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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant, predominantly de novo HP:0000006

ALS27 is caused by heterozygous, dominantly acting SPTLC1 variants. Most reported probands are simplex cases in whom the variant arose de novo, but vertical transmission has been documented in at least one pedigree carrying p.Leu39del, and one Japanese proband inherited p.Ala20Thr from a clinically unaffected father who was mosaic for the variant in blood leukocytes.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:34059824 SUPPORT Human Clinical

"We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS."

Establishes dominant (heterozygous) action of the ALS-causing SPTLC1 variants.

PMID:39666121 SUPPORT Human Clinical

"We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism."

Documents parental mosaicism as an alternative to a true de novo event, which matters for recurrence-risk counselling.

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Discussions and Knowledge Gaps

3

Why are motor neurons selectively vulnerable to SPT overactivity while sensory neurons are selectively vulnerable to deoxysphingolipid accumulation, when both phenotypes arise from variants in the same gene?

KNOWLEDGE GAP OPEN gap_als27_motor_neuron_selective_vulnerability

Attached to

pathophysiology#Unrestrained De Novo Sphingolipid Synthesis pathophysiology#Upper and Lower Motor Neuron Degeneration

ALS27 and HSAN1 are both SPTLC1 diseases, but they hit opposite neuronal populations according to which lipid species accumulates. Nothing in the current model explains the cell-type selectivity; the pathway from excess canonical sphingolipid to motor neuron death is entirely uncharacterized, which is also why no rational neuroprotective target exists downstream of SPT itself.

Show evidence (2 references)

PMID:34059824 SUPPORT Human Clinical

"We do not yet understand why motor and sensory neurons show selective vulnerability to distinct biochemical changes in sphingolipid synthesis and homeostasis."

The authors state the gap explicitly.

PMID:38788085 SUPPORT Other

"future fundamental studies to establish the downstream cellular consequences of abnormal SPT activity, the selective vulnerability of sensory and motor neurons to distinct biochemical changes in SPT function"

The 2024 review restates the same gap as an outstanding research priority, three years after it was first flagged.

Does any existing animal model reproduce human ALS27, given that heterozygous Sptlc1 exon-2-deletion mice show neither motor deficits nor ALS-like neuropathology?

HUMAN MODEL MISMATCH OPEN mismatch_als27_no_faithful_in_vivo_model

Attached to

pathophysiology#Upper and Lower Motor Neuron Degeneration

The human disease is a dominant gain-of-function requiring an assembled but unrestrained SPT complex. The available mouse deletes exon 2 outright, which behaves as a loss-of-function (homozygous lethal) and leaves heterozygotes unaffected. Until a knock-in carrying an actual ALS27 missense or in-frame-deletion allele is characterized, therapeutic candidates such as allele-selective siRNA cannot be tested in vivo, and the in vitro rescue result stands alone.

Proposed experiments

Knock-in mouse carrying a human ALS27 missense allele

exp_als27_missense_knockin_mouse

Generate heterozygous knock-in mice carrying Sptlc1 p.Ala20Ser or p.Leu39del (rather than an exon deletion) and phenotype for motor behaviour, spinal motor neuron counts, neuromuscular junction integrity, and CNS/plasma sphingolipidomics.

Show evidence (2 references)

PMID:42392979 SUPPORT Model Organism

"Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely."

The negative in vivo result that defines the mismatch.

PMID:38788085 SUPPORT Other

"No murine models with SPT-related ALS or HSP variants have been reported so far."

As of the 2024 review no murine ALS27 model existed; the 2026 exon-2-deletion mouse is the first attempt and it fails to recapitulate, so the gap remains open.

Are SPTLC1-related motor and sensory phenotypes two discrete diseases or a continuum?

OPEN QUESTION OPEN open_als27_hsan1_continuum_vs_discrete_entities

Attached to

pathophysiology#Unrestrained De Novo Sphingolipid Synthesis

The classical dichotomy (exon 2 / transmembrane variants cause ALS27; C-terminal variants cause HSAN1) is complicated by patients with mixed sensorimotor features (p.Ser331Tyr "juvenile ALS-Plus") and by the demonstration that L-serine availability can shift an ALS lipid signature toward an HSAN1-like one within a single pedigree. How dismech splits these entities affects whether ALS27 should remain a standalone entry or be modeled as one pole of an SPTLC1 spectrum.

Show evidence (3 references)

PMID:35900868 SUPPORT Human Clinical

"This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency."

Shows an ALS27 genotype producing an HSAN1 phenotype under serine limitation, blurring the entity boundary.

PMID:35627278 SUPPORT Human Clinical

"It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment."

States the continuum hypothesis explicitly.

PMID:38788085 SUPPORT Human Clinical

"These findings suggest that SPTLC1-related HSAN1 and ALS phenotypes are not mutually exclusive, and aspects of both phenotypes may co-occur."

The p.Ser331 hybrid cases show concurrent 1-deoxysphingolipid and canonical-sphingolipid excess, so the two SPTLC1 entities are not cleanly disjoint.

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Pathophysiology

6

SPTLC1 Transmembrane-Domain Gain-of-Function Variant

Heterozygous missense or small in-frame deletion variants in SPTLC1 (p.Ala20Ser, p.Ala20Thr, p.Tyr23Phe, p.Leu38Arg, p.Leu39del, p.Phe40_Ser41del) cluster within the single membrane-spanning domain encoded by exon 2 — the surface through which SPTLC1 contacts the ORMDL regulatory subunits. The variants are dominantly acting and, in the originally described cohort, arose de novo. p.Ser331Tyr is deliberately NOT listed here: S331 sits near the active site rather than in the transmembrane domain, and although it interacts with ORMDLs it produces a mixed sensorimotor ("ALS-Plus") phenotype with concurrent 1-deoxysphingolipid excess. It is treated as a hybrid allele throughout this entry, not as a member of the exon-2 cluster.

SPTLC1 hgnc:11277

Genetic context SPTLC1 hgnc:11277 variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Monoallelic, dominantly acting exon 2 variants that increase serine palmitoyltransferase activity rather than abolishing it.

Downstream

Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase Because the ALS27 residues lie in the SPTLC1 transmembrane helix that binds ORMDL, the variants weaken the SPT-ORMDL interaction and blunt ceramide sensing.

Show evidence (4 references)

PMID:34459874 SUPPORT Human Clinical

"De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."

Identifies specific de novo SPTLC1 variants in juvenile ALS probands.

PMID:36204986 SUPPORT Human Clinical

"Recent studies have reported mutations in SPLTC1 may cause juvenile amyotrophic lateral sclerosis (JALS), especially in the first transmembrane domain of SPTLC1(exon 2)."

States the exon 2 / first transmembrane domain clustering of the ALS-associated SPTLC1 variants.

PMID:42392979 SUPPORT Other

"ALS-associated SPTLC1 variants, including Y23F, L38R, L39del, and F40S41del, are clustered in exon 2"

Enumerates the exon-2 cluster; note that p.Ser331Tyr is absent from it, which is why this entry does not list S331 as a cluster member.

+ 1 more reference

Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase

Serine palmitoyltransferase is an endoplasmic-reticulum heterocomplex whose activity is held in check by the ORMDL1-3 regulatory subunits, which inhibit the enzyme when they sense rising ceramide. ALS27 variants sit on the SPTLC1 face that contacts ORMDL, so ORMDL binding and ceramide sensing are impaired and the negative feedback arm of sphingolipid homeostasis fails. The catalytic function itself is intact — it is the restraint that is lost, which is why this is a gain-of-function rather than a deficiency state.

serine palmitoyltransferase complex GO:0017059

negative regulation of sphingolipid biosynthetic process GO:0090155 ⇓ LOSS OF FUNCTION

serine C-palmitoyltransferase activity GO:0004758 ⇑ GAIN OF FUNCTION

endoplasmic reticulum GO:0005783

Downstream

Unrestrained De Novo Sphingolipid Synthesis With ORMDL restraint lost, SPT runs unregulated and de novo sphingolipid production rises.

Show evidence (3 references)

PMID:35900868 SUPPORT In Vitro

"SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity."

Localizes the ALS27 variants to the ORMDL-interacting transmembrane domain and identifies ORMDL as the negative regulator.

PMID:37308477 SUPPORT In Vitro

"we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants"

Structural and biochemical work showing the ALS27 variants specifically break ceramide-dependent feedback sensing by the SPT-ORMDL3 complex.

PMID:37348646 SUPPORT In Vitro

"All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT."

Confirms the shared mechanism across ALS27 alleles, including p.L38R.

Unrestrained De Novo Sphingolipid Synthesis

Loss of feedback restraint drives excess condensation of L-serine with palmitoyl-CoA, elevating canonical sphingoid bases and their downstream products. Patient plasma and variant-expressing cells show globally increased sphingolipids, with a particularly marked rise in dihydrosphingolipids (sphinganine and dihydroceramides), which have been linked to neurotoxicity. In the exon-2 / transmembrane-domain alleles, 1-deoxysphingolipid levels are NOT elevated — that is the HSAN1 signature — so the two SPTLC1 diseases are separated by which lipid species accumulates, not merely by how much SPT activity there is. This dichotomy is real but not absolute: patients with p.Ser331 substitutions show a CONCURRENT rise in 1-deoxysphingolipids and canonical sphingolipids, and one p.Leu39del carrier with a raised alanine/serine ratio showed both. The clean separation therefore holds for the exon-2 cluster, not for every SPTLC1-ALS allele.

sphingolipid biosynthetic process GO:0030148 ↑ INCREASED

Experimental models

SPTLC1 variant-expressing HEK293 cells CELL LINE Variant-expressing cells show increased SPT activity and increased de novo sphingolipid synthesis, matching the patient plasma lipid signature.

