Spastic Paraplegia 90A, Autosomal Dominant

Mendelian MONDO:0957308 Pathograph 23 Show in embeddings browser Hereditary Spastic Paraplegia Complex Hereditary Spastic Paraplegia

Spastic paraplegia 90A (SPG90A) is an ultra-rare, early-childhood-onset complex (complicated) hereditary spastic paraplegia caused by monoallelic activating missense variants in SPTSSA, which encodes the small activating subunit A of serine palmitoyltransferase (SPT) — the endoplasmic-reticulum enzyme that catalyses the rate-limiting first step of de novo sphingolipid biosynthesis. SPT activity is held in check by the ORMDL proteins, which bind the complex and inhibit it when sphingolipid levels rise. The SPTSSA disease variants sit on the face of the small subunit that participates in this regulation, so ORMDL-mediated feedback inhibition fails and sphingolipid synthesis runs unrestrained. This is a gain of function in the sense of lost restraint, not a deficiency state. Affected children present with progressive lower-limb spasticity and motor impairment on a background of neurodevelopmental delay, with variable sensorineural hearing loss and language/cognitive dysfunction. Only four SPG90 patients have been published in total, and the recurrent p.Thr51Ile allele accounts for three of them: two of the founding three carried it, and so did the fourth. It is the only SPTSSA allele reported more than once, and on current evidence it is effectively the SPG90A allele. SPG90A is deliberately curated as the MONDO-recognised autosomal DOMINANT pole of SPG90 (OMIM #620416); the biallelic/recessive pole is a separate MONDO concept (SPG90B, OMIM #620417) and is not folded in here. It is also mechanistically the sibling — not a duplicate — of the SPTLC1/SPTLC2 juvenile amyotrophic lateral sclerosis entries, which share the same loss-of-ORMDL-restraint biochemistry but produce combined upper and lower motor neuron disease rather than the neurodevelopmentally complicated, upper-motor-neuron-predominant picture seen here. Why the same biochemical lesion in different SPT subunits yields different clinical syndromes is an explicitly unresolved question, and is recorded as a knowledge gap rather than papered over.

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Inheritance
6
Pathophys.
9
Phenotypes
2
Gaps
23
Pathograph
1
Genes
1
Variants
6
Medical Actions
2
Models
8
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
SPG90A is the monoallelic (heterozygous) pole of SPTSSA-related spastic paraplegia. The published SPG90 patients carry either monoallelic or biallelic SPTSSA variants; the monoallelic cases — including both reported carriers of the recurrent p.Thr51Ile allele and the fourth patient — define this dominant entity, while the biallelic cases belong to the separate recessive concept SPG90B.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:40533086 SUPPORT Human Clinical
"Spastic paraplegia 90 (SPG90; OMIM #620416, 620417) is a rare neurologic disease caused by monoallelic or biallelic variants in the serine palmitoyltransferase small subunit A (SPTSSA) gene."
Establishes that SPG90 comprises a monoallelic and a biallelic pole with distinct OMIM numbers, which is the basis for scoping this entry to the dominant (#620416) concept.
PMID:40533086 SUPPORT Human Clinical
"Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
Documents a heterozygous (monoallelic) pathogenic allele recurring across independent patients, supporting dominant action of the p.Thr51Ile variant.
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Discussions and Knowledge Gaps

2
Why does loss of ORMDL restraint on serine palmitoyltransferase produce an upper-motor-neuron-predominant, neurodevelopmentally complicated spastic paraplegia when the lesion is in SPTSSA, but combined upper and lower motor neuron disease when the same biochemical lesion is in SPTLC1 or SPTLC2?
KNOWLEDGE GAP OPEN sptssa_vs_sptlc_phenotype_divergence
Attached to
pathophysiology#Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
The SPTSSA, SPTLC1 and SPTLC2 disease variants converge on the same mechanism — impaired ORMDL regulation and unrestrained SPT activity — yet give clinically distinct syndromes. One reported difference is that the SPTSSA cHSP variants, unlike the ALS variants, do not increase and may decrease the activity of SPTSSB-containing SPT, which would change which sphingolipid species accumulate and in which cells. Until this is resolved, no entry in this family should assert a single shared downstream lipid species as the neurotoxic effector.
Proposed experiments
Comparative sphingolipidomics across SPT-subunit disease alleles
exp_spg90a_comparative_sphingolipidomics
Untargeted sphingolipidomic profiling of patient-derived cells and neurons carrying SPTSSA cHSP versus SPTLC1/SPTLC2 juvenile-ALS alleles, resolving SPTSSA- versus SPTSSB-containing holoenzyme output, to test whether the accumulating species differ in a way that tracks the clinical divergence.
Show evidence (2 references)
PMID:38788085 SUPPORT Other
"Despite the biochemical similarities and differences between SPT-related juvenile ALS and cHSP, the mechanisms underlying the phenotypic differences remain poorly understood."
The discovering group states the gap explicitly.
PMID:38788085 SUPPORT Other
"It is notable that unlike the SPTLC1 and SPTLC2-related ALS variants, the cHSP-related SPTSSA variants do not increase, and likely decrease (via ORMDL inhibition) the activity of SPTSSB-containing SPT."
Records the one concrete biochemical difference proposed to explain the divergence, including the authors' own hedge.
Does the Drosophila SPTSSA model, which has neither a corticospinal tract nor myelin, license the inference that excess sphingolipid synthesis causes length-dependent upper-motor-neuron axonal degeneration in humans?
HUMAN MODEL MISMATCH OPEN no_mammalian_model_of_sptssa_hsp
Attached to
pathophysiology#Distal Degeneration of Long Corticospinal Axons
The only in vivo model of SPTSSA disease variants is in Drosophila, and no murine model of an SPT-related ALS or HSP variant had been reported as of the 2024 review. The corticospinal localisation curated in this entry therefore rests on the clinical pattern of selective upper-motor-neuron signs plus class-level HSP knowledge, not on demonstrated pathology in this disorder or in a mammalian model of it. The nearest mammalian evidence, the Stellar mouse, carries a different gene (SPTSSB), a different molecular mechanism (altered substrate affinity rather than lost ORMDL restraint) and a different phenotype (ataxia rather than spastic paraparesis).
Proposed experiments
Knock-in mouse carrying the recurrent SPTSSA p.Thr51Ile allele
exp_spg90a_t51i_knockin_mouse
Generate and characterise a mouse knock-in of the recurrent human allele, testing specifically for length-dependent corticospinal axonal degeneration with sparing of lower motor neurons, and for the developmental and auditory components of the human phenotype.
Show evidence (1 reference)
PMID:38788085 SUPPORT Other
"No murine models with SPT-related ALS or HSP variants have been reported so far."
Establishes the absence of a mammalian model, which is the basis for this mismatch.
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Pathophysiology

6
SPTSSA Activating Missense Variant
SPTSSA encodes the small subunit A of serine palmitoyltransferase. It carries no catalytic centre of its own — the pyridoxal-phosphate active site sits in the SPTLC1/SPTLC2 heterodimer — but it coordinates the acyl-CoA substrate and thereby both stimulates SPT activity and sets its substrate selectivity. The disease alleles are missense changes affecting the transmembrane face of the subunit, and they act by activating (de-restraining) the enzyme rather than by abolishing it. This node is the disorder-specific instance of the module's lipid-metabolism route to long-axon maintenance failure.
SPTSSA hgnc:20361 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPTSSA (hgnc:20361). hgnc:20361 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SPTSSA hgnc:20361 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SPTSSA (hgnc:20361). hgnc:20361 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
The recurrent SPG90A allele is the heterozygous missense change p.Thr51Ile. It was found in two of the founding three patients and again in the fourth, so it accounts for three of the four published SPG90 patients. The remaining founding patient carries the other of the two variants reported in that series; the cached abstracts do not state whether that patient is monoallelic or biallelic, so this entry does not assert which pole they belong to and therefore does not claim a denominator restricted to SPG90A. It is recorded as GAIN_OF_FUNCTION at the variant level because the review literature calls the SPTSSA disease variants activating and because the measured consequence is escape from ORMDL restraint rather than loss of enzyme output. This is a claim about the VARIANT's consequence and is a different assertion from the pathway-activity `modifier` values on the downstream ORMDL node, which describe the state of the process regardless of cause.
`variant_origin` is deliberately left unset. Deep-research output described SPG90A as "de novo-dominant", but the phrase "de novo" appears in none of the three cached sources this entry relies on for the genetics (PMID:40533086, PMID:36718090, PMID:38788085), so parental testing status is not curated either way.
serine palmitoyltransferase complex GO:0017059 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves serine palmitoyltransferase complex (GO:0017059). GO:0017059 is a protein complex from the Gene Ontology.
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase The variants sit where the small subunit participates in the regulated assembly, so the ORMDL negative-feedback arm is the function that fails.
Show evidence (3 references)
PMID:36718090 SUPPORT Human Clinical
"Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia."
Establishes SPTSSA variants as the genetic cause of the complex hereditary spastic paraplegia phenotype curated here.
PMID:36718090 SUPPORT Other
"Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA."
States the role of SPTSSA as the activating subunit of the rate-limiting enzyme, which is the function perturbed at this node.
PMID:33558762 SUPPORT In Vitro
"SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity."
Cryo-EM and biochemical work defining what the small subunit does in the holoenzyme — substrate coordination and activity stimulation, not catalysis.
Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
Sphingolipids are simultaneously essential and cytotoxic, so their synthesis is held under tight homeostatic control. The ORMDL proteins bind the SPT holoenzyme and inhibit it when sphingolipid levels become excessive; ORMDL3 sits in the centre of the complex and stabilises the assembly. In SPG90A the catalytic machinery is intact — what is lost is the restraint on it, which is why this is modelled as a gain of function of the pathway rather than an enzyme deficiency.
serine palmitoyltransferase complex GO:0017059 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves serine palmitoyltransferase complex (GO:0017059). GO:0017059 is a protein complex from the Gene Ontology.
negative regulation of sphingolipid biosynthetic process GO:0090155 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves negative regulation of sphingolipid biosynthetic process (GO:0090155), qualified as loss of function. GO:0090155 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
serine C-palmitoyltransferase activity GO:0004758 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves serine C-palmitoyltransferase activity (GO:0004758), qualified as gain of function. GO:0004758 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Unrestrained De Novo Sphingolipid Synthesis With the negative-feedback arm broken, flux through the first committed step of sphingolipid biosynthesis rises.
Show evidence (5 references)
PMID:36718090 SUPPORT Other
"Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive."
States the normal regulatory relationship whose failure defines this node.
PMID:36718090 SUPPORT Other
"Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated."
Supports the framing that the regulatory arm, not the catalytic arm, is the disease-relevant vulnerability.
PMID:37308477 SUPPORT In Vitro
"Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity."
Identifies the ceramide-binding site through which ORMDL suppresses SPT activity, defining the specific regulatory function that is lost at this node.
+ 2 more references
Unrestrained De Novo Sphingolipid Synthesis
Loss of feedback restraint raises de novo sphingolipid production. This matters disproportionately in the nervous system, where sphingolipids are abundant structural components of membranes and especially of myelin, so a shift in the size and composition of the sphingolipid pool changes the membrane environment on which long axons and their oligodendrocyte partners depend. The excess was demonstrated biochemically in HEK293 cells and patient fibroblasts and in vivo in Drosophila; it has not been measured in human nervous tissue.
sphingolipid biosynthetic process GO:0030148 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sphingolipid biosynthetic process (GO:0030148). GO:0030148 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Drosophila SPTSSA-variant hereditary spastic paraplegia model Drosophila melanogaster recapitulates The variants produce elevated sphingolipids in vivo in the fly, which is the in-animal demonstration of the excess-synthesis node.
Downstream
Distal Degeneration of Long Corticospinal Axons Excess sphingolipid synthesis is the proposed proximate driver of the corticospinal syndrome. The intervening steps between the lipid excess and selective upper-motor-neuron axonal failure are not established in humans; the strongest in vivo support is the Drosophila model, in which the same variants produce elevated sphingolipids together with motor deficits.
Broader CNS Neurodevelopmental and Neurodegenerative Involvement The discovering study attributed the phenotype not only to axonal degeneration but to defects in early brain development and function, which is what makes SPG90A a complicated rather than a pure spastic paraplegia.
Show evidence (2 references)
PMID:36718090 SUPPORT In Vitro
"The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila."
Identifies the experimental systems in which the excess synthesis was measured, which is the basis for the caveat that human nervous tissue was not assayed.
PMID:36718090 SUPPORT Other
"Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes."
Supports why an altered sphingolipid pool is expected to be neurologically consequential rather than metabolically silent.
Distal Degeneration of Long Corticospinal Axons
The clinical signature of SPG90A is upper-motor-neuron dysfunction without lower motor neuron disease, which localises the lesion to the corticospinal tract and is the disorder-specific instance of the module's length-dependent dying-back axonopathy. This localisation is inferred from the clinical and review description of selective upper-motor-neuron involvement; no human neuropathological or neurophysiological study of an SPG90A patient has been published, so the length-dependent distal pattern is imported from the HSP class rather than demonstrated in this disorder.
upper motor neuron CL:0008048 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves upper motor neuron (CL:0008048). CL:0008048 is a cell type from the Cell Ontology.
spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Drosophila SPTSSA-variant hereditary spastic paraplegia model Drosophila melanogaster partially recapitulates The variant-expressing flies show motor deficits and shortened lifespan, which the review describes as consistent with motor neuron degeneration. This is the organismal readout that carries the model's relevance to the degeneration node, and it is separated from the lipid link because motor performance is a readout of neurodegeneration, not of a lipid measurement.
Stellar (Sptssb H56L) mouse Mus musculus partially recapitulates Demonstrates in a mammal that a small-subunit lesion which dysregulates SPT output causes axon degeneration.
Downstream
Loss of Supraspinal Inhibitory Control of the Stretch Reflex Degeneration of descending corticospinal axons removes the supraspinal inhibitory input that normally restrains the spinal stretch reflex.
Show evidence (2 references)
PMID:38788085 SUPPORT Human Clinical
"In this disease, symptoms emerge in early childhood predominantly with upper motor neuron dysfunction leading to lower extremity spasticity without lower motor neuron disease."
Establishes selective upper-motor-neuron involvement, which is what localises the lesion to the corticospinal tract in this disorder.
PMID:33439395 SUPPORT Other
"Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders which involve the corticospinal tracts and present with distinct spasticity and weakness of the lower extremities."
Class-level statement that the HSP phenotype reflects corticospinal tract involvement. Evidence source is OTHER because this is a review, and it is cited as the basis for the imported class-level localisation.
Loss of Supraspinal Inhibitory Control of the Stretch Reflex
Disinhibition of the spinal stretch reflex produces the velocity-dependent hypertonia that defines spasticity. As the module records, the hypertonia of an upper-motor-neuron syndrome is not purely reflex-mediated: secondary soft tissue change contributes a non-reflex component, which is the mechanistic reason physiotherapy is curated alongside antispastic drugs in this entry.
spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Lower limb spasticity Disinhibited stretch reflexes plus loss of descending motor drive produce the lower-limb spasticity that dominates the clinical picture.
Spastic paraplegia The combination of spasticity and weakness in the lower limbs constitutes the spastic paraparesis that names the disease.
Inability to walk Progressive spasticity and weakness of the lower limbs can prevent independent ambulation; the fourth reported patient was unable to walk.
Show evidence (1 reference)
PMID:25530960 SUPPORT Other
"Therefore, in patients with UMNS, hypertonia can be divided into two components: hypertonia mediated by the stretch reflex, which corresponds to spasticity, and hypertonia due to soft tissue changes, which is often referred as nonreflex hypertonia or intrinsic hypertonia."
Supports the two-component account of hypertonia stated in this node, and the rehabilitation arm of treatment that follows from it.
Broader CNS Neurodevelopmental and Neurodegenerative Involvement
What makes SPG90A a complicated rather than a pure HSP is involvement beyond the corticospinal tract: neurodevelopmental delay from early life, variable sensorineural hearing loss, and language/cognitive dysfunction with progressive cognitive decline. The review literature on SPT-related disease describes this class as showing selective upper-motor-neuron involvement together with more broad CNS neurodegeneration. Whether the developmental and the degenerative components are one process or two is not resolved.
Downstream
Global developmental delay Neurodevelopmental delay is a defining feature of the syndrome; the cellular route from sphingolipid excess to it is not established.
Sensorineural hearing impairment Sensorineural hearing loss is a variable feature. Whether it arises cochlear or retrocochlear has not been determined in any reported patient.
Mental deterioration Cognitive decline is described as progressive, distinguishing it from a purely static developmental deficit.
Dystonia Dystonia was documented in the fourth reported patient, indicating involvement beyond the corticospinal tract.
Axial hypotonia Axial hypotonia coexisting with appendicular spasticity was documented in the fourth reported patient, a combination typical of a neurodevelopmentally complicated upper-motor-neuron syndrome.
Neurogenic bladder Neurogenic bladder was a novel finding in the fourth patient and is proposed, not established, as a component of the syndrome.
Show evidence (2 references)
PMID:36718090 SUPPORT Human Clinical
"two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals"
Enumerates the extra-corticospinal features that define the complicated phenotype represented by this node.
PMID:38788085 SUPPORT Other
"a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration"
Places the disorder in the complicated-HSP category with CNS involvement wider than the corticospinal tract.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spastic Paraplegia 90A, Autosomal Dominant Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Ear 1
Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36718090 SUPPORT Human Clinical
"progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction"
Documents variable sensorineural hearing loss in the founding cohort.
Genitourinary 1
Neurogenic bladder HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"The neurogenic bladder and primary polydipsia found in our patient are novel findings, and we propose that genitourinary problems may be a component of the syndrome."
Reports the finding in one patient and explicitly frames syndrome membership as a proposal, so this is marked PARTIAL.
Musculoskeletal 1
Spastic paraplegia HP:0001258 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic paraplegia (HP:0001258), qualified as course progressive; childhood onset. HP:0001258 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: CHILDHOOD
Show evidence (1 reference)
PMID:36718090 SUPPORT Human Clinical
"three children presenting with a complex form of hereditary spastic paraplegia"
Establishes the spastic paraplegia phenotype and its childhood onset in the reported patients.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"This syndrome is characterized by neurodevelopmental delay, sensorineural hearing loss, progressive motor impairment"
Names neurodevelopmental delay as a characteristic feature of the syndrome.
Mental deterioration HP:0001268 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mental deterioration (HP:0001268), qualified as course progressive. HP:0001268 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:38788085 SUPPORT Human Clinical
"Progressive cognitive decline and sensorineural hearing loss were also reported as clinical features."
States that the cognitive involvement is progressive.
Dystonia HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"axial hypotonia, extremity spasticity, dystonia, distal renal tubular acidosis"
Documents dystonia among the neurological findings in a reported patient.
Other 3
Lower limb spasticity HP:0002061 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity (HP:0002061). HP:0002061 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"progressive motor impairment, and lower extremity spasticity"
Names lower-extremity spasticity as a characteristic feature of the syndrome.
Inability to walk HP:0002540 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inability to walk (HP:0002540). HP:0002540 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"a 10-year-old female patient with global developmental delay, inability to walk"
Documents inability to walk in a reported patient at age 10.
Axial hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"inability to walk, axial hypotonia, extremity spasticity"
Documents axial hypotonia in a reported patient.
🧬

