6IP1 is bound on the ER membrane shaping node. HGNC records SPG61 as an alias of ARL6IP1
    (rest.genenames.org, read 2026-09-30). The committed ClinGen gene-disease validity cache in
    this repository holds no ARL6IP1 assertion, and the Bookshelf index at
    cache/bookshelf/genereviews.csv has no chapter for ARL6IP1 or for spastic paraplegia 61;
    as with NT5C2 the ClinGen statement describes the committed snapshot, the full CSV being
    gitignored and absent.
  evidence:
  - reference: PMID:31272422
    reference_title: Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1
      that segregated with the phenotype and was predicted to result in loss of the protein.
    explanation: >-
      A homozygous nonsense ARL6IP1 allele segregating with the phenotype, and predicted to
      abolish the protein, is the human genetic basis for this record and its recessive mode.
  - reference: PMID:28471035
    reference_title: 'ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we described a new patient with congenital insensitivity to pain, sensory neuropathy,
      acromutilation, and spastic paraplegia.
    explanation: >-
      A second, independently reported patient with biallelic ARL6IP1 loss, widening the
      phenotype this gene record covers to pain insensitivity and acromutilation.
- name: KIF5A
  gene_term:
    preferred_term: KIF5A
    term:
      id: hgnc:6323
      label: KIF5A
  subtype: AD Complex HSP
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    KIF5A is bound on the kinesin axonal-transport node. It points at the autosomal dominant
    complex HSP row because this entry has no gene-defined SPG10 row. The original SPG10 family
    had pure HSP; the complex-category placement rests on the French series cited below.
  evidence:
  - reference: PMID:18853458
    reference_title: 'Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that
      mutations in KIF5A represent the major cause of complicated AD-HSP in France.
    explanation: >-
      Places heterozygous KIF5A variants among the autosomal dominant complicated HSPs, the
      subtype row this record points at.
  - reference: PMID:12355402
    reference_title: 'A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have identified a missense mutation in the motor domain of the neuronal kinesin heavy
      chain gene KIF5A, in a family with hereditary spastic paraplegia.
    explanation: >-
      The founding identification of KIF5A as the SPG10 gene.
- name: ALDH18A1
  gene_term:
    preferred_term: ALDH18A1
    term:
      id: hgnc:9722
      label: ALDH18A1
  subtype: AD Complex HSP
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  notes: >-
    ALDH18A1 is bound on the pyrroline-5-carboxylate synthase node. Its allelic series (SPG9A,
    SPG9B, and the cutis laxa forms) is curated in ALDH18A1_De_Barsy_Spectrum; this record
    covers only the dominant SPG9A presentation that this entry's autosomal dominant complex
    HSP row names.
  evidence:
  - reference: PMID:26026163
    reference_title: 'Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified monoallelic ALDH18A1 mutations segregating in three independent families with
      autosomal dominant pure or complex hereditary spastic paraplegia,
    explanation: >-
      Heterozygous ALDH18A1 variants segregate with autosomal dominant complex spastic
      paraplegia, the basis for this record and its dominant mode.

treatments:
- name: Antispasticity Pharmacotherapy
  description: >
    Symptomatic reduction of lower-limb spasticity with agents such as baclofen
    (oral or intrathecal), tizanidine, and dantrolene, plus selective botulinum
    toxin injection. Treatment is symptomatic — no disease-modifying therapy
    exists for HSP.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: tizanidine
      term:
        id: CHEBI:63629
        label: tizanidine
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intrathecal Lioresal or oral Dantrolene or Tizanidine and selective injection of botulinum toxin (Botox)"
    explanation: >
      Antispasticity agents (Lioresal is the baclofen brand, plus dantrolene,
      tizanidine, and botulinum toxin) are used for symptomatic spasticity in
      HSP.
- name: Physical Therapy
  description: >
    Regular physiotherapy to maintain range of motion, reduce contractures, and
    preserve ambulation, a mainstay of supportive HSP management.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:23897027
    reference_title: "Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy is generally recommended to improve range of motion, maintain and increase lower extremity strength"
    explanation: Physical therapy is a core supportive intervention recommended in HSP.
- name: Genetic Counseling
  description: >
    Genetic counseling addressing the relevant inheritance mode (autosomal
    dominant, autosomal recessive, or X-linked) for the specific SPG subtype.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301682
    reference_title: "Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Inform genetic counseling of family members"
    explanation: >
      Genetic counseling of at-risk family members is a recommended component of
      HSP management.

notes: >
  Complex HSP (MONDO:0015150) is a syndromic grouping term rather than a single
  gene disease; the autosomal dominant complex form is MONDO:0015087. It is the
  sibling of pure/uncomplicated HSP under the broader hereditary spastic
  paraplegia entry (MONDO:0019064), which carries the shared corticospinal-tract
  pathophysiology and the gene-level SPG subtypes. The pure-versus-complex clinical
  split correlates imperfectly with genetic type, and many loci can present as
  either form.

  Subtype structure. The entry carries two layers of `has_subtypes` rows. Three
  rows (AD, AR, XL Complex HSP) stratify the category by inheritance and list
  representative loci; some genes named there have their own disease entries
  instead of a row here (ALDH18A1, for example, is curated as ALDH18A1_Cutis_Laxa
  and ALDH18A1_De_Barsy_Spectrum). Beneath them sit gene-defined rows, each bound
  to its own MONDO class and carrying the causal gene, so that a specific complex
  form is addressable without a separate disease file. A gene's `genetic` record
  points at the gene-defined row wherever one exists, and at an inheritance row
  only where it does not; the gene-defined target is the more informative of the
  two.
  Routing between this entry and the pure HSP entry follows the rule recorded
  there: a gene-defined SPG form sits on the pure entry when the literature puts
  it in the pure clinical category and here when it puts it in the complex
  category. Every gene-defined row added here is placed in the complex category
  by the source cited on that row or by the label of the MONDO class it binds.

  Anchor. The `disease_term` binding MONDO:0015150 was checked against the
  over-broad-anchor pattern of dismech#12184 and left in place: this entry is the
  syndromic grouping, not a gene-specific disease wearing a grouping term, and
  MONDO defines the class as "A hereditary spastic paraplegia that is part of a
  larger syndrome" (read from OLS 2026-09-26). ClinGen independently curates five
  of the genes recorded here - DSTYK, B4GALNT1, VPS37A, ENTPD1 and MAG - directly
  against MONDO:0015150, so the anchor is the class the field itself uses for
  these gene-disease relationships.

  AP-4-associated HSP is one row with four genes, not four rows. GeneReviews has
  a single AP-4-HSP chapter whose diagnostic criterion is biallelic variants in
  AP4B1, AP4E1, AP4M1 or AP4S1; ClinGen curates all four subunit genes as
  Definitive against one entity, AP-4 deficiency syndrome (MONDO:0100176); and
  MONDO supplies that integrated class itself, defined as "A genetic disorder
  associated with variation(s) in the AP4 genes: AP4B1, AP4E1, AP4M1, and AP4S1".
  MONDO also keeps four gene-generated classes for the same biology
  (MONDO:0013551 SPG47/AP4B1, MONDO:0013048 SPG50/AP4M1, MONDO:0013401
  SPG51/AP4E1, MONDO:0013552 SPG52/AP4S1), each defined in the bare form "Any
  hereditary spastic paraplegia in which the cause of the disease is a mutation in
  the <gene> gene". Carrying both granularities is not an ontology defect: the
  same bare definition form appears on MONDO:0014975 (SPG78/ATP13A2) and
  MONDO:0014729 (SPG75/MAG), two classes this entry does bind, so an argument
  against it would condemn rows kept here as well as rows declined.

  Allelic-series routings, recorded so the same gene is not curated twice. SPG78
  (ATP13A2) is allelic with Kufor-Rakeb syndrome, which has its own entry;
  SPG43 (C19orf12) with neurodegeneration with brain iron accumulation, which has
  its own entry; SPG39 (PNPLA6) with the Boucher-Neuhauser presentation, which has
  its own entry; SPG85 (RNF170) with autosomal dominant sensory ataxia 1, which
  has its own entry and already lists SPG85 as a differential diagnosis; SPG63
  (AMPD2) with pontocerebellar hypoplasia type 9; and SPG74 (IBA57) with the
  mitochondrial-disease entity ClinGen curates. In each case the
  spastic-paraplegia presentation is what this entry holds.

  Sources consulted. GeneReviews (the AP-4-HSP, SPG11, L1 syndrome, PLP1 and pure
  HSP overview chapters), the committed ClinGen gene-disease validity snapshot,
  and primary literature. Orphanet could not be consulted: no ORPHA_*.md record
  for any of these spastic-paraplegia concepts is present in references_cache, and
  populating one needs a maintainer-level Orphadata refresh.

  SPG45 (NT5C2) and SPG61 (ARL6IP1) are gene-defined rows for two direct children of
  MONDO:0015150. Both carry
  "autosomal recessive complex spastic paraplegia caused by mutation in" the
  respective gene among their synonyms, so the complex-category routing rule above
  places them here rather than on the pure HSP entry. MONDO:0013165 holds SPG45 and
  SPG65 as synonyms of one class, consistent with HGNC recording SPG45 as a previous
  symbol of NT5C2 and SPG65 as an alias.

  Two mechanism nodes carry those genes. Purine Nucleotide Metabolic Imbalance
  collects NT5C2 with the two other purine enzymes on this entry, AMPD2 (SPG63) and
  ENTPD1 (SPG64), which the founding exome study assigns to one purine-metabolism
  module; those two genes sit there rather than on the pleiotropic node, which holds
  the genes with diverse housekeeping roles rather than enzymes of a single pathway.
  Tubular Endoplasmic Reticulum Membrane Shaping Failure holds ARL6IP1 and is kept
  distinct from the IP3-receptor calcium-release node, whose genes act on receptor
  degradation and ER calcium handling rather than on ER membrane geometry.

  Reciprocal anchor check. Every subtype row binding a MONDO class sits inside the
  MONDO:0015150 subtree except the AP-4-HSP row: MONDO:0100176 is filed under disease
  of genetic or genomic mechanism rather than under hereditary spastic paraplegia (OLS
  hierarchicalAncestors, read 2026-09-30). The four gene-generated AP-4 SPG classes
  named above sit outside that subtree as well, so splitting the row into four would
  not bring it inside, and the binding is left as it is.

  As more specific complex-HSP leaf entries are curated, a kb/groupings/ union
  over them would be a natural follow-up.

📚

References & Deep Research

References

PMID:30543385

AP-4-Associated Hereditary Spastic Paraplegia.

No top-level findings curated for this source.

PMID:20301682

Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview.

No top-level findings curated for this source.

PMID:20301389

Spastic Paraplegia 11.

No top-level findings curated for this source.

PMID:20301657

L1 Syndrome.

No top-level findings curated for this source.

PMID:20301361

PLP1-Related Disorders.

No top-level findings curated for this source.

PMID:23897027

Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Claude Code ▸

Complex Hereditary Spastic Paraplegia (HSP): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 67 citations 2026-07-01T20:34:26.651341

Complex Hereditary Spastic Paraplegia (HSP): Comprehensive Research Report

1. Disease Information

Overview. Hereditary spastic paraplegia (HSP) is not a single disease but a large, clinically and genetically heterogeneous group of inherited neurodegenerative disorders whose unifying pathological feature is retrograde ("dying-back"), length-dependent axonal degeneration of the corticospinal tracts (and often the dorsal columns), producing progressive lower-limb spasticity and weakness (MedLink Neurology; PMC6827077). HSPs are clinically split into: - Pure (uncomplicated) HSP — progressive spastic paraplegia with hyperreflexia, extensor plantar responses (Babinski sign), and urinary urgency/bladder dysfunction as essentially the only findings (GeneReviews NBK1509). - Complex (complicated) HSP — spastic paraplegia plus additional neurological features (ataxia, peripheral neuropathy, epilepsy, intellectual disability/cognitive decline, extrapyramidal signs/parkinsonism, optic atrophy, retinopathy, deafness) and/or non-neurological systemic features (dysmorphism, skeletal deformity, skin changes) (PMC4939695; PMC8749458).

More than 88 spastic paraplegia (SPG) gene loci have been described, with 40+ confirmed causal genes, spanning autosomal dominant (AD), autosomal recessive (AR), X-linked, and (rarely) mitochondrial inheritance (PMC8662366; Pharos disease page). Complex forms are disproportionately autosomal recessive, with SPG11 (spatacsin), SPG15/ZFYVE26 (spastizin), SPG7 (paraplegin), SPG5A/CYP7B1, SPG35/FA2H, SPG20 (Troyer syndrome), and the AP-4 complex disorders (SPG47/50/51/52) among the most frequent/best characterized complex etiologies.

Key identifiers. - Pharos lists "complex hereditary spastic paraplegia" as a distinct disease-concept entry (Pharos). - There is no single unifying MONDO/OMIM ID for "complex HSP" as a category — it is a cross-cutting clinical descriptor applied across dozens of individually MONDO/OMIM-coded SPG subtypes. Representative examples: pure-or-complex AD spastic paraplegia group MONDO:0008438; AR complex spastic paraplegia (SPG23) MONDO:0010046; pure-or-complex AR spastic paraplegia (SPG48) MONDO:0013342 (search aggregation). - Individual OMIM entries exist per subtype, e.g., SPG3A OMIM #182600, SPG5A OMIM #270800, SPG7 OMIM #607259, SPG12 OMIM #604805 (OMIM). - Orphanet groups HSP under ORPHA:99013 ("Hereditary spastic paraplegia"), with individual ORPHA codes per numbered SPG subtype and clinical form (pure vs. complicated). - ICD-10: G11.4 (hereditary spastic paraplegia); ICD-11: 8A02.1. - MeSH: D015419 (Spastic Paraplegia, Hereditary).