Patient-derived fibroblasts carrying SPTLC1-ALS variants PRIMARY CELL CULTURE Patient fibroblasts reproduce the enzyme overactivity and were used to demonstrate allele-specific rescue.

iPSC-derived lower motor neuron-like cells (compound-heterozygous SPTLC1 delF40_S41/delExon2) IPSC DERIVED MODEL Elevated canonical sphingolipids in an ALS27-genotype motor neuron-like cell.

Downstream

Upper and Lower Motor Neuron Degeneration Excess sphingoid base and dihydrosphingolipid production is the proposed proximate driver of motor neuron injury in ALS27. The step from lipid excess to selective motor neuron death is inferred rather than directly demonstrated in human tissue.

Show evidence (4 references)

PMID:34059824 SUPPORT Human Clinical

"Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS."

States the core mechanism — unrestrained sphingoid base synthesis causing monogenic ALS.

PMID:37348646 SUPPORT Human Clinical

"Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma."

Demonstrates globally increased sphingolipids in ALS27 patient plasma.

PMID:37348646 SUPPORT In Vitro

"Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations."

Proposes dihydrosphingolipid accumulation as the neurotoxic species; the hedged wording is preserved deliberately.

+ 1 more reference

Upper and Lower Motor Neuron Degeneration

Degeneration involves both motor neuron compartments. Upper motor neuron involvement presents first in most patients as early-childhood lower-limb spasticity and toe walking, and is followed by diffuse lower motor neuron degeneration in cranial, cervical and lumbar myotomes, so that patients meet revised El Escorial criteria for ALS. Sensory neurons are characteristically spared, distinguishing ALS27 from HSAN1.

motor neuron CL:0000100 spinal cord motor neuron CL:0011001

spinal cord UBERON:0002240 primary motor cortex UBERON:0001384

Experimental models

iPSC-derived lower motor neuron-like cells (compound-heterozygous SPTLC1 delF40_S41/delExon2) IPSC DERIVED MODEL No effect on differentiation, morphology, or survival was observed in these ALS27-genotype motor neuron-like cells.

Animal models

Sptlc1 exon 2 deletion knock-in mouse Mouse fails to recapitulate Heterozygous exon-2-deletion mice, the genotype corresponding to the human dominant disease, showed no motor defects and no ALS-like neuropathology.

Downstream

Lower Limb Spasticity Upper motor neuron involvement produces the early lower-limb spasticity that opens the clinical course.

Toe Walking (Tip-Toe Gait) Toe walking follows from the lower-limb spasticity produced by upper motor neuron degeneration.

Hyperreflexia Loss of corticospinal inhibition from upper motor neuron degeneration produces brisk reflexes and an exaggerated jaw jerk.

Dysarthria Degeneration of bulbar motor neurons weakens the articulatory musculature.

Dysphagia Bulbar motor neuron loss weakens the swallowing musculature.

Progressive Denervation and Neurogenic Muscle Atrophy Lower motor neuron loss denervates skeletal muscle, producing the acute and chronic neurogenic changes seen on muscle biopsy and the active/chronic denervation seen on EMG.

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"All six individuals had upper and lower motor neuron signs and symptoms in the cranial, cervical and lumbar myotomes and thus met the revised El Escorial criteria for the clinical definition of ALS"

Documents combined upper and lower motor neuron involvement meeting formal ALS diagnostic criteria.

Progressive Denervation and Neurogenic Muscle Atrophy

Chronic denervation produces generalized muscle wasting and weakness, most visibly in the tongue (wasting with fasciculations) and in the limbs, with a positive Gower sign and exaggerated lumbar lordosis reflecting proximal weakness. Muscle biopsy in ALS27 has also shown mild inflammatory change on proteomic and transcript profiling.

Downstream

Progressive Muscle Weakness Denervated muscle loses force output, producing progressive weakness.

Skeletal Muscle Atrophy Chronic denervation produces neurogenic muscle wasting.

Tongue Fasciculations Denervation of the tongue produces wasting with fasciculation.

Fasciculations Denervated motor units discharge spontaneously, producing fasciculations.

Diffuse Denervation on Electromyography Denervation is what the electrodiagnostic study measures - acute and chronic denervation across multiple myotomes.

Loss of Ambulation and Respiratory Insufficiency Cumulative denervation of limb and respiratory musculature ends in wheelchair dependence and ventilatory failure.

Show evidence (1 reference)

PMID:35627278 SUPPORT Human Clinical

"Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels."

Documents the muscle-tissue findings accompanying denervation in an SPTLC1 p.A20S patient.

Loss of Ambulation and Respiratory Insufficiency

The organism-level endpoint of ALS27. Progression is slower than in sporadic adult ALS: in the longest-followed case, independent ambulation was lost at age 45 after onset at 22, with forced vital capacity falling from 94% to 49% of predicted over 20 years and two admissions for respiratory failure. Some patients require tracheostomy and ventilation.

Downstream

Loss of Ambulation Cumulative limb weakness ends independent walking.

Respiratory Insufficiency Denervation of respiratory musculature produces ventilatory failure.

Show evidence (2 references)

PMID:37497262 SUPPORT Human Clinical

"Pulmonary function declined from a forced vital capacity of 94% predicted at 27 years to 49% predicted at 47 years, and she was hospitalized twice for respiratory failure."

Quantifies the respiratory decline over a 30-year follow-up of a genetically confirmed ALS27 patient.

PMID:37497262 SUPPORT Human Clinical

"She lost independent ambulation at age 45 years."

Documents loss of ambulation and the slow tempo of decline in ALS27.

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Pathograph

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

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Phenotypes

15

Digestive 1

Dysphagia OCCASIONAL HP:0002015

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"She presented at age 10 years with a deteriorating gait, hand weakness, right foot paresthesia, dysphagia, and increased sweating."

Documents dysphagia in an ALS27 (ALS-Plus) patient. OCCASIONAL is a derived count: 1 of the 4 probands in this cohort had dysphagia and another explicitly did not, i.e. 25%, within the 5-29% band.

Musculoskeletal 2

Progressive Muscle Weakness VERY_FREQUENT HP:0003323

Show evidence (2 references)

PMID:34059824 SUPPORT Human Clinical

"followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs"

Progressive lower motor neuron weakness in all six index-cohort probands.

PMID:37348646 SUPPORT Human Clinical

"The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs."

Independent case confirming the weakness/atrophy phenotype.

Skeletal Muscle Atrophy VERY_FREQUENT HP:0003202

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"Her neurological examination at presentation revealed a body mass index less than the first percentile, exaggerated lumbar lordosis, tongue fasciculations and wasting, generalized muscle atrophy and weakness, brisk asymmetric ankle reflexes, a positive Gower sign, and normal sensation"

Documents generalized muscle atrophy and weakness with preserved sensation in an ALS27 patient.

Nervous System 4

Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"Examination revealed marked atrophy, postural tachycardia, bilateral cataracts, a wasted and fasciculating tongue with an exaggerated jaw jerk, generalized fasciculations and weakness associated with hyperreflexia, and decreased pinprick sensation in a glove-and-stocking distribution"

Documents hyperreflexia (with an exaggerated jaw jerk) in an ALS27 patient. `frequency` is deliberately omitted - the available evidence is single-patient description with no denominator.

Fasciculations HP:0002380

Show evidence (1 reference)

PMID:37497262 SUPPORT Human Clinical

"She experienced gradual decline in muscle strength with development of weakness and hyperreflexia in lower extremities and diffuse fasciculations in the upper extremities at 26 years."

Documents diffuse fasciculations alongside weakness and hyperreflexia in a genetically confirmed ALS27 patient.

Dysarthria OCCASIONAL HP:0001260

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"tongue fasciculations and weakness, dysarthria, mild cognitive dysfunction, and respiratory failure requiring tracheostomy and ventilation"

Documents dysarthria as part of the bulbar phenotype. OCCASIONAL is a derived count: 1 of the 4 probands in this cohort, i.e. 25%, which falls in the 5-29% band.

Cognitive Impairment OCCASIONAL HP:0100543

Severity: MILD

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"Decreased sustained attention and impaired executive functioning were evident in neuropsychological evaluation."

Formal neuropsychological documentation of executive/attentional impairment in an ALS27 patient. OCCASIONAL is a derived count: 2 of the 4 probands in this cohort had some cognitive finding, but see the description - a 2024 review reports none, so the band is provisional.

Respiratory 1

Respiratory Insufficiency FREQUENT HP:0002093

Course: PROGRESSIVE

Show evidence (2 references)

PMID:34059824 SUPPORT Human Clinical

"The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."

Respiratory insufficiency of variable degree in all index-cohort patients.

PMID:34459874 SUPPORT Human Clinical

"By age 20 years, she had quadriplegia with marked muscle atrophy and diminished weight, brisk lower limb reflexes, tongue fasciculations and weakness, dysarthria, mild cognitive dysfunction, and respiratory failure requiring tracheostomy and ventilation."

Documents respiratory failure requiring tracheostomy and ventilation.

Growth 1

Failure to Thrive and Growth Failure FREQUENT HP:0001508

Show evidence (2 references)

PMID:34459874 SUPPORT Human Clinical

"De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."

Three of the four probands in this study carried a juvenile ALS diagnosis together with failure to thrive.

PMID:34459874 SUPPORT Human Clinical

"Patient 1 presented with gradually progressive spastic diplegia and growth retardation beginning at age 5 years."

Growth retardation from early childhood in an ALS27 patient.

Other 6

Lower Limb Spasticity VERY_FREQUENT HP:0002061

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"We identified six individuals from six unrelated families who developed early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs"

Six of six probands in the index cohort presented with early-childhood lower extremity spasticity, supporting a VERY_FREQUENT band.