Genetic Associations

1
SPTSSA activating missense variant (Causative)
Gene: SPTSSA hgnc:20361 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPTSSA (hgnc:20361). hgnc:20361 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:40533086 SUPPORT Human Clinical
"Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
Identifies the recurrent heterozygous p.Thr51Ile allele and its recurrence across independent patients.
PMID:38788085 SUPPORT Other
"those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP"
Places the SPTSSA disease variants in the transmembrane structural class associated with the unrestrained-SPT phenotypes rather than with HSAN1.
Variants (1)
p.Thr51Ile Pathogenic
The recurrent SPTSSA allele and the only one reported in more than one patient. Heterozygous missense; found in two of the founding three patients and again in the fourth, giving three of the four published SPG90 patients. It is the allele that makes allele-specific approaches conceivable in this disease at all, which is why the entry curates a small-subunit knockdown concept alongside partial enzyme inhibition.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
Names the allele, its heterozygous state, its pathogenic classification and its recurrence across independent patients.
💊

Medical Actions

6
Supportive and symptomatic care
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No disease-modifying therapy exists for SPG90A. Management is supportive and directed at spasticity, mobility, communication, hearing, and developmental needs, as for other complicated hereditary spastic paraplegias.
Physical therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physiotherapy, stretching and limb mobilisation to manage spasticity, preserve range of motion and maintain function. This addresses the non-reflex (intrinsic) component of hypertonia that soft-tissue change contributes on top of the disinhibited stretch reflex.
Mechanism Target:
MODULATES Loss of Supraspinal Inhibitory Control of the Stretch Reflex — Mobilisation and stretching target the hypertonia produced by the disinhibited stretch reflex and the secondary soft-tissue changes that accompany it. This is symptomatic management, not modification of the underlying lipid lesion.
Show evidence (1 reference)
PMID:25530960 SUPPORT Other
"Therefore, in patients with UMNS, hypertonia can be divided into two components: hypertonia mediated by the stretch reflex, which corresponds to spasticity, and hypertonia due to soft tissue changes, which is often referred as nonreflex hypertonia or intrinsic hypertonia."
Identifies the soft-tissue component of hypertonia that rehabilitation addresses, which is why physiotherapy is linked to this node.
Antispasticity pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: baclofen CHEBI:2972 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baclofen (CHEBI:2972). CHEBI:2972 is a therapeutic agent from Chemical Entities of Biological Interest.
Symptomatic antispastic agents such as baclofen are used to reduce lower-limb spasticity, as in other hereditary spastic paraplegias. No trial evidence specific to SPG90A exists.
Mechanism Target:
INHIBITS Loss of Supraspinal Inhibitory Control of the Stretch Reflex — Antispastic agents act on the reflex-mediated component of the hypertonia produced by loss of descending inhibitory control — the component the source below identifies as spasticity proper, as distinct from the non-reflex soft-tissue hypertonia that rehabilitation addresses. This is symptomatic suppression of a downstream node; it does not touch the sphingolipid lesion.
Show evidence (1 reference)
PMID:25530960 SUPPORT Other
"hypertonia mediated by the stretch reflex, which corresponds to spasticity"
Identifies the reflex-mediated component of hypertonia that antispastic pharmacotherapy targets. Marked PARTIAL because the quoted review characterises the target component rather than naming baclofen or reporting a trial, and no antispastic trial specific to SPG90A exists.
Avoidance of L-Serine Supplementation
Category: Counseling / Informational
L-serine supplementation must NOT be given in SPG90A. This is not a gap in the treatment list, it is an active contraindication, and it is a trap specific to this disease family: L-serine is an established supplement strategy in hereditary sensory and autonomic neuropathy type 1, which is caused by variants in the SAME serine palmitoyltransferase complex. HSAN1 variants make the enzyme promiscuous so that it uses L-alanine and generates neurotoxic 1-deoxysphingolipids, and flooding the enzyme with its correct substrate outcompetes that side reaction. SPG90A is the opposite lesion — the enzyme is not promiscuous, it is unrestrained — so supplying more substrate would be predicted to drive the very overproduction that causes the disease. A clinician who recognises "a serine palmitoyltransferase disorder" and reaches for the familiar intervention would be expected to make the patient worse.
Show evidence (1 reference)
PMID:38788085 SUPPORT Other
"In SPT-related motor neuron diseases, which are caused by unrestrained SPT activity, serine supplementation would be predicted to exacerbate sphingolipid overproduction, with the potential to accelerate the disease progression"
The discovering group's own statement of the contraindication for the unrestrained-SPT diseases, of which SPG90A is one. The authors' hedge ("would be predicted") is quoted intact and is preserved in the notes.
Partial Serine Palmitoyltransferase Inhibition (investigational)
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: myriocin (tool compound) CHEBI:582124 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses myriocin (tool compound), annotated with myriocin (CHEBI:582124). CHEBI:582124 is a therapeutic agent from Chemical Entities of Biological Interest.
The mechanistically rational direction for a disease of unrestrained SPT activity is to inhibit the enzyme partially. Myriocin is the canonical tool compound, a fungal natural product that inhibits SPT through a dual mechanism. Nothing here is clinically available for SPG90A: this is curated as the rational therapeutic axis implied by the mechanism, not as a treatment, and the toxicity caveat is part of the claim rather than a footnote to it — complete SPT inhibition causes systemic toxicity, so any viable approach has to be partial.
Mechanism Target:
INHIBITS Unrestrained De Novo Sphingolipid Synthesis — Partial pharmacological inhibition of serine palmitoyltransferase would act directly on the node that the loss of ORMDL restraint drives. No such agent has been given to an SPG90A patient.
Show evidence (1 reference)
PMID:38788085 SUPPORT Other
"To counteract SPT overactivity, partial SPT inhibition provides a more rational therapeutic approach, though one must act with caution as complete inhibition of SPT is associated with systemic toxicity."
States both the rationale for targeting this node and the toxicity limit on doing so, which is why the treatment is curated as investigational.
Show evidence (1 reference)
PMID:38788085 SUPPORT Other
"Myriocin (also known as thermozymocidin or ISP-10) was first isolated as a natural fungal product and exerts a potent inhibitory effect on SPT via a dual inhibitory mechanism."
Identifies the canonical SPT inhibitor and its mechanism.
SPT Small-Subunit Knockdown (preclinical concept)
Category: Therapeutic
Because the small subunits set SPT activity and substrate selectivity without being catalytic, knocking down SPTSSA or SPTSSB has been argued to offer theoretical advantages over small-molecule inhibition or allele-specific knockdown. For SPG90A specifically this is attractive in principle — a dominant activating lesion in a non-catalytic subunit with a single recurrent allele — but it is a preclinical argument, not a programme: no construct, modality, delivery route or animal efficacy result is reported, which is why `therapeutic_modality` is OTHER rather than SIRNA or ANTISENSE_OLIGONUCLEOTIDE and no `aso_details` block is curated.
Mechanism Target:
INHIBITS Unrestrained De Novo Sphingolipid Synthesis — Reducing small-subunit abundance would lower SPT output, acting on the same node as pharmacological inhibition but through a different lever.
Show evidence (1 reference)
PMID:38788085 SUPPORT Other
"knockdown of small subunits of SPT (SPTSSA or SPTSSB) instead of SPTLC1 or SPTLC2 provides theoretical advantages over small molecules or allele-specific knockdown approaches"
States the rationale for targeting the small subunits. Marked PARTIAL because the source argues a theoretical advantage rather than reporting an experimental or clinical result.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Four patients with SPG90 had been reported at the time of the 2026 case report — three in the founding series and the fourth in that report. Both the dominant and recessive poles are included in that count, so the number of published SPG90A cases is smaller still. No population-based prevalence estimate exists.
Show evidence (1 reference)
PMID:40533086 SUPPORT Human Clinical
"To date, only three patients have been reported."
States the published case count before the fourth patient was added, supporting the ultra-rare classification.
🐁

Animal Models

2
Drosophila SPTSSA-variant hereditary spastic paraplegia model
The founding study used Drosophila to test the SPTSSA variants in vivo, showing that they raise sphingolipid levels in a whole animal rather than only in transfected cells. The review by the same group reports that these flies also show motor deficits and shortened lifespan.
Species
Drosophila melanogaster
Genotype
SPTSSA hereditary-spastic-paraplegia variant expressed in Drosophila
Publication
PMID:36718090
Pathograph links
Unrestrained De Novo Sphingolipid Synthesis recapitulates fidelity: moderate The variants produce elevated sphingolipids in vivo in the fly, which is the in-animal demonstration of the excess-synthesis node.
Limitations: Drosophila has no corticospinal tract and no myelin, so the model can demonstrate the metabolic lesion and a motor consequence but cannot reproduce the specific upper-motor-neuron anatomy of human SPG90A. The human sphingolipid excess itself was measured in HEK293 cells and patient fibroblasts, not in nervous tissue.
Readouts
Whole-animal sphingolipid levels
Direction: INCREASED
Interpretation: Elevated sphingolipids in the variant-expressing fly are the in vivo readout of failed feedback restraint.
Show evidence (1 reference)
PMID:38788085 SUPPORT Model Organism
"Drosophila models of SPTSSA-related HSP variants show elevated sphingolipids"
Reports the direction of the lipid measurement in the fly model.
Show evidence (1 reference)
PMID:36718090 SUPPORT Model Organism
"leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila"
Establishes that the Drosophila work is one of the two evidence streams supporting the excess-synthesis node, which is what makes this model informative for it.
Distal Degeneration of Long Corticospinal Axons partially recapitulates fidelity: low The variant-expressing flies show motor deficits and shortened lifespan, which the review describes as consistent with motor neuron degeneration. This is the organismal readout that carries the model's relevance to the degeneration node, and it is separated from the lipid link because motor performance is a readout of neurodegeneration, not of a lipid measurement.
Limitations: Drosophila has no corticospinal tract, no upper motor neurons and no myelin, so a fly motor deficit cannot evidence a LENGTH-DEPENDENT CENTRAL axonopathy specifically; it evidences that excess sphingolipid synthesis is neurologically damaging in a whole animal. The cited wording is "consistent with motor neuron degeneration", which is an inference from behaviour and lifespan rather than a demonstration of axonal pathology.
Readouts
Motor performance and lifespan
Direction: DECREASED
Interpretation: Motor deficits and shortened lifespan are the organismal consequence attributed to the elevated sphingolipids in this model, and are the closest available in vivo correlate of the degeneration node.
Show evidence (1 reference)
PMID:38788085 SUPPORT Model Organism
"with motor deficits and shorter lifespans, consistent with motor neuron degeneration"
Reports the motor and lifespan readouts of the fly model and the authors' interpretation of them.
Show evidence (1 reference)
PMID:38788085 SUPPORT Model Organism
"Drosophila models of SPTSSA-related HSP variants show elevated sphingolipids, with motor deficits and shorter lifespans, consistent with motor neuron degeneration"
Links the fly model to a neurodegenerative interpretation. Marked PARTIAL because the inference is from motor behaviour and lifespan in an animal with no corticospinal tract.
Stellar (Sptssb H56L) mouse
A spontaneous mouse mutation in the paralogous SPT small subunit SPTSSB that alters SPT substrate affinity and produces neurodegeneration with axon degeneration. It is included here as the closest available mammalian model of a dysregulated SPT small subunit, not as a model of SPTSSA disease.
Species
Mus musculus
Genotype
Sptssb Stellar (Stl) spontaneous mutation
Publication
PMID:26438849
Pathograph links
Distal Degeneration of Long Corticospinal Axons partially recapitulates fidelity: low Demonstrates in a mammal that a small-subunit lesion which dysregulates SPT output causes axon degeneration.
Limitations: The allele is in SPTSSB, not SPTSSA, and it acts by changing acyl-CoA substrate affinity and elevating C20 long-chain bases rather than by breaking ORMDL feedback restraint — a different molecular route to a different lipid species. The phenotype is ataxia with premature death, not a spastic paraparesis, and no corticospinal-tract-specific pathology is claimed.
Readouts
Axon degeneration and membrane protein-homeostasis abnormality
Direction: INCREASED
Interpretation: Axon degeneration is the readout that makes this model informative for a neurodegenerative consequence of SPT small-subunit dysregulation.
Show evidence (1 reference)
PMID:26438849 SUPPORT Model Organism
"resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration"
Reports the neurodegenerative readouts, including axon degeneration, in the mutant mouse.
Show evidence (1 reference)
PMID:26438849 SUPPORT Model Organism
"Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo."
Establishes the general principle that SPT small subunits control enzyme output in vivo, which is what makes this model partially informative. Marked PARTIAL because the gene and lipid species differ from SPG90A.
{ }

Source YAML

click to show 
name: Spastic Paraplegia 90A, Autosomal Dominant
creation_date: "2026-08-25T00:00:00Z"
category: Mendelian
description: >-
  Spastic paraplegia 90A (SPG90A) is an ultra-rare, early-childhood-onset
  complex (complicated) hereditary spastic paraplegia caused by monoallelic
  activating missense variants in SPTSSA, which encodes the small activating
  subunit A of serine palmitoyltransferase (SPT) — the endoplasmic-reticulum
  enzyme that catalyses the rate-limiting first step of de novo sphingolipid
  biosynthesis. SPT activity is held in check by the ORMDL proteins, which bind
  the complex and inhibit it when sphingolipid levels rise. The SPTSSA disease
  variants sit on the face of the small subunit that participates in this
  regulation, so ORMDL-mediated feedback inhibition fails and sphingolipid
  synthesis runs unrestrained. This is a gain of function in the sense of lost
  restraint, not a deficiency state. Affected children present with progressive
  lower-limb spasticity and motor impairment on a background of
  neurodevelopmental delay, with variable sensorineural hearing loss and
  language/cognitive dysfunction. Only four SPG90 patients have been published in
  total, and the recurrent p.Thr51Ile allele accounts for three of them: two of
  the founding three carried it, and so did the fourth. It is the only SPTSSA
  allele reported more than once, and on current evidence it is effectively the
  SPG90A allele.