Synonyms: Familial spastic paraplegia; Strümpell-Lorrain disease/syndrome; hereditary spastic paraparesis; French settlement disease (historical); "complicated"/"complex" HSP.

Evidence base: Predominantly aggregated disease-level literature (case series, natural-history cohorts, genetic-diagnostic cohorts) rather than large-scale EHR studies, though a few population-based epidemiologic studies exist (Norway, England/Northern Ireland; see Section 9) (PMC12210554).

2. Etiology

Primary cause: Monogenic — pathogenic variants in one of >88 SPG loci disrupting core cell-biological processes in long CNS axons (see Section 6). Genetic architecture, not environmental exposure, is the dominant causal factor; complex forms are enriched for AR inheritance and biallelic loss-of-function alleles.

Genetic risk factors: - Causal, highly penetrant variants in SPAST (SPG4), ATL1 (SPG3A), REEP1 (SPG31) account for pure HSP; SPAST/ATL1/REEP1 together account for well over 50% of all HSP (JCI PMC2846052). - Complex/recessive HSP causal genes: SPG11 (spatacsin) — most prevalent AR complex HSP gene (~8% of registered AR HSP cases) (Frontiers/PMC search synthesis); SPG15/ZFYVE26; SPG7 (paraplegin); CYP7B1 (SPG5A); FA2H (SPG35); SPG20 (spartin, Troyer syndrome); AP4B1/AP4M1/AP4E1/AP4S1 (SPG47/50/51/52). - Consanguinity is a strong risk-enrichment factor for AR complex HSP, particularly in Mediterranean and Middle Eastern populations with high consanguinity rates (PMC8944001). - Modifier genes/digenic inheritance: recent work reports digenic SPG7/AFG3L2 interactions modulating motor neuron and cerebellar phenotypes (medRxiv preprint, 2025) (medRxiv).

Environmental/risk modifiers: No established environmental or infectious causal contributors; age at onset and severity are influenced by genotype (see Section 8) rather than known exposures. No consistent sex-ratio skew has been reported ("no differences in rate relating to gender were found") (PMC8944001).

Protective factors: None well established at the population level; some evidence that later disease onset in certain genotypes (e.g., SPG3A vs. SPG4) correlates with slower progression, which may reflect allelic/genetic background effects rather than a true protective factor (Springer natural history).

Gene-environment interaction: Not a major feature of this disease group; HSP is considered predominantly monogenic with modifier-gene (not environmental) modulation of expressivity.

3. Phenotypes

Core "pure" phenotype (present in virtually all HSP, complex or pure)

Phenotype	HPO term	Notes
Lower limb spasticity	HP:0002061 (Spastic paraplegia) / HP:0007256	Core feature; progressive
Hyperreflexia	HP:0001347	93.9% in SPG4 cohorts
Babinski sign (extensor plantar response)	HP:0003487	71.9% in SPG4
Lower limb muscle weakness	HP:0007340	54.2% (proximal) in SPG4
Urinary bladder sphincter dysfunction / urgency	HP:0002839 / HP:0000012	~28.7–50%
Pes cavus	HP:0001761	Frequent secondary orthopedic finding
Ankle clonus	HP:0013359	Common exam finding

Frequencies above from a large SPG4/SPAST-HSP cohort (Neurology Genetics NXG.0000000000000664).

Complex-form additional phenotypes (by representative subtype)

Subtype/Gene	Additional phenotypes	HPO terms
SPG11 (spatacsin) / SPG15 (spastizin)	Thin corpus callosum, cognitive impairment/intellectual disability, cerebellar ataxia, cataracts, pigmentary retinopathy, early-onset parkinsonism, peripheral neuropathy	HP:0033725 (thin corpus callosum), HP:0001249 (ID), HP:0001251 (ataxia), HP:0000518 (cataract), HP:0000580 (pigmentary retinopathy), HP:0002548 (parkinsonism)
SPG7 (paraplegin)	Cerebellar ataxia, optic atrophy, progressive external ophthalmoplegia, nystagmus/dysmetric saccades, peripheral neuropathy	HP:0001251, HP:0000648 (optic atrophy), HP:0000544, HP:0000639
SPG5A (CYP7B1)	Afferent ataxia (dorsal-column sensory loss), sometimes optic atrophy/white-matter changes	HP:0001251, HP:0000648
SPG35 (FA2H)	Intellectual disability, seizures, leukodystrophy (white-matter abnormalities), extrapyramidal signs, sometimes brain iron accumulation	HP:0001249, HP:0001250 (seizure), HP:0002171 (leukoencephalopathy)
SPG20 (spartin, Troyer syndrome)	Distal amyotrophy (small hand-muscle wasting), dysarthria, short stature, mild intellectual disability, skeletal deformity	HP:0003693 (distal amyotrophy), HP:0001260 (dysarthria), HP:0004322 (short stature)
AP-4-HSP (SPG47/50/51/52)	Severe global developmental delay, microcephaly, seizures, brain malformation, early hypotonia progressing to hypertonia/spasticity, loss of ambulation, stereotypic laughter	HP:0001263 (developmental delay), HP:0000252 (microcephaly), HP:0001250, HP:0001252 (hypotonia)→HP:0001276 (hypertonia)

Age of onset / progression / severity: Highly variable — from congenital/infantile (AP-4-HSP) to childhood (SPG11, SPG35) to adult/late-onset (SPG4, SPG7, SPG3A), with mean HSP onset age around 24 years across pooled cohorts (PMC8944001). Complex forms tend to progress faster than pure forms: Spastic Paraplegia Rating Scale (SPRS) annual progression ~1.3 points/year in complicated HSP vs. 0.6 points/year in pure HSP (Austrian natural history cohort, Springer 2025). Disease severity/progression is genotype-dependent: SPG11 carries the highest severity burden; SPG3A tends to progress more slowly than SPG4 (same source).

Quality of life: Direct QoL instrument data specific to HSP is sparse in the literature surveyed; management studies report substantial impact on mobility/independent ambulation and increased psychiatric comorbidity (anxiety/depression) documented in the England/N. Ireland epidemiologic cohort (PMC12210554).

4. Genetic/Molecular Information

Causal genes (selected, complex-form-relevant): | Gene | HGNC | Locus/OMIM | Protein | Inheritance | |---|---|---|---|---| | SPAST | HGNC:11233 | SPG4, OMIM #182601 | Spastin (microtubule-severing AAA-ATPase) | AD | | ATL1 | HGNC:30288 | SPG3A, OMIM #182600 | Atlastin-1 (ER-shaping GTPase) | AD | | REEP1 | HGNC:13703 | SPG31 | REEP1 (ER-shaping hairpin protein) | AD | | SPG11 | HGNC:11226 | SPG11, OMIM #604360 | Spatacsin | AR | | ZFYVE26 | HGNC:29128 | SPG15 | Spastizin | AR | | SPG7 | HGNC:11237 | SPG7, OMIM #607259 | Paraplegin (m-AAA mitochondrial protease subunit) | AR (occasionally digenic w/ AFG3L2) | | CYP7B1 | HGNC:2652 | SPG5A, OMIM #270800 | Oxysterol 7α-hydroxylase | AR | | FA2H | HGNC:20139 | SPG35 | Fatty acid 2-hydroxylase | AR | | SPART (SPG20) | HGNC:11227 | SPG20 (Troyer syndrome) | Spartin | AR | | AP4B1 | HGNC:567 | SPG47 | AP-4 complex β subunit | AR | | AP4M1 | HGNC:569 | SPG50 | AP-4 complex μ subunit | AR | | AP4E1 | HGNC:568 | SPG51 | AP-4 complex ε subunit | AR | | AP4S1 | HGNC:571 | SPG52 | AP-4 complex σ subunit | AR |

Pathogenic variant types: Loss-of-function (nonsense, frameshift, splice-site) predominates in AR complex forms (e.g., SPG11, SPG20, AP-4 genes are essentially null alleles: "the pathogenesis of Troyer syndrome results from a loss-of-function mechanism" rather than a toxic truncated protein) (Wikipedia SPG20 synthesis). Missense variants with dominant-negative or haploinsufficient effects predominate in AD pure forms (SPAST, ATL1). Variant classification should follow ACMG/AMP criteria via ClinVar/ClinGen; allele frequencies for pathogenic variants are characteristically rare/absent in gnomAD, consistent with a rare Mendelian disease, though specific founder alleles exist in consanguineous/isolate populations.

Functional consequences: - Spastin: loss of microtubule-severing activity → disrupted axonal microtubule dynamics/transport. - Atlastin-1/REEP1: loss of ER tubule-fusion/shaping activity, disrupting the tubular ER network's coordination with microtubules in long axons (PMC2846052). - Spatacsin/spastizin (SPG11/SPG15): loss of AP-5-adaptor accessory function → defective lysosomal reformation/tubulation and autophagosome-lysosome fusion, causing autophagosome/enlarged-lysosome accumulation (PMC4078876). - Paraplegin (SPG7): loss of m-AAA mitochondrial protease function → mitochondrial proteostasis failure, permeability-transition-pore dysregulation, ATPase deficiency (Lancet eBioMedicine). - CYP7B1: loss of oxysterol 7α-hydroxylase activity → toxic accumulation of 25- and 27-hydroxycholesterol, which are neurotoxic and blood-brain-barrier permeable (ScienceDirect; PubMed 18252231). - AP-4 complex subunits: loss of AP-4-mediated vesicular sorting (notably ATG9A trafficking) → autophagy-initiation defects; Ap4b1-knockout mice show "ATG9A mislocalization" (PMC9825813).

Modifier genes: AFG3L2 as a digenic modifier/co-causal partner with SPG7 in some motor neuron/cerebellar presentations (medRxiv 2025).

Epigenetics/chromosomal abnormalities: Not a prominent feature of HSP pathogenesis in the literature surveyed; disease is driven by point/small indel variants in nuclear-encoded genes rather than large chromosomal rearrangements or a described episignature.

5. Environmental Information

No specific toxin, infectious agent, or lifestyle exposure has been causally linked to HSP; the searched literature identifies HSP as a purely genetic disease group. Environmental/behavioral factors have not been studied as HSP risk modifiers in the sources reviewed. This section is largely not applicable for this Mendelian disease class beyond noting that catabolic stress or intercurrent illness is not a described trigger (in contrast to some other neurogenetic disease classes in this KB, e.g., metabolic intoxication disorders).

6. Mechanism / Pathophysiology

Core convergent pathophysiology: Regardless of causal gene, HSP mechanistically converges on length-dependent ("dying-back") retrograde axonal degeneration of the corticospinal tract (and often dorsal columns), because these are the longest axons in the human CNS (up to ~1 m) and are maximally dependent on efficient long-range organelle/cargo transport and membrane maintenance (PMC6827077). "The central nervous system's long axons are hotspots and the first site of hereditary spastic paraplegia axonopathy."

Major convergent molecular pathway clusters (from PMC8004882 and PMC6031053):

ER shaping / membrane trafficking (SPAST, ATL1, REEP1 axis). Atlastin-1 (a GTPase) mediates homotypic fusion of ER tubules to form three-way junctions of the tubular ER network; it physically interacts with spastin (microtubule-severing AAA-ATPase) and REEP1 (a hairpin ER-shaping protein), and this tripartite complex "coordinate[s] microtubule interactions with the tubular ER network" specifically within long corticospinal axons (JCI, PubMed 20200447). Loss of any one component destabilizes ER-microtubule coupling, impairing axonal ER distribution and organelle transport.
Lysosomal/autophagosome maturation (SPG11/SPG15 axis). Spatacsin (SPG11) and spastizin (SPG15) form a complex, cooperating with the AP-5 adaptor complex in late-endosome/lysosome membrane sorting; loss of function causes defective autophagosome-to-lysosome fusion, lysosome depletion, and enlarged/dysfunctional lysosomes, driving neurodegeneration with the distinctive thin-corpus-callosum, cognitive, and retinal phenotype (PMC4078876; PMC4540459). A 2024 zebrafish spastizin model additionally shows axon demyelination and degeneration, implicating oligodendrocyte/myelin dysfunction as a downstream mechanism (bioRxiv/PMC11539067).
Mitochondrial quality control (SPG7 axis). Paraplegin, part of the mitochondrial inner-membrane m-AAA protease, is required for mitochondrial protein quality control and ribosome assembly; its loss causes ATPase deficiency, impaired permeability-transition-pore "flickering," and secondary anterograde/retrograde axonal transport failure, producing progressive distal axonopathy of spinal and peripheral nerves that faithfully recapitulates the human SPG7 phenotype in Spg7-knockout mice (Lancet eBioMedicine).
Cholesterol/oxysterol metabolism (CYP7B1/SPG5A axis). Loss of oxysterol 7α-hydroxylase blocks the alternative bile-acid synthesis pathway, causing toxic accumulation of 25- and 27-hydroxycholesterol, which cross the blood-brain barrier and are directly neurotoxic to corticospinal and dorsal-column axons (ScienceDirect).
Complex sphingolipid/myelin lipid metabolism (FA2H/SPG35 axis). Loss of fatty acid 2-hydroxylase impairs synthesis of 2-hydroxylated sphingolipids required for normal myelin composition, producing a leukodystrophy-like phenotype with white-matter abnormalities, sometimes overlapping neurodegeneration with brain iron accumulation (the entity is also called fatty acid hydroxylase-associated neurodegeneration, FAHN) (PMC6238570; PubMed 38353247).
AP-4 vesicular sorting (SPG47/50/51/52 axis). Loss of any AP-4 complex subunit disrupts anterograde sorting of ATG9A (an autophagy-initiation transmembrane protein) from the trans-Golgi network, impairing autophagosome biogenesis; Ap4b1-knockout mice show motor dysfunction, aberrant brain morphology, and ATG9A mislocalization, closely mirroring the profound infantile/childhood-onset human phenotype (PMC9825813).
Non-cell-autonomous glial mechanism. Emerging evidence (in vitro/model organism) implicates impaired lipid/cholesterol homeostasis in astrocytes as a non-cell-autonomous driver of cortical projection-neuron degeneration in HSP, expanding the mechanism beyond a purely neuron-intrinsic model (PMC7720406).
Lipid metabolism broadly. A dedicated review ("Lipids in the Physiopathology of Hereditary Spastic Paraplegias") frames disrupted lipid/membrane metabolism (cholesterol, sphingolipids, phospholipids) as a unifying downstream theme across many complex-HSP genes (PMC7059351).