Tongue Fasciculations VERY_FREQUENT HP:0001308

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"this initial manifestation was almost universally followed by diffuse and progressive lower motor neuron degeneration, including tongue fasciculations, which is highly unusual for classic forms of HSP but consistent with ALS"

The quoted sentence says tongue fasciculations followed "almost universally", which maps to the VERY_FREQUENT band (80-100%); the same sentence is the discriminator from hereditary spastic paraplegia.

Absence of Sensory Neuropathy

Show evidence (3 references)

PMID:34059824 REFUTE Human Clinical

"the patients with ALS reported here presented with childhood-onset motor neuron disease, normal sensory findings (by clinical examination, electrophysiologic studies and nerve biopsy when available) and normal deoxysphingolipid levels."

Refutes sensory impairment as a feature of typical ALS27; sensory findings were normal across the index cohort.

PMID:34059824 REFUTE Human Clinical

"Patient 3 also had a sural nerve biopsy that failed to reveal any abnormalities in myelinated or unmyelinated sensory nerve fibers"

Histological confirmation of sensory sparing; moved here from the motor-neuron-degeneration node, which it does not evidence.

PMID:34459874 SUPPORT Human Clinical

"She was diagnosed with juvenile ALS-Plus syndrome owing to her prominent motor symptoms and modest sensory-autonomic involvement."

A minority of SPTLC1-ALS patients do have modest sensory-autonomic involvement, so sensory sparing is typical rather than absolute.

Toe Walking (Tip-Toe Gait) VERY_FREQUENT HP:0030051

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities"

Toe walking and gait abnormality as the presenting manifestation in all six index-cohort probands.

Diffuse Denervation on Electromyography VERY_FREQUENT EMG: chronic denervation signs HP:0003444

Show evidence (1 reference)

PMID:38788085 SUPPORT Human Clinical

"Electrodiagnostic studies show normal sensory studies and diffuse acute and chronic denervation in multiple myotomes without demyelinating features"

Defines the characteristic electrodiagnostic signature of SPTLC1-related juvenile ALS.

Loss of Ambulation FREQUENT HP:0002505

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."

Loss of independent ambulation was universal in the index cohort.

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Genetic Associations

1

SPTLC1

Gene: SPTLC1 hgnc:11277 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (3 references)

PMID:34059824 SUPPORT Human Clinical

"all patients in this family carried the same SPTLC1 variant (NM_006415.4:c.115_117delCTT, p.(L39del)), which was recurrent in two unrelated childhood ALS patients"

Documents the recurrent p.Leu39del allele and its transmission within a pedigree.

PMID:34059824 SUPPORT Human Clinical

"Consistent with the sporadic occurrence of the disease, SPTLC1 variants occurred de novo (that is, were absent in the unaffected parents"

Establishes the predominantly de novo origin of ALS27 variants.

PMID:42392979 SUPPORT Other

"All known ALS-linked SPTLC1 mutations cluster within exon 2, and a specific variant, c.58G>T, results in exon 2 skipping."

States the exon 2 clustering of ALS-linked SPTLC1 variants and the splicing consequence of c.58G>T.

💊

Medical Actions

5

Allele-Selective SPTLC1 siRNA (investigational)

Action: Gene Silencing Therapy Ontology label: Pharmacotherapy NCIT:C15986

Custom small interfering RNAs designed to degrade the mutant SPTLC1 allele while sparing the wild-type allele normalized sphingolipid levels in patient-derived cells. This is a proof-of-concept in vitro result only — no in vivo or clinical data exist, and the negative heterozygous mouse model means there is currently no animal system in which to test efficacy.

Mechanism Target:

INHIBITS Unrestrained De Novo Sphingolipid Synthesis — Selective knockdown of the mutant transcript removes the unregulated SPT subunit and restores normal sphingolipid levels.

Show evidence (1 reference)

PMID:34059824 SUPPORT In Vitro

"We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro."

Demonstrates allele-selective knockdown normalizing sphingolipid levels, establishing the mechanistic target.

Show evidence (3 references)

PMID:34059824 SUPPORT In Vitro

"We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro."

The only reported disease-modifying strategy for ALS27, at in vitro proof-of-concept stage.

PMID:38788085 SUPPORT Other

"While effective, and imposing little chance for over-inhibition of SPT, this approach has limited generalizability and needs to be custom-designed and validated for each disease-causing SPT variant."

Records the translational limitation - each ALS27 allele needs its own bespoke siRNA - which is why this has not scaled beyond proof of concept.

PMID:38788085 SUPPORT Other

"SPT genes are thought to be haplosufficient; that is, loss of function or deletion of one gene copy does not cause a phenotype. Thus, allele-specific knockdown is a feasible approach in correcting the dominant gain of function in all SPT-related diseases."

Establishes the genetic precondition (haplosufficiency) that makes allele-specific knockdown a safe strategy in principle.

High-Dose Oral L-Serine Supplementation (compassionate use; predicted harmful)

Action: Nutritional Support NCIT:C15433

NOT a recommended ALS27 therapy, and recorded here as a safety caution. High-dose (10 g/day) oral L-serine was given on a compassionate basis to one ALS27 patient; body weight increased for the first time in years, ceramide levels stayed within the normal range, and no neurological improvement was observed. The rationale was not simply borrowed from HSAN1. The JAMA Neurology authors ran their own assay and found the p.Ala20Ser complex had an altered L-alanine and glycine preference over L-serine, and that serine supplementation reversed those defects toward wild-type in culture — an HSAN1-like biochemistry in an exon-2 allele, pointing opposite to the harm prediction. The prevailing view is nevertheless that supplementation is harmful here: in SPT-related motor neuron disease the enzyme is unrestrained rather than substrate-promiscuous, L-serine is the substrate it is consuming, and serine supplementation of iPSC-derived motor neurons carrying SPTLC1 p.Phe40_Ser41del accentuated the consequences of SPT overactivity. Both sides are curated below rather than only the one that supports the caution; the unresolved direction of effect is tracked in the open_als27_serine_direction_of_effect discussion.

Show evidence (6 references)

PMID:38788085 REFUTE 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"

Authoritative review states that serine supplementation is predicted to be harmful, not helpful, in SPT-related motor neuron disease including ALS27.

PMID:38788085 REFUTE In Vitro

"serine supplementation in iPSC-derived motor neurons with the SPTLC1del40 - 41 variant accentuated the consequences of SPT overactivity"

Experimental corroboration in an ALS27-genotype iPSC motor neuron model that serine makes the biochemical defect worse.

PMID:34459874 SUPPORT Human Clinical

"We did not observe evidence of neurological improvement, although prolonged therapy would be required to detect such an effect."

The only clinical exposure of an ALS27 patient to L-serine produced no demonstrated neurological benefit.

+ 3 more references

Partial Serine Palmitoyltransferase Inhibition (investigational concept)

Action: Pharmacotherapy NCIT:C15986

The mechanistically rational counter to unrestrained SPT is to inhibit the enzyme partially. No agent has reached clinical evaluation for ALS27. Myriocin is a potent suicide inhibitor but is too toxic for clinical development; L-cycloserine and other inhibitors show dose-related toxicity; D-cycloserine (an approved second-line antitubercular) is the one tolerable exception but has never been systematically tested for SPT overactivity. Two caveats are load-bearing: complete SPT inhibition is systemically toxic, and inhibition does not restore the lost dynamic regulation — it only lowers the setpoint.

Mechanism Target:

INHIBITS Unrestrained De Novo Sphingolipid Synthesis — Partial pharmacological inhibition of SPT would lower flux through the de novo pathway without abolishing it.

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 the therapeutic target and the dose-window caution.

Show evidence (1 reference)

PMID:38788085 SUPPORT Other

"All of these inhibitors show dose-related toxicity or off-target activity that have hampered their clinical development"

Explains why no SPT inhibitor is clinically available for ALS27 despite a clear target.

Dietary Serine and Glycine Restriction (theoretical)

Action: Dietary Intervention NCIT:C15447

Because SPT overproduction depends on L-serine availability, restricting dietary serine and glycine (glycine is readily converted to serine) is a theoretically feasible way to reduce substrate supply. It is the exact inverse of HSAN1 management and has not been tested clinically in ALS27. Note the countervailing risk documented in the mechanistic literature: severe serine limitation shifts SPTLC1-ALS cells toward the neurotoxic 1-deoxysphingolipid (HSAN1-like) signature, so this is a two-sided intervention rather than a simple substrate-reduction strategy.

Show evidence (2 references)

PMID:38788085 SUPPORT Other

"Since overproduction of canonical sphingolipids relies on availability of L-serine as a substrate, in addition to SPT inhibition, serine depletion is another theoretically feasible approach to ameliorate SPT overactivity."

States the substrate-restriction rationale and marks it as theoretical.

PMID:35900868 REFUTE In Vitro

"Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature."

Documents the countervailing hazard of serine restriction, which is why this remains theoretical rather than recommended.

Respiratory Support

Action: Supportive Care NCIT:C15747

Non-invasive ventilation progressing to tracheostomy and long-term ventilation as forced vital capacity declines. Supportive rather than disease-modifying.

Target Phenotypes: Respiratory insufficiency HP:0002093

Show evidence (1 reference)

PMID:34459874 SUPPORT Human Clinical

"respiratory failure requiring tracheostomy and ventilation"

Documents ventilatory support as the required intervention for ALS27 respiratory failure.

🔬

Biochemical Markers

2

Elevated Plasma Sphingolipids

Show evidence (3 references)

PMID:39666121 SUPPORT Human Clinical

"Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents."

Direct within-family comparison showing raised plasma sphingolipids in the affected proband.