  SPG90A is deliberately curated as the MONDO-recognised autosomal DOMINANT pole
  of SPG90 (OMIM #620416); the biallelic/recessive pole is a separate MONDO
  concept (SPG90B, OMIM #620417) and is not folded in here. It is also
  mechanistically the sibling — not a duplicate — of the SPTLC1/SPTLC2 juvenile
  amyotrophic lateral sclerosis entries, which share the same
  loss-of-ORMDL-restraint biochemistry but produce combined upper and lower
  motor neuron disease rather than the neurodevelopmentally complicated,
  upper-motor-neuron-predominant picture seen here. Why the same biochemical
  lesion in different SPT subunits yields different clinical syndromes is an
  explicitly unresolved question, and is recorded as a knowledge gap rather than
  papered over.
disease_term:
  preferred_term: spastic paraplegia 90A, autosomal dominant
  term:
    id: MONDO:0957308
    label: spastic paraplegia 90A, autosomal dominant
synonyms:
- SPG90A
- spastic paraplegia 90, autosomal dominant
- SPTSSA-related complex hereditary spastic paraplegia
parents:
- Hereditary Spastic Paraplegia
- Complex Hereditary Spastic Paraplegia
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Placed with the neurologic disorders: the defining axis is a progressive
      corticospinal-tract syndrome with neurodevelopmental involvement.
      Harrison's does not list SPG90A by name; this is a mechanism-based
      placement.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    SPG90A is the monoallelic (heterozygous) pole of SPTSSA-related spastic
    paraplegia. The published SPG90 patients carry either monoallelic or
    biallelic SPTSSA variants; the monoallelic cases — including both reported
    carriers of the recurrent p.Thr51Ile allele and the fourth patient — define
    this dominant entity, while the biallelic cases belong to the separate
    recessive concept SPG90B.
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spastic paraplegia 90 (SPG90; OMIM #620416, 620417) is a rare neurologic disease caused by monoallelic or biallelic variants in the serine palmitoyltransferase small subunit A (SPTSSA) gene."
    explanation: >-
      Establishes that SPG90 comprises a monoallelic and a biallelic pole with
      distinct OMIM numbers, which is the basis for scoping this entry to the
      dominant (#620416) concept.
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
    explanation: >-
      Documents a heterozygous (monoallelic) pathogenic allele recurring across
      independent patients, supporting dominant action of the p.Thr51Ile variant.
pathophysiology:
- name: SPTSSA Activating Missense Variant
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "corticospinal_tract_axonopathy#Long-Axon Maintenance Machinery Defect"
  description: >-
    SPTSSA encodes the small subunit A of serine palmitoyltransferase. It carries
    no catalytic centre of its own — the pyridoxal-phosphate active site sits in
    the SPTLC1/SPTLC2 heterodimer — but it coordinates the acyl-CoA substrate and
    thereby both stimulates SPT activity and sets its substrate selectivity.
    The disease alleles are missense changes affecting the transmembrane face of
    the subunit, and they act by activating (de-restraining) the enzyme rather
    than by abolishing it. This node is the disorder-specific instance of the
    module's lipid-metabolism route to long-axon maintenance failure.
  genes:
  - preferred_term: SPTSSA
    term:
      id: hgnc:20361
      label: SPTSSA
  genetic_context:
    gene:
      preferred_term: SPTSSA
      term:
        id: hgnc:20361
        label: SPTSSA
    allele_type: missense
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      The recurrent SPG90A allele is the heterozygous missense change p.Thr51Ile.
      It was found in two of the founding three patients and again in the fourth,
      so it accounts for three of the four published SPG90 patients. The
      remaining founding patient carries the other of the two variants reported
      in that series; the cached abstracts do not state whether that patient is
      monoallelic or biallelic, so this entry does not assert which pole they
      belong to and therefore does not claim a denominator restricted to SPG90A.
      It is recorded as GAIN_OF_FUNCTION at the variant level because the review
      literature calls the SPTSSA disease variants activating and because the
      measured consequence is escape from ORMDL restraint rather than loss of
      enzyme output. This is a claim about the VARIANT's consequence and is a
      different assertion from the pathway-activity `modifier` values on the
      downstream ORMDL node, which describe the state of the process regardless
      of cause.
    notes: >-
      `variant_origin` is deliberately left unset. Deep-research output described
      SPG90A as "de novo-dominant", but the phrase "de novo" appears in none of
      the three cached sources this entry relies on for the genetics
      (PMID:40533086, PMID:36718090, PMID:38788085), so parental testing status
      is not curated either way.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  protein_complexes:
  - preferred_term: serine palmitoyltransferase complex
    term:
      id: GO:0017059
      label: serine palmitoyltransferase complex
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia."
    explanation: >-
      Establishes SPTSSA variants as the genetic cause of the complex hereditary
      spastic paraplegia phenotype curated here.
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Serine palmitoyltransferase, the enzyme that catalyses the rate-limiting reaction of sphingolipid synthesis, is composed of multiple subunits including an activating subunit, SPTSSA."
    explanation: >-
      States the role of SPTSSA as the activating subunit of the rate-limiting
      enzyme, which is the function perturbed at this node.
  - reference: PMID:33558762
    reference_title: "Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity."
    explanation: >-
      Cryo-EM and biochemical work defining what the small subunit does in the
      holoenzyme — substrate coordination and activity stimulation, not catalysis.
  downstream:
  - target: Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
    causal_link_type: DIRECT
    description: >-
      The variants sit where the small subunit participates in the regulated
      assembly, so the ORMDL negative-feedback arm is the function that fails.
    evidence:
    - reference: PMID:36718090
      reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila."
      explanation: >-
        Directly links the SPTSSA variants to failure of ORMDL-mediated negative
        regulation.
- name: Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    Sphingolipids are simultaneously essential and cytotoxic, so their synthesis
    is held under tight homeostatic control. The ORMDL proteins bind the SPT
    holoenzyme and inhibit it when sphingolipid levels become excessive; ORMDL3
    sits in the centre of the complex and stabilises the assembly. In SPG90A the
    catalytic machinery is intact — what is lost is the restraint on it, which is
    why this is modelled as a gain of function of the pathway rather than an
    enzyme deficiency.
  molecular_functions:
  - preferred_term: serine C-palmitoyltransferase activity
    term:
      id: GO:0004758
      label: serine C-palmitoyltransferase activity
    modifier: GAIN_OF_FUNCTION
  biological_processes:
  - preferred_term: negative regulation of sphingolipid biosynthetic process
    term:
      id: GO:0090155
      label: negative regulation of sphingolipid biosynthetic process
    modifier: LOSS_OF_FUNCTION
  protein_complexes:
  - preferred_term: serine palmitoyltransferase complex
    term:
      id: GO:0017059
      label: serine palmitoyltransferase complex
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive."
    explanation: >-
      States the normal regulatory relationship whose failure defines this node.
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated."
    explanation: >-
      Supports the framing that the regulatory arm, not the catalytic arm, is the
      disease-relevant vulnerability.
  - reference: PMID:37308477
    reference_title: "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity."
    explanation: >-
      Identifies the ceramide-binding site through which ORMDL suppresses SPT
      activity, defining the specific regulatory function that is lost at this
      node.
  - reference: PMID:37308477
    reference_title: "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The ORM/ORMDL family proteins function as regulatory subunits of the serine palmitoyltransferase (SPT) complex, which is the initiating and rate-limiting enzyme in sphingolipid biosynthesis."
    explanation: >-
      States the regulatory-subunit relationship between ORMDL and SPT that this
      node depends on.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Similar to juvenile ALS variants, SPTSSA variants seem to interfere with ORMDL regulation of the SPT complex, thus resulting in unrestrained SPT activity."
    explanation: >-
      A review by the discovering group restating the mechanism and placing it
      alongside the SPTLC1/SPTLC2 juvenile-ALS variants. The hedged wording
      ("seem to") is preserved deliberately.
  downstream:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    causal_link_type: DIRECT
    description: >-
      With the negative-feedback arm broken, flux through the first committed
      step of sphingolipid biosynthesis rises.
    evidence:
    - reference: PMID:36718090
      reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis"
      explanation: >-
        States the causal step from failed ORMDL regulation to excessive
        sphingolipid synthesis.
- name: Unrestrained De Novo Sphingolipid Synthesis
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Loss of feedback restraint raises de novo sphingolipid production. This
    matters disproportionately in the nervous system, where sphingolipids are
    abundant structural components of membranes and especially of myelin, so a
    shift in the size and composition of the sphingolipid pool changes the
    membrane environment on which long axons and their oligodendrocyte partners
    depend. The excess was demonstrated biochemically in HEK293 cells and patient
    fibroblasts and in vivo in Drosophila; it has not been measured in human
    nervous tissue.
  biological_processes:
  - preferred_term: sphingolipid biosynthetic process
    term:
      id: GO:0030148
      label: sphingolipid biosynthetic process
    modifier: INCREASED
  chemical_entities:
  - preferred_term: sphingolipid
    term:
      id: CHEBI:26739
      label: sphingolipid
    modifier: INCREASED
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The effect of these variants on the catalytic activity and homeostatic regulation of serine palmitoyltransferase was investigated in human embryonic kidney cells, patient fibroblasts and Drosophila."
    explanation: >-
      Identifies the experimental systems in which the excess synthesis was
      measured, which is the basis for the caveat that human nervous tissue was
      not assayed.
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes."
    explanation: >-
      Supports why an altered sphingolipid pool is expected to be
      neurologically consequential rather than metabolically silent.
  downstream:
  - target: Distal Degeneration of Long Corticospinal Axons
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess sphingolipid synthesis is the proposed proximate driver of the
      corticospinal syndrome. The intervening steps between the lipid excess and
      selective upper-motor-neuron axonal failure are not established in humans;
      the strongest in vivo support is the Drosophila model, in which the same
      variants produce elevated sphingolipids together with motor deficits.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Drosophila models of SPTSSA-related HSP variants show elevated sphingolipids, with motor deficits and shorter lifespans, consistent with motor neuron degeneration"
      explanation: >-
        The in vivo link from lipid excess to a motor phenotype is made in
        Drosophila, which is why this edge is typed as having unknown
        intermediates in humans.
    - reference: PMID:26438849
      reference_title: "Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration"
      explanation: >-
        Independent mouse evidence that dysregulated SPT small-subunit function
        produces axon degeneration. Marked PARTIAL because the allele is in the
        paralogous small subunit SPTSSB, not SPTSSA.
  - target: Broader CNS Neurodevelopmental and Neurodegenerative Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The discovering study attributed the phenotype not only to axonal
      degeneration but to defects in early brain development and function, which
      is what makes SPG90A a complicated rather than a pure spastic paraplegia.
    evidence:
    - reference: PMID:36718090
      reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function"
      explanation: >-
        The authors' own causal attribution from excess sphingolipid synthesis to
        disturbed early brain development and function.
- name: Distal Degeneration of Long Corticospinal Axons
  biological_scale: TISSUE
  role: effector
  conforms_to: "corticospinal_tract_axonopathy#Distal Length-Dependent Degeneration of Long CNS Axons"
  description: >-
    The clinical signature of SPG90A is upper-motor-neuron dysfunction without
    lower motor neuron disease, which localises the lesion to the corticospinal
    tract and is the disorder-specific instance of the module's length-dependent
    dying-back axonopathy. This localisation is inferred from the clinical and
    review description of selective upper-motor-neuron involvement; no human
    neuropathological or neurophysiological study of an SPG90A patient has been
    published, so the length-dependent distal pattern is imported from the HSP
    class rather than demonstrated in this disorder.
  cell_types:
  - preferred_term: upper motor neuron
    term:
      id: CL:0008048
      label: upper motor neuron
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this disease, symptoms emerge in early childhood predominantly with upper motor neuron dysfunction leading to lower extremity spasticity without lower motor neuron disease."
    explanation: >-
      Establishes selective upper-motor-neuron involvement, which is what
      localises the lesion to the corticospinal tract in this disorder.
  - reference: PMID:33439395
    reference_title: Hereditary spastic paraplegia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative
      disorders which involve the corticospinal tracts and present with distinct
      spasticity and weakness of the lower extremities.
    explanation: >-
      Class-level statement that the HSP phenotype reflects corticospinal tract
      involvement. Evidence source is OTHER because this is a review, and it is
      cited as the basis for the imported class-level localisation.
  downstream:
  - target: Loss of Supraspinal Inhibitory Control of the Stretch Reflex
    causal_link_type: DIRECT
    description: >-
      Degeneration of descending corticospinal axons removes the supraspinal
      inhibitory input that normally restrains the spinal stretch reflex.
    evidence:
    - reference: PMID:25530960
      reference_title: "Pathophysiology of spasticity: implications for neurorehabilitation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The central lesion causing the UMNS disrupts the balance of supraspinal
        inhibitory and excitatory inputs directed to the spinal cord, leading to a
        state of disinhibition of the stretch reflex.
      explanation: >-
        States the causal step from a central upper-motor-neuron lesion to
        disinhibition of the stretch reflex.
- name: Loss of Supraspinal Inhibitory Control of the Stretch Reflex
  biological_scale: TISSUE
  role: effector
  conforms_to: "corticospinal_tract_axonopathy#Loss of Supraspinal Inhibitory Control of the Stretch Reflex"
  description: >-
    Disinhibition of the spinal stretch reflex produces the velocity-dependent
    hypertonia that defines spasticity. As the module records, the hypertonia of
    an upper-motor-neuron syndrome is not purely reflex-mediated: secondary soft
    tissue change contributes a non-reflex component, which is the mechanistic
    reason physiotherapy is curated alongside antispastic drugs in this entry.
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:25530960
    reference_title: "Pathophysiology of spasticity: implications for neurorehabilitation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Therefore, in patients with UMNS, hypertonia can be divided into two
      components: hypertonia mediated by the stretch reflex, which corresponds to
      spasticity, and hypertonia due to soft tissue changes, which is often
      referred as nonreflex hypertonia or intrinsic hypertonia.
    explanation: >-
      Supports the two-component account of hypertonia stated in this node, and
      the rehabilitation arm of treatment that follows from it.
  downstream:
  - target: Lower limb spasticity
    causal_link_type: DIRECT
    description: >-
      Disinhibited stretch reflexes plus loss of descending motor drive produce
      the lower-limb spasticity that dominates the clinical picture.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "upper motor neuron dysfunction leading to lower extremity spasticity without lower motor neuron disease"
      explanation: >-
        Directly attributes the lower-extremity spasticity to upper-motor-neuron
        dysfunction in this disorder.
  - target: Spastic paraplegia
    causal_link_type: DIRECT
    description: >-
      The combination of spasticity and weakness in the lower limbs constitutes
      the spastic paraparesis that names the disease.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This syndrome is characterized by neurodevelopmental delay, sensorineural hearing loss, progressive motor impairment, and lower extremity spasticity."
      explanation: >-
        Names lower-extremity spasticity and progressive motor impairment as
        defining features of the syndrome.
  - target: Inability to walk
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Progressive spasticity and weakness of the lower limbs can prevent
      independent ambulation; the fourth reported patient was unable to walk.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we present a 10-year-old female patient with global developmental delay, inability to walk, axial hypotonia, extremity spasticity, dystonia"
      explanation: >-
        Documents inability to walk alongside the extremity spasticity in a
        reported patient.
- name: Broader CNS Neurodevelopmental and Neurodegenerative Involvement
  biological_scale: ORGANISM
  role: consequence
  description: >-
    What makes SPG90A a complicated rather than a pure HSP is involvement beyond
    the corticospinal tract: neurodevelopmental delay from early life, variable
    sensorineural hearing loss, and language/cognitive dysfunction with
    progressive cognitive decline. The review literature on SPT-related disease
    describes this class as showing selective upper-motor-neuron involvement
    together with more broad CNS neurodegeneration. Whether the developmental and
    the degenerative components are one process or two is not resolved.
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two different pathogenic variants in SPTSSA caused a hereditary spastic paraplegia resulting in progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction in three individuals"
    explanation: >-
      Enumerates the extra-corticospinal features that define the complicated
      phenotype represented by this node.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "a complicated form of hereditary spastic paraplegia with selective involvement of the upper motor neurons and more broad CNS neurodegeneration"
    explanation: >-
      Places the disorder in the complicated-HSP category with CNS involvement
      wider than the corticospinal tract.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neurodevelopmental delay is a defining feature of the syndrome; the
      cellular route from sphingolipid excess to it is not established.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This syndrome is characterized by neurodevelopmental delay, sensorineural hearing loss, progressive motor impairment, and lower extremity spasticity."
      explanation: >-
        Names neurodevelopmental delay as a defining feature of the syndrome.
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Sensorineural hearing loss is a variable feature. Whether it arises
      cochlear or retrocochlear has not been determined in any reported patient.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cognitive decline and sensorineural hearing loss were also reported as clinical features."
      explanation: >-
        Reports sensorineural hearing loss as a clinical feature of this
        disorder.
  - target: Mental deterioration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cognitive decline is described as progressive, distinguishing it from a
      purely static developmental deficit.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Progressive cognitive decline and sensorineural hearing loss were also reported as clinical features."
      explanation: >-
        States that the cognitive involvement is progressive, which is what this
        phenotype records.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dystonia was documented in the fourth reported patient, indicating
      involvement beyond the corticospinal tract.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "inability to walk, axial hypotonia, extremity spasticity, dystonia"
      explanation: >-
        Documents dystonia in a reported SPG90 patient.
  - target: Axial hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Axial hypotonia coexisting with appendicular spasticity was documented in
      the fourth reported patient, a combination typical of a
      neurodevelopmentally complicated upper-motor-neuron syndrome.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "global developmental delay, inability to walk, axial hypotonia, extremity spasticity"
      explanation: >-
        Documents axial hypotonia alongside extremity spasticity in a reported
        patient.
  - target: Neurogenic bladder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Neurogenic bladder was a novel finding in the fourth patient and is
      proposed, not established, as a component of the syndrome.
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The neurogenic bladder and primary polydipsia found in our patient are novel findings, and we propose that genitourinary problems may be a component of the syndrome."
      explanation: >-
        Reports the finding and explicitly frames it as a proposal, which is why
        this edge and its phenotype are marked PARTIAL.
phenotypes:
- name: Spastic paraplegia
  category: Neurological
  description: >-
    Progressive lower-limb spastic paraparesis, the feature that names the
    disorder and places it in the hereditary spastic paraplegias.
  phenotype_term:
    preferred_term: Spastic paraplegia
    term:
      id: HP:0001258
      label: Spastic paraplegia
    clinical_course: PROGRESSIVE
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three children presenting with a complex form of hereditary spastic paraplegia"
    explanation: >-
      Establishes the spastic paraplegia phenotype and its childhood onset in the
      reported patients.
- name: Lower limb spasticity
  category: Neurological
  description: >-
    Spasticity of the lower extremities, the dominant motor sign and the direct
    expression of the upper-motor-neuron lesion.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive motor impairment, and lower extremity spasticity"
    explanation: >-
      Names lower-extremity spasticity as a characteristic feature of the
      syndrome.
- name: Inability to walk
  category: Neurological
  description: >-
    Loss or failure of independent ambulation. The fourth reported patient, aged
    10 years, was unable to walk.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 10-year-old female patient with global developmental delay, inability to walk"
    explanation: >-
      Documents inability to walk in a reported patient at age 10.
- name: Global developmental delay
  category: Neurological
  description: >-
    Neurodevelopmental delay is listed among the characteristic features of the
    syndrome and was global in the fourth reported patient.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This syndrome is characterized by neurodevelopmental delay, sensorineural hearing loss, progressive motor impairment"
    explanation: >-
      Names neurodevelopmental delay as a characteristic feature of the syndrome.
- name: Sensorineural hearing impairment
  category: Otologic
  description: >-
    Sensorineural hearing loss, described as variable across the reported
    patients.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36718090
    reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive motor disturbance with variable sensorineural hearing loss and language/cognitive dysfunction"
    explanation: >-
      Documents variable sensorineural hearing loss in the founding cohort.
- name: Mental deterioration
  category: Neurological
  description: >-
    Progressive cognitive decline, reported alongside the language/cognitive
    dysfunction seen in the founding cohort. Curated as deterioration rather than
    static impairment because the source describes it as progressive.
  phenotype_term:
    preferred_term: Mental deterioration
    term:
      id: HP:0001268
      label: Mental deterioration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Progressive cognitive decline and sensorineural hearing loss were also reported as clinical features."
    explanation: >-
      States that the cognitive involvement is progressive.
- name: Dystonia
  category: Neurological
  description: >-
    Dystonia documented in the fourth reported patient, indicating extrapyramidal
    involvement in addition to the corticospinal syndrome.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "axial hypotonia, extremity spasticity, dystonia, distal renal tubular acidosis"
    explanation: >-
      Documents dystonia among the neurological findings in a reported patient.
- name: Axial hypotonia
  category: Neurological
  description: >-
    Truncal hypotonia coexisting with appendicular spasticity in the fourth
    reported patient.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "inability to walk, axial hypotonia, extremity spasticity"
    explanation: >-
      Documents axial hypotonia in a reported patient.
- name: Neurogenic bladder
  category: Genitourinary
  description: >-
    Neurogenic bladder reported in the fourth patient. The authors present this
    as a novel finding and propose — rather than establish — that genitourinary
    involvement is part of the syndrome; it has not been reported in the other
    patients. Distal renal tubular acidosis, nephrolithiasis, recurrent urinary
    tract infection and primary polydipsia were reported in the same single
    patient and are not curated as separate phenotypes for the same reason.
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The neurogenic bladder and primary polydipsia found in our patient are novel findings, and we propose that genitourinary problems may be a component of the syndrome."
    explanation: >-
      Reports the finding in one patient and explicitly frames syndrome
      membership as a proposal, so this is marked PARTIAL.
genetic:
- name: SPTSSA activating missense variant
  gene_term:
    preferred_term: SPTSSA
    term:
      id: hgnc:20361
      label: SPTSSA
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous SPTSSA missense variants cause the dominant pole of SPG90
    (OMIM #620416). The p.Thr51Ile allele is recurrent: found in two of the
    founding three patients and again in the fourth, it accounts for three of the
    four published SPG90 patients and is the only SPTSSA allele reported more
    than once. The remaining founding patient carries the other variant reported
    in that series; the cached abstracts do not say whether that patient is
    monoallelic or biallelic, so no SPG90A-only denominator is asserted here. SPTSSA disease
    variants affect the transmembrane region of the small subunit, the same
    structural class of lesion that produces juvenile ALS when it falls in the
    corresponding transmembrane domain of SPTLC1. Biallelic SPTSSA variants
    cause the separate recessive concept SPG90B (OMIM #620417) and are out of
    scope for this entry.
  variants:
  - name: p.Thr51Ile
    description: >-
      The recurrent SPTSSA allele and the only one reported in more than one
      patient. Heterozygous missense; found in two of the founding three patients
      and again in the fourth, giving three of the four published SPG90 patients.
      It is the allele that makes allele-specific approaches conceivable in this
      disease at all, which is why the entry curates a small-subunit knockdown
      concept alongside partial enzyme inhibition.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:40533086
      reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
      explanation: >-
        Names the allele, its heterozygous state, its pathogenic classification
        and its recurrence across independent patients.
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome."
    explanation: >-
      Identifies the recurrent heterozygous p.Thr51Ile allele and its recurrence
      across independent patients.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP"
    explanation: >-
      Places the SPTSSA disease variants in the transmembrane structural class
      associated with the unrestrained-SPT phenotypes rather than with HSAN1.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Four patients with SPG90 had been reported at the time of the 2026 case
    report — three in the founding series and the fourth in that report. Both
    the dominant and recessive poles are included in that count, so the number of
    published SPG90A cases is smaller still. No population-based prevalence
    estimate exists.
  evidence:
  - reference: PMID:40533086
    reference_title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only three patients have been reported."
    explanation: >-
      States the published case count before the fourth patient was added,
      supporting the ultra-rare classification.
animal_models:
- name: Drosophila SPTSSA-variant hereditary spastic paraplegia model
  species: Drosophila melanogaster
  genotype: SPTSSA hereditary-spastic-paraplegia variant expressed in Drosophila
  publication: PMID:36718090
  description: >-
    The founding study used Drosophila to test the SPTSSA variants in vivo,
    showing that they raise sphingolipid levels in a whole animal rather than
    only in transfected cells. The review by the same group reports that these
    flies also show motor deficits and shortened lifespan.
  modeled_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The variants produce elevated sphingolipids in vivo in the fly, which is
      the in-animal demonstration of the excess-synthesis node.
    limitations: >-
      Drosophila has no corticospinal tract and no myelin, so the model can
      demonstrate the metabolic lesion and a motor consequence but cannot
      reproduce the specific upper-motor-neuron anatomy of human SPG90A. The
      human sphingolipid excess itself was measured in HEK293 cells and patient
      fibroblasts, not in nervous tissue.
    readouts:
    - name: Whole-animal sphingolipid levels
      target: Unrestrained De Novo Sphingolipid Synthesis
      direction: INCREASED
      interpretation: >-
        Elevated sphingolipids in the variant-expressing fly are the in vivo
        readout of failed feedback restraint.
      evidence:
      - reference: PMID:38788085
        reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Drosophila models of SPTSSA-related HSP variants show elevated sphingolipids"
        explanation: >-
          Reports the direction of the lipid measurement in the fly model.
    evidence:
    - reference: PMID:36718090
      reference_title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila"
      explanation: >-
        Establishes that the Drosophila work is one of the two evidence streams
        supporting the excess-synthesis node, which is what makes this model
        informative for it.
  - target: Distal Degeneration of Long Corticospinal Axons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The variant-expressing flies show motor deficits and shortened lifespan,
      which the review describes as consistent with motor neuron degeneration.
      This is the organismal readout that carries the model's relevance to the
      degeneration node, and it is separated from the lipid link because motor
      performance is a readout of neurodegeneration, not of a lipid measurement.
    limitations: >-
      Drosophila has no corticospinal tract, no upper motor neurons and no
      myelin, so a fly motor deficit cannot evidence a LENGTH-DEPENDENT CENTRAL
      axonopathy specifically; it evidences that excess sphingolipid synthesis is
      neurologically damaging in a whole animal. The cited wording is
      "consistent with motor neuron degeneration", which is an inference from
      behaviour and lifespan rather than a demonstration of axonal pathology.
    readouts:
    - name: Motor performance and lifespan
      target: Distal Degeneration of Long Corticospinal Axons
      direction: DECREASED
      interpretation: >-
        Motor deficits and shortened lifespan are the organismal consequence
        attributed to the elevated sphingolipids in this model, and are the
        closest available in vivo correlate of the degeneration node.
      evidence:
      - reference: PMID:38788085
        reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "with motor deficits and shorter lifespans, consistent with motor neuron degeneration"
        explanation: >-
          Reports the motor and lifespan readouts of the fly model and the
          authors' interpretation of them.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Drosophila models of SPTSSA-related HSP variants show elevated sphingolipids, with motor deficits and shorter lifespans, consistent with motor neuron degeneration"
      explanation: >-
        Links the fly model to a neurodegenerative interpretation. Marked PARTIAL
        because the inference is from motor behaviour and lifespan in an animal
        with no corticospinal tract.
- name: Stellar (Sptssb H56L) mouse
  species: Mus musculus
  genotype: Sptssb Stellar (Stl) spontaneous mutation
  publication: PMID:26438849
  description: >-
    A spontaneous mouse mutation in the paralogous SPT small subunit SPTSSB that
    alters SPT substrate affinity and produces neurodegeneration with axon
    degeneration. It is included here as the closest available mammalian model of
    a dysregulated SPT small subunit, not as a model of SPTSSA disease.
  modeled_mechanisms:
  - target: Distal Degeneration of Long Corticospinal Axons
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Demonstrates in a mammal that a small-subunit lesion which dysregulates SPT
      output causes axon degeneration.
    limitations: >-
      The allele is in SPTSSB, not SPTSSA, and it acts by changing acyl-CoA
      substrate affinity and elevating C20 long-chain bases rather than by
      breaking ORMDL feedback restraint — a different molecular route to a
      different lipid species. The phenotype is ataxia with premature death, not
      a spastic paraparesis, and no corticospinal-tract-specific pathology is
      claimed.
    readouts:
    - name: Axon degeneration and membrane protein-homeostasis abnormality
      target: Distal Degeneration of Long Corticospinal Axons
      direction: INCREASED
      interpretation: >-
        Axon degeneration is the readout that makes this model informative for a
        neurodegenerative consequence of SPT small-subunit dysregulation.
      evidence:
      - reference: PMID:26438849
        reference_title: "Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration"
        explanation: >-
          Reports the neurodegenerative readouts, including axon degeneration, in
          the mutant mouse.
    evidence:
    - reference: PMID:26438849
      reference_title: "Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo."
      explanation: >-
        Establishes the general principle that SPT small subunits control enzyme
        output in vivo, which is what makes this model partially informative.
        Marked PARTIAL because the gene and lipid species differ from SPG90A.
treatments:
- name: Supportive and symptomatic care
  description: >-
    No disease-modifying therapy exists for SPG90A. Management is supportive and
    directed at spasticity, mobility, communication, hearing, and developmental
    needs, as for other complicated hereditary spastic paraplegias.
  therapeutic_modality: OTHER
  action_category: THERAPEUTIC
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Physical therapy
  description: >-
    Physiotherapy, stretching and limb mobilisation to manage spasticity,
    preserve range of motion and maintain function. This addresses the non-reflex
    (intrinsic) component of hypertonia that soft-tissue change contributes on
    top of the disinhibited stretch reflex.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Loss of Supraspinal Inhibitory Control of the Stretch Reflex
    treatment_effect: MODULATES
    description: >-
      Mobilisation and stretching target the hypertonia produced by the
      disinhibited stretch reflex and the secondary soft-tissue changes that
      accompany it. This is symptomatic management, not modification of the
      underlying lipid lesion.
    evidence:
    - reference: PMID:25530960
      reference_title: "Pathophysiology of spasticity: implications for neurorehabilitation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Therefore, in patients with UMNS, hypertonia can be divided into two
        components: hypertonia mediated by the stretch reflex, which corresponds to
        spasticity, and hypertonia due to soft tissue changes, which is often
        referred as nonreflex hypertonia or intrinsic hypertonia.
      explanation: >-
        Identifies the soft-tissue component of hypertonia that rehabilitation
        addresses, which is why physiotherapy is linked to this node.
- name: Antispasticity pharmacotherapy
  description: >-
    Symptomatic antispastic agents such as baclofen are used to reduce lower-limb
    spasticity, as in other hereditary spastic paraplegias. No trial evidence
    specific to SPG90A exists.
  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
  target_mechanisms:
  - target: Loss of Supraspinal Inhibitory Control of the Stretch Reflex
    treatment_effect: INHIBITS
    description: >-
      Antispastic agents act on the reflex-mediated component of the hypertonia
      produced by loss of descending inhibitory control — the component the
      source below identifies as spasticity proper, as distinct from the
      non-reflex soft-tissue hypertonia that rehabilitation addresses. This is
      symptomatic suppression of a downstream node; it does not touch the
      sphingolipid lesion.
    evidence:
    - reference: PMID:25530960
      reference_title: "Pathophysiology of spasticity: implications for neurorehabilitation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        hypertonia mediated by the stretch reflex, which corresponds to
        spasticity
      explanation: >-
        Identifies the reflex-mediated component of hypertonia that antispastic
        pharmacotherapy targets. Marked PARTIAL because the quoted review
        characterises the target component rather than naming baclofen or
        reporting a trial, and no antispastic trial specific to SPG90A exists.
- name: Avoidance of L-Serine Supplementation
  description: >-
    L-serine supplementation must NOT be given in SPG90A. This is not a gap in
    the treatment list, it is an active contraindication, and it is a trap
    specific to this disease family: L-serine is an established supplement
    strategy in hereditary sensory and autonomic neuropathy type 1, which is
    caused by variants in the SAME serine palmitoyltransferase complex. HSAN1
    variants make the enzyme promiscuous so that it uses L-alanine and generates
    neurotoxic 1-deoxysphingolipids, and flooding the enzyme with its correct
    substrate outcompetes that side reaction. SPG90A is the opposite lesion —
    the enzyme is not promiscuous, it is unrestrained — so supplying more
    substrate would be predicted to drive the very overproduction that causes the
    disease. A clinician who recognises "a serine palmitoyltransferase disorder"
    and reaches for the familiar intervention would be expected to make the
    patient worse.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  notes: >-
    Deliberately carries no `target_mechanisms` link. The action curated here is
    withholding an intervention, which neither inhibits nor activates a node; a
    link either way would encode a clinical caution as a causal edge and would
    export as a false mechanistic assertion. The mechanistic content — that
    serine loading would exacerbate the sphingolipid overproduction node — is in
    the description and in the quoted evidence instead. Note also that the
    prediction is explicitly a prediction: no SPG90A patient has been given
    L-serine and reported.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In SPT-related motor neuron diseases, which are caused by unrestrained SPT activity, serine supplementation would be predicted to exacerbate sphingolipid overproduction, with the potential to accelerate the disease progression"
    explanation: >-
      The discovering group's own statement of the contraindication for the
      unrestrained-SPT diseases, of which SPG90A is one. The authors' hedge
      ("would be predicted") is quoted intact and is preserved in the notes.
- name: Partial Serine Palmitoyltransferase Inhibition (investigational)
  description: >-
    The mechanistically rational direction for a disease of unrestrained SPT
    activity is to inhibit the enzyme partially. Myriocin is the canonical tool
    compound, a fungal natural product that inhibits SPT through a dual
    mechanism. Nothing here is clinically available for SPG90A: this is curated
    as the rational therapeutic axis implied by the mechanism, not as a
    treatment, and the toxicity caveat is part of the claim rather than a
    footnote to it — complete SPT inhibition causes systemic toxicity, so any
    viable approach has to be partial.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: myriocin (tool compound)
      term:
        id: CHEBI:582124
        label: myriocin
  target_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    treatment_effect: INHIBITS
    description: >-
      Partial pharmacological inhibition of serine palmitoyltransferase would act
      directly on the node that the loss of ORMDL restraint drives. No such agent
      has been given to an SPG90A patient.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "To counteract SPT overactivity, partial SPT inhibition provides a more rational therapeutic approach, though one must act with caution as complete inhibition of SPT is associated with systemic toxicity."
      explanation: >-
        States both the rationale for targeting this node and the toxicity limit
        on doing so, which is why the treatment is curated as investigational.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myriocin (also known as thermozymocidin or ISP-10) was first isolated as a natural fungal product and exerts a potent inhibitory effect on SPT via a dual inhibitory mechanism."
    explanation: >-
      Identifies the canonical SPT inhibitor and its mechanism.
- name: SPT Small-Subunit Knockdown (preclinical concept)
  description: >-
    Because the small subunits set SPT activity and substrate selectivity without
    being catalytic, knocking down SPTSSA or SPTSSB has been argued to offer
    theoretical advantages over small-molecule inhibition or allele-specific
    knockdown. For SPG90A specifically this is attractive in principle — a
    dominant activating lesion in a non-catalytic subunit with a single recurrent
    allele — but it is a preclinical argument, not a programme: no construct,
    modality, delivery route or animal efficacy result is reported, which is why
    `therapeutic_modality` is OTHER rather than SIRNA or
    ANTISENSE_OLIGONUCLEOTIDE and no `aso_details` block is curated.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  notes: >-
    The cited source frames subunit knockdown as having theoretical advantages
    "over small molecules or allele-specific knockdown approaches"; it does not
    report an agent. Curated so the rational axis is visible and queryable
    without implying that a therapy exists.
  target_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    treatment_effect: INHIBITS
    description: >-
      Reducing small-subunit abundance would lower SPT output, acting on the same
      node as pharmacological inhibition but through a different lever.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "knockdown of small subunits of SPT (SPTSSA or SPTSSB) instead of SPTLC1 or SPTLC2 provides theoretical advantages over small molecules or allele-specific knockdown approaches"
      explanation: >-
        States the rationale for targeting the small subunits. Marked PARTIAL
        because the source argues a theoretical advantage rather than reporting
        an experimental or clinical result.
discussions:
- discussion_id: sptssa_vs_sptlc_phenotype_divergence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does loss of ORMDL restraint on serine palmitoyltransferase produce an
    upper-motor-neuron-predominant, neurodevelopmentally complicated spastic
    paraplegia when the lesion is in SPTSSA, but combined upper and lower motor
    neuron disease when the same biochemical lesion is in SPTLC1 or SPTLC2?
  attaches_to:
  - "pathophysiology#Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase"
  rationale: >-
    The SPTSSA, SPTLC1 and SPTLC2 disease variants converge on the same
    mechanism — impaired ORMDL regulation and unrestrained SPT activity — yet
    give clinically distinct syndromes. One reported difference is that the
    SPTSSA cHSP variants, unlike the ALS variants, do not increase and may
    decrease the activity of SPTSSB-containing SPT, which would change which
    sphingolipid species accumulate and in which cells. Until this is resolved,
    no entry in this family should assert a single shared downstream lipid
    species as the neurotoxic effector.
  proposed_experiments:
  - experiment_id: exp_spg90a_comparative_sphingolipidomics
    name: Comparative sphingolipidomics across SPT-subunit disease alleles
    description: >-
      Untargeted sphingolipidomic profiling of patient-derived cells and neurons
      carrying SPTSSA cHSP versus SPTLC1/SPTLC2 juvenile-ALS alleles, resolving
      SPTSSA- versus SPTSSB-containing holoenzyme output, to test whether the
      accumulating species differ in a way that tracks the clinical divergence.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite the biochemical similarities and differences between SPT-related juvenile ALS and cHSP, the mechanisms underlying the phenotypic differences remain poorly understood."
    explanation: >-
      The discovering group states the gap explicitly.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It is notable that unlike the SPTLC1 and SPTLC2-related ALS variants, the cHSP-related SPTSSA variants do not increase, and likely decrease (via ORMDL inhibition) the activity of SPTSSB-containing SPT."
    explanation: >-
      Records the one concrete biochemical difference proposed to explain the
      divergence, including the authors' own hedge.
- discussion_id: no_mammalian_model_of_sptssa_hsp
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the Drosophila SPTSSA model, which has neither a corticospinal tract nor
    myelin, license the inference that excess sphingolipid synthesis causes
    length-dependent upper-motor-neuron axonal degeneration in humans?
  attaches_to:
  - "pathophysiology#Distal Degeneration of Long Corticospinal Axons"
  rationale: >-
    The only in vivo model of SPTSSA disease variants is in Drosophila, and no
    murine model of an SPT-related ALS or HSP variant had been reported as of the
    2024 review. The corticospinal localisation curated in this entry therefore
    rests on the clinical pattern of selective upper-motor-neuron signs plus
    class-level HSP knowledge, not on demonstrated pathology in this disorder or
    in a mammalian model of it. The nearest mammalian evidence, the Stellar
    mouse, carries a different gene (SPTSSB), a different molecular mechanism
    (altered substrate affinity rather than lost ORMDL restraint) and a different
    phenotype (ataxia rather than spastic paraparesis).
  proposed_experiments:
  - experiment_id: exp_spg90a_t51i_knockin_mouse
    name: Knock-in mouse carrying the recurrent SPTSSA p.Thr51Ile allele
    description: >-
      Generate and characterise a mouse knock-in of the recurrent human allele,
      testing specifically for length-dependent corticospinal axonal degeneration
      with sparing of lower motor neurons, and for the developmental and auditory
      components of the human phenotype.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "No murine models with SPT-related ALS or HSP variants have been reported so far."
    explanation: >-
      Establishes the absence of a mammalian model, which is the basis for this
      mismatch.
notes: >-
  Scope: this entry is the autosomal dominant (monoallelic) pole of SPG90,
  MONDO:0957308 / OMIM #620416. The recessive pole, SPG90B (OMIM #620417), is a
  separate MONDO concept with its own stub and is not curated here; the shared
  SPTSSA biochemistry means the two entries will duplicate much of the upstream
  chain, which is expected rather than a defect.