Suggested GO terms: GO:0007018 (microtubule-based movement), GO:0016183 (ER tubular network organization), GO:0007009 (plasma membrane organization) → more precisely GO:0071786 (ER tubular network organization), GO:0006914 (autophagy), GO:0007009, GO:1902774 (late endosome to lysosome transport), GO:0007005 (mitochondrion organization), GO:0034599 (cellular response to oxidative stress), GO:0008203 (cholesterol metabolic process), GO:0030149 (sphingolipid catabolic process), GO:0007041 (lysosomal transport).

Suggested CL terms: CL:0000029 (corticospinal tract upper motor neuron)/CL:0011005 (corticospinal neuron), CL:0000030 (glutamatergic neuron, alt.), CL:0000127 (astrocyte, for the non-cell-autonomous glial mechanism), CL:0000128 (oligodendrocyte, for SPG15 demyelination).

Causal chain summary (generalized template for a complex-HSP disorder node): Gene-specific lesion (e.g., biallelic SPG11 loss-of-function) → organelle-specific dysfunction (lysosomal/autophagic dysfunction) → impaired long-axon maintenance (corticospinal + additional tract/structure involvement, e.g., corpus callosum, cerebellum, retina) → length-dependent retrograde axonal degeneration → progressive spasticity plus complex-form-specific extra-pyramidal features (cognitive decline, ataxia, retinopathy, etc.).

7. Anatomical Structures Affected

Organ/system level: - Primary: central nervous system — corticospinal tracts (upper motor neuron), often dorsal (posterior) spinal columns. - Secondary (complex forms): cerebellum (ataxia), corpus callosum (SPG11/15 thinning), peripheral nerves (neuropathy — SPG7, AP-4 disorders), optic nerve (atrophy — SPG7), retina (pigmentary retinopathy — SPG11/15), lens (cataracts — SPG11/15), skeletal system (pes cavus, scoliosis, short stature — SPG20), bladder (neurogenic bladder/urgency), white matter broadly (leukodystrophy — SPG35).

Tissue/cell level (Cell Ontology): - CL:0011005 corticospinal neuron / CL:0000029 (upper motor neuron parent term via UBERON:0002240 spinal cord) - CL:0000127 astrocyte (non-cell-autonomous mechanism) - CL:0000128 oligodendrocyte (myelin/demyelination component) - CL:0000540 neuron (general) - Retinal photoreceptor cells (SPG11/15 retinopathy) - Peripheral sensory/motor neurons (SPG7, AP-4 neuropathy)

Subcellular level (GO Cellular Component): - GO:0005783 endoplasmic reticulum (tubular ER; SPAST/ATL1/REEP1) - GO:0005739 mitochondrion, specifically GO:0005743 mitochondrial inner membrane (SPG7 m-AAA protease) - GO:0005764 lysosome / GO:0005776 autophagosome (SPG11/SPG15, AP-4) - GO:0005874 microtubule / GO:0015630 microtubule cytoskeleton - GO:0030134 COPII-coated ER-to-Golgi transport vesicle (AP-4-related Golgi sorting)

Localization (UBERON): - UBERON:0002240 (spinal cord), UBERON:0001133 (corticospinal tract), UBERON:0002756 (corpus callosum), UBERON:0002037 (cerebellum), UBERON:0000966 (retina), UBERON:0000970 (eye), UBERON:0001021 (nerve/peripheral nervous system). - Lateralization: HSP motor findings are typically bilateral and symmetric (a distinguishing feature from unilateral corticospinal lesions of other etiologies).

8. Temporal Development

Onset: Ranges continuously from congenital/infantile (AP-4-HSP: global developmental delay from infancy) through childhood (SPG11 median onset in the first two decades; SPG35 childhood-onset with seizures/leukodystrophy) to adult-onset (SPG4, SPG7 — onset can occur "as late as age 72 years" for SPG7) (PMC8793673). Mean HSP onset across pooled cohorts ≈ 24 years (PMC8944001). SPG5A median onset ~13 years (range 1–63) (Elsevier).

Onset pattern: Insidious/chronic-progressive in essentially all forms; not acute or episodic.

Progression: - Generally slow but genotype-dependent; overall SPRS progression ~0.9 points/year pooled, but 1.3 points/year in complicated HSP vs. 0.6 points/year in pure HSP (Springer 2025). - SPG11 carries higher severity and a more rapid course, with "limited lifespan of 3 to 4 decades after disease-onset" reported in some cohorts and rapid deterioration described in Dutch SPG11 cohorts (PMC3798836). - Loss of independent ambulation: variable — from within 1–2 decades of onset to intact ambulation after 24 years in milder genotypes; later age at onset is paradoxically associated with faster loss of independent walking in some analyses. - SPG3A tends to progress more slowly than SPG4. - AP-4-HSP: children who achieve independent walking typically lose this ability months to a few years later as hypotonia converts to hypertonia/spasticity (Boston Children's Hospital).

Disease course pattern: Chronic, progressive, non-remitting (not relapsing-remitting or episodic). No spontaneous-remission pattern is described.

Critical periods: For the AP-4 disorders and other infantile-onset complex forms, early diagnosis is critical because gene-therapy intervention windows are being defined pre-symptomatically or in very early disease (see Section 12) — the SPG50 trial specifically dosed a pre-symptomatic 5-month-old alongside symptomatic children to test whether earlier intervention alters outcome (CGTlive).

9. Inheritance and Population

Epidemiology: - Pooled global HSP prevalence estimates: 2–7.4/100,000 across most populations, with a range of 0.1–9.6/100,000 reported worldwide and modeling estimates converging around 3.6/100,000 overall (PMC8944001). - Genotype-specific global prevalence estimates: SPG4 ≈ 0.90/100,000; SPG7 ≈ 0.22/100,000; SPG11 ≈ 0.34/100,000; SPG15 ≈ 0.13/100,000 (BMC Neurology, Springer). - Norway (population >2.5M): prevalence 7.4/100,000 (2009 study) — among the highest reported. - Spain: ~2.24/100,000 (lower). - Higher prevalence reported in Mediterranean/Middle Eastern populations with high consanguinity. - Incidence in England/Northern Ireland rose from 0.12/100,000 person-years (2000) to 0.29/100,000 person-years (2021) (PMC12210554) — likely reflecting improved genetic diagnosis rather than true incidence increase.

Inheritance pattern: All classical Mendelian modes reported — AD (SPG3A, SPG4, SPG31, SPG12), AR (SPG5A, SPG7, SPG11, SPG15, SPG20, SPG35, AP-4 disorders SPG47/50/51/52), X-linked (e.g., SPG1/L1CAM, SPG2/PLP1), and rare mitochondrial-associated presentations.

Penetrance/expressivity: AD forms (SPAST, ATL1) show high but sometimes age-dependent penetrance and marked intra-familial variable expressivity (age of onset and severity can differ substantially between relatives carrying the same variant). AR complex forms are generally fully penetrant when biallelic loss-of-function variants are present, given the severe cellular consequences (e.g., near-complete loss of AP-4 complex function).

Genetic anticipation: Not a characteristic feature of HSP (unlike repeat-expansion disorders); HSP genes are not repeat-expansion loci in the mainstream classification.

Consanguinity: A major risk-enrichment factor for AR complex HSP; complex AR forms are relatively more frequent in populations/regions with high consanguinity rates.

Founder effects: Population-specific founder alleles have been described for several SPG genes in isolated/consanguineous populations (implicit in the geographic prevalence variation, though the sources reviewed did not enumerate specific founder variants in detail).

Population demographics: No described sex-ratio skew; age at onset varies as above by genotype; geographic distribution shows Mediterranean/Middle Eastern enrichment for consanguinity-associated AR complex subtypes and higher Norwegian/Northern European prevalence for AD pure forms.

10. Diagnostics

Clinical exam/tests: - Neurological exam: lower-limb spasticity, hyperreflexia, Babinski sign, clonus, pes cavus. - MRI brain/spine: thin corpus callosum (SPG11/15 — a key distinguishing neuroimaging clue), white-matter/leukodystrophic changes (SPG35), cerebellar atrophy (SPG7), "ears of the lynx" sign (classically associated with SPG11/15 thin corpus callosum + periventricular white matter changes). - Ophthalmologic exam: optic disc pallor/atrophy (SPG7), retinal pigmentary changes (SPG11/15), cataract exam. - Nerve conduction studies/EMG: to detect peripheral neuropathy component in complex forms (SPG7, AP-4 disorders). - Urodynamic studies for neurogenic bladder assessment. - Biochemical: elevated serum/CSF 25- and 27-hydroxycholesterol as a diagnostic/monitoring biomarker specific to SPG5A/CYP7B1 (ScienceDirect).

Genetic testing: - Recommended approach: Given >90 implicated genes, next-generation sequencing gene panels are the recommended cost-effective first-line test; a representative panel (SpastiSure3.0) covers 118 HSP-associated genes. - Diagnostic yield: Overall genetic diagnosis achieved in ~29–31% of clinically suspected pediatric HSP cohorts using panel testing; yield rises with age-stratified analysis (up to 37% in ages 0–5 when panel is followed by exome) (Human Genomics, Springer). Diagnostic rate is markedly inheritance-pattern-dependent: 56.7% in AD HSP, 55.5% in AR HSP, but only 21.2% in sporadic HSP cases, and overall diagnostic gap of ~25% remains even in the best-studied cohorts. - Whole exome sequencing (WES): Recommended when panel testing is negative, particularly for complicated/complex phenotypes; "exome sequencing is a useful diagnostic tool for complicated forms of hereditary spastic paraplegia" (PubMed 23438842); WES clearly benefits children with suspected HSP when panels are non-diagnostic (PMC13040777). - Chromosomal microarray/karyotype: not first-line, as HSP is overwhelmingly a single-gene/small-variant disease rather than a copy-number/structural disorder, though CNV analysis is sometimes included in comprehensive panels.

Clinical diagnostic criteria: No single formal DSM/ICD-based criteria set beyond the clinical pure-vs-complex classification described above; diagnosis rests on clinical phenotype plus molecular confirmation, given marked genetic heterogeneity and phenocopy overlap with other upper-motor-neuron disorders (differential diagnosis includes primary lateral sclerosis, multiple sclerosis, dopa-responsive dystonia, cerebral palsy [static, non-progressive — a key distinguishing feature], vitamin B12/E deficiency, and adrenomyeloneuropathy).

Screening: No population-based newborn or carrier screening program specific to HSP; genetic counseling and cascade testing are recommended in families with a known pathogenic variant, particularly for AR complex forms in consanguineous families.

11. Outcome/Prognosis

Survival/mortality: HSP itself is not typically directly life-limiting in pure/adult-onset forms; however, severe complex forms (notably SPG11) are associated with reduced functional lifespan — "limited lifespan of 3 to 4 decades after disease-onset" in some SPG11 cohorts — reflecting cumulative disability and complications rather than the spasticity itself being acutely fatal ([derived from natural history literature above]).

Morbidity/function: - Progressive loss of independent ambulation is the dominant functional endpoint; timing is highly genotype-dependent (see Section 8). - SPRS (Spastic Paraplegia Rating Scale) is the standard longitudinal functional/severity outcome measure, with annual progression rates of ~0.6 (pure) to ~1.3 (complicated) points/year. - Complex-form comorbidities (cognitive decline, ataxia, visual impairment from retinopathy/optic atrophy, neurogenic bladder, orthopedic deformity) compound disability beyond the pure motor phenotype. - Increased burden of common mental health outcomes (anxiety, depression) documented in a large England/Northern Ireland epidemiologic cohort of HSP patients (PMC12210554).

Complications: Contractures, scoliosis/orthopedic deformity, neurogenic bladder/urinary tract complications, falls/fractures from gait instability, and (in complex forms) seizures, visual impairment, and cognitive decline.

Recovery potential: No spontaneous recovery; disease-modifying interventions are only now emerging (gene therapy — Section 12) and remain investigational/single-patient/early-phase.

Prognostic factors: Genotype is the dominant prognostic factor (SPG11 = more severe/faster; SPG3A = slower than SPG4); age at onset; presence of complex-form features generally predicts faster SPRS progression than pure HSP.

12. Treatment

Current standard of care: There is no disease-modifying therapy approved for the great majority of HSP subtypes; management is symptomatic and multidisciplinary ("symptomatic management should be multidisciplinary to achieve better control of motor symptoms... and prevent skeletal deformities") (Merck Manual; PMC10858081).

Pharmacotherapy (symptomatic): - Antispastic agents: baclofen (first-line), tizanidine, diazepam, clonazepam, dantrolene — MAXO/NCIT: NCIT:C15986 Pharmacotherapy, with therapeutic_agent CHEBI baclofen (CHEBI:2942), tizanidine. - Botulinum toxin type A/B (BTX-A/BTX-B) — intramuscular injection for focal spasticity; reduces spasticity and fatigue without affecting depression/excessive daytime sleepiness; combined BTX + intensive physiotherapy shows added benefit (PMC7046620; recent comprehensive 2025 review, PMC12567745). MAXO/NCIT: could map to NCIT:C1198 (Botulinum Toxin) as therapeutic_agent under Pharmacotherapy. - Oxybutynin for urinary urgency/neurogenic bladder. - Historical clinical-trial pharmacologic agents (mostly negative or inconclusive for disease modification): atorvastatin, gabapentin, L-threonine, dalfampridine (4-aminopyridine), methylphenidate (PMC9321931). - SPG5A/CYP7B1-specific: atorvastatin + chenodeoxycholic acid (± resveratrol) trialed to normalize elevated 25-/27-hydroxycholesterol and restore bile-acid profile; a randomized controlled trial (Schöls et al., Brain 2017, PMID 29126212) found atorvastatin reduced serum 27-OHC/25-OHC (though CSF 27-OHC reduction was not significant) (PubMed 29126212).

Advanced/gene-targeted therapeutics (investigational, complex-HSP-specific): - SPG50 (AP4M1) gene therapy: Intrathecal AAV9/AP4M1 gene replacement. A single-patient phase 1 trial (NCT06069687) dosed a 4-year-old boy intrathecally with 1×10¹⁵ vg AAV9-AP4M1 in March 2022 — among the largest AAV9 CSF doses ever given — with 12-month follow-up showing apparent disease-course stabilization and no serious adverse events (Nature Medicine 2024, PMC11271397). Elpida Therapeutics' "Melpida" program (NCT05518188, Phase I/II) has since dosed additional participants (ages 3–5 years at 1×10�1⁵ vg; a pre-symptomatic 5-month-old at 4×10¹⁴ vg), with FDA clearance to proceed to a Phase III trial (8 children, initiated August 2024) (Clinical Trials Arena; CGTlive). Preclinical AAV9/AP4M1 work established safety/efficacy in mouse models first (PMC10178841). - SPG47 (AP4B1) gene therapy: Preclinical AAV9-hAP4B1 delivered into the cisterna magna in a mouse model, with "restoration of various hallmarks of disease" (PMC11554807); patient-advocacy-driven programs coordinated via Cure AP-4/Cure SPG47 foundations. - SPG5 (CYP7B1) gene therapy: AAV8-based gene-replacement therapy in preclinical development (PMC12309954); an mRNA-based therapeutic strategy for SPG5 has also been proposed (Molecular Therapy Methods & Clinical Development, Cell.com). - Modality classification: therapeutic_modality: GENE_THERAPY for the AAV programs above (AAV9/AAV8 capsid, intrathecal or intra-cisterna-magna delivery, gene-replacement mechanism — not gene editing).

Surgical/interventional: Orthopedic surgery for severe contractures/scoliosis; intrathecal baclofen pump for refractory severe spasticity; selective dorsal rhizotomy considered in select cases (extrapolated from general spasticity-management literature, not HSP-specific data in the sources reviewed).

Supportive/rehabilitative: - Physical therapy/exercise: maintains mobility, muscle strength, range of motion, reduces fatigue and spasms (MAXO:0000011 physical therapy) — non-pharmacological systematic review (2023) supports benefit (PMC10858081; Springer). - Occupational therapy, orthotics (ankle-foot orthoses for foot drop/pes cavus), gait aids/wheelchairs as disease progresses. - Emerging modality: radial extracorporeal shock wave therapy reported efficacious in an HSP case report (PMC12338253).

Experimental (clinical trials): Natural history/biomarker studies (NCT02859428 for SPG3A/SPG4/SPG31; SPG5 natural history/RCT [PubMed 29126212]); NCT04712812 registry/natural history study for early-onset HSP; the SPG50 gene-therapy trials above.

Treatment strategy: No formal disease-specific treatment algorithm exists analogous to oncology guidelines; management is individualized/multidisciplinary (neurology, physiatry/rehabilitation, urology, orthopedics, ophthalmology for complex forms, genetics/genetic counseling). Personalized/genotype-guided approaches are emerging specifically for SPG5A (biochemical-pathway-targeted therapy) and the AP-4 disorders/SPG50 (gene replacement).

13. Prevention

Primary prevention: Not applicable in the traditional sense (no modifiable risk-factor exposure to eliminate); the only "primary prevention" avenue is reproductive risk reduction via genetic counseling, carrier screening, and preimplantation genetic diagnosis (PGD) in families with a known pathogenic variant, particularly relevant for AR complex forms in consanguineous unions.

Secondary prevention: Early molecular diagnosis (panel/WES) to enable early initiation of symptomatic/supportive management and, increasingly, eligibility screening for investigational gene therapy (the SPG50 program explicitly enrolled a pre-symptomatic infant to test whether earlier intervention alters the trajectory).

Tertiary prevention: Prevention of secondary complications — regular physical therapy/stretching to prevent contractures, orthopedic surveillance for scoliosis, urological surveillance for bladder complications, ophthalmologic monitoring in complex forms with retinal/optic involvement.

Genetic counseling: Central to management in families with identified variants — risk assessment for future pregnancies, cascade testing of at-risk relatives, and discussion of reproductive options (PGD, prenatal testing) given the autosomal recessive predominance of complex HSP and the consanguinity risk factor.

Public health/behavioral/immunization/prophylaxis: Not applicable — no described environmental, infectious, or vaccine-preventable component to this disease group.

14. Other Species / Natural Disease

The literature reviewed focused on induced/engineered models (Section 15) rather than naturally occurring veterinary HSP. No spontaneous naturally-occurring canine/feline/equine HSP orthologous disease was identified in the sources searched (unlike some other neurogenetic disorders with well-documented veterinary natural disease counterparts). This section is likely not well populated for this disease from available searches; a targeted OMIA search would be needed to confirm whether any spontaneous animal spastic paraplegia orthologs are catalogued (not performed here due to no hits surfacing in general search).

Orthologous genes (NCBI Gene, for model-organism cross-reference): Spast (mouse Gene ID: 232265), Atl1 (mouse), Spg7 (mouse Gene ID: 105875), Ap4b1 (mouse), Ap4m1 (mouse), Spg20/Spart (mouse) — all with characterized knockout mouse models (below).

15. Model Organisms

Mouse models (most extensively characterized): - Spg7−/− (paraplegin-null) mouse: Progressive motor impairment from ~4.5 months of age; retrograde axonal degeneration of long descending (corticospinal) and ascending (dorsal column) spinal tracts plus peripheral and optic nerves; early appearance of ultrastructurally abnormal mitochondria in affected axons, worsening with age. Explicitly stated to "successfully recapitulate the key phenotypic and pathological features observed in SPG7 patients" (PMC5628248 synthesis; PMC7469654). - Ap4b1-knockout mouse (SPG47 model): Motor dysfunction, aberrant brain morphology, and ATG9A mislocalization, providing mechanistic and preclinical-therapeutic validation for the AAV9-hAP4B1 gene-therapy program (PMC9825813). - Spg20−/− mouse (Troyer syndrome model): Reveals multimodal spartin functions in lipid-droplet maintenance, cytokinesis, and BMP signaling — expanding the mechanistic understanding of spartin beyond a single pathway (PMC3406757). - SPG50 preclinical AAV9/AP4M1 efficacy studies were conducted in a corresponding Ap4m1 mouse model prior to human dosing (PMC10178841).

Zebrafish models: - Spastizin (SPG15/ZFYVE26) zebrafish model: Shows axon demyelination and degeneration, extending the disease-relevant phenotype into a myelin-dysfunction axis not previously emphasized in mammalian models — a 2024 bioRxiv/PMC study (PMC11539067).

Cellular/iPSC and patient-derived models: - Patient-derived fibroblasts (SPG11, SPG15) show autophagosome accumulation and enlarged lysosomes, directly demonstrating defective autophagosome-lysosome fusion in a human cellular context (PMC4078876). - iPSC-derived neuronal models comparing SPG7 vs. SPAST patient-derived stem cells show that mitochondrial functional deficits are specific to SPG7, not SPAST, patient cells — an important cross-genotype mechanistic distinction (title: "Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells") (PMC7469654). - Patient-derived fibroblasts were also used directly for translational validation of AAV2/AP4M1 gene-therapy vectors prior to the human SPG50 trial (phenotypic rescue demonstrated in vitro).

Model limitations: Mouse Spg7 and Ap4b1 knockouts recapitulate core motor/axonal-degeneration phenotypes reasonably well, but full complex-HSP multisystem features (e.g., human-specific cognitive/retinal phenotypes in SPG11/15) are less completely captured in rodent models — this is consistent with the general caveat that mouse CNS models often under-represent human-specific cortical/cognitive phenotypes. Zebrafish models add a demyelination phenotype not otherwise emphasized in mouse data, suggesting species-dependent phenotypic emphasis.

Applications: These models have been directly used for (a) mechanistic dissection of the axonal-transport/ER/mitochondrial/lysosomal/autophagy pathways described in Section 6, and (b) as the essential preclinical efficacy/safety platform for the AAV gene-therapy programs now in human trials for SPG47 and SPG50.

Summary Table: Suggested Ontology Terms for KB Curation

Category	Suggested terms
MONDO (subtype-level; no single "complex HSP" term)	MONDO:0008438 (AD group), MONDO:0010046 (SPG23), MONDO:0013342 (SPG48) — plus individual per-subtype MONDO IDs
HP (phenotypes)	HP:0002061 (spastic paraplegia), HP:0001347 (hyperreflexia), HP:0003487 (Babinski sign), HP:0002839 (bladder dysfunction), HP:0001761 (pes cavus), HP:0033725 (thin corpus callosum), HP:0001249 (intellectual disability), HP:0001251 (ataxia), HP:0000648 (optic atrophy), HP:0000580 (pigmentary retinopathy), HP:0000518 (cataract), HP:0002548 (parkinsonism), HP:0003693 (distal amyotrophy), HP:0004322 (short stature), HP:0001250 (seizure), HP:0002171 (leukoencephalopathy)
GO (biological process)	GO:0071786 (ER tubular network organization), GO:0006914 (autophagy), GO:1902774 (late endosome to lysosome transport), GO:0007005 (mitochondrion organization), GO:0008203 (cholesterol metabolic process), GO:0030149 (sphingolipid catabolic process), GO:0007018 (microtubule-based movement)
CL (cell types)	CL:0011005 (corticospinal neuron), CL:0000127 (astrocyte), CL:0000128 (oligodendrocyte)
GENO/HGNC (genes)	SPAST hgnc:11233, ATL1 hgnc:30288, REEP1 hgnc:13703, SPG11 hgnc:11226, ZFYVE26 hgnc:29128, SPG7 hgnc:11237, CYP7B1 hgnc:2652, FA2H hgnc:20139, SPART hgnc:11227, AP4B1 hgnc:567, AP4M1 hgnc:569, AP4E1 hgnc:568, AP4S1 hgnc:571
MAXO/NCIT (treatment)	MAXO:0000011 (physical therapy), NCIT:C15986 (Pharmacotherapy) + therapeutic_agent (baclofen, tizanidine, botulinum toxin, atorvastatin, chenodeoxycholic acid)
Therapeutic modality	GENE_THERAPY (AAV9/AAV8 replacement — SPG47, SPG50, SPG5)

Sources

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1. Disease Information

Edison Scientific Literature 68 citations 2026-07-01T20:52:05.577835

1. Disease Information

Overview

Complex hereditary spastic paraplegia (complex HSP, also termed "complicated HSP") is a heterogeneous group of rare, inherited neurodegenerative disorders characterized by progressive lower-limb spasticity due to corticospinal tract degeneration, combined with additional neurological and non-neurological manifestations that distinguish it from "pure" or "uncomplicated" HSP (meyyazhagan2022thepuzzleof pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 1-2). These additional features may include intellectual disability, seizures, dementia, cerebellar ataxia, peripheral neuropathy, optic atrophy, dysarthria, extrapyramidal disturbances, and skeletal deformities (meyyazhagan2022hereditaryspasticparaplegia pages 1-2). Complex HSP represents approximately 55% of HSP cases in some cohorts, highlighting its significant contribution to the overall HSP spectrum (amprosi2026naturalhistoryin pages 1-2).

Key Identifiers

MONDO ID: MONDO:0015150 (complex hereditary spastic paraplegia) (OpenTargets Search: hereditary spastic paraplegia)
MONDO ID (parent): MONDO:0019064 (hereditary spastic paraplegia)
Orphanet: ORPHA:100987 (complex hereditary spastic paraplegia)
ICD-10: G11.4 (Hereditary spastic paraplegia)
ICD-11: 8A60.1
MeSH: D015419 (Spastic Paraplegia, Hereditary)

Synonyms

Common synonyms include: complicated hereditary spastic paraplegia, complex HSP, complicated spastic paraplegia, HSP-plus, and complicated familial spastic paraplegia (meyyazhagan2022thepuzzleof pages 1-2, yu2023clinicalfeaturesand pages 1-2).

2. Etiology

Disease Causal Factors

Complex HSP is caused primarily by monogenic mutations in genes affecting neuronal function, with over 90 genetic loci (designated SPG1–SPG83+) identified to date (meyyazhagan2022hereditaryspasticparaplegia pages 2-4, cipriano2025fluidbiomarkersin pages 1-2). The disorder is exclusively genetic in origin, with mutations in approximately 80 genes affecting diverse biochemical pathways including lipid droplet formation, endoplasmic reticulum (ER) shaping, axonal transport, endosome trafficking, and mitochondrial function (meyyazhagan2022thepuzzleof pages 1-2).

Genetic Risk Factors

Complex forms of HSP are most commonly autosomal recessive (AR), in contrast to pure HSP which is more often autosomal dominant (AD) (fereshtehnejad2023movementdisordersin pages 4-5). In a systematic review and meta-analysis of 1,413 HSP cases with movement disorders, AR inheritance was present in 58.4% and AD in 31.4% (fereshtehnejad2023movementdisordersin pages 4-5). Consanguinity is a major risk factor, particularly for AR forms such as SPG11, where consanguinity odds ratio was 4.1 compared to SPG7 (fereshtehnejad2023movementdisordersin pages 5-6). In the MENA region, SPG11 (19.8%), FA2H (8.5%), and ZFYVE26 (7.7%) were the most frequently identified genes, with AR HSP with thin corpus callosum being common (meyyazhagan2022thepuzzleof pages 1-2).

Environmental and Gene-Environment Interactions

Complex HSP is fundamentally a genetic disorder, and no specific environmental risk factors have been established as causal. However, environmental modifiers and gene-environment interactions remain poorly characterized. Lifestyle factors such as physical activity level may influence symptom severity and functional decline, but specific data are lacking.

3. Phenotypes

The following table summarizes the major phenotypic features of complex HSP with associated frequencies and HPO terms:

Phenotype/Feature	Frequency (%)	HPO Term	Severity	Notes
Lower limb spasticity	~98%	HP:0001257 Spasticity; HP:0002061 Lower limb spasticity	Core; often progressive	Hallmark feature of complex HSP; in SPG15, lower-limb spasticity/pyramidal signs were nearly universal and typically progressed from distal to proximal involvement (saffari2023theclinicaland pages 3-5, saffari2023theclinicaland pages 1-2)
Cognitive impairment / decline	~89%; progressive decline ~69%	HP:0100543 Cognitive impairment; HP:0001268 Mental deterioration	Moderate-severe; progressive in many	Common in SPG15 and other complex forms; may include learning disability and later decline (saffari2023theclinicaland pages 3-5, saffari2023theclinicaland pages 1-2)
Thin corpus callosum	~100% in SPG15 cohort; classic for SPG11/SPG15	HP:0002079 Thin corpus callosum	Imaging marker; often prominent	Highly characteristic neuroimaging feature of SPG15 and a major clue in SPG11/SPG15 diagnosis (saffari2023theclinicaland pages 3-5, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 4-6, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 2-4)
Cerebellar ataxia	~64%	HP:0001251 Ataxia	Moderate-severe	Common extrapyramidal/cerebellar manifestation in SPG15 and many complex genotypes (saffari2023theclinicaland pages 1-2, fereshtehnejad2023movementdisordersin pages 5-6)
Dysarthria	~68%	HP:0001260 Dysarthria	Mild-moderate; progressive	Often accompanies cerebellar dysfunction and contributes to disability (saffari2023theclinicaland pages 3-5, saffari2023theclinicaland pages 6-8)
Developmental delay	~68%	HP:0001263 Global developmental delay	Variable; often early-onset	Often precedes overt motor syndrome by years in early-onset complex HSP such as SPG15 and AP-4 deficiency disorders (saffari2023theclinicaland pages 3-5, saffari2023theclinicaland pages 1-2)
Peripheral neuropathy / polyneuropathy	~38%	HP:0009830 Peripheral neuropathy	Variable	More frequent in some genotypes such as SPG11; nerve conduction studies may show sensorimotor polyneuropathy (saffari2023theclinicaland pages 3-5, fereshtehnejad2023movementdisordersin pages 5-6, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 2-4)
Epilepsy / seizures	~18% in pediatric complex HSP cohort; variable by genotype	HP:0001250 Seizure	Variable; can be severe	Seen in pediatric complex HSP and AP-4 deficiency/SPG50; not universal across all complex HSPs (ikeda2023geneticandclinical pages 3-4, awuah2024hereditaryspasticparaplegia pages 8-10)
Dystonia	~11%	HP:0001332 Dystonia	Variable	Recognized movement-disorder component of complex HSP, especially selected genotypes (saffari2023theclinicaland pages 1-2, fereshtehnejad2023movementdisordersin pages 5-6)
Parkinsonism	~16%	HP:0001300 Parkinsonism	Variable; usually minority feature	Reported in a subset of SPG15 and particularly enriched in some SPG11-related phenotypes (saffari2023theclinicaland pages 1-2, fereshtehnejad2023movementdisordersin pages 5-6)
Urinary dysfunction / neurogenic bladder	~54%	HP:0000009 Functional urinary incontinence; HP:0000013 Hypoplasia of the bladder not appropriate; prefer HP:0000508 Neurogenic bladder	Moderate; progressive in many	Includes urgency/incontinence; common non-motor burden in complex HSP (saffari2023theclinicaland pages 3-5, saffari2023theclinicaland pages 1-2)
Upper limb spasticity	~64%	HP:0001258 Spasticity of upper limbs	Moderate	Reflects spread beyond lower-limb-predominant syndrome in more advanced/complex disease (saffari2023theclinicaland pages 1-2, saffari2023theclinicaland pages 3-5)
Intellectual disability	~76% in pediatric-onset complex HSP	HP:0001249 Intellectual disability	Moderate-severe	Particularly common in pediatric complex HSP cohorts and AP-4 deficiency disorders (ikeda2023geneticandclinical pages 3-4, dowling2024aavgenetherapy pages 1-2)
Scoliosis	~21%	HP:0002650 Scoliosis	Mild-moderate	Orthopedic complication seen in complex HSP cohorts such as SPG15 (saffari2023theclinicaland pages 3-5)
Foot deformity	~28%	HP:0001760 Pes planus / HP:0001761 Pes cavus / HP:0001824 Foot deformity	Mild-moderate	Deformities vary; relevant to gait impairment and rehabilitation planning (saffari2023theclinicaland pages 3-5)
Visual abnormalities / optic pathway involvement	Variable	HP:0000505 Visual impairment; HP:0000648 Optic atrophy	Variable	Optic atrophy/retinal abnormalities occur in some complex HSP forms; visual findings are genotype-dependent rather than universal (meyyazhagan2022hereditaryspasticparaplegia pages 1-2, fereshtehnejad2023movementdisordersin pages 5-6)

Table: This table summarizes major clinical and imaging features reported in complex hereditary spastic paraplegia, emphasizing frequencies from recent cohorts—especially SPG15 and pediatric-onset complex HSP. It is useful for phenotype-driven diagnosis, ontology mapping, and genotype-phenotype curation.

Detailed Phenotypic Characteristics

Age of Onset: Complex HSP typically presents earlier than pure HSP. In a pediatric-onset Japanese cohort, the median age of onset for complex-type was 16 months (IQR 12–26 months) (ikeda2023geneticandclinical pages 3-4). For SPG15, symptom onset occurred at a median of 24 months with developmental symptoms preceding motor manifestations by several years (saffari2023theclinicaland pages 1-2, saffari2023theclinicaland pages 3-5). In adult-onset movement disorder cases, mean age of onset was 20.5 ± 16.0 years (fereshtehnejad2023movementdisordersin pages 4-5).

Symptom Progression: The disease is progressive, with spasticity initially affecting distal lower limbs before progressing proximally (saffari2023theclinicaland pages 1-2). In SPG15, loss of independent ambulation occurred at a mean age of 17 years, with wheelchair dependency developing by mean age 20 years (saffari2023theclinicaland pages 8-9). An Austrian natural history study demonstrated complicated HSP progresses faster than pure HSP (1.3 vs. 0.6 SPRS points/year; p < 0.001) (amprosi2026naturalhistoryin pages 1-2, amprosi2026naturalhistoryin pages 13-14).

Quality of Life Impact: Complex HSP significantly impairs quality of life, with modified Rankin Scale scores significantly higher in complex-type (3.5 ± 1.0) compared to pure-type HSP (2.1 ± 0.9; p < 0.001) (ikeda2023geneticandclinical pages 3-4). The progressive nature leads to walking cane or wheelchair dependence over time. In the Austrian cohort, 17.5% of patients were wheelchair-bound, while over 50% did not require assistive devices (amprosi2026naturalhistoryin pages 11-13). Although HSP does not typically reduce lifespan, it significantly impairs quality of life, particularly with more severe symptoms (awuah2024hereditaryspasticparaplegia pages 1-2). However, some complex forms such as SPG11 are associated with restricted life expectancy (chojdakłukasiewicz2023hereditaryspasticparaplegia pages 4-6).

4. Genetic/Molecular Information

Causal Genes

The following table provides a comprehensive overview of the major genes associated with complex HSP:

SPG designation / subtype	Gene	Protein	Typical inheritance	Key complex HSP clinical features	OMIM / phenotype note
SPG11	SPG11	Spatacsin	AR	Early-onset progressive spastic paraplegia, thin corpus callosum, cognitive decline/intellectual disability, peripheral neuropathy, dysarthria, bladder dysfunction, ataxia/parkinsonism in some patients (vijayaraghavan2025roleofglial pages 2-3, meyyazhagan2022hereditaryspasticparaplegia pages 12-14, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 7-8, saffari2023theclinicaland pages 3-5)	Phenotype OMIM not established here from retrieved evidence; gene-disease association strongly supported (OpenTargets Search: hereditary spastic paraplegia, vijayaraghavan2025roleofglial pages 2-3)
SPG15	ZFYVE26	Spastizin	AR	Early-childhood developmental delay, adolescent-onset progressive lower-limb spasticity, thin corpus callosum, “ears of the lynx” MRI sign, ataxia, dysarthria, cognitive decline, urinary dysfunction, peripheral neuropathy, dystonia/parkinsonism subset (saffari2023theclinicaland pages 1-2, saffari2023theclinicaland pages 6-8, saffari2023theclinicaland pages 3-5)	Phenotype OMIM not established here from retrieved evidence; gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG7	SPG7	Paraplegin	AR (occasionally AD/digenic reported in broader literature, not established here)	Adult-onset or variable-onset spastic paraplegia, frequent cerebellar ataxia, optic/extraocular movement abnormalities, seizures or movement disorder features in some patients (meyyazhagan2022thepuzzleof pages 1-2, fereshtehnejad2023movementdisordersin pages 5-6)	Gene-disease association supported in Open Targets (OpenTargets Search: hereditary spastic paraplegia)
SPG20	SPART	Spartin	AR	Complex HSP/Troyer syndrome phenotype with spastic paraplegia plus distal amyotrophy, dysarthria, developmental/cognitive involvement; lipid droplet turnover implicated (vijayaraghavan2025roleofglial pages 2-3)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG21	SPG21	Maspardin	AR	Complex spastic paraplegia with cognitive impairment, extrapyramidal features, thin corpus callosum reported in broader HSP spectrum; intracellular trafficking defect (vijayaraghavan2025roleofglial pages 2-3, meyyazhagan2022hereditaryspasticparaplegia pages 12-14)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG35	FA2H	Fatty acid 2-hydroxylase	AR	Complex HSP with spasticity, leukodystrophy/myelin involvement, dystonia/ataxia and cognitive features in some cases; myelin lipid synthesis defect (vijayaraghavan2025roleofglial pages 2-3, meyyazhagan2022hereditaryspasticparaplegia pages 12-14)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG39	PNPLA6	Neuropathy target esterase / patatin-like phospholipase domain-containing protein 6	AR	Complex HSP with spastic paraplegia plus ataxia, neuropathy, retinal/visual and endocrine/cognitive features across PNPLA6 spectrum; lipid regulation defect (vijayaraghavan2025roleofglial pages 2-3, fereshtehnejad2023movementdisordersin pages 5-6)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG47	AP4B1	Adaptor related protein complex 4 subunit beta 1	AR	Childhood-onset AP-4 deficiency syndrome with spastic paraplegia, global developmental delay, intellectual disability, epilepsy; preclinical gene replacement therapy in development (awuah2024hereditaryspasticparaplegia pages 8-10, wiseman2024preclinicaldevelopmentof pages 13-15)	Phenotype OMIM not established here from retrieved evidence
SPG50	AP4M1	Adaptor related protein complex 4 subunit mu 1	AR	Childhood-onset complex HSP with progressive spastic paraplegia, developmental delay, intellectual disability, secondary microcephaly, epilepsy; target of first individualized AAV therapy (dowling2024aavgenetherapy pages 1-2, chen2023intrathecalaav9ap4m1gene pages 1-2)	Phenotype OMIM not established here from retrieved evidence
SPG51	AP4E1	Adaptor related protein complex 4 subunit epsilon 1	AR	AP-4 deficiency syndrome with severe developmental delay, intellectual disability, early hypotonia evolving to spastic paraplegia, epilepsy (awuah2024hereditaryspasticparaplegia pages 8-10, wiseman2024preclinicaldevelopmentof pages 13-15)	Phenotype OMIM not established here from retrieved evidence
SPG52	AP4S1	Adaptor related protein complex 4 subunit sigma 1	AR	AP-4 deficiency syndrome with developmental delay, severe intellectual disability, childhood-onset complex spastic paraplegia, epilepsy (awuah2024hereditaryspasticparaplegia pages 8-10, wiseman2024preclinicaldevelopmentof pages 13-15)	Phenotype OMIM not established here from retrieved evidence
SPG1	L1CAM	L1 cell adhesion molecule	X-linked	Complex spastic paraplegia with intellectual disability, hydrocephalus/corpus callosum abnormalities and other L1 syndrome manifestations; axon guidance/myelination effects (meyyazhagan2022hereditaryspasticparaplegia pages 12-14, awuah2024hereditaryspasticparaplegia pages 8-10)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG2	PLP1	Proteolipid protein 1	X-linked	Spastic paraplegia with dysmyelination spectrum, variable cognitive/visual features; abnormal myelin maintenance central to disease (vijayaraghavan2025roleofglial pages 2-3, awuah2024hereditaryspasticparaplegia pages 8-10)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG30 / KIF1A-associated HSP	KIF1A	Kinesin family member 1A	AD or AR depending on variant/context	Pediatric complex HSP with spastic paraplegia, developmental delay/intellectual disability, cerebellar signs, optic atrophy/neuropathy in some patients; common pediatric complex HSP gene (OpenTargets Search: hereditary spastic paraplegia, ikeda2023geneticandclinical pages 3-4)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG18	ERLIN2	ER lipid raft associated 2	AR	Early-onset complicated HSP with spasticity, intellectual disability, joint contractures or seizures reported in spectrum; ER-associated pathway defect (OpenTargets Search: hereditary spastic paraplegia)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG26	B4GALNT1	Beta-1,4-N-acetyl-galactosaminyltransferase 1	AR	Complex HSP with spasticity, cognitive impairment, cerebellar signs/neuropathy in reported spectrum; ganglioside biosynthesis defect (OpenTargets Search: hereditary spastic paraplegia)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG5A	CYP7B1	Cytochrome P450 7B1	AR	Often pure HSP, but complicated cases can include ataxia/neuropathy; notable because disease-specific biochemical biomarkers (oxysterols) exist (meyyazhagan2022hereditaryspasticparaplegia pages 12-14, meyyazhagan2022thepuzzleof pages 11-12, cipriano2025fluidbiomarkersin pages 1-2)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG42	SLC33A1	Acetyl-CoA transporter 1	AD	Spastic paraplegia with variable complex manifestations; listed among established HSP genes (meyyazhagan2022hereditaryspasticparaplegia pages 4-6, meyyazhagan2022hereditaryspasticparaplegia pages 20-21)	Open Targets association noted for SPG4 locus-related data; phenotype details limited here (OpenTargets Search: hereditary spastic paraplegia)
SPG31	REEP1	Receptor expression-enhancing protein 1	AD	Usually pure HSP, but complicated phenotypes with neuropathy can occur; ER shaping defect shared with major HSP mechanisms (meyyazhagan2022thepuzzleof pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 4-6, meyyazhagan2022hereditaryspasticparaplegia pages 14-16)	Established HSP gene; phenotype details from retrieved evidence are limited
SPG3A	ATL1	Atlastin-1	AD	Usually early-onset pure HSP, but part of core mechanistic ER-network genes and occasional complex presentations reported (meyyazhagan2022thepuzzleof pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 12-14, meyyazhagan2022hereditaryspasticparaplegia pages 14-16)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
SPG4	SPAST	Spastin	AD	Most common AD HSP; generally pure but complex phenotypes exist, especially pediatric or severe cases; microtubule-severing/axonal transport defect (meyyazhagan2022thepuzzleof pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 12-14, meyyazhagan2022thepuzzleof pages 12-14)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
Novel AR HSP (no SPG number specified here)	AMFR	Autocrine motility factor receptor / gp78	AR	Pure or complex HSP with developmental delay, mild intellectual disability, progressive spasticity; lipid droplet accumulation and ER morphology defects in preclinical models (garg2024divingdeepzebrafish pages 5-6)	Newly described AR-HSP gene in retrieved evidence; OMIM phenotype not established here
Complex HSP spectrum	ALDH18A1	Delta-1-pyrroline-5-carboxylate synthase	AD or AR	Spastic paraplegia with variable developmental/cognitive and neuropathy features across inheritance contexts (OpenTargets Search: hereditary spastic paraplegia)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)
Complex HSP spectrum	ATP13A2	Lysosomal P5-type ATPase	AR	Complex HSP with parkinsonism/cognitive features and lysosomal-autophagic dysfunction in some patients (OpenTargets Search: hereditary spastic paraplegia, awuah2024hereditaryspasticparaplegia pages 8-10)	Gene-disease association supported (OpenTargets Search: hereditary spastic paraplegia)

Table: This table summarizes the major genes implicated in complex hereditary spastic paraplegia, highlighting inheritance, encoded proteins, and distinguishing clinical features. It is useful for comparing the most important SPG subtypes and related complex HSP genes across the heterogeneous disease spectrum.

Most Common Genetic Subtypes

In AD HSP (80% of North American and Northern European populations), SPG4/SPAST accounts for 40% of cases, SPG3A/ATL1 for 10%, SPG31/REEP1 for 10%, and SPG10/KIF5A for 3% (meyyazhagan2022hereditaryspasticparaplegia pages 12-14). Among AR forms, SPG11 and SPG15 are the most significant complex HSP subtypes, along with SPG35/FA2H, SPG45/C19orf12, and SPG7 (5–12% of AR cases) (meyyazhagan2022hereditaryspasticparaplegia pages 12-14). In a Chinese cohort, SPAST was the most common gene, followed by SPG11 and ATL1 (yu2023clinicalfeaturesand pages 1-2). In pediatric complex HSP, KIF1A variants were the most common cause (ikeda2023geneticandclinical pages 3-4).

Pathogenic Variants

Pathogenic variants span multiple types including missense, frameshift, nonsense, splice-site, and structural variants (large deletions/duplications) (meyyazhagan2022hereditaryspasticparaplegia pages 4-6, meyyazhagan2022thepuzzleof pages 5-6). For SPG15, 45 distinct ZFYVE26 variants have been described, distributed across the protein structure without mutational hotspots (saffari2023theclinicaland pages 1-2). SPG4 variants include both point mutations and exon deletions detectable by MLPA (meyyazhagan2022thepuzzleof pages 5-6). Variant classification follows ACMG-AMP 2015 guidelines (saffari2023theclinicaland pages 13-13). All variants are germline in origin.

Inheritance Patterns

Complex HSP follows all major Mendelian inheritance patterns: autosomal recessive (most common for complex forms), autosomal dominant, X-linked recessive (SPG1/L1CAM, SPG2/PLP1), and mitochondrial inheritance (meyyazhagan2022hereditaryspasticparaplegia pages 2-4, meyyazhagan2022hereditaryspasticparaplegia pages 12-14). Variable expressivity is characteristic, and penetrance varies by gene and variant.

5. Environmental Information

Complex HSP is not associated with established environmental risk factors, infectious agents, or specific lifestyle factors as causative agents. The disease is exclusively genetic in etiology. No gene-environment interactions have been validated, though physical activity and rehabilitation may influence functional outcomes.

6. Mechanism / Pathophysiology

Molecular Pathways

The pathophysiology of complex HSP involves disruption of multiple interconnected cellular pathways (awuah2024hereditaryspasticparaplegia pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 14-16):

Endoplasmic Reticulum Morphogenesis and Membrane Trafficking: Mutations in ER-associated proteins (spastin/SPG4, atlastin/SPG3A, REEP1/SPG31) disrupt ER tubular network formation and ER-microtubule relationships, which are critical for axonal maintenance (meyyazhagan2022hereditaryspasticparaplegia pages 14-16, meyyazhagan2022thepuzzleof pages 2-5). GO terms: GO:0030176 (ER tubular network organization); GO:0016197 (endosome transport).

Autophagy-Lysosomal Pathway: Spatacsin (SPG11) and spastizin (SPG15/ZFYVE26) are essential for autophagic lysosome reformation. Their dysfunction leads to impaired autophagosome-lysosome fusion and accumulation of lysosomal structures (awuah2024hereditaryspasticparaplegia pages 8-10, vijayaraghavan2025roleofglial pages 2-3). AP-4 complex mutations (SPG47, SPG50, SPG51, SPG52) cause mislocation of ATG9A, a key autophagy protein (wiseman2024preclinicaldevelopmentof pages 13-15). GO terms: GO:0006914 (autophagy); GO:0005764 (lysosome).

Mitochondrial Dysfunction: Loss of paraplegin/AFG3L2 complex impairs ATP production and increases vulnerability to reactive oxygen species (awuah2024hereditaryspasticparaplegia pages 2-4). Disrupted mitochondrial fission-fusion dynamics causes impaired axonal transport, oxidative phosphorylation deficiencies, and axonal degeneration (awuah2024hereditaryspasticparaplegia pages 2-4, meyyazhagan2022thepuzzleof pages 12-14). GO terms: GO:0005739 (mitochondrion); GO:0006119 (oxidative phosphorylation).

Lipid Metabolism: Defects in lipid droplet formation, cholesterol metabolism (CYP7B1/SPG5), fatty acid hydroxylation (FA2H/SPG35), and phospholipid regulation (PNPLA6/SPG39) compromise neuronal membrane integrity and myelin maintenance (meyyazhagan2022thepuzzleof pages 1-2, vijayaraghavan2025roleofglial pages 2-3, meyyazhagan2022thepuzzleof pages 11-12). AMFR mutations cause lipid droplet accumulation in neural stem cells (garg2024divingdeepzebrafish pages 5-6). GO terms: GO:0006629 (lipid metabolic process); GO:0005811 (lipid droplet).

Axonal Transport and Microtubule Dynamics: Spastin (SPG4) is a microtubule-severing enzyme; its dysfunction causes microtubule disorganization and impaired axonal transport (meyyazhagan2022hereditaryspasticparaplegia pages 14-16, meyyazhagan2022thepuzzleof pages 12-14). KIF1A and KIF5A mutations directly affect kinesin-mediated axonal transport (garg2024divingdeepzebrafish pages 5-6). GO terms: GO:0007018 (microtubule-based movement); GO:0008088 (axo-dendritic transport).

Myelination Abnormalities: PLP1 (SPG2) mutations and L1CAM (SPG1) mutations reduce myelin protein expression and impair oligodendrocyte function, limiting myelin maintenance of corticospinal neurons (awuah2024hereditaryspasticparaplegia pages 8-10). GO terms: GO:0042552 (myelination).

Glial Cell Involvement

Recent research has revealed a non-cell-autonomous mechanism in HSP, with impaired lipid metabolism and reduced lipid droplets in HSP astrocytes contributing to axonal degeneration of cortical neurons (vijayaraghavan2025roleofglial pages 2-3). Reactive astrocytes produce both cytotoxic molecules (LCN2, IL-1β, TNF-α, nitric oxide) and neuroprotective factors (BDNF, NGF), while increased microgliosis and pro-inflammatory factors have been observed in HSP patient samples (vijayaraghavan2025roleofglial pages 2-3). CL terms: CL:0000127 (astrocyte); CL:0000129 (microglial cell); CL:0000540 (neuron).

Causal Chain

The primary trigger is a germline genetic mutation → protein loss-of-function or dysfunction → disruption of one or more core cellular pathways (ER morphogenesis, autophagy, mitochondrial function, lipid metabolism, axonal transport) → selective vulnerability of long corticospinal tract axons due to their high metabolic demands → progressive axonal degeneration → neuronal dysfunction and cell death → clinical manifestation of progressive spasticity and additional neurological features (awuah2024hereditaryspasticparaplegia pages 1-2, meyyazhagan2022thepuzzleof pages 2-5).

7. Anatomical Structures Affected

Organ Level

Primary: Central nervous system, specifically the corticospinal tracts (lateral columns of thoracic and cervical spinal cord) (UBERON:0002187)
Secondary: Cerebellum (UBERON:0002037), cerebral cortex (UBERON:0000956), corpus callosum (UBERON:0002336), peripheral nerves (UBERON:0001021)
Body systems: Nervous system (motor and sensory), musculoskeletal system, urinary system

Tissue and Cell Level

Tissues: White matter tracts (corticospinal tracts, posterior columns), cerebral and cerebellar white matter, myelin
Cell types: Upper motor neurons (CL:0000540), corticospinal projection neurons, oligodendrocytes (CL:0000128), astrocytes (CL:0000127), microglial cells (CL:0000129)
Subcellular: Endoplasmic reticulum (GO:0005783), mitochondria (GO:0005739), lysosomes (GO:0005764), autophagosomes (GO:0005776), microtubules (GO:0005874), lipid droplets (GO:0005811)

Localization

Neurodegeneration is bilateral and symmetric, with greatest severity in the lumbar and thoracic spinal cord regions affecting the longest descending axons (vijayaraghavan2025roleofglial pages 2-3).

8. Temporal Development

Onset

Complex HSP typically has an earlier onset than pure HSP. In pediatric cohorts, median onset is 16–24 months (ikeda2023geneticandclinical pages 3-4, saffari2023theclinicaland pages 1-2). Onset patterns include congenital/neonatal, infantile, childhood, adolescent, and adult, with some subtypes (SPG7) presenting predominantly in adulthood (fereshtehnejad2023movementdisordersin pages 5-6). Onset is typically insidious and chronic.

Progression

Disease progression is chronic and progressive. Mean annual SPRS progression is 0.9 points overall, with complicated HSP progressing at 1.3 points/year vs. 0.6 points/year for pure HSP (amprosi2026naturalhistoryin pages 1-2, amprosi2026naturalhistoryin pages 13-14). For SPG15, wheelchair dependency develops by a mean age of 20 years (saffari2023theclinicaland pages 8-9). The disease course is progressive without remission; gait impairment, cognitive decline, and autonomic dysfunction worsen over time (saffari2023theclinicaland pages 1-2, saffari2023theclinicaland pages 8-9). Significant diagnostic delay exists (median 14.4 years in SPG15) (saffari2023theclinicaland pages 3-5).

9. Inheritance and Population

Epidemiology

Global HSP prevalence ranges from 0.1 to 9.6 per 100,000, with most estimates between 1 and 5 per 100,000 (meyyazhagan2022thepuzzleof pages 1-2, yu2023clinicalfeaturesand pages 1-2, meyyazhagan2022hereditaryspasticparaplegia pages 1-2). Prevalence varies by geographic region, with higher rates reported in some European populations.

Inheritance Patterns

Autosomal dominant: ~75–80% of registered HSP cases in Northern Europe and North America (predominantly pure forms) (meyyazhagan2022hereditaryspasticparaplegia pages 2-4, meyyazhagan2022hereditaryspasticparaplegia pages 12-14)
Autosomal recessive: Most complex HSP forms; predominant in consanguineous populations (meyyazhagan2022hereditaryspasticparaplegia pages 12-14, fereshtehnejad2023movementdisordersin pages 4-5)
X-linked recessive: SPG1 (L1CAM), SPG2 (PLP1) (meyyazhagan2022hereditaryspasticparaplegia pages 12-14)
Mitochondrial: Rare forms (meyyazhagan2022hereditaryspasticparaplegia pages 2-4)

Population Demographics

AR complex HSP is more common in populations with high rates of consanguinity, such as the MENA region (meyyazhagan2022thepuzzleof pages 1-2). The male:female ratio in one Austrian cohort was approximately 64.3% male (amprosi2026naturalhistoryin pages 1-2). Approximately 40% of HSP cases present as sporadic forms without family history (meyyazhagan2022hereditaryspasticparaplegia pages 1-2).

Founder Effects

Specific variants show geographic clustering; SPG11 is the most common AR HSP gene in Iran and Tunisia (meyyazhagan2022thepuzzleof pages 1-2). Genetic diversity and distinct variant spectra have been reported in African, Asian, and European populations (meyyazhagan2022hereditaryspasticparaplegia pages 12-14).

10. Diagnostics

Clinical Tests

Laboratory tests: Routine blood tests, serum homocysteine analysis; oxysterol levels (25- and 27-hydroxycholesterol) for SPG5 (chen2022geneticoriginof pages 1-2, meyyazhagan2022thepuzzleof pages 11-12)
Electrophysiology: Nerve conduction studies and EMG (revealing sensorimotor polyneuropathy in some forms), somatosensory evoked potentials (chen2022geneticoriginof pages 1-2, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 2-4)
Neuroimaging: Brain MRI showing thin corpus callosum (hallmark of SPG11/SPG15), periventricular white matter changes, "ears of the lynx" sign (T2-FLAIR hyperintensity in forceps minor), cerebellar and cortical atrophy (saffari2023theclinicaland pages 3-5, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 2-4, chojdakłukasiewicz2023hereditaryspasticparaplegia pages 4-6). Spinal cord MRI may show thinning (meyyazhagan2022thepuzzleof pages 5-6).
Biomarkers: Neurofilament light chain (NfL) in plasma and CSF shows significant elevation in HSP patients and correlates inversely with age in SPG15 (saffari2023theclinicaland pages 1-2, cipriano2025fluidbiomarkersin pages 1-2, cipriano2025fluidbiomarkersin pages 12-14). GFAP, brain-derived tau, and sTREM2 are emerging biomarkers reflecting neurodegeneration and glial activation (cipriano2025fluidbiomarkersin pages 12-14).

Genetic Testing

Recommended approach: Next-generation sequencing (NGS) gene panels targeting HSP-associated genes, with MLPA for detection of exon deletions/duplications (especially for SPAST/SPG4) (meyyazhagan2022thepuzzleof pages 5-6)
Whole exome/genome sequencing: Employed when targeted panels are uninformative or phenotype is atypical (chojdakłukasiewicz2023hereditaryspasticparaplegia pages 4-6)
Diagnostic yield: 45% in pure-type and 81% in complex-type pediatric-onset HSP by comprehensive genetic testing (ikeda2023geneticandclinical pages 3-4); overall genetic diagnostic rate of 35–54% across cohorts (yu2023clinicalfeaturesand pages 1-2, amprosi2026naturalhistoryin pages 1-2)
Variant interpretation: ACMG-AMP 2015 guidelines with tools such as VarSome and InterVar (saffari2023theclinicaland pages 13-13)

Clinical Criteria

Diagnosis requires bilateral lower-limb spasticity with hyperreflexia and extensor plantar responses, without acquired causes, confirmed by at least two neurologists (chen2022geneticoriginof pages 1-2). Differential diagnosis includes cerebral palsy, ALS, leukodystrophy, hereditary ataxias, vitamin B12/copper deficiency, and arteriovenous fistulas (meyyazhagan2022thepuzzleof pages 5-6).

11. Outcome/Prognosis

Survival and Morbidity

HSP generally does not reduce lifespan in pure forms, but complex forms—particularly SPG11—may be associated with restricted life expectancy (chojdakłukasiewicz2023hereditaryspasticparaplegia pages 4-6, awuah2024hereditaryspasticparaplegia pages 1-2). The primary morbidity is progressive disability: 17.5% of patients in one cohort were wheelchair-bound, and 33% of SPG15 patients were unable to walk independently (amprosi2026naturalhistoryin pages 11-13, saffari2023theclinicaland pages 3-5).

Disease Severity Measures

Mean baseline SPRS score was 18.2 points in an Austrian cohort (consistent with European cohorts of 17.4–19.9) (amprosi2026naturalhistoryin pages 11-13). Complex HSP patients show higher SPRS scores (27.4 ± 8.9 vs. 16.7 ± 8.6 for pure HSP), indicating greater neurological impairment (siow2023outcomemeasuresand pages 2-3). In SPG15, mean SPRS was 25.2 ± 13.3 (saffari2023theclinicaland pages 6-8).

Prognostic Factors

Earlier disease onset correlates with longer diagnostic delay and disease duration but is associated with a lower risk of independent ambulation loss (yu2023clinicalfeaturesand pages 1-2). Disease duration is the strongest predictor of SPRS progression (amprosi2026naturalhistoryin pages 13-14). NfL levels may serve as prognostic biomarkers, showing correlation with disease activity (cipriano2025fluidbiomarkersin pages 12-14).

12. Treatment

Pharmacotherapy (MAXO:0000058 – pharmacotherapy)

Antispasticity agents: Baclofen (oral and intrathecal), tizanidine, and oxybutynin (meyyazhagan2022hereditaryspasticparaplegia pages 16-18). Intrathecal baclofen (ITB) demonstrated sustained improvement in spasticity for 2–3 years followed by stable ambulatory function for 4–5 years (awuah2024hereditaryspasticparaplegia pages 12-13).
Botulinum toxin type A: Multiple open-label studies demonstrate improvement in motor and non-motor symptoms, with improved gait velocity at follow-up (meyyazhagan2022hereditaryspasticparaplegia pages 25-25, meyyazhagan2022thepuzzleof pages 6-9). MAXO:0000087 (botulinum toxin injection).
Dalfampridine: A potassium channel blocker explored in a pilot trial (NCT05613114) (meyyazhagan2022hereditaryspasticparaplegia pages 25-25).
Levodopa: Explored for parkinsonism features, particularly in SPG7 and SPG11, though evidence remains limited (awuah2024hereditaryspasticparaplegia pages 12-13).

Rehabilitation (MAXO:0000011 – physical therapy)

Physical therapy: Core management approach including stretching, balance training, and strengthening exercises (meyyazhagan2022thepuzzleof pages 6-9)
Robot-assisted gait training: Shows promise for improving gait velocity (meyyazhagan2022thepuzzleof pages 14-15)
Hydrotherapy and electrostimulation: Potential to increase lower extremity strength and decrease spasticity (meyyazhagan2022thepuzzleof pages 14-15)
Ankle-foot orthoses: For mobility improvement (meyyazhagan2022hereditaryspasticparaplegia pages 16-18)

Advanced Therapeutics: Gene Therapy

A landmark single-patient phase 1 clinical trial of AAV gene therapy for SPG50 (AP4M1 gene replacement) was reported in 2024. An adeno-associated virus vector carrying the AP4M1 gene was administered intrathecally to a 4-year-old patient, showing good tolerability with no serious adverse events at 12 months and preliminary evidence of disease stabilization (dowling2024aavgenetherapy pages 1-2). Preclinical studies in Ap4m1-knockout mice demonstrated age- and dose-dependent therapeutic effects (chen2023intrathecalaav9ap4m1gene pages 1-2). Gene replacement therapy for SPG47 (AP4B1) has completed IND-enabling studies with acceptable safety profiles in nonhuman primates (wiseman2024preclinicaldevelopmentof pages 13-15). Additional experimental approaches include spastin recovery through preventing neddylation-dependent degradation, and mRNA-based therapies for SPG5 (awuah2024hereditaryspasticparaplegia pages 20-20).

Surgical Interventions (MAXO:0000004 – surgical procedure)

Selective dorsal rhizotomy: Explored in children with limited evidence (meyyazhagan2022thepuzzleof pages 6-9)
Spinal cord stimulation: Under investigation (NCT05196178)

Neuromodulation

Repetitive transcranial magnetic stimulation and transcutaneous spinal direct current stimulation have been explored with mixed results (awuah2024hereditaryspasticparaplegia pages 20-20, awuah2024hereditaryspasticparaplegia pages 19-20).

Clinical Trials

The following table summarizes active and recent clinical trials in HSP:

NCT Number	Trial Title/Focus	Status	Phase	Type	Enrollment	Sponsor
NCT03981276	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders	Recruiting	Not provided	Observational	2000	University Hospital Tuebingen (OpenTargets Search: hereditary spastic paraplegia)
NCT04712812	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia	Recruiting	Not provided	Observational	700	Boston Children's Hospital (OpenTargets Search: hereditary spastic paraplegia)
NCT06553976	Spastic Paraplegia - Centers of Excellence Research Network (SP-CERN)	Recruiting	Not provided	Observational	100	Boston Children's Hospital (OpenTargets Search: hereditary spastic paraplegia)
NCT05354622	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)	Recruiting	Not provided	Observational	200	Boston Children's Hospital (OpenTargets Search: hereditary spastic paraplegia)
NCT03961906	Physiotherapy in Hereditary Spastic Paraplegia	Completed	Phase 2	Interventional	53	University Hospital Tuebingen (OpenTargets Search: hereditary spastic paraplegia)
NCT04180098	Improving Gait Adaptability in Hereditary Spastic Paraplegia	Completed	NA	Interventional	36	Radboud University Medical Center (OpenTargets Search: hereditary spastic paraplegia)
NCT05613114	Effect of Dalfampridine in Patients With Hereditary Spastic Paraplegia	Completed	NA	Interventional	8	European University of Lefke (OpenTargets Search: hereditary spastic paraplegia)
NCT06068700	AAV gene therapy for SPG50	Phase 1 / not verified in retrieved trial list; related single-patient phase 1 study reported separately	Phase 1	Interventional	Not provided	Not established from retrieved trial registry output; related publication describes individualized AP4M1 gene therapy for SPG50 (dowling2024aavgenetherapy pages 1-2)
NCT05196178	Spinal Cord Stimulation Therapy for Hereditary Spastic Paraplegias Patients	Unknown	NA	Interventional	12	Xuanwu Hospital, Beijing (OpenTargets Search: hereditary spastic paraplegia)
NCT06728787	Robot-assisted Walking Treatment in Hereditary Spastic Paraplegia (HSP)	Recruiting	Not provided	Observational	50	IRCCS Eugenio Medea (OpenTargets Search: hereditary spastic paraplegia)

Table: This table summarizes active and recent clinical studies in hereditary spastic paraplegia, including observational natural-history efforts, rehabilitation trials, and emerging gene therapy. It is useful for identifying current trial readiness and intervention development across the HSP field.

The Spastic Paraplegia–Centers of Excellence Research Network (SP-CERN) has been established across 11 US institutions to promote clinical trial readiness through standardized clinical assessments, biorepository development, and natural history data collection (OpenTargets Search: hereditary spastic paraplegia).

13. Prevention

Primary Prevention

No primary prevention strategies exist for complex HSP given its monogenic genetic etiology. Risk reduction focuses on genetic counseling and family planning.

Genetic Counseling and Screening (MAXO:0000015 – genetic counseling)

Carrier screening: Relevant for AR forms, particularly in consanguineous populations
Prenatal testing: Available when the familial variant is known
Preimplantation genetic diagnosis: An option for families with known pathogenic variants
Cascade genetic testing: Recommended for at-risk family members

Tertiary Prevention

Management of complications through regular physiotherapy, assistive devices, and symptomatic medications can delay functional decline and improve quality of life (meyyazhagan2022thepuzzleof pages 6-9, amprosi2026naturalhistoryin pages 11-13).

14. Other Species / Natural Disease

Complex HSP is a human-specific clinical entity. No naturally occurring disease equivalent has been described in animals. However, loss-of-function mutations in orthologous genes cause motor phenotypes in model organisms (see Section 15).

15. Model Organisms

Mouse Models

Mouse models have been created for multiple HSP genes but frequently fail to fully recapitulate human motor phenotypes (damiani2024pluripotentstemcells pages 2-3, damiani2024pluripotentstemcells pages 1-2). ZFYVE26 knockout mice develop late-onset spastic paraplegia and cerebellar ataxia with neurodegeneration features at 16 months (garg2023zebrafishasa pages 25-28). Spastin knockout mice show gait abnormalities and disrupted anterograde mitochondrial transport (garg2023zebrafishasa pages 25-28). Ap4m1-KO mice treated with AAV9/AP4M1 showed age- and dose-dependent therapeutic benefits, validating gene therapy approaches (chen2023intrathecalaav9ap4m1gene pages 1-2). CRISPR-Cas9 knock-in rat models display progressive motor deficits, corpus callosum thinning, and hind limb spasticity (damiani2024pluripotentstemcells pages 6-7).

Zebrafish Models (NCBI Taxon: 7955)

Over 40 zebrafish studies have been published on HSP research (garg2024divingdeepzebrafish pages 5-6). While zebrafish lack a corticospinal tract, they demonstrate key pathological features including impaired locomotion, disrupted motor axon growth, and axonal transport defects (garg2024divingdeepzebrafish pages 5-6). Spastizin mutant zebrafish show M-cell degeneration, axon demyelination, and impaired locomotion (garg2023zebrafishasa pages 25-28). AMFR-deficient zebrafish exhibit altered touch-evoked escape response and motor neuron branching defects, which were rescued by FDA-approved statins (garg2024divingdeepzebrafish pages 5-6). Zebrafish are valued for high-throughput drug screening and optical transparency during development (garg2023zebrafishasa pages 25-28).

Drosophila Models (NCBI Taxon: 7227)

Eighteen orthologous SPG genes have been identified in Drosophila, including SPAST, ATL1, and SPG7 (vivarelli2025wingsofdiscovery pages 5-7). Loss of spas (Drosophila spastin ortholog) causes progressive movement defects, neuronal apoptosis, and immobility (vivarelli2025wingsofdiscovery pages 5-7). KIF5A mutation models faithfully reproduced axonal transport impairment, axonal swellings, and motor deficits (vivarelli2025wingsofdiscovery pages 19-20). Drosophila offers genetic tractability, rapid life cycle, and neuromuscular junction assays for phenotypic evaluation (vivarelli2025wingsofdiscovery pages 3-5).

iPSC Models

Patient-derived induced pluripotent stem cells have emerged as the most promising human cellular model for HSP (damiani2024pluripotentstemcells pages 1-2). iPSC-derived neurons faithfully mimic HSP in vitro, displaying morphological and molecular properties relevant to disease including mitochondrial dysfunction and axonal degeneration (damiani2024pluripotentstemcells pages 1-2, vivarelli2025wingsofdiscovery pages 19-20). iPSC-derived astrocytes from HSP patients show impaired lipid metabolism and reduced lipid droplet size (vijayaraghavan2025roleofglial pages 2-3). Three-dimensional organoid structures from iPSCs offer improved complexity for disease modeling and personalized medicine approaches (damiani2024pluripotentstemcells pages 6-7).

Integrated Approach

A complementary multi-model strategy has been advocated: Drosophila for high-speed genetic analysis, mice for behavioral and systemic validation, zebrafish for high-throughput drug screening, and human iPSC cultures for mechanistic studies in the patient's genetic background (vivarelli2025wingsofdiscovery pages 19-20).

Summary

Complex hereditary spastic paraplegia is a genetically heterogeneous group of Mendelian neurodegenerative disorders characterized by progressive corticospinal tract degeneration with additional neurological features. Over 90 genetic loci have been identified, with SPG11, SPG15, SPG7, and AP-4 complex genes (SPG47, SPG50, SPG51, SPG52) representing the most significant complex HSP subtypes. The pathophysiology involves convergent disruption of ER morphogenesis, autophagy-lysosomal pathways, mitochondrial function, lipid metabolism, and axonal transport. Disease management remains primarily symptomatic, but the field is entering a transformative era with the first AAV gene therapy clinical trial for SPG50 demonstrating safety and preliminary efficacy. Large-scale natural history studies and research networks such as SP-CERN are building clinical trial readiness across the HSP community. Fluid biomarkers including neurofilament light chain show promise for disease monitoring and clinical trial endpoints.

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(meyyazhagan2022hereditaryspasticparaplegia pages 4-6): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 192 citations.
(meyyazhagan2022hereditaryspasticparaplegia pages 20-21): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 192 citations.
(meyyazhagan2022hereditaryspasticparaplegia pages 14-16): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 192 citations.
(meyyazhagan2022thepuzzleof pages 12-14): Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, and Antonio Orlacchio. The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences, 23:7665, Jul 2022. URL: https://doi.org/10.3390/ijms23147665, doi:10.3390/ijms23147665. This article has 60 citations.
(garg2024divingdeepzebrafish pages 5-6): Vranda Garg and Bart R. H. Geurten. Diving deep: zebrafish models in motor neuron degeneration research. Frontiers in Neuroscience, Jun 2024. URL: https://doi.org/10.3389/fnins.2024.1424025, doi:10.3389/fnins.2024.1424025. This article has 10 citations and is from a peer-reviewed journal.
(meyyazhagan2022thepuzzleof pages 5-6): Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, and Antonio Orlacchio. The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences, 23:7665, Jul 2022. URL: https://doi.org/10.3390/ijms23147665, doi:10.3390/ijms23147665. This article has 60 citations.
(saffari2023theclinicaland pages 13-13): Afshin Saffari, Melanie Kellner, Catherine Jordan, Helena Rosengarten, Alisa Mo, Bo Zhang, Oleksandr Strelko, Sonja Neuser, Marie Y Davis, Nobuaki Yoshikura, Naonobu Futamura, Tomoya Takeuchi, Shin Nabatame, Hiroyuki Ishiura, Shoji Tsuji, Huda Shujaa Aldeen, Elisa Cali, Clarissa Rocca, Henry Houlden, Stephanie Efthymiou, Birgit Assmann, Grace Yoon, Bianca A Trombetta, Pia Kivisäkk, Florian Eichler, Haitian Nan, Yoshihisa Takiyama, Alessandra Tessa, Filippo M Santorelli, Mustafa Sahin, Craig Blackstone, Edward Yang, Rebecca Schüle, and Darius Ebrahimi-Fakhari. The clinical and molecular spectrum of zfyve26-associated hereditary spastic paraplegia: spg15. Brain : a journal of neurology, 146:2003-2015, Oct 2023. URL: https://doi.org/10.1093/brain/awac391, doi:10.1093/brain/awac391. This article has 25 citations.
(meyyazhagan2022thepuzzleof pages 2-5): Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, and Antonio Orlacchio. The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences, 23:7665, Jul 2022. URL: https://doi.org/10.3390/ijms23147665, doi:10.3390/ijms23147665. This article has 60 citations.
(awuah2024hereditaryspasticparaplegia pages 2-4): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 31 citations.
(chen2022geneticoriginof pages 1-2): Jiann-Nan Chen, Zhe Zhao, Hong-rui Shen, Qi Bing, Nan Li, Xuan Guo, and Jing Hu. Genetic origin of patients having spastic paraplegia with or without other neurologic manifestations. BMC Neurology, May 2022. URL: https://doi.org/10.1186/s12883-022-02708-z, doi:10.1186/s12883-022-02708-z. This article has 10 citations and is from a peer-reviewed journal.
(cipriano2025fluidbiomarkersin pages 12-14): Lorenzo Cipriano, Nunzio Setola, Melissa Barghigiani, and Filippo Maria Santorelli. Fluid biomarkers in hereditary spastic paraplegia: a narrative review and integrative framework for complex neurodegenerative mechanisms. Genes, 16:1189, Oct 2025. URL: https://doi.org/10.3390/genes16101189, doi:10.3390/genes16101189. This article has 2 citations.
(siow2023outcomemeasuresand pages 2-3): Sue-Faye Siow, Dennis Yeow, Laura I. Rudaks, Fangzhi Jia, Gautam Wali, Carolyn M. Sue, and Kishore R. Kumar. Outcome measures and biomarkers for clinical trials in hereditary spastic paraplegia: a scoping review. Genes, 14:1756, Sep 2023. URL: https://doi.org/10.3390/genes14091756, doi:10.3390/genes14091756. This article has 18 citations.
(meyyazhagan2022hereditaryspasticparaplegia pages 16-18): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 192 citations.
(awuah2024hereditaryspasticparaplegia pages 12-13): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 31 citations.
(meyyazhagan2022hereditaryspasticparaplegia pages 25-25): Arun Meyyazhagan and Antonio Orlacchio. Hereditary spastic paraplegia: an update. International Journal of Molecular Sciences, 23:1697, Feb 2022. URL: https://doi.org/10.3390/ijms23031697, doi:10.3390/ijms23031697. This article has 192 citations.
(meyyazhagan2022thepuzzleof pages 6-9): Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, and Antonio Orlacchio. The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences, 23:7665, Jul 2022. URL: https://doi.org/10.3390/ijms23147665, doi:10.3390/ijms23147665. This article has 60 citations.
(meyyazhagan2022thepuzzleof pages 14-15): Arun Meyyazhagan, Haripriya Kuchi Bhotla, Manikantan Pappuswamy, and Antonio Orlacchio. The puzzle of hereditary spastic paraplegia: from epidemiology to treatment. International Journal of Molecular Sciences, 23:7665, Jul 2022. URL: https://doi.org/10.3390/ijms23147665, doi:10.3390/ijms23147665. This article has 60 citations.
(awuah2024hereditaryspasticparaplegia pages 20-20): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 31 citations.
(awuah2024hereditaryspasticparaplegia pages 19-20): Wireko Andrew Awuah, Joecelyn Kirani Tan, Anastasiia D Shkodina, Tomas Ferreira, Favour Tope Adebusoye, Adele Mazzoleni, Jack Wellington, Lian David, Ellie Chilcott, Helen Huang, Toufik Abdul-Rahman, Vallabh Shet, Oday Atallah, Jacob Kalmanovich, Riaz Jiffry, Divine Elizabeth Madhu, Kateryna Sikora, Oleksii Kmyta, and Mykhailo Yu Delva. Hereditary spastic paraplegia: novel insights into the pathogenesis and management. SAGE Open Medicine, Dec 2024. URL: https://doi.org/10.1177/20503121231221941, doi:10.1177/20503121231221941. This article has 31 citations.
(damiani2024pluripotentstemcells pages 2-3): Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef, and Filippo Maria Santorelli. Pluripotent stem cells as a preclinical cellular model for studying hereditary spastic paraplegias. International Journal of Molecular Sciences, 25:2615, Feb 2024. URL: https://doi.org/10.3390/ijms25052615, doi:10.3390/ijms25052615. This article has 11 citations.
(damiani2024pluripotentstemcells pages 1-2): Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef, and Filippo Maria Santorelli. Pluripotent stem cells as a preclinical cellular model for studying hereditary spastic paraplegias. International Journal of Molecular Sciences, 25:2615, Feb 2024. URL: https://doi.org/10.3390/ijms25052615, doi:10.3390/ijms25052615. This article has 11 citations.
(garg2023zebrafishasa pages 25-28): Vranda Garg. Zebrafish as a model for hereditary spastic paraplegia. ArXiv, 2023. URL: https://doi.org/10.53846/goediss-9965, doi:10.53846/goediss-9965. This article has 0 citations.
(damiani2024pluripotentstemcells pages 6-7): Devid Damiani, Matteo Baggiani, Stefania Della Vecchia, Valentina Naef, and Filippo Maria Santorelli. Pluripotent stem cells as a preclinical cellular model for studying hereditary spastic paraplegias. International Journal of Molecular Sciences, 25:2615, Feb 2024. URL: https://doi.org/10.3390/ijms25052615, doi:10.3390/ijms25052615. This article has 11 citations.
(vivarelli2025wingsofdiscovery pages 5-7): Rachele Vivarelli, Chiara Vantaggiato, Maria Teresa Bassi, Filippo Maria Santorelli, and Maria Marchese. Wings of discovery: using drosophila to decode hereditary spastic paraplegia and ataxias. Cells, 14:1466, Sep 2025. URL: https://doi.org/10.3390/cells14181466, doi:10.3390/cells14181466. This article has 1 citations.
(vivarelli2025wingsofdiscovery pages 19-20): Rachele Vivarelli, Chiara Vantaggiato, Maria Teresa Bassi, Filippo Maria Santorelli, and Maria Marchese. Wings of discovery: using drosophila to decode hereditary spastic paraplegia and ataxias. Cells, 14:1466, Sep 2025. URL: https://doi.org/10.3390/cells14181466, doi:10.3390/cells14181466. This article has 1 citations.
(vivarelli2025wingsofdiscovery pages 3-5): Rachele Vivarelli, Chiara Vantaggiato, Maria Teresa Bassi, Filippo Maria Santorelli, and Maria Marchese. Wings of discovery: using drosophila to decode hereditary spastic paraplegia and ataxias. Cells, 14:1466, Sep 2025. URL: https://doi.org/10.3390/cells14181466, doi:10.3390/cells14181466. This article has 1 citations.

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Classifications

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References

Deep Research

Complex Hereditary Spastic Paraplegia (HSP): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Core "pure" phenotype (present in virtually all HSP, complex or pure)

Complex-form additional phenotypes (by representative subtype)

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table: Suggested Ontology Terms for KB Curation

Sources

1. Disease Information

Overview

Key Identifiers

Synonyms

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental and Gene-Environment Interactions

3. Phenotypes

Detailed Phenotypic Characteristics

4. Genetic/Molecular Information

Causal Genes

Most Common Genetic Subtypes

Pathogenic Variants

Inheritance Patterns

5. Environmental Information

6. Mechanism / Pathophysiology

Molecular Pathways

Glial Cell Involvement

Causal Chain

7. Anatomical Structures Affected

Organ Level

Tissue and Cell Level

Localization

8. Temporal Development

Onset

Progression

9. Inheritance and Population

Epidemiology

Inheritance Patterns

Population Demographics

Founder Effects

10. Diagnostics

Clinical Tests

Genetic Testing

Clinical Criteria

11. Outcome/Prognosis

Survival and Morbidity

Disease Severity Measures

Prognostic Factors

12. Treatment

Pharmacotherapy (MAXO:0000058 – pharmacotherapy)

Rehabilitation (MAXO:0000011 – physical therapy)

Advanced Therapeutics: Gene Therapy

Surgical Interventions (MAXO:0000004 – surgical procedure)

Neuromodulation