PMID:37348646 SUPPORT Human Clinical

"Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells."

Identifies dihydrosphingolipids as the most raised species in patient plasma (quoted verbatim, including the source's typographical errors).

PMID:42392979 REFUTE Human Clinical

"One study indicated an increase in serum sphingolipids (5), whereas another group reported no changes in plasma ceramide or sphingomyelin levels in patients carrying the exon 2 skipping variant (3)"

Records a conflicting negative human result - not every reported ALS27 patient has measurably raised plasma sphingolipids - so this marker is not curated as a settled finding.

Normal 1-Deoxysphingolipid Levels (exon-2 alleles)

Show evidence (2 references)

PMID:34059824 SUPPORT Human Clinical

"normal sensory findings (by clinical examination, electrophysiologic studies and nerve biopsy when available) and normal deoxysphingolipid levels."

Documents normal deoxysphingolipid levels in the exon-2-allele ALS27 cohort, in contrast with HSAN1.

PMID:38788085 REFUTE Human Clinical

"Sphingolipidomic evaluation of patient serum and patient-derived cells with SPTLC1 p.S331 substitutions have identified a concurrent increase in 1-deoxysphingolipis (a feature of HSAN1 variants) as well as an overproduction of canonical sphingolipids likely by disrupting ORMDL inhibition (a..."

Refutes any blanket claim that deoxysphingolipids are normal in all SPTLC1-ALS; the S331 hybrid alleles raise both lipid classes.

📈

Progression

4

Onset

Age: mean 7.9 years (SD 4.6) in the SPTLC1-mutated juvenile ALS cohort

In the largest genotyped juvenile ALS cohort to date (17 SPTLC1 patients), mean age at onset was 7.9 +/- 4.6 years, significantly earlier than in FUS-mutated juvenile ALS (18.1 +/- 3.9 years). Onset was exclusively spinal in the SPTLC1 group, with no bulbar-onset cases, in contrast to the 37.2% bulbar onset seen with FUS.

Show evidence (1 reference)

PMID:36801857 SUPPORT Human Clinical

"mutations also had a large proportion of bulbar onset (37.2%, 16/43), while those with SPTLC1 mutations only presented spinal onset"

Establishes that onset is exclusively spinal in the SPTLC1 group, which is what distinguishes its onset pattern from FUS-mutated juvenile ALS.

Disease duration

Disease duration is an order of magnitude longer than in FUS-mutated juvenile ALS: a median 512.0 months (roughly 43 years, IQR 416.7-607.3) against 33.4 months for FUS. This is the quantitative basis for describing the SPTLC1 course as slowly progressive rather than merely "slower than adult sporadic ALS".

Show evidence (1 reference)

PMID:36801857 SUPPORT Human Clinical

"tended to have an earlier AAO and the initial symptoms of lower limb spasticity and toe walking with longer disease duration"

Gives the median disease duration for the SPTLC1 group together with its characteristic presenting symptoms.

Onset

Age: 3-25 years (most commonly early childhood)

Initial symptoms are usually upper motor neuron (lower-limb spasticity, toe walking) or lower motor neuron (weakness, atrophy), without sensory symptoms. Onset as early as 3-4 years is documented, but a minority present in the second or third decade.

Show evidence (1 reference)

PMID:38788085 SUPPORT Human Clinical

"Initial symptoms were reported as early as 3-4 years of age but in some individuals the disease onset was in the second or third decade of life"

Defines the age-at-onset range for SPTLC1-related juvenile ALS.

Progressive

The course is relentlessly progressive but markedly slower than adult sporadic ALS, with bulbar and respiratory involvement emerging late. Rate varies between individuals and families.

Show evidence (2 references)

PMID:38788085 SUPPORT Human Clinical

"The disease course has been universally and relentlessly progressive, albeit with variability in its rate, and includes involvement of the bulbar and respiratory function"

Characterizes the progressive course including late bulbar and respiratory involvement.

PMID:34059824 SUPPORT Human Clinical

"Despite its childhood onset and resulting severe disability, the rate of progression of SPTLC1-associated ALS is still slower than sporadic ALS and thus mirrors other juvenile-onset hereditary ALS cases"

Establishes the slower tempo relative to sporadic ALS.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Amyotrophic Lateral Sclerosis 27, Juvenile:

Hereditary Spastic Paraplegia

Overlapping Features The most common early misdiagnosis. ALS27 begins with lower-limb spasticity and toe walking, which looks like HSP; HSP does not go on to produce diffuse lower motor neuron degeneration with tongue fasciculations and multi-myotomal denervation.

Distinguishing Features

Presence of lower motor neuron signs (tongue fasciculations, wasting) and diffuse acute/chronic denervation on EMG favours ALS27 over HSP.

Show evidence (1 reference)

PMID:34059824 SUPPORT Human Clinical

"this initial manifestation was almost universally followed by diffuse and progressive lower motor neuron degeneration, including tongue fasciculations, which is highly unusual for classic forms of HSP but consistent with ALS"

States the discriminating feature between ALS27 and hereditary spastic paraplegia.

🧫

Experimental Models

3

SPTLC1 variant-expressing HEK293 cells CELL_LINE

HEK293 (and SPTLC1-knockout HEK293) cells stably expressing wild-type or ALS27-variant SPTLC1 are the workhorse system for ALS27. They reproduce the core biochemical phenotype — increased SPT activity, increased de novo sphingolipid synthesis, raised dihydrosphingolipids, and impaired ORMDL binding — and were the system in which allele-selective siRNA rescue was demonstrated.

Pathograph links

Unrestrained De Novo Sphingolipid Synthesis recapitulates fidelity: moderate Variant-expressing cells show increased SPT activity and increased de novo sphingolipid synthesis, matching the patient plasma lipid signature.

Limitations: HEK293 is a non-neuronal, transformed embryonic kidney line. It reproduces the enzymology and the lipid signature but says nothing about why motor neurons in particular die, and expression is typically supraphysiological.

Show evidence (1 reference)

PMID:37348646 SUPPORT In Vitro

"An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells."

Confirms the cell model reproduces increased SPT activity and de novo sphingolipid synthesis.

Show evidence (1 reference)

PMID:35900868 SUPPORT In Vitro

"We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature."

Cell models establish the impaired ORMDL binding and the distinct ALS lipid signature.

Patient-derived fibroblasts carrying SPTLC1-ALS variants PRIMARY_CELL_CULTURE

Primary fibroblasts from ALS27 patients show the unrestrained SPT activity and the canonical-sphingolipid excess seen in patient serum, and were the system in which allele-specific siRNA knockdown rescued the enzyme overactivity.

Cell source

Patient skin biopsy

Pathograph links

Unrestrained De Novo Sphingolipid Synthesis recapitulates fidelity: moderate Patient fibroblasts reproduce the enzyme overactivity and were used to demonstrate allele-specific rescue.

Limitations: Fibroblasts are not motor neurons; they capture the enzymology and the lipid signature but cannot report on the selective neuronal vulnerability that defines the disease.

Show evidence (1 reference)

PMID:38788085 SUPPORT In Vitro

"siRNA mediated allele-specific knockdown of SPTLC1-related ALS variants rescued the enzyme overactivity in patient derived fibroblasts"

Documents the rescue experiment performed in this model system.

Show evidence (1 reference)

PMID:38788085 SUPPORT In Vitro

"Studies of cell models (transfected HEK293 cells), patient-derived fibroblasts, and serum samples have been invaluable in understanding the primary effects of these mutations on SPT."

Establishes patient-derived fibroblasts as an informative model system for the primary enzymatic defect in SPT-related disease.

iPSC-derived lower motor neuron-like cells (compound-heterozygous SPTLC1 delF40_S41/delExon2) IPSC_DERIVED_MODEL

iPSC-derived lower motor neuron-like cells carrying an ALS27 allele reproduce the biochemical phenotype (elevated canonical sphingolipids) but notably show no effect on differentiation, morphology, or survival — so the model does NOT yet reproduce the neurodegeneration itself. Serine supplementation of these cells accentuated the consequences of SPT overactivity, which is the experimental basis for the L-serine safety caution.

Cell source

Patient-derived induced pluripotent stem cells

Pathograph links

Unrestrained De Novo Sphingolipid Synthesis recapitulates fidelity: moderate Elevated canonical sphingolipids in an ALS27-genotype motor neuron-like cell.

Limitations: Reproduces the lipid abnormality only. Differentiation, morphology, and survival were unaffected, so the model does not capture motor neuron death, and detailed characterization has not been reported. A published genotype objection also applies: the line is compound heterozygous (SPTLC1 delF40_S41 / delExon2), whereas no reported ALS27 patient carries compound-heterozygous variants, so the sphingolipid rise in this model may be driven by a different mechanism than the human disease. This matters because the same model supplies the experimental leg of the L-serine safety caution.

Show evidence (2 references)

PMID:38788085 SUPPORT In Vitro

"Studies of iPSC-derived lower motor neuron-like cells harboring the SPTLC1-related ALS variant (p.F40_S41del) have shown elevated canonical sphingolipids without an effect on differentiation, morphology, and survival in these cells"

Reports the lipid phenotype together with the explicit absence of a cellular degeneration phenotype.

+ 1 more reference

Upper and Lower Motor Neuron Degeneration fails to recapitulate fidelity: low No effect on differentiation, morphology, or survival was observed in these ALS27-genotype motor neuron-like cells.

Limitations: iPSC-derived motor neuron-like cells are developmentally immature and were assessed over a short culture period, against a human disease that takes years to decades to kill motor neurons; the absence of a survival phenotype may reflect the model's time course rather than the absence of a cell-autonomous mechanism. Detailed characterization of these cells has not been reported.

Show evidence (1 reference)

PMID:38788085 REFUTE In Vitro

"elevated canonical sphingolipids without an effect on differentiation, morphology, and survival in these cells"

Explicit negative result for a degeneration phenotype in the iPSC motor neuron model.

Show evidence (1 reference)

PMID:38788085 SUPPORT In Vitro

"however, more detailed characterization of these cells has not been reported yet."

Marks the iPSC motor neuron model as informative but only shallowly characterized, so conclusions drawn from it should stay provisional.

🐁

Animal Models

1

Sptlc1 exon 2 deletion knock-in mouse GENETIC

A CRISPR/Cas9 knock-in mouse deleting exon 2 of the endogenous murine Sptlc1 locus, modelling the consequence of the human c.58G>T variant that causes exon 2 skipping. Heterozygous mice — the genotype matching the human dominant disease — developed neither motor deficits nor ALS-like neuropathology; homozygotes died prematurely. There is therefore currently no faithful in vivo model of ALS27; as of the 2024 authoritative review none had been reported at all, and this first attempt does not reproduce the phenotype.

Species

Mouse

Genotype

Sptlc1 exon 2 deletion (CRISPR/Cas9 knock-in), heterozygous and homozygous

Genes

SPTLC1 hgnc:11277

Publication

PMID:42392979

Pathograph links

Upper and Lower Motor Neuron Degeneration fails to recapitulate fidelity: low Heterozygous exon-2-deletion mice, the genotype corresponding to the human dominant disease, showed no motor defects and no ALS-like neuropathology.

Limitations: Exon 2 deletion is not the same lesion as a heterozygous missense/in-frame-deletion allele: the human ALS27 mechanism requires a full-length SPTLC1 protein that still assembles into SPT but escapes ORMDL restraint, whereas deleting the exon removes the transmembrane segment entirely. Homozygous lethality also indicates the allele behaves as a severe loss-of-function in mice rather than the human gain-of-function. Species differences in sphingolipid handling and the short murine lifespan relative to the decades-long human course are further confounds.

Show evidence (1 reference)

PMID:42392979 REFUTE Model Organism

"Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely."

Explicit negative result — the heterozygous model does not reproduce the human ALS27 phenotype.

Show evidence (1 reference)

PMID:42392979 SUPPORT Model Organism

"Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel knock-in mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus."

Describes construction of the model.

{ }

Source YAML

click to show

name: Amyotrophic Lateral Sclerosis 27, Juvenile
creation_date: '2026-08-19T00:00:00Z'
category: Mendelian
description: >-
  Juvenile amyotrophic lateral sclerosis type 27 (ALS27) is a childhood- to
  young-adult-onset motor neuron disease caused by heterozygous, usually de novo,
  variants in SPTLC1, which encodes the LCB1 subunit of serine palmitoyltransferase
  (SPT) — the rate-limiting enzyme of de novo sphingolipid biosynthesis. ALS27
  variants cluster in the first transmembrane domain encoded by exon 2 and act by a
  gain-of-function mechanism: they impair the interaction with (and ceramide-dependent
  feedback inhibition by) the ORMDL regulatory subunits, so SPT activity escapes
  homeostatic control and canonical sphingoid bases, dihydrosphingolipids, and
  ceramides accumulate. Patients typically present in early childhood with lower-limb
  spasticity and toe walking, followed by diffuse, progressive lower motor neuron
  weakness and atrophy with tongue fasciculations, growth failure or failure to thrive,
  and eventual loss of ambulation and respiratory insufficiency, while sensory
  examination and nerve conduction are typically normal. Progression is slower than in
  sporadic adult ALS. ALS27 is mechanistically the mirror image of the other SPTLC1
  disease, hereditary sensory and autonomic neuropathy type 1 (HSAN1), in which
  C-terminal SPTLC1 variants shift SPT substrate usage from L-serine to L-alanine and
  generate neurotoxic 1-deoxysphingolipids; ALS27 patients have normal
  deoxysphingolipid levels. This entry is the SPTLC1-specific, metabolically driven
  monogenic form and is deliberately kept separate from the broad
  `Amyotrophic Lateral Sclerosis` entry, whose canonical mechanism is TDP-43
  proteinopathy and proteostatic failure rather than a primary metabolic disturbance.
disease_term:
  preferred_term: amyotrophic lateral sclerosis 27, juvenile
  term:
    id: MONDO:0859529
    label: amyotrophic lateral sclerosis 27, juvenile
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
parents:
- Amyotrophic Lateral Sclerosis
- Motor Neuron Disease
synonyms:
- ALS27
- SPTLC1-related juvenile amyotrophic lateral sclerosis
- childhood-onset amyotrophic lateral sclerosis due to excess sphingolipid synthesis
inheritance:
- name: Autosomal dominant, predominantly de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    ALS27 is caused by heterozygous, dominantly acting SPTLC1 variants. Most
    reported probands are simplex cases in whom the variant arose de novo, but
    vertical transmission has been documented in at least one pedigree carrying
    p.Leu39del, and one Japanese proband inherited p.Ala20Thr from a clinically
    unaffected father who was mosaic for the variant in blood leukocytes.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS."
    explanation: Establishes dominant (heterozygous) action of the ALS-causing SPTLC1 variants.
  - reference: PMID:39666121
    reference_title: "Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a pathogenic c.58G>A, p.Ala20Thr SPTLC1 variant in a patient with juvenile ALS, likely inherited from an asymptomatic parent with mosaicism."
    explanation: Documents parental mosaicism as an alternative to a true de novo event, which matters for recurrence-risk counselling.
pathophysiology:
- name: SPTLC1 Transmembrane-Domain Gain-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous missense or small in-frame deletion variants in SPTLC1 (p.Ala20Ser,
    p.Ala20Thr, p.Tyr23Phe, p.Leu38Arg, p.Leu39del, p.Phe40_Ser41del) cluster within the
    single membrane-spanning domain encoded by exon 2 — the surface through which
    SPTLC1 contacts the ORMDL regulatory subunits. The variants are dominantly acting
    and, in the originally described cohort, arose de novo. p.Ser331Tyr is deliberately
    NOT listed here: S331 sits near the active site rather than in the transmembrane
    domain, and although it interacts with ORMDLs it produces a mixed sensorimotor
    ("ALS-Plus") phenotype with concurrent 1-deoxysphingolipid excess. It is treated as a
    hybrid allele throughout this entry, not as a member of the exon-2 cluster.
  genes:
  - preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  genetic_context:
    gene:
      preferred_term: SPTLC1
      term:
        id: hgnc:11277
        label: SPTLC1
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Monoallelic, dominantly acting exon 2 variants that increase serine
      palmitoyltransferase activity rather than abolishing it.
  downstream:
  - target: Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
    causal_link_type: DIRECT
    description: >-
      Because the ALS27 residues lie in the SPTLC1 transmembrane helix that binds
      ORMDL, the variants weaken the SPT-ORMDL interaction and blunt ceramide sensing.
    evidence:
    - reference: PMID:35900868
      reference_title: "SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature."
      explanation: Directly links the ALS27 alleles to loss of ORMDL binding and consequent excess sphingolipid synthesis.
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."
    explanation: Identifies specific de novo SPTLC1 variants in juvenile ALS probands.
  - reference: PMID:36204986
    reference_title: "A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent studies have reported mutations in SPLTC1 may cause juvenile amyotrophic lateral sclerosis (JALS), especially in the first transmembrane domain of SPTLC1(exon 2)."
    explanation: States the exon 2 / first transmembrane domain clustering of the ALS-associated SPTLC1 variants.
  - reference: PMID:42392979
    reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ALS-associated SPTLC1 variants, including Y23F, L38R, L39del, and F40S41del, are clustered in exon 2"
    explanation: Enumerates the exon-2 cluster; note that p.Ser331Tyr is absent from it, which is why this entry does not list S331 as a cluster member.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPTLC1 S331 residue interacts both with ORMDLs and is near the active site. Substitutions at this residue typically cause a mixed phenotype of sensory neuropathy and motor neuron disease."
    explanation: Places S331 outside the transmembrane cluster and explains why S331 substitutions give a mixed rather than pure motor phenotype.
- name: Impaired ORMDL-Mediated Feedback Inhibition of Serine Palmitoyltransferase
  biological_scale: MOLECULAR
  description: >-
    Serine palmitoyltransferase is an endoplasmic-reticulum heterocomplex whose activity
    is held in check by the ORMDL1-3 regulatory subunits, which inhibit the enzyme when
    they sense rising ceramide. ALS27 variants sit on the SPTLC1 face that contacts
    ORMDL, so ORMDL binding and ceramide sensing are impaired and the negative feedback
    arm of sphingolipid homeostasis fails. The catalytic function itself is intact — it
    is the restraint that is lost, which is why this is a gain-of-function rather than a
    deficiency state.
  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
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  downstream:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    causal_link_type: DIRECT
    description: >-
      With ORMDL restraint lost, SPT runs unregulated and de novo sphingolipid
      production rises.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products."
      explanation: States the causal step from loss of ORMDL regulation to unregulated SPT activity and elevated canonical products.
  evidence:
  - reference: PMID:35900868
    reference_title: "SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity."
    explanation: Localizes the ALS27 variants to the ORMDL-interacting transmembrane domain and identifies ORMDL as the negative regulator.
  - reference: PMID:37308477
    reference_title: "Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrate that childhood amyotrophic lateral sclerosis (ALS) variants in the SPTLC1 subunit cause impaired ceramide sensing in the SPT-ORMDL3 mutants"
    explanation: Structural and biochemical work showing the ALS27 variants specifically break ceramide-dependent feedback sensing by the SPT-ORMDL3 complex.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT."
    explanation: Confirms the shared mechanism across ALS27 alleles, including p.L38R.
- name: Unrestrained De Novo Sphingolipid Synthesis
  biological_scale: MOLECULAR
  description: >-
    Loss of feedback restraint drives excess condensation of L-serine with palmitoyl-CoA,
    elevating canonical sphingoid bases and their downstream products. Patient plasma and
    variant-expressing cells show globally increased sphingolipids, with a particularly
    marked rise in dihydrosphingolipids (sphinganine and dihydroceramides), which have
    been linked to neurotoxicity. In the exon-2 / transmembrane-domain alleles,
    1-deoxysphingolipid levels are NOT elevated — that is the HSAN1 signature — so the
    two SPTLC1 diseases are separated by which lipid species accumulates, not merely by
    how much SPT activity there is. This dichotomy is real but not absolute: patients with
    p.Ser331 substitutions show a CONCURRENT rise in 1-deoxysphingolipids and canonical
    sphingolipids, and one p.Leu39del carrier with a raised alanine/serine ratio showed
    both. The clean separation therefore holds for the exon-2 cluster, not for every
    SPTLC1-ALS allele.
  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
  - preferred_term: sphinganine (dihydrosphingosine)
    term:
      id: CHEBI:16566
      label: sphinganine
    modifier: INCREASED
  - preferred_term: ceramide
    term:
      id: CHEBI:17761
      label: ceramide
    modifier: INCREASED
  downstream:
  - target: Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess sphingoid base and dihydrosphingolipid production is the proposed proximate
      driver of motor neuron injury in ALS27. The step from lipid excess to selective
      motor neuron death is inferred rather than directly demonstrated in human tissue.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease."
      explanation: Supports excess sphingolipid biosynthesis as the disease mechanism for this motor neuron disease; marked PARTIAL because the intervening steps to motor-neuron death are not directly demonstrated.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS."
    explanation: States the core mechanism — unrestrained sphingoid base synthesis causing monogenic ALS.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma."
    explanation: Demonstrates globally increased sphingolipids in ALS27 patient plasma.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations."
    explanation: Proposes dihydrosphingolipid accumulation as the neurotoxic species; the hedged wording is preserved deliberately.
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy."
    explanation: Establishes the biochemical dichotomy separating ALS27 from HSAN1.
- name: Upper and Lower Motor Neuron Degeneration
  biological_scale: CELLULAR
  description: >-
    Degeneration involves both motor neuron compartments. Upper motor neuron involvement
    presents first in most patients as early-childhood lower-limb spasticity and toe
    walking, and is followed by diffuse lower motor neuron degeneration in cranial,
    cervical and lumbar myotomes, so that patients meet revised El Escorial criteria for
    ALS. Sensory neurons are characteristically spared, distinguishing ALS27 from HSAN1.
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  - preferred_term: primary motor cortex
    term:
      id: UBERON:0001384
      label: primary motor cortex
  downstream:
  - target: Lower Limb Spasticity
    causal_link_type: DIRECT
    description: >-
      Upper motor neuron involvement produces the early lower-limb spasticity that opens
      the clinical course.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities"
      explanation: Links upper motor neuron involvement to the presenting spastic phenotype.
  - target: Toe Walking (Tip-Toe Gait)
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Toe walking follows from the lower-limb spasticity produced by upper motor neuron
      degeneration.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities"
      explanation: The spasticity is stated to manifest as toe walking and gait abnormality.
  - target: Hyperreflexia
    causal_link_type: DIRECT
    description: >-
      Loss of corticospinal inhibition from upper motor neuron degeneration produces brisk
      reflexes and an exaggerated jaw jerk.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "All six individuals had upper and lower motor neuron signs and symptoms in the cranial, cervical and lumbar myotomes"
      explanation: Establishes upper motor neuron signs across myotomes; hyperreflexia is the specific sign documented in the JAMA cohort.
  - target: Dysarthria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Degeneration of bulbar motor neurons weakens the articulatory musculature.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "includes involvement of the bulbar and respiratory function"
      explanation: Bulbar involvement is part of the motor neuron degeneration course; dysarthria is its articulatory expression.
  - target: Dysphagia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Bulbar motor neuron loss weakens the swallowing musculature.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "includes involvement of the bulbar and respiratory function"
      explanation: Bulbar involvement is part of the disease course; dysphagia is its swallowing expression.
  - target: Progressive Denervation and Neurogenic Muscle Atrophy
    causal_link_type: DIRECT
    description: >-
      Lower motor neuron loss denervates skeletal muscle, producing the acute and chronic
      neurogenic changes seen on muscle biopsy and the active/chronic denervation seen on
      EMG.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes"
      explanation: Muscle histology confirms denervation as the direct consequence of lower motor neuron loss.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All six individuals had upper and lower motor neuron signs and symptoms in the cranial, cervical and lumbar myotomes and thus met the revised El Escorial criteria for the clinical definition of ALS"
    explanation: Documents combined upper and lower motor neuron involvement meeting formal ALS diagnostic criteria.
- name: Progressive Denervation and Neurogenic Muscle Atrophy
  biological_scale: TISSUE
  description: >-
    Chronic denervation produces generalized muscle wasting and weakness, most visibly in
    the tongue (wasting with fasciculations) and in the limbs, with a positive Gower sign
    and exaggerated lumbar lordosis reflecting proximal weakness. Muscle biopsy in ALS27
    has also shown mild inflammatory change on proteomic and transcript profiling.
  downstream:
  - target: Progressive Muscle Weakness
    causal_link_type: DIRECT
    description: Denervated muscle loses force output, producing progressive weakness.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs"
      explanation: Directly attributes the progressive weakness to lower motor neuron loss.
  - target: Skeletal Muscle Atrophy
    causal_link_type: DIRECT
    description: Chronic denervation produces neurogenic muscle wasting.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes"
      explanation: Muscle histology confirms the neurogenic basis of the atrophy.
  - target: Tongue Fasciculations
    causal_link_type: DIRECT
    description: Denervation of the tongue produces wasting with fasciculation.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including tongue fasciculations, which is highly unusual for classic forms of HSP but consistent with ALS"
      explanation: Attributes tongue fasciculations to the lower motor neuron degeneration.
  - target: Fasciculations
    causal_link_type: DIRECT
    description: Denervated motor units discharge spontaneously, producing fasciculations.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "diffuse and progressive lower motor neuron degeneration"
      explanation: Diffuse lower motor neuron degeneration is the substrate for the widespread fasciculations.
  - target: Diffuse Denervation on Electromyography
    causal_link_type: DIRECT
    description: >-
      Denervation is what the electrodiagnostic study measures - acute and chronic
      denervation across multiple myotomes.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Electrodiagnostic studies show normal sensory studies and diffuse acute and chronic denervation in multiple myotomes without demyelinating features"
      explanation: The EMG finding is the direct electrophysiological readout of the denervation node.
  - target: Loss of Ambulation and Respiratory Insufficiency
    causal_link_type: DIRECT
    description: >-
      Cumulative denervation of limb and respiratory musculature ends in wheelchair
      dependence and ventilatory failure.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."
      explanation: Directly states the clinical endpoint of progressive denervation.
  evidence:
  - reference: PMID:35627278
    reference_title: "New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, we describe associated muscle pathology findings, including signs of mild inflammation accompanied by dysregulation of respective markers on both the protein and transcript levels."
    explanation: Documents the muscle-tissue findings accompanying denervation in an SPTLC1 p.A20S patient.
- name: Loss of Ambulation and Respiratory Insufficiency
  biological_scale: ORGANISM
  downstream:
  - target: Loss of Ambulation
    causal_link_type: DIRECT
    description: Cumulative limb weakness ends independent walking.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."
      explanation: States loss of independent ambulation as the clinical endpoint.
  - target: Respiratory Insufficiency
    causal_link_type: DIRECT
    description: Denervation of respiratory musculature produces ventilatory failure.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."
      explanation: States respiratory insufficiency as the clinical endpoint.

  description: >-
    The organism-level endpoint of ALS27. Progression is slower than in sporadic adult
    ALS: in the longest-followed case, independent ambulation was lost at age 45 after
    onset at 22, with forced vital capacity falling from 94% to 49% of predicted over
    20 years and two admissions for respiratory failure. Some patients require
    tracheostomy and ventilation.
  evidence:
  - reference: PMID:37497262
    reference_title: "Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary function declined from a forced vital capacity of 94% predicted at 27 years to 49% predicted at 47 years, and she was hospitalized twice for respiratory failure."
    explanation: Quantifies the respiratory decline over a 30-year follow-up of a genetically confirmed ALS27 patient.
  - reference: PMID:37497262
    reference_title: "Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She lost independent ambulation at age 45 years."
    explanation: Documents loss of ambulation and the slow tempo of decline in ALS27.
phenotypes:
- category: Neurologic
  name: Lower Limb Spasticity
  description: >-
    Early-childhood-onset lower extremity spasticity, typically manifesting as toe
    walking and gait abnormality, is the presenting feature in most ALS27 patients and
    can initially suggest hereditary spastic paraplegia.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six individuals from six unrelated families who developed early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs"
    explanation: Six of six probands in the index cohort presented with early-childhood lower extremity spasticity, supporting a VERY_FREQUENT band.
- category: Neurologic
  name: Progressive Muscle Weakness
  description: >-
    Diffuse, progressive lower motor neuron weakness follows the initial spastic phase,
    involving limbs and bulbar musculature.
  phenotype_term:
    preferred_term: Progressive muscle weakness
    term:
      id: HP:0003323
      label: Progressive muscle weakness
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs"
    explanation: Progressive lower motor neuron weakness in all six index-cohort probands.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs."
    explanation: Independent case confirming the weakness/atrophy phenotype.
- category: Neurologic
  name: Skeletal Muscle Atrophy
  description: >-
    Generalized neurogenic muscle atrophy accompanies the weakness and is often marked,
    with a positive Gower sign and exaggerated lumbar lordosis from proximal wasting.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her neurological examination at presentation revealed a body mass index less than the first percentile, exaggerated lumbar lordosis, tongue fasciculations and wasting, generalized muscle atrophy and weakness, brisk asymmetric ankle reflexes, a positive Gower sign, and normal sensation"
    explanation: Documents generalized muscle atrophy and weakness with preserved sensation in an ALS27 patient.
- category: Neurologic
  name: Tongue Fasciculations
  description: >-
    A wasted, fasciculating tongue is a characteristic bulbar lower motor neuron sign in
    ALS27 and is a key discriminator from hereditary spastic paraplegia, which the early
    spastic presentation otherwise mimics.
  phenotype_term:
    preferred_term: Tongue fasciculations
    term:
      id: HP:0001308
      label: Tongue fasciculations
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this initial manifestation was almost universally followed by diffuse and progressive lower motor neuron degeneration, including tongue fasciculations, which is highly unusual for classic forms of HSP but consistent with ALS"
    explanation: >-
      The quoted sentence says tongue fasciculations followed "almost universally", which
      maps to the VERY_FREQUENT band (80-100%); the same sentence is the discriminator
      from hereditary spastic paraplegia.
- category: Neurologic
  name: Hyperreflexia
  description: >-
    Brisk or exaggerated deep tendon reflexes, including an exaggerated jaw jerk, reflect
    the upper motor neuron component of ALS27.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination revealed marked atrophy, postural tachycardia, bilateral cataracts, a wasted and fasciculating tongue with an exaggerated jaw jerk, generalized fasciculations and weakness associated with hyperreflexia, and decreased pinprick sensation in a glove-and-stocking distribution"
    explanation: Documents hyperreflexia (with an exaggerated jaw jerk) in an ALS27 patient. `frequency` is deliberately omitted - the available evidence is single-patient description with no denominator.
- category: Neurologic
  name: Fasciculations
  description: >-
    Diffuse fasciculations in limb and bulbar muscles are a lower motor neuron sign in
    ALS27.
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: PMID:37497262
    reference_title: "Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She experienced gradual decline in muscle strength with development of weakness and hyperreflexia in lower extremities and diffuse fasciculations in the upper extremities at 26 years."
    explanation: Documents diffuse fasciculations alongside weakness and hyperreflexia in a genetically confirmed ALS27 patient.
- category: Growth
  name: Failure to Thrive and Growth Failure
  description: >-
    Severe growth restriction, failure to gain weight, and profound low body mass are a
    conspicuous non-motor feature of ALS27 — prominent enough that the JAMA Neurology
    cohort was ascertained as "juvenile ALS and severe growth retardation". It is not a
    universal feature; at least one long-surviving patient had normal weight.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  frequency: FREQUENT
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."
    explanation: Three of the four probands in this study carried a juvenile ALS diagnosis together with failure to thrive.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 1 presented with gradually progressive spastic diplegia and growth retardation beginning at age 5 years."
    explanation: Growth retardation from early childhood in an ALS27 patient.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    Progressive ventilatory failure from respiratory muscle denervation is the principal
    cause of morbidity; some patients require tracheostomy and long-term ventilation.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."
    explanation: Respiratory insufficiency of variable degree in all index-cohort patients.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By age 20 years, she had quadriplegia with marked muscle atrophy and diminished weight, brisk lower limb reflexes, tongue fasciculations and weakness, dysarthria, mild cognitive dysfunction, and respiratory failure requiring tracheostomy and ventilation."
    explanation: Documents respiratory failure requiring tracheostomy and ventilation.
- category: Neurologic
  name: Dysarthria
  description: >-
    Bulbar involvement produces dysarthria in a subset of patients.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tongue fasciculations and weakness, dysarthria, mild cognitive dysfunction, and respiratory failure requiring tracheostomy and ventilation"
    explanation: "Documents dysarthria as part of the bulbar phenotype. OCCASIONAL is a derived count: 1 of the 4 probands in this cohort, i.e. 25%, which falls in the 5-29% band."
- category: Neurologic
  name: Dysphagia
  description: >-
    Swallowing difficulty from bulbar motor neuron involvement is reported in some
    patients but is not universal — one long-surviving patient had no dysphagia at
    age 34.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She presented at age 10 years with a deteriorating gait, hand weakness, right foot paresthesia, dysphagia, and increased sweating."
    explanation: "Documents dysphagia in an ALS27 (ALS-Plus) patient. OCCASIONAL is a derived count: 1 of the 4 probands in this cohort had dysphagia and another explicitly did not, i.e. 25%, within the 5-29% band."
- category: Neurologic
  name: Cognitive Impairment
  description: >-
    Mild cognitive dysfunction — decreased sustained attention and impaired executive
    function on formal neuropsychological testing — has been documented in a minority of
    ALS27 patients. Reporting is inconsistent and contested: the 2024 authoritative
    review states that cognitive dysfunction has not been reported in SPTLC1-ALS
    (in contrast to SPTLC2-ALS, where frontotemporal dementia occurs), while the JAMA
    Neurology cohort documented mild cognitive dysfunction in one patient and formally
    measured attentional/executive impairment in another. Cognition has not been
    systematically assessed in this disease, so the honest reading is that the question
    is open rather than settled either way.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
    severity: MILD
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased sustained attention and impaired executive functioning were evident in neuropsychological evaluation."
    explanation: "Formal neuropsychological documentation of executive/attentional impairment in an ALS27 patient. OCCASIONAL is a derived count: 2 of the 4 probands in this cohort had some cognitive finding, but see the description - a 2024 review reports none, so the band is provisional."
- category: Neurologic
  name: Absence of Sensory Neuropathy
  diagnostic: true
  description: >-
    Curated as a REFUTED phenotype, and deliberately carries NO `phenotype_term`: the
    schema has no negation slot, so binding HP:0002936 here would export as an assertion
    that ALS27 patients HAVE distal sensory impairment. Normal sensory examination, normal
    sensory nerve conduction, and a normal sural nerve biopsy are characteristic of ALS27
    and are what separate it from HSAN1, so the absence is worth recording in prose rather
    than merely omitting. The separation is not
    absolute: one JAMA Neurology proband (p.Ser331Tyr) had glove-and-stocking pinprick
    loss and a sensorimotor axonal neuropathy and was labelled "juvenile ALS-Plus", and
    one member of an SPTLC1-ALS pedigree with L-serine deficiency presented with an HSAN1
    phenotype.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the patients with ALS reported here presented with childhood-onset motor neuron disease, normal sensory findings (by clinical examination, electrophysiologic studies and nerve biopsy when available) and normal deoxysphingolipid levels."
    explanation: Refutes sensory impairment as a feature of typical ALS27; sensory findings were normal across the index cohort.
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 3 also had a sural nerve biopsy that failed to reveal any abnormalities in myelinated or unmyelinated sensory nerve fibers"
    explanation: Histological confirmation of sensory sparing; moved here from the motor-neuron-degeneration node, which it does not evidence.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was diagnosed with juvenile ALS-Plus syndrome owing to her prominent motor symptoms and modest sensory-autonomic involvement."
    explanation: A minority of SPTLC1-ALS patients do have modest sensory-autonomic involvement, so sensory sparing is typical rather than absolute.
- category: Neurologic
  name: Toe Walking (Tip-Toe Gait)
  description: >-
    Toe walking and an abnormal gait are the usual presenting complaint, typically before
    age 10 and sometimes as early as 3-4 years. This is the feature that most often sends
    an ALS27 child down a hereditary-spastic-paraplegia diagnostic path.
  phenotype_term:
    preferred_term: Toe walking (tip-toe gait)
    term:
      id: HP:0030051
      label: Tip-toe gait
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early-childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities"
    explanation: Toe walking and gait abnormality as the presenting manifestation in all six index-cohort probands.
- category: Neurologic
  name: Diffuse Denervation on Electromyography
  description: >-
    Electrodiagnostic testing shows normal sensory studies together with diffuse acute and
    chronic denervation across multiple myotomes and no demyelinating features. This
    combination is the practical discriminator from hereditary spastic paraplegia (which
    lacks the denervation) and from HSAN1 (which has abnormal sensory studies).
  phenotype_term:
    preferred_term: Diffuse acute and chronic denervation on EMG
    term:
      id: HP:0003444
      label: "EMG: chronic denervation signs"
  diagnostic: true
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electrodiagnostic studies show normal sensory studies and diffuse acute and chronic denervation in multiple myotomes without demyelinating features"
    explanation: Defines the characteristic electrodiagnostic signature of SPTLC1-related juvenile ALS.
- category: Neurologic
  name: Loss of Ambulation
  description: >-
    Progressive weakness leads to wheelchair dependence, but far later than in adult
    sporadic ALS — in reported patients between the third and fifth decades despite
    childhood onset.
  phenotype_term:
    preferred_term: Loss of ambulation
    term:
      id: HP:0002505
      label: Loss of ambulation
  frequency: FREQUENT
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees."
    explanation: Loss of independent ambulation was universal in the index cohort.
biochemical:
- name: Elevated Plasma Sphingolipids
  notes: >-
    Untargeted and targeted plasma sphingolipidomics in ALS27 patients shows globally
    increased canonical sphingolipids relative to unaffected relatives, with
    dihydrosphingolipids (sphinganine, dihydroceramides) most conspicuously raised. This
    is the biochemical readout that distinguishes ALS27 from HSAN1, where the abnormal
    species are 1-deoxysphingolipids.
  evidence:
  - reference: PMID:39666121
    reference_title: "Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma sphingolipid levels in the patient were significantly increased compared to her asymptomatic parents."
    explanation: Direct within-family comparison showing raised plasma sphingolipids in the affected proband.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells."
    explanation: Identifies dihydrosphingolipids as the most raised species in patient plasma (quoted verbatim, including the source's typographical errors).
  - reference: PMID:42392979
    reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "One study indicated an increase in serum sphingolipids (5), whereas another group reported no changes in plasma ceramide or sphingomyelin levels in patients carrying the exon 2 skipping variant (3)"
    explanation: Records a conflicting negative human result - not every reported ALS27 patient has measurably raised plasma sphingolipids - so this marker is not curated as a settled finding.
- name: Normal 1-Deoxysphingolipid Levels (exon-2 alleles)
  notes: >-
    In patients carrying the exon-2 / transmembrane-domain alleles, deoxysphingolipid
    levels are normal, unlike HSAN1. This negative biochemical finding is diagnostically
    load-bearing, because both diseases are caused by SPTLC1 variants and are separated by
    which lipid class accumulates. The exception, recorded explicitly so this node is not
    read as a blanket rule: p.Ser331 substitutions raise 1-deoxysphingolipids AND
    canonical sphingolipids at the same time, and the p.Leu39del pedigree member with
    serum L-serine deficiency did the same.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal sensory findings (by clinical examination, electrophysiologic studies and nerve biopsy when available) and normal deoxysphingolipid levels."
    explanation: Documents normal deoxysphingolipid levels in the exon-2-allele ALS27 cohort, in contrast with HSAN1.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Sphingolipidomic evaluation of patient serum and patient-derived cells with SPTLC1 p.S331 substitutions have identified a concurrent increase in 1-deoxysphingolipis (a feature of HSAN1 variants) as well as an overproduction of canonical sphingolipids likely by disrupting ORMDL inhibition (a feature of ALS variants)"
    explanation: Refutes any blanket claim that deoxysphingolipids are normal in all SPTLC1-ALS; the S331 hybrid alleles raise both lipid classes.
progression:
- phase: Onset
  age_range: mean 7.9 years (SD 4.6) in the SPTLC1-mutated juvenile ALS cohort
  notes: >-
    In the largest genotyped juvenile ALS cohort to date (17 SPTLC1 patients), mean
    age at onset was 7.9 +/- 4.6 years, significantly earlier than in FUS-mutated
    juvenile ALS (18.1 +/- 3.9 years). Onset was exclusively spinal in the SPTLC1
    group, with no bulbar-onset cases, in contrast to the 37.2% bulbar onset seen
    with FUS.
  evidence:
  - reference: PMID:36801857
    reference_title: "Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations also had a large proportion of bulbar onset (37.2%, 16/43), while
      those with SPTLC1 mutations only presented spinal onset
    explanation: >-
      Establishes that onset is exclusively spinal in the SPTLC1 group, which is
      what distinguishes its onset pattern from FUS-mutated juvenile ALS.
- phase: Disease duration
  notes: >-
    Disease duration is an order of magnitude longer than in FUS-mutated juvenile
    ALS: a median 512.0 months (roughly 43 years, IQR 416.7-607.3) against 33.4
    months for FUS. This is the quantitative basis for describing the SPTLC1 course
    as slowly progressive rather than merely "slower than adult sporadic ALS".
  evidence:
  - reference: PMID:36801857
    reference_title: "Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tended to have an earlier AAO and the initial symptoms of lower limb
      spasticity and toe walking with longer disease duration
    explanation: >-
      Gives the median disease duration for the SPTLC1 group together with its
      characteristic presenting symptoms.
- phase: Onset
  age_range: 3-25 years (most commonly early childhood)
  notes: >-
    Initial symptoms are usually upper motor neuron (lower-limb spasticity, toe walking)
    or lower motor neuron (weakness, atrophy), without sensory symptoms. Onset as early as
    3-4 years is documented, but a minority present in the second or third decade.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial symptoms were reported as early as 3-4 years of age but in some individuals the disease onset was in the second or third decade of life"
    explanation: Defines the age-at-onset range for SPTLC1-related juvenile ALS.
- phase: Progressive
  notes: >-
    The course is relentlessly progressive but markedly slower than adult sporadic ALS,
    with bulbar and respiratory involvement emerging late. Rate varies between individuals
    and families.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disease course has been universally and relentlessly progressive, albeit with variability in its rate, and includes involvement of the bulbar and respiratory function"
    explanation: Characterizes the progressive course including late bulbar and respiratory involvement.
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite its childhood onset and resulting severe disability, the rate of progression of SPTLC1-associated ALS is still slower than sporadic ALS and thus mirrors other juvenile-onset hereditary ALS cases"
    explanation: Establishes the slower tempo relative to sporadic ALS.
differential_diagnoses:
- name: Hereditary Spastic Paraplegia
  description: >-
    The most common early misdiagnosis. ALS27 begins with lower-limb spasticity and toe
    walking, which looks like HSP; HSP does not go on to produce diffuse lower motor
    neuron degeneration with tongue fasciculations and multi-myotomal denervation.
  distinguishing_features:
  - "Presence of lower motor neuron signs (tongue fasciculations, wasting) and diffuse acute/chronic denervation on EMG favours ALS27 over HSP."
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this initial manifestation was almost universally followed by diffuse and progressive lower motor neuron degeneration, including tongue fasciculations, which is highly unusual for classic forms of HSP but consistent with ALS"
    explanation: States the discriminating feature between ALS27 and hereditary spastic paraplegia.
- name: Hereditary Sensory and Autonomic Neuropathy Type 1 (SPTLC1-related)
  description: >-
    The other SPTLC1 disease. Same gene, opposite biochemistry and opposite target
    neurons: HSAN1 comes from C-terminal variants that make SPT substrate-promiscuous and
    generate 1-deoxysphingolipids, and presents with sensory loss and painless ulceration.
  disease_term:
    preferred_term: hereditary sensory and autonomic neuropathy
    term:
      id: MONDO:0015364
      label: hereditary sensory and autonomic neuropathy
  distinguishing_features:
  - "Sensory neuropathy with elevated 1-deoxysphingolipids (HSAN1) versus pure motor neuron disease with elevated canonical sphingolipids and normal deoxysphingolipids (ALS27). Motor neuropathy does occur in HSAN1 but is length-dependent, always accompanied by sensory neuropathy, and does not affect bulbar or respiratory function."
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unlike the SPT-associated motor neuron diseases, motor neuropathy in HSAN1 is typically length-dependent, always associated with sensory neuropathy and does not affect bulbar or respiratory function."
    explanation: Gives the clinical rule separating HSAN1 motor involvement from SPT-related motor neuron disease.
- name: SPTLC2-Related Juvenile Amyotrophic Lateral Sclerosis
  description: >-
    Mechanistically the closest mimic: SPTLC2 variants (p.E260K, p.M68R, p.A71V) also
    disrupt ORMDL regulation and cause childhood-onset upper and lower motor neuron
    disease with the same canonical-sphingolipid signature. Distinguished only by
    sequencing, plus a tendency to cognitive dysfunction and frontotemporal dementia that
    is not typical of SPTLC1-ALS.
  distinguishing_features:
  - "Causal gene on sequencing; cognitive dysfunction/FTD reported in a few SPTLC2 patients but not typical of SPTLC1-ALS."
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast with SPTLC1-ALS, a few individuals with SPTLC2-related juvenile ALS are noted to develop cognitive dysfunction including frontotemporal dementia, likely due to broader neurodegeneration"
    explanation: Names the clinical feature that separates the two SPT-subunit juvenile ALS entities.
- name: SPTSSA-Related Complicated Hereditary Spastic Paraplegia
  description: >-
    Also caused by activating SPT-component variants escaping ORMDL regulation, but with
    selective upper motor neuron involvement, progressive cognitive decline, and
    sensorineural hearing loss rather than combined UMN/LMN motor neuron disease.
  distinguishing_features:
  - "Absence of lower motor neuron disease; presence of cognitive decline and sensorineural hearing loss."
  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: Distinguishes SPTSSA-related complicated HSP from ALS27 by the absence of lower motor neuron disease.
- name: FUS-Related Juvenile Amyotrophic Lateral Sclerosis
  description: >-
    The most common genetic cause of juvenile ALS, and the main alternative on a
    childhood-onset ALS gene panel. Its course is far more aggressive than SPTLC1-ALS.
  distinguishing_features:
  - "Causal gene on sequencing; FUS-JALS progresses rapidly whereas SPTLC1-JALS is slowly progressive over decades."
  evidence:
  - reference: PMID:36801857
    reference_title: "Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "FUS mutations are the most common cause of JALS."
    explanation: Establishes FUS as the leading alternative genetic diagnosis in juvenile ALS.
genetic:
- name: SPTLC1
  gene_term:
    preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    SPTLC1 encodes the LCB1 subunit of serine palmitoyltransferase. ALS27-causing
    variants are heterozygous and cluster in exon 2, encoding the first transmembrane
    domain. Reported alleles include c.58G>T p.Ala20Ser, c.58G>A p.Ala20Thr, c.113T>C
    p.Leu38Arg, c.115_117delCTT p.Leu39del, and c.992C>A p.Ser331Tyr. p.Leu39del is
    recurrent and associated with slow progression. C-terminal SPTLC1 variants instead
    cause HSAN1.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all patients in this family carried the same SPTLC1 variant (NM_006415.4:c.115_117delCTT, p.(L39del)), which was recurrent in two unrelated childhood ALS patients"
    explanation: Documents the recurrent p