  No `datasets:` block is curated. Searches of the reported literature surfaced
  no disease-specific omics accession for SPG90A; the founding study's data are
  targeted lipidomic and enzymatic assays rather than a deposited dataset.


  ORPHA coverage was not asserted. The local Orphanet refresh recipe is
  currently failing on a manifest checksum mismatch, and no cached ORPHA record
  for this concept was available, so no ORPHA-sourced evidence is claimed.


  Features deliberately NOT curated, and why. Deep-research output attributes
  several further findings to the full text of the founding paper — nevus
  flammeus and short stature in two of three patients, raised serum
  sphingolipids in all three, and rolandic epileptiform EEG activity — but the
  cached record for PMID:36718090 is `content_type: abstract_only` and contains
  none of those sentences. They are recorded here as unverified leads rather
  than curated as phenotypes or biochemical findings; anyone with access to the
  full text should promote them with real quotes. Two further full-text-only
  items were considered and are named here so a reader can see they were not
  simply overlooked. First, NERVE CONDUCTION STUDIES AND EMG ARE REPORTED NORMAL
  in all three founding patients, showing no polyneuropathy or motor neuron
  disease; that negative finding is the electrophysiological anchor for the
  pure-upper-motor-neuron localisation this entry infers, and is what separates
  SPG90A from the SPTLC1 juvenile-ALS phenotype, so it is the single most
  valuable item to promote if the full text becomes quotable. Second, MRI and MR
  SPECTROSCOPY findings including decreased N-acetylaspartate and increased
  lactate are described, which would be the only in vivo human evidence of a
  bioenergetic component and could justify a biochemical node. The EEG
  observation would need particular care, since epileptiform activity on EEG and
  clinical seizures are different claims, and reviews listing seizures for this
  disorder may be pooling in the SPG90B patient.
references:
- reference: PMID:36718090
  title: "SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia."
  findings: []
- reference: PMID:40533086
  title: "Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum."
  findings: []
- reference: PMID:38788085
  title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
  findings: []
- reference: PMID:33558762
  title: "Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex."
  findings: []
- reference: PMID:26438849
  title: "Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration."
  findings: []
- reference: PMID:25530960
  title: "Pathophysiology of spasticity: implications for neurorehabilitation."
  findings: []
- reference: PMID:33439395
  title: Hereditary spastic paraplegia.
  findings: []
- reference: PMID:37308477
  title: "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis."
  findings: []
📚

References & Deep Research

References

8
PMID:36718090
SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia.
No top-level findings curated for this source.
PMID:40533086
Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum.
No top-level findings curated for this source.
PMID:38788085
Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
No top-level findings curated for this source.
PMID:33558762
Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex.
No top-level findings curated for this source.
PMID:26438849
Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration.
No top-level findings curated for this source.
PMID:25530960
Pathophysiology of spasticity: implications for neurorehabilitation.
No top-level findings curated for this source.
PMID:33439395
Hereditary spastic paraplegia.
No top-level findings curated for this source.
PMID:37308477
Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-fable-5, claude-haiku-4-5-20251001, claude-opus-5 37 citations 2026-08-25T18:54:40.635934

1. Disease Information

Overview

Spastic paraplegia 90A is a monogenic neurodevelopmental-and-neurodegenerative disorder in which progressive lower-limb spasticity from upper motor neuron dysfunction is superimposed on global developmental delay. It sits in the complicated (complex) tier of the hereditary spastic paraplegias — features extend well beyond the corticospinal tract, including intellectual disability, sensorineural hearing loss, epileptiform EEG changes, dysmorphic/cutaneous findings, and growth failure.

The disease was defined in 2023 by Srivastava and colleagues in Brain, working through the Undiagnosed Diseases Network:

"Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia." — PMID:36718090

Important nosological point. SPG90 splits into two OMIM concepts by zygosity, and only the dominant pole is SPG90A:

Concept OMIM Zygosity Variant(s) reported
SPG90A (this entry) #620416 Monoallelic / heterozygous p.Thr51Ile (c.152C>T)
SPG90B #620417 Biallelic / homozygous c.171_172del, p.Gln58AlafsTer10

Of the three children in the founding Brain paper, Patients 1 and 2 are SPG90A (both heterozygous de novo p.Thr51Ile) and Patient 3 is SPG90B (homozygous frameshift). The fourth published SPG90 patient (PMID:40533086, Duzenli et al., Clin Genet 2026) is heterozygous p.Thr51Ile and therefore SPG90A. Total published SPG90A cases: three.

Key identifiers

Resource Identifier
MONDO MONDO:0957308 — spastic paraplegia 90A, autosomal dominant
OMIM (disease) #620416
OMIM (gene) 613540 (SPTSSA*)
MedGen C5830574 (CUI 1841210)
HGNC hgnc:20361 (SPTSSA)
Ensembl ENSG00000165389
UniProt Q969W0 (SPTSSA_HUMAN)
Cytoband 14q13.1
MGI (mouse ortholog) MGI:1913399 (Sptssa)

Not found / not applicable: No dedicated Orphanet code exists for SPG90A. The nearest Orphanet concept is the group term ORPHA:102013 "Complex hereditary spastic paraplegia", which is explicitly a category rather than a disease. ICD-10 G11.4 (hereditary spastic paraplegia) and ICD-11 8A41 apply only at the class level — neither codes SPG90A specifically, and I could not verify a SPG90A-specific code in either system. No MeSH descriptor exists below "Spastic Paraplegia, Hereditary" (D015419).

Synonyms

  • SPG90A
  • Spastic paraplegia 90, autosomal dominant
  • SPTSSA-related complex/complicated hereditary spastic paraplegia
  • SPTSSA-related cHSP (the usage preferred in the mechanistic literature)

Data provenance

All disease-level knowledge derives from individual published case reports and their functional workups — three patients across two papers. There is no registry, no EHR-derived cohort, no natural-history study, and no aggregated disease-level resource with independent content. Every aggregator entry (MalaCards, MedGen, GeneCards, HPO annotations) traces back to PMID:36718090. Curators should treat these aggregators as redistributions of a single n=2 source, not as independent corroboration.

2. Etiology

Primary causal factor

A heterozygous activating missense variant in SPTSSA, arising de novo in both index patients. There is no environmental, infectious, or multifactorial component. This is a fully penetrant Mendelian dominant disorder with a single reported allele.

Mechanistic causal factor

The variant does not damage the catalytic machinery — SPTSSA has no catalytic centre. It disables the regulatory brake:

"The variants in SPTSSA impaired the negative regulation of serine palmitoyltransferase by ORMDLs leading to excessive sphingolipid synthesis based on biochemical studies and in vivo studies in Drosophila." — PMID:36718090

"Similar to juvenile ALS variants, SPTSSA variants seem to interfere with ORMDL regulation of the SPT complex, thus resulting in unrestrained SPT activity." — Mohassel et al. 2024, PMID:38788085

Genetic risk factors

  • Causal variant: SPTSSA c.152C>T, p.Thr51Ile (NM_138288.4), heterozygous, de novo.
  • Susceptibility loci / modifier genes: None identified. No GWAS, no PheGenI signal, no polygenic contribution described. With n=3, no modifier analysis is possible.
  • Candidate modifier hypothesis (not established): ORMDL1/2/3 expression levels are a mechanistically plausible modifier class, since the disease is a failure of ORMDL restraint, and ORMDL3 dosage is itself a well-known asthma locus. No data support this in SPG90A — flagging it as a hypothesis worth a knowledge-gap discussion, not a curatable claim.

Environmental risk factors

None known. No toxin, occupational exposure, infection, or lifestyle factor has been implicated. Age, sex, and family history are non-contributory: both index cases were de novo, and the two SPG90A patients from the Brain paper plus the Turkish patient are all female — a sex distribution with no statistical meaning at n=3.

Protective factors

None known — with one important inversion. There is a documented anti-protective dietary factor: L-serine, which is therapeutic in the sibling disorder HSAN1, is expected to be harmful here (see §12).

Gene–environment interactions

One substantiated interaction, and it is a therapeutic one rather than an etiologic one — substrate availability modulates the biochemical lesion:

"Elevated serine exacerbates the overproduction of SLs associated with the SPTLC1 juvenile ALS variants and the SPTSSA variants described here... Thus serine supplementation is not a rational therapeutic strategy and may even be detrimental for these patients." — PMID:36718090

L-serine is the amino-acid substrate SPT condenses with palmitoyl-CoA. Because the enzyme is de-restrained, increasing substrate supply increases flux through an already-runaway pathway. This is a genuine gene–diet interaction with direct management implications.

3. Phenotypes

Source and frequency caveat

HPO annotations for OMIM:620416 derive entirely from PMID:36718090 and are scored over two patients (denominators of "2/2", "1/2", "1/1" in the table below). Frequencies are therefore illustrative of which features were present in the index pair, not population estimates. The fourth patient (PMID:40533086) is not yet folded into HPO annotations.

Curated HPO phenotype table

HPO ID Phenotype Frequency (source cohort) Notes
HP:0003593 Infantile onset 2/2 Onset in infancy, before the spasticity is apparent
HP:0034353 Appendicular spasticity 2/2 The defining motor sign
HP:0008936 Axial hypotonia 2/2 Coexists with limb spasticity
HP:0031936 Delayed ability to walk 2/2
HP:0001249 Intellectual disability 2/2
HP:0004322 Short stature 2/2 Under-appreciated non-neurological feature
HP:0001052 Nevus flammeus (port-wine stain) 2/2 Unexplained; see below
HP:0002064 Spastic gait 1/1 Only assessable in the ambulatory patient
HP:0000750 Delayed speech and language development 1/1
HP:0002650 Scoliosis 1/1
HP:0000407 Sensorineural hearing impairment 1/2 Variable across the wider SPG90 cohort
HP:0001332 Dystonia 1/2 Also present in the 4th patient
HP:0001344 Absent speech 1/2 Severe end of the language spectrum
HP:0002144 Tethered cord 1/2 Structural; a confounder for the spasticity
HP:0002360 Sleep disturbance 1/2
HP:0001508 Failure to thrive 1/2
HP:0002015 Dysphagia 1/2
HP:0002020 Gastroesophageal reflux 1/2
HP:0002307 Drooling 1/2
HP:0000256 Macrocephaly 1/2
HP:0001250 Seizure 0/2 See EEG note — SPG90A patients had epileptiform EEG without clinical seizures

Additional phenotypes from the fourth patient (PMID:40533086), each n=1 and therefore provisional:

HPO ID Phenotype Status
HP:0002540 Inability to walk Documented at age 10
HP:0001263 Global developmental delay Documented
HP:0000011 Neurogenic bladder Proposed, not established
HP:0004918 (or HP:0008341) Distal renal tubular acidosis Proposed
HP:0000787 Nephrolithiasis Proposed
HP:0000010 Recurrent urinary tract infections Proposed
HP:0001959 Polydipsia (primary) Proposed, not established

The authors are explicit that the genitourinary cluster is a hypothesis:

"The neurogenic bladder and primary polydipsia found in our patient are novel findings, and we propose that genitourinary problems may be a component of the syndrome." — PMID:40533086

Three phenotype findings worth curator attention

1. Nevus flammeus (port-wine stain) at 2/2 is a striking and unexplained association. Both SPG90A index patients had a capillary malformation — present at birth in Patient 1, apparent in infancy in Patient 2. At 100% of the dominant cohort this is as frequent as the spasticity itself. No mechanism has been proposed linking sphingolipid overproduction to capillary malformation, and the classic port-wine-stain gene (GNAQ, somatic) is unrelated. This is either (a) a genuine and mechanistically unexplained component of SPG90A, or (b) a two-patient coincidence. It cannot be resolved at n=2, but it deserves recording — it is potentially the most useful diagnostic handle for recognizing the next case, and it is a real knowledge gap.

2. The EEG/seizure dissociation matters for accurate curation. All three founding patients had epileptiform EEG abnormalities, but only Patient 3 — the SPG90B (recessive) patient — had clinical seizures:

Patient 1: "Electroencephalography at 2 years of age showed frequent sleep potentiated multifocal spikes which rarely synchronized but no evidence of clinical seizures." Patient 2: "Her EEG showed mild diffuse background slowing, multifocal polymorphic sharp waves, and sharp slow waves during sleep, but no seizures." Patient 3 (SPG90B): "Around 6 years of age, he developed rolandic seizures with temporoparietal spike-waves evident on EEG." — PMID:36718090

HPO correctly scores Seizure as 0/2 for OMIM:620416. Review-level sources that list "seizures" as a cHSP feature (e.g. Table 1 of PMID:38788085) are pooling SPG90A and SPG90B. Abnormal EEG (HP:0002353) should be curated for SPG90A; clinical seizure should not, or should be curated as absent.

3. Nerve conduction and EMG were normal in all three patients — "showed no evidence of polyneuropathy or motor neuron disease." This is the electrophysiological anchor for pure upper-motor-neuron localization and the key discriminator from the SPTLC1/SPTLC2 juvenile ALS phenotype. It is a negative finding with high diagnostic value (see §10).

Onset, severity, progression

  • Onset: Infantile (HP:0003593), 2/2. Developmental concerns precede recognizable spasticity.
  • Severity: Severe and markedly variable even between two carriers of the identical allele. Patient 1 achieved sitting at 11–12 months and a scissoring gait with a walker by age 3–4, with 4–6-word phrases at age 4. Patient 2 "never acquired the ability to sit independently," had no leg control by age 8, and was non-verbal, communicating "through facial/eye expressions." This is dramatic intrafamilial-equivalent variable expressivity on a single de novo allele.
  • Progression: Progressive on both motor and cognitive axes. Patient 2's serial MRI showed "progressive cerebral volume loss and development of cerebellar atrophy." The review describes "Progressive cognitive decline and sensorineural hearing loss" as clinical features (PMID:38788085) — i.e. this is neurodegeneration layered on a neurodevelopmental baseline, not static encephalopathy.

Quality of life

No QoL instrument (EQ-5D, SF-36, PROMIS, SPRS) has been administered in any SPG90A patient. Inferring from the documented function: non-ambulatory or walker-dependent mobility, absent-to-limited expressive language, dysphagia and reflux requiring feeding management, and hearing impairment together imply near-total dependence for activities of daily living. Patient 3's hearing loss "improved with hearing aids" and normal subsequent language development is the one documented instance of an intervention meaningfully changing a functional trajectory in this gene — though that patient is SPG90B.

4. Genetic / Molecular Information

Causal gene

SPTSSA — serine palmitoyltransferase small subunit A (hgnc:20361; OMIM *613540; 14q13.1; UniProt Q969W0; Ensembl ENSG00000165389). Also known as C14orf147, ssSPTa, SSSPTA.

The protein is tiny and purely regulatory:

"The deduced 71-amino acid SSSPTA peptide contains 2 predicted transmembrane spans and shares 45% identity with SSSPTB, with most similarity in a central 28-amino acid domain that overlaps transmembrane span 2." — OMIM *613540

Function, from cryo-EM:

"SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity." — Li et al. 2021, PMID:33558762

Pathogenic variants

Variant cDNA Protein Zygosity Origin Disease Consequence
Recurrent SPG90A allele c.152C>T p.Thr51Ile Heterozygous de novo (P1, P2) SPG90A Activating / loss-of-restraint
SPG90B allele c.171_172del p.Gln58AlafsTer10 Homozygous Inherited (non-consanguineous Ashkenazi parents) SPG90B — out of scope C-terminal 14 aa replaced by 10 out-of-frame residues

p.Thr51Ile is the only known SPG90A allele. All three published SPG90A patients carry it:

"Exome sequencing revealed a heterozygous pathogenic variant (p.Thr51Ile), which was detected in two of the reported patients, suggesting a recurrent variant in this syndrome." — PMID:40533086

Variant classification (ACMG/AMP): Pathogenic. The supporting criteria are unusually strong for an ultra-rare allele — de novo occurrence in two independent probands with consistent phenotype (PS2, applied twice), well-established functional studies demonstrating the damaging mechanism (PS3, from HEK293, patient fibroblast, and Drosophila work), and absence from population databases (PM2).

Variant type: Missense, located in the transmembrane region of the small subunit. This structural placement is the shared feature of the unrestrained-SPT phenotypes:

"those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP" — PMID:38788085

Allele frequency: p.Thr51Ile is absent from gnomAD (consistent with de novo occurrence and a severe pediatric dominant phenotype). For contrast, the SPG90B frameshift c.171_172del is present at 0.0000517 overall and 0.001191 in the Ashkenazi Jewish population, with no homozygotes — a carrier frequency that suggests a modest Ashkenazi founder effect for the recessive pole (see §9). Note: I could not directly retrieve the gnomAD gene-constraint page for SPTSSA; pLI, LOEUF, and missense-Z values should be looked up directly at gnomad.broadinstitute.org before being curated as facts.

Somatic vs germline: Germline, de novo. No somatic or mosaic mechanism described.

Functional consequence: This requires care, because the mechanism does not map cleanly onto standard categories. The variant is activating — a gain of pathway function achieved through loss of a regulatory interaction. In dismech's schema terms this argues for functional_impact_category: GAIN_OF_FUNCTION on the variant (the allele confers unrestrained activity) with a modifier: LOSS_OF_FUNCTION on the negative regulation of sphingolipid biosynthetic process node. Both descriptions are true of different objects; conflating them into one slot loses the mechanism. Direct evidence for the de-restraint:

  • SPT carrying T51I was "less responsive to inhibition by co-transfected ORMDL3."
  • "ORMDL silencing had minimal effect on T51I-containing SPT activity" — i.e. the brake was already off.
  • Patient fibroblasts showed reduced responsiveness to C8-ceramide feedback inhibition.
  • Microsomal SPT activity in Patients 1 and 2 was "comparable to that from age and gender matched control fibroblasts" — the enzyme is not hyperactive in isolation; it is unregulated in the cell. This is an important subtlety: bulk enzyme assays are normal while cellular flux is elevated.

Modifier genes, epigenetics, chromosomal abnormalities

None reported for any of these categories. No methylation, histone, or chromatin data exist for SPG90A. No CNV, aneuploidy, translocation, or inversion mechanism — this is a single-nucleotide dominant disorder. Chromosomal microarray has no role.

5. Environmental Information

Environmental factors: None. No entry in CTD, no toxicological or radiation association.

Lifestyle factors: One, and it is dietary and harmful: L-serine supplementation should be avoided (see §2, §12). This is the only lifestyle/nutritional variable with a mechanistic rationale in this disease, and its sign is negative.

Infectious agents: Not applicable.

6. Mechanism / Pathophysiology

The causal chain

SPTSSA p.Thr51Ile (transmembrane face of the small subunit)
   ↓ DIRECT
Impaired ORMDL binding / failed ceramide-triggered feedback inhibition of SPT
   ↓ DIRECT
Unrestrained de novo sphingolipid synthesis (elevated serum + fibroblast SLs)
   ↓ INDIRECT, intermediates unknown in humans
   ├──→ Distal degeneration of long corticospinal axons ──→ loss of supraspinal
   │      inhibitory control of the stretch reflex ──→ lower-limb spasticity,
   │      spastic paraparesis, loss of ambulation
   └──→ Broader CNS developmental + degenerative involvement ──→ global
  developmental delay, intellectual disability, progressive cognitive
  decline, cerebral/cerebellar volume loss, SNHL, dystonia,
  epileptiform EEG

The founding authors' own attribution of the terminal step:

"These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function." — PMID:36718090

Molecular pathway

De novo sphingolipid biosynthesis (KEGG hsa00600 Sphingolipid metabolism; Reactome R-HSA-1660661 Sphingolipid de novo biosynthesis). SPT catalyzes the first, committed, rate-limiting step: condensation of L-serine with palmitoyl-CoA to form 3-ketodihydrosphingosine, via a PLP-dependent mechanism.

The holoenzyme architecture, from cryo-EM (PMID:33558762):

"SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly."

The homeostatic sensing mechanism was solved two years later (Xie et al., Nat Commun 2023, PMID:37308477, DOI 10.1038/s41467-023-39274-y):

"purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide... Structure-guided mutational analyses reveal the essential function of this ceramide binding site for the suppression of SPT activity... ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation."

That paper also showed that "childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants" — establishing broken ceramide-sensing as the shared molecular lesion class into which the SPTSSA variants fall. This structural work is highly relevant to SPG90A and is not currently cited in the draft KB entry.

Normal homeostatic logic:

"Sphingolipids are both essential and cytotoxic and their synthesis must therefore be tightly regulated. Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive." — PMID:36718090

Suggested GO terms

GO ID Label Modifier
GO:0004758 serine C-palmitoyltransferase activity GAIN_OF_FUNCTION
GO:0090155 negative regulation of sphingolipid biosynthetic process LOSS_OF_FUNCTION
GO:0030148 sphingolipid biosynthetic process INCREASED
GO:0017059 serine palmitoyltransferase complex — (cellular component / complex)
GO:0005783 endoplasmic reticulum — (subcellular site of SPT)
GO:0046513 ceramide biosynthetic process INCREASED (inferred)
GO:0006672 ceramide metabolic process INCREASED (inferred)

Cellular processes

Established: Dysregulated lipid homeostasis at the ER membrane. Inferred but not demonstrated in SPG90A: membrane composition change in myelin and axolemma, axonal transport failure, and length-dependent dying-back degeneration. The rationale for expecting neurological rather than systemic consequences:

"Sphingolipids are a diverse family of lipids with critical structural and signalling functions in the mammalian nervous system, where they are abundant in myelin membranes." — PMID:36718090

The strongest mechanistic analogy for how excess/aberrant sphingoid bases damage neurons comes from the Sptssb Stellar mouse (PMID:26438849):

"resulting in surprising neurodegenerative effects including aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration... our studies also suggest that excessive C20 LCBs or C20 LCB-containing sphingolipids impair protein homeostasis and neural functions."

Note carefully: this is a different gene (Sptssb), a different molecular lesion (altered acyl-CoA substrate affinity, not lost ORMDL restraint), and a different lipid species (C20 long-chain bases). It supports the general principle that SPT small-subunit dysregulation is neurodegenerative; it does not establish the SPG90A mechanism.

Protein dysfunction

No misfolding or aggregation of SPTSSA itself is described. The defect is a lost protein–protein interaction interface — the variant sits on the transmembrane face where the small subunit participates in the ORMDL-regulated assembly. Structures available: PDB 7YIU (C6-ceramide-bound SPT–ORMDL3), 7YIY (SPT–ORMDL3), 7YJ1 (ORMDL3-ΔN2), 7YJ2 (ORMDL3-N13A). These provide a direct structural framework for modeling p.Thr51Ile, which to my knowledge has not been published.

Metabolic changes

Elevated de novo sphingolipid synthesis, measured in two compartments:

  • Serum: "Serum levels of SLs were increased in all three patients."
  • Fibroblasts: Patients 1 and 2 "showed substantially elevated synthesis compared to controls."

Critically, 1-deoxysphingolipids are NOT the accumulating species. The full text does not report deoxySL elevation, and the mechanistic distinction is central to the disease family: HSAN1 variants shift SPT's substrate preference from L-serine to L-alanine/glycine, generating toxic 1-deoxySLs; the unrestrained-SPT variants instead overproduce canonical sphingolipids. Per the 2024 review, SPTLC1-ALS variants show "unrestrained SPT activity and overproduction of canonical sphingolipid species instead of overproduction of 1-deoxysphingolipids." The same logic applies to SPTSSA. A curated entry should not import deoxySL toxicity from HSAN1.

Gap: No untargeted sphingolipidomic profile of an SPG90A patient distinguishing which specific ceramide/sphingomyelin/hexosylceramide species accumulate has been published with quantitative values.

Immune system involvement

None described. (Worth noting that ORMDL3 — the regulatory partner — is a major asthma susceptibility locus, but no immune or atopic phenotype has been reported in any SPG90 patient.)

Tissue damage mechanisms

Axonal degeneration and progressive brain volume loss. Patient 2's magnetic resonance spectroscopy showed "decreased NAA and increased lactate signals" — decreased N-acetylaspartate indicating neuronal/axonal loss, and elevated lactate suggesting impaired oxidative metabolism. This is the only in vivo human evidence of a bioenergetic component and is a notable, uncurated finding.

Molecular profiling status

Modality Status
Targeted lipidomics (LC-MS) Done — serum + fibroblasts, all 3 founding patients
Enzymatic/microsomal SPT assays Done
Transcriptomics Not done. No GEO/ArrayExpress accession for SPG90A
Proteomics Not done
Untargeted metabolomics / full sphingolipidomics Not done in SPG90A (done for SPTLC1-ALS)
Single-cell / spatial transcriptomics Not done
CRISPR/RNAi functional screens Not done for this disease

There is no disease-specific omics dataset accession for SPG90A. The founding study's data are targeted assays, not deposited datasets. A datasets: block cannot be honestly curated.

7. Anatomical Structures Affected

Organ level

  • Primary: Central nervous system. Specifically the corticospinal tract (UBERON:0002314 / UBERON:0001075 pyramidal tract), inferred from selective upper-motor-neuron signs with normal EMG/NCS.
  • Secondary CNS: Cerebrum (progressive volume loss), cerebellum (UBERON:0002037 — atrophy on serial MRI in Patient 2), corpus callosum (UBERON:0002336 — thinning, in the SPG90B patient), lateral ventricles (UBERON:0002285 — ventriculomegaly), cerebral white matter (UBERON:0002316 — depressed volume).
  • Cochlea / auditory system (UBERON:0001844): sensorineural hearing loss.
  • Genitourinary (bladder UBERON:0001255; kidney UBERON:0002113): proposed only, from a single patient.
  • Skeletal: scoliosis (vertebral column, UBERON:0000955... more precisely UBERON:0002240 spinal cord vs UBERON:0001130 vertebral column — use the latter for scoliosis).
  • Skin (UBERON:0002097): nevus flammeus / capillary malformation.
  • Body systems: Nervous (primary), auditory, musculoskeletal, gastrointestinal (dysphagia, GERD), integumentary, genitourinary (provisional).

Explicitly spared: Peripheral nerve and lower motor neurons. "All three patients showed no evidence of polyneuropathy or motor neuron disease" on NCS/EMG. This negative localization is diagnostically load-bearing.

Tissue and cell level

CL / UBERON Term Basis
CL:0008048 upper motor neuron Inferred from clinical localization
CL:0000679 glutamatergic neuron (corticospinal projection neurons) Inferred
CL:0000128 oligodendrocyte Inferred — sphingolipids are myelin components; not demonstrated
CL:0000855 sensory hair cell Inferred from SNHL; cochlear vs retrocochlear localization never determined
UBERON:0002240 spinal cord Site of corticospinal axon degeneration

Every cell-type assignment here is inferential. No neuropathological examination of an SPG90A patient has been published. There is no autopsy, no biopsy, no iPSC-derived neuron model of SPTSSA p.Thr51Ile. Curators should mark these as inferred from clinical localization plus class-level HSP knowledge.

Subcellular level

  • GO:0005783 endoplasmic reticulum — SPT is an ER-resident membrane complex; this is where the lesion physically sits.
  • GO:0005789 endoplasmic reticulum membrane — more precise.
  • GO:0017059 serine palmitoyltransferase complex — the affected assembly.
  • Inferred downstream: axonal plasma membrane, myelin sheath (GO:0043209).

Localization and lateralization

Bilateral and symmetric, as expected for a genetic corticospinal tract disorder. Length-dependent distal predominance is the class-level HSP expectation and is imported, not demonstrated in SPG90A.

8. Temporal Development

Onset: Infantile (HP:0003593, 2/2). Perinatal history was unremarkable in both index patients; Patient 2 was "born at 39 weeks after uneventful pregnancy." The first manifestation is developmental — delayed motor and language milestones — with spasticity becoming apparent as the child fails to acquire or loses ambulation. The port-wine stain was present at birth (P1) or appeared in infancy (P2), making it potentially the earliest observable sign.

Onset pattern: Insidious and chronic. No acute or subacute presentation.

Progression rate and stages: Slow but unequivocally progressive, on two independent axes:

  • Motor: P1 — sitting at 11–12 months → scissoring gait with walker by 3–4 years. P2 — never sat independently → no leg control by age 8. Patient 4 — unable to walk at age 10. For contrast, the SPG90B patient walked independently at 24 months and lost ambulation by age 10, documenting frank regression.
  • Cognitive/structural: "Progressive cognitive decline" (PMID:38788085); serial MRI in P2 showed "progressive cerebral volume loss and development of cerebellar atrophy."

Course pattern: Progressive. Not episodic, relapsing-remitting, or fluctuating.

Duration: Chronic, lifelong. No published patient has died; the oldest SPG90A patient reported is 10 years old, so adult outcomes are entirely unknown.

Remission: None, spontaneous or treatment-induced.

Critical periods: Not established. Two considerations argue that an intervention window would be early: the disorder has a genuine neurodevelopmental component ("defects in early brain development and function"), implying that damage accrues before diagnosis; and the one intervention with a documented benefit — hearing aids from age 3 in the SPG90B patient, after which "normal language development" followed — was an early sensory intervention. This is a reasonable but unproven basis for arguing that any future SPT-directed therapy would need to start young.

9. Inheritance and Population

Epidemiology

Prevalence: not estimable. Three published SPG90A patients worldwide. Use measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE, and do not assign a rate_per_100000.

"To date, only three patients have been reported." — PMID:40533086, writing before adding their own (i.e., 4 total SPG90; 3 of them SPG90A).

For class-level context only — do not attribute these figures to SPG90A — the pooled global HSP prevalence from the standard systematic review (Ruano et al., Neuroepidemiology 2014;42(3):174–83, PMID:24603320, DOI 10.1159/000358801) is:

"The prevalence of autosomal dominant (AD) HSP ranged from 0.5 to 5.5/10⁵ and that of AR-HSP from 0.0 to 5.3/10⁵, with pooled averages of 1.8/10⁵ (95% CI: 1.0–2.7/10⁵) and 1.8/10⁵ (95% CI: 1.0–2.6/10⁵), respectively."

SPG4 dominates AD-HSP, followed by SPG3A. SPG90A is a vanishingly small fraction of that total.

Inheritance

Autosomal dominant (HP:0000006), arising de novo in both index cases. There has been no transmission from an affected parent to a child in any published pedigree — every SPG90A case to date is sporadic.

Penetrance: Complete in reported cases (n=3), but this is uninformative — de novo ascertainment guarantees affected probands and tells you nothing about whether a milder carrier would come to attention.

Expressivity: highly variable, and this is a substantive finding rather than a hedge. Patients 1 and 2 carry the identical de novo allele on different genetic backgrounds and differ profoundly: walker-assisted ambulation with phrase speech versus never sitting and non-verbal. Whatever determines severity in SPG90A is not the allele. This is the single strongest argument that unidentified modifiers exist.

Genetic anticipation: Not applicable — no repeat expansion, no multigenerational pedigree.

Germline mosaicism: Not reported. Given two independent de novo events at the same nucleotide, recurrence risk counseling should nonetheless mention gonadal mosaicism as a small but non-zero possibility, per standard de novo-dominant practice.

Founder effects: None for SPG90A (p.Thr51Ile is absent from gnomAD and arose de novo twice — a recurrent mutational event, not a founder haplotype). A possible Ashkenazi founder effect applies to the recessive SPG90B allele: c.171_172del has an Ashkenazi allele frequency of 0.001191 (~1 in 420 carriers) versus 0.0000517 overall, with no homozygotes in gnomAD. This is an SPG90B fact and must not be attributed to SPG90A.

Consanguinity: No role in SPG90A. (The SPG90B patient's parents were explicitly non-consanguineous, with the homozygosity attributable to the founder allele frequency.)

Carrier frequency: Not applicable to a de novo dominant disorder.

Population demographics

  • Ethnic/geographic: No population enrichment. Reported patients come from the US Undiagnosed Diseases Network (P1, P2) and Türkiye (P4). The Ashkenazi association is exclusive to SPG90B.
  • Sex ratio: All three SPG90A patients are female. At n=3 this is statistically meaningless and should not be curated as a sex bias. There is no mechanistic basis for one (autosomal gene, autosomal dominant).
  • Age distribution: All reported patients are children (ages 5, 10, and 10 at report). No adult SPG90A patient has been described.

10. Diagnostics

The diagnostic pathway in practice

Both index patients reached diagnosis through the Undiagnosed Diseases Network via exome sequencing — i.e., SPG90A is currently a diagnosis of genomic discovery, not of clinical suspicion. There is no clinician who diagnoses SPG90A from the bedside.

Genetic testing

Exome or genome sequencing is the appropriate first-tier test. Rationale: the phenotype (global developmental delay + spasticity + hearing loss) is not specific enough to direct single-gene testing, and SPTSSA is a recently described gene that may be absent from older HSP panels. GeneReviews' general HSP guidance applies:

"A multigene panel that includes some or all the genes listed in Tables 1 and 2 is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants." — GeneReviews, Hereditary Spastic Paraplegia Overview, NBK1509

Practical caveat for curators and clinicians: verify that any HSP panel offered actually includes SPTSSA. Given the 2023 gene-disease discovery date, panel inclusion is not guaranteed. Trio exome/genome is preferable because it establishes de novo status directly — which is both the strongest ACMG evidence (PS2) and the key to accurate recurrence counseling.

Test Utility in SPG90A
Trio WES / WGS First-line. How all reported cases were diagnosed
HSP multigene panel Useful if it contains SPTSSA — confirm before ordering
Single-gene SPTSSA sequencing Reasonable only for targeted confirmation or family testing of the known p.Thr51Ile allele
Chromosomal microarray No role — no CNV mechanism
Karyotype / FISH No role
mtDNA testing No role (though it may feature in the differential given the elevated MRS lactate)
Repeat expansion testing No role

Biomarkers and laboratory tests

Plasma/serum sphingolipid profiling is the disease-relevant biochemical assay and is currently the only candidate biomarker: "Serum levels of SLs were increased in all three patients" (PMID:36718090). The 2024 review positions "untargeted sphingolipidomic studies of patient serum samples" as the key modality for distinguishing mechanisms across the SPT disease family — HSAN1 (1-deoxySL elevation) versus unrestrained-SPT disorders (canonical SL elevation).

However, this is a research assay, not a validated clinical diagnostic. No reference interval, sensitivity, specificity, or clinical LOINC code exists for SPG90A. It should be curated as an investigational biomarker with validation_status explicitly unvalidated — not as a diagnostic test.

De novo sphingolipid synthesis assay in cultured patient fibroblasts is the functional confirmatory test used in the founding study, and is a legitimate route to reclassifying a SPTSSA VUS. Note the pitfall documented in that paper: microsomal SPT activity was normal in the SPG90A patients — only the cellular flux and the responsiveness to ORMDL/ceramide inhibition were abnormal. An assay measuring bulk enzyme activity will return a false negative. The informative readout is feedback-inhibition responsiveness.

Imaging

Brain MRI findings are non-specific but support a progressive process: - Ventriculomegaly with depressed white matter volume (P1, age 1) - Progressive cerebral volume loss and cerebellar atrophy on serial imaging (P2, age 4) - MR spectroscopy: decreased NAA, increased lactate (P2) - Thinning of the corpus callosum (P3 — SPG90B)

Serial rather than single MRI is what carries information here, since it was the change between studies that revealed progression.

Spinal MRI is warranted given tethered cord in 1/2 patients — a surgically actionable finding that independently causes spasticity and must be assessed rather than assumed to be part of the genetic syndrome.

Electrophysiology

EEG: Abnormal in all founding patients (multifocal sleep-potentiated spikes, polymorphic sharp waves, background slowing). Should be obtained; expect epileptiform abnormality without necessarily clinical seizures in SPG90A.

NCS/EMG: Should be normal. "All three patients showed no evidence of polyneuropathy or motor neuron disease." This normal result is diagnostically informative — it excludes the SPTLC1/SPTLC2 juvenile ALS and HSAN1 phenotypes, which is precisely the discrimination that matters within this gene family.

Audiometry: Required — SNHL is present in a substantial fraction and is the one deficit with a demonstrably effective intervention.

Biopsy / pathology

No histopathology, immunohistochemistry, or autopsy data exist for any SPG90A patient. Nerve biopsy has no role (peripheral nerve is spared).

Clinical criteria and differential diagnosis

No standardized diagnostic criteria exist for SPG90A. Diagnosis is molecular.

Differential diagnosis for a child with global developmental delay plus progressive lower-limb spasticity:

Category Entities Distinguishing features
Within the SPT family SPTLC1/SPTLC2 juvenile ALS Combined UMN and LMN signs; atrophy, weakness, fasciculations; abnormal EMG
Within the SPT family HSAN1 (SPTLC1, SPTLC2) Sensory-predominant neuropathy; 1-deoxySL elevation; adult onset; serine is therapeutic
Other complicated HSPs SPG11, SPG15, SPG50 (AP4M1), SPG7 Panel/exome resolves
Non-genetic mimic Cerebral palsy The most important practical mimic — a non-progressive presumption delays diagnosis. Progression on serial exam/MRI is the discriminator
Structural Tethered cord Present in 1/2 SPG90A patients; must be imaged and may be independently treatable
Treatable metabolic Dopa-responsive dystonia, cobalamin C, biotinidase deficiency, homocystinuria GeneReviews flags these as must-excludes because they are treatable
Other Leukodystrophies, spinocerebellar ataxias, MS, HTLV-1/HIV myelopathy Per GeneReviews HSP Overview

Screening

No newborn screening, carrier screening, or population screening applies. A de novo dominant disorder with no carrier state and a single ultra-rare allele is not screenable. Cascade testing of parents is appropriate solely to confirm de novo status for recurrence counseling — not to identify at-risk relatives.

11. Outcome / Prognosis

This section is the most data-poor in the report, and the honest summary is that SPG90A prognosis is unknown.

  • Survival, life expectancy, mortality rate, disease-specific mortality: No data. No SPG90A patient death has been reported. The oldest reported patient is 10. Any survival figure would be fabrication. Note for contrast that the Drosophila model shows shortened lifespan and the Sptssb Stellar mouse shows premature death — neither licenses a human life-expectancy claim.
  • Morbidity: Severe. Documented outcomes include non-ambulation by age 8–10, absent speech, intellectual disability, dysphagia, and hearing impairment — a combination implying full-time care dependence.
  • Disability outcomes: No ICF-coded or standardized disability assessment has been performed.
  • Quality of life measures: None administered. No EQ-5D, SF-36, PROMIS, or the HSP-specific Spastic Paraplegia Rating Scale (SPRS).
  • Complications: Reported or expected — aspiration secondary to dysphagia, GERD, scoliosis (progressive, potentially surgical), contractures from chronic spasticity, failure to thrive, and (provisionally, from the fourth patient) nephrolithiasis, recurrent UTI, and neurogenic bladder with its attendant renal risk.
  • Recovery potential: None for the neurological deficit. The one documented functional gain in the gene family is auditory: the SPG90B patient's hearing loss "improved with hearing aids," after which language developed normally — a strong argument for aggressive early audiological management.
  • Prognostic factors: Unknown, and notably not predicted by genotype — the two patients sharing the identical p.Thr51Ile allele had radically different severity. Whatever predicts outcome here is not the variant.
  • Prognostic biomarkers: None validated. Whether the magnitude of serum sphingolipid elevation tracks severity is an obvious and untested hypothesis — worth recording as a proposed experiment.

12. Treatment

Current state

No disease-modifying therapy exists. Management is entirely symptomatic and supportive, following general complicated-HSP practice. No clinical trial has ever enrolled an SPG90A patient, and no NCT or ICTRP identifier exists for this disorder.

The one disease-specific management directive

Avoid L-serine supplementation. This is the single most important treatment fact for SPG90A and it is a contraindication, which makes it easy to miss:

"Elevated serine exacerbates the overproduction of SLs associated with the SPTLC1 juvenile ALS variants and the SPTSSA variants described here... Thus serine supplementation is not a rational therapeutic strategy and may even be detrimental for these patients." — PMID:36718090

The 2024 review's Table 1 lists the cHSP (SPTSSA) treatment strategy as, verbatim, "Avoid serine supplementation; SPT inhibition."

Why this is a real clinical hazard rather than a theoretical one: L-serine supplementation is the established rationale for HSAN1, caused by variants in the same enzyme complex. A clinician who recognizes "serine palmitoyltransferase disorder" and reaches for the familiar intervention would be actively worsening the disease. Any KB entry for SPG90A should carry this as an explicit contraindication, not merely omit serine from the treatment list.

Symptomatic pharmacotherapy

Extrapolated from general HSP management (GeneReviews NBK1509); no trial evidence specific to SPG90A:

"Baclofen, botulinum toxin, dantrolene, tizanidine (used 1 at a time), especially early in disease course to decrease cramps."

with the caution that dantrolene should be avoided in ambulatory patients due to risk of irreversible weakness.

Treatment Agent NCIT Modality
Antispasticity pharmacotherapy baclofen (CHEBI:2972) NCIT:C15986 Pharmacotherapy SMALL_MOLECULE
Antispasticity pharmacotherapy tizanidine (CHEBI:63631) NCIT:C15986 SMALL_MOLECULE
Focal spasticity injection botulinum toxin type A (NCIT:C1090) NCIT:C15986 OTHER/PROTEIN
Intrathecal baclofen (for refractory spasticity) baclofen NCIT:C15986 / device DEVICE
Anticholinergic for neurogenic bladder oxybutynin (CHEBI:7856), solifenacin NCIT:C15986 SMALL_MOLECULE
Anticonvulsant (SPG90B; consider if clinical seizures) per seizure type NCIT:C15986 SMALL_MOLECULE

Supportive, rehabilitative, and surgical

Intervention NCIT Rationale
Physical therapy NCIT:C15302 Addresses the non-reflex soft-tissue component of hypertonia, not just the reflex component (PMID:25530960); preserves range of motion
Occupational therapy NCIT:C121351 Adaptive equipment, ADL support
Speech and language therapy NCIT:C159273 Delayed/absent speech; also dysphagia management
Hearing aids / audiological management (device) The one intervention with documented functional benefit in this gene — SPG90B patient's language normalized after aids at age 3
Nutritional support / feeding management NCIT:C15433 Dysphagia, GERD, failure to thrive. Note: this is nutritional supplementation, not a "dietary modification" — and it must not include serine
Orthopedic surgery (scoliosis, contractures) NCIT:C16186 Progressive scoliosis
Neurosurgery for tethered cord NCIT:C15329 Independently treatable contributor to spasticity — must be evaluated
Genetic counseling NCIT:C15240 De novo recurrence risk; gonadal mosaicism
Supportive care (overall) NCIT:C15747

Botulinum toxin in HSP specifically has a recent dedicated review (PMC12567745, 2025).

Experimental and future therapeutics

None in or near clinical trial for SPG90A. The 2024 review outlines the rational targets:

  • SPT inhibition. "Myriocin (also known as thermozymocidin or ISP-10)" is the canonical potent SPT inhibitor but faces "toxicity" barriers to clinical development. This is the mechanistically correct target — the pathway is overactive — but no tolerable clinical-stage SPT inhibitor exists.
  • Allele-specific knockdown / ASOs. The review states "allele-specific knockdown is a feasible approach" and that "antisense oligonucleotides (ASOs), improves on the generalizability limitations." A single recurrent allele (p.Thr51Ile) in a dominant gain-of-function disorder is close to the ideal ASO/siRNA target profile — arguably SPG90A's most tractable future therapeutic avenue.
  • Open questions the authors flag: the need to "establish the tolerated threshold for SPT inhibition" and determine "optimal timing of interventions." Both are unresolved, and the second is sharpened by SPG90A's neurodevelopmental component.

Precedent from the HSP field: AAV9 gene therapy for SPG50 (AP4M1) reached a single-patient phase 1 trial and "was well tolerated, showing preliminary evidence of disease stabilization" (Nat Med 2024, PMC11271397). Note that this is a gene replacement strategy for a loss-of-function disorder and is not transferable to SPG90A — a gain-of-function disease needs knockdown or inhibition, not replacement. ASO work targeting GM3 synthase in an SPG11 model is a closer conceptual analog.

Pharmacogenomics

None. No PharmGKB or CPIC guidance applies.

Treatment outcomes, response rates, adverse events

No data for SPG90A. Response rates and adverse-event profiles for baclofen, tizanidine, and botulinum toxin come from the general spasticity literature and should be cited as such, never as SPG90A-specific.

13. Prevention

Primary prevention: not possible. A de novo dominant mutation cannot be prevented by risk-factor modification, immunization, or environmental intervention.

Secondary prevention (early detection): No screening program applies. The realistic lever is reducing diagnostic delay — earlier trio exome in children with unexplained global developmental delay plus progressive spasticity, and resisting a default "cerebral palsy" label when the course is progressive.

Tertiary prevention (complication prevention) is where the actionable content sits:

Target complication Preventive action
Contractures, joint deformity Early and sustained physiotherapy, stretching, orthotics
Progressive scoliosis Serial spine monitoring; timely orthopedic referral
Aspiration pneumonia Dysphagia assessment; feeding modification
Language deprivation from undetected SNHL Early audiology and hearing aids — the one measure with demonstrated benefit in this gene
Renal damage from neurogenic bladder Urological surveillance (provisional, based on the 4th patient)
Iatrogenic disease worsening Do not prescribe L-serine supplementation

Genetic counseling: Recurrence risk for the parents of a de novo proband is low but not zero (gonadal mosaicism). An affected individual would have a 50% transmission risk, though no SPG90A patient has reproduced. Prenatal diagnosis and PGT are technically straightforward once the familial p.Thr51Ile variant is known — a defined single-nucleotide target.

Immunization, public health, environmental interventions, prophylaxis: Not applicable.

14. Other Species / Natural Disease

Naturally occurring SPG90A does not exist in any non-human species. No OMIA entry, no veterinary case, no wildlife or companion-animal disease. Not zoonotic; no cross-species transmission concept applies.

Orthologs and conservation

Species NCBI Taxon Gene Resource
Homo sapiens NCBITaxon:9606 SPTSSA HGNC:20361
Mus musculus NCBITaxon:10090 Sptssa MGI:1913399
Drosophila melanogaster NCBITaxon:7227 sptssa / small subunit ortholog FlyBase

Breed (VBO): Not applicable.

Comparative biology

The SPT complex is deeply conserved — the ORM/ORMDL regulatory system was first characterized in yeast (Orm1/Orm2), and the human ORMDL proteins are its direct descendants. This conservation is what makes the Drosophila model informative for the biochemistry despite the fly's total lack of the relevant anatomy.

A conserved-mechanism observation worth recording: the paralogous small subunit SPTSSB produces neurodegeneration in mouse when dysregulated (PMID:26438849):

"Our work demonstrates that SPT small subunits play a major role in controlling SPT activity and substrate affinity, and in specifying sphingolipid LCB chain length in vivo."

That the general principle "SPT small-subunit dysregulation → neurodegeneration" holds across mouse and human, via two different genes and two different molecular routes, is the strongest cross-species support available for SPG90A's pathogenesis.

15. Model Organisms

Models that exist

1. Drosophila melanogaster — the only model of the actual SPG90A variant.

  • Type: Invertebrate, transgenic overexpression (single-chain SPT construct, "scSPT," carrying the human p.Thr51Ile change), with GAL4-driven neuronal or ubiquitous expression.
  • Publication: PMID:36718090
  • Phenotypes: Neuronal expression caused "severely compromised climbing activity and... very short lifespan"; ubiquitous expression caused lethality at various developmental stages.
  • The key rescue experiment — this is the elegant part of the study: "ORMDL3 expression rescues the lifespan in flies expressing WT scSPT but not in flies expressing the p.Thr51Ile scSPT variant." Correspondingly, ORMDL3 co-expression "abolished the C18 SL levels" with wild-type SPT but "did not fully suppress the production of C18 SLs" with T51I. This is a clean in-vivo demonstration that the variant's defect is specifically insensitivity to ORMDL restraint — not merely elevated activity.
  • Readouts: climbing/motor performance (DECREASED), lifespan (DECREASED), whole-animal C18 sphingolipid levels (INCREASED).
  • Fidelity: MODERATE for the biochemistry, absent for the anatomy. Drosophila has no corticospinal tract, no myelin, and no oligodendrocytes. The model demonstrates the metabolic lesion and an organismal motor consequence; it cannot demonstrate length-dependent upper-motor-neuron degeneration. It is also an overexpression model, which is a further remove from the human heterozygous knock-in situation.

2. Sptssb "Stellar" (Stl) mouse — a related-but-different mammalian model.

  • Type: Spontaneous chemically-arising mutation in the paralogous small subunit Sptssb.
  • Publication: PMID:26438849, PNAS 2015.
  • Mechanism: "increased the SPT affinity toward the C18 fatty acyl-CoA substrate by twofold and significantly elevated 20-carbon (C20) LCB production in the mutant mouse brain and eye."
  • Phenotypes: "aberrant membrane structures, accumulation of ubiquitinated proteins on membranes, and axon degeneration"; ataxia and premature death.
  • Fidelity: LOW. Wrong gene (Sptssb), wrong molecular mechanism (altered substrate affinity, not lost ORMDL restraint), wrong accumulating species (C20 LCBs, not canonical C18 SLs), wrong phenotype (ataxia, not spastic paraparesis). Curate as PARTIALLY_RECAPITULATES / LOW fidelity with explicit limitations. It supports a general principle, not the specific disease.

3. Sptssa knockout mouse — exists, but is embryonic-lethal and therefore not a disease model.

MGI records 7 alleles. The null phenotype (MGI:1913399): "decreased embryo size, failure of primitive streak formation, absent primitive node and head folds, failure to gastrulate, and complete embryonic lethality by E9.5."

This is a mechanistically important negative. Complete loss of SPTSSA is incompatible with gastrulation, which independently confirms that SPG90A cannot be a haploinsufficiency/loss-of-function disorder — the phenotype of losing this gene is embryonic death, not childhood spasticity. It corroborates the gain-of-function interpretation from an orthogonal direction.

The critical model gap

"No murine models with SPT-related ALS or HSP variants have been reported so far." — PMID:38788085 (2024)

There is no mammalian model of any unrestrained-SPT disease variant — not for SPG90A, not for SPTLC1-ALS. Combined with the absence of human neuropathology, this means the corticospinal localization of SPG90A rests entirely on clinical inference (selective UMN signs, normal EMG/NCS) plus class-level HSP knowledge. This should be curated as a HUMAN_MODEL_MISMATCH discussion, not glossed.

Models that do not exist but should

Proposed model What it would resolve
Knock-in mouse carrying Sptssa p.Thr51Ile (heterozygous, matching human dosage) Whether the lesion produces length-dependent corticospinal degeneration with LMN sparing; whether the developmental and auditory components reproduce; a substrate for preclinical SPT-inhibitor and ASO testing
Patient-derived iPSC → cortical/spinal motor neurons The first neuronal measurement of sphingolipid excess in this disease — currently measured only in HEK293, fibroblasts, and fly
Comparative sphingolipidomics across SPT-subunit alleles Whether SPTSSA-cHSP and SPTLC1-ALS accumulate different species, which is the leading hypothesis for the phenotypic divergence

Available model resources

MGI, IMSR (11 Sptssa strains/lines available), IMPC, Alliance of Genome Resources, FlyBase. No SPG90A-specific patient cell line is deposited in Coriell or Cellosaurus that I could identify; the patient fibroblasts used in PMID:36718090 appear to be lab-held.

The central unresolved question

Worth stating on its own because it governs how much any SPG90A entry can claim. The SPTSSA, SPTLC1, and SPTLC2 disease variants converge on the same biochemical lesion — impaired ORMDL regulation, unrestrained SPT — yet produce clinically distinct diseases: upper-motor-neuron-predominant complicated HSP with neurodevelopmental involvement versus combined UMN/LMN juvenile ALS. The founding authors are direct about not knowing why:

"We do not yet understand why mutations in different subunits of SPT that similarly impact ORMDL regulation cause such distinct clinical presentations." — PMID:36718090

They offer the leading structural hypothesis:

"All SPT isozymes contain SPTLC1 and are thus dysregulated in the ALS patients, but in the HSP patients only the isozymes containing SPTSSA are affected."

And the 2024 review adds a second, biochemical, hedged observation:

"It is notable that unlike the SPTLC1 and SPTLC2-related ALS variants, the cHSP-related SPTSSA variants do not increase, and likely decrease (via ORMDL inhibition) the activity of SPTSSB-containing SPT." — PMID:38788085

"Despite the biochemical similarities and differences between SPT-related juvenile ALS and cHSP, the mechanisms underlying the phenotypic differences remain poorly understood."

Practical consequence: no entry in this disease family should assert a specific downstream neurotoxic sphingolipid species as the effector. The identity of the toxic species in SPG90A is unknown.

Findings that differ from, or are missing in, the existing draft KB entry

I read kb/disorders/Spastic_Paraplegia_90A_Autosomal_Dominant.yaml before researching. The draft is mechanistically sound and its evidence discipline is good. Five things surfaced that would change it:

1. A factual error about the recurrent allele. The draft's description says p.Thr51Ile "has now been reported in a third of the very small published cohort." The actual position: T51I is in 3 of 4 published SPG90 patients and 3 of 3 published SPG90A patients — it is the only known SPG90A allele, at 100%. The "one third" reading appears to misparse "detected in two of the reported patients." The genetic: block's notes also says T51I was "found in two of the first three reported patients," but the third of those (homozygous p.Gln58AlafsTer10) is the SPG90B patient, so within the dominant entity the denominator is two, not three.

2. Substantial phenotype under-coverage. HPO annotations for OMIM:620416 (all from PMID:36718090) include several features present in 2/2 patients that the draft omits entirely: nevus flammeus / port-wine stain (HP:0001052, 2/2), short stature (HP:0004322, 2/2), intellectual disability (HP:0001249, 2/2), delayed ability to walk (HP:0031936, 2/2), and appendicular spasticity (HP:0034353, 2/2). Also missing at 1/2 or 1/1: tethered cord, scoliosis, macrocephaly, dysphagia, GERD, drooling, failure to thrive, sleep disturbance, absent speech, delayed speech and language development. The port-wine stain at 2/2 is the most striking omission — it is as frequent as the spasticity and entirely unexplained.

3. Missing clinical findings with diagnostic weight. The draft does not record (a) abnormal EEG in all patients without clinical seizures in the SPG90A pair — the HPO annotation for Seizure is explicitly 0/2, so review sources listing "seizures" for cHSP are pooling in the SPG90B patient; (b) normal NCS/EMG, the negative finding that localizes the lesion and separates this from SPTLC1-ALS; (c) the MRI/MRS findings, including decreased NAA and increased lactate, the only in-vivo human evidence of a bioenergetic component.

4. A missing treatment contraindication. The draft's treatments: block lists supportive care, physiotherapy, and antispastic drugs but does not record that L-serine supplementation should be avoided and may be harmful — the one disease-specific management directive in the literature, and a real hazard precisely because serine is therapeutic in HSAN1, a disorder of the same enzyme complex.

5. Two uncited highly relevant references. PMID:37308477 (Xie et al., Nat Commun 2023) solves the ceramide-sensing mechanism that the disease breaks, with structures 7YIU/7YIY/7YJ1/7YJ2 and a demonstration that ALS variants impair ceramide sensing. The Sptssa knockout mouse being embryonic-lethal by E9.5 (MGI:1913399) is a strong orthogonal argument that SPG90A cannot be haploinsufficiency — useful support for the entry's own gain-of-function framing.

I have not modified the file; you asked for research, so this is a report. Say the word and I'll apply these as edits, fetch the missing references through just fetch-reference, and run the validation loop.

Sources

Primary literature - Srivastava S, Shaked HM, Gable K, et al. SPTSSA variants alter sphingolipid synthesis and cause a complex hereditary spastic paraplegia. Brain. 2023;146(4):1420–1435. PMID:36718090 · DOI 10.1093/brain/awac460 · PMC10319774 · Oxford Academic - Duzenli T, Yusufova V, Cetin H, et al. Identifying the Fourth Patient With Spastic Paraplegia 90, Extending the Phenotype Spectrum. Clin Genet. 2026. PMID:40533086 · DOI 10.1111/cge.70009 - Mohassel P, Abdullah M, Eichler FS, Dunn TM. Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders. J Neuromuscul Dis. 2024;11(4):735–747. PMID:38788085 · DOI 10.3233/JND-240014 · PMC11307022 · SAGE - Li S, Xie T, Liu P, Wang L, Gong X. Structural insights into the assembly and substrate selectivity of human SPT–ORMDL3 complex. Nat Struct Mol Biol. 2021;28(3):249–257. PMID:33558762 · DOI 10.1038/s41594-020-00553-7 - Xie T, Liu P, Wu X, et al. Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis. Nat Commun. 2023. PMID:37308477 · DOI 10.1038/s41467-023-39274-y · PMC10261145 - Zhao L, Spassieva S, Gable K, et al. Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration. PNAS. 2015. PMID:26438849 · DOI 10.1073/pnas.1516733112 - SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins. J Clin Invest. 2022;132(18):e161908. DOI 10.1172/JCI161908 · PMC9479574 · JCI - Ruano L, Melo C, Silva MC, Coutinho P. The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies. Neuroepidemiology. 2014;42(3):174–183. PMID:24603320 · DOI 10.1159/000358801 · Karger - AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient. Nat Med. 2024. PMC11271397 · Nature Medicine - Botulinum Toxin Treatment in Hereditary Spastic Paraplegia — A Comprehensive Review and Update. PMC12567745 - Cipriano L, Angelini C, Santorelli FM. Hereditary spastic paraplegia: from decades of therapy to future innovations. Ther Adv Neurol Disord. 2026. SAGE

Databases and reference resources - OMIM #620416 — SPG90A · OMIM #620417 — SPG90B · OMIM *613540 — SPTSSA - MedGen C5830574 — Spastic paraplegia 90A - HPO annotations for OMIM:620416 - MGI:1913399 — mouse Sptssa - Human Protein Atlas — SPTSSA (ENSG00000165389) - GeneCards — SPTSSA - MalaCards — Spastic Paraplegia 90A, Autosomal Dominant - GeneReviews — Hereditary Spastic Paraplegia Overview (NBK1509) - Orphanet ORPHA:102013 — Complex hereditary spastic paraplegia - RCSB PDB: 7YIU · 7YIY · 7YJ1 · 7YJ2 - Atlas of Genetics and Cytogenetics — SPTSSA - Undiagnosed Diseases Network — SPTSSA

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 23
Resolved 23
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 18
Quoted claims found in source 12
Quoted claims not found in source 6
References weighed for topical relevance 23
On topic 7
Off topic 1

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:36718090 (abstract only): "Elevated serine exacerbates the overproduction of SLs associated with the SPTLC1 juvenile ALS variants and the SPTSSA variants described here... Thus serine supplementation is not a rational therapeutic strategy and may even be detrimental for these patients."
  • closest text in source: "These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function."
  • PMID:36718090 (abstract only): "Around 6 years of age, he developed rolandic seizures with temporoparietal spike-waves evident on EEG."
  • Text part not found as substring: 'Around 6 years of age, he developed rolandic seizures with temporoparietal spike-waves evident on EEG.' (note: only abstract available for PMID:36718090, full text may contain this excerpt)
  • PMID:36718090 (abstract only): "Serum levels of SLs were increased in all three patients"
  • closest text in source: "Exome sequencing identified potential disease-causing variants in SPTSSA in three children presenting with a complex form of hereditary spastic paraplegia"
  • PMID:36718090 (abstract only): "Elevated serine exacerbates the overproduction of SLs associated with the SPTLC1 juvenile ALS variants and the SPTSSA variants described here... Thus serine supplementation is not a rational therapeutic strategy and may even be detrimental for these patients."
  • closest text in source: "These findings support the pathogenicity of the SPTSSA variants and point to excessive sphingolipid synthesis due to impaired homeostatic regulation of serine palmitoyltransferase as responsible for defects in early brain development and function."
  • PMC:PMC11271397 (abstract only): "was well tolerated, showing preliminary evidence of disease stabilization"
  • closest text in source: "Preliminary efficacy measures suggest a stabilization of the disease course"
  • PMID:36718090 (abstract only): "We do not yet understand why mutations in different subunits of SPT that similarly impact ORMDL regulation cause such distinct clinical presentations."
  • closest text in source: "Key to the homeostatic regulation are the ORMDL proteins that are bound to serine palmitoyltransferase and mediate feedback inhibition of enzymatic activity when sphingolipid levels become excessive"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.1073/pnas.1516733112 (1 mention) - Elevation of 20-carbon long chain bases due to a mutation in serine palmitoyltransferase small subunit b results in neurodegeneration
  • shared terms: sphingolipid, serine

Weighed against this report's own most characteristic terms: spg90a, patient, disease, sptssa, spt, variant, gene, sphingolipid, clinical, novo, dominant, disorder, spasticity, spg90b, thr51ile, mechanism, allele, als, serine, sptlc1.