Spastic Paraplegia 90A, Autosomal Dominant

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:

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

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

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

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

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

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

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

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.

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:

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.

Supportive, rehabilitative, and surgical

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:

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

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

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.

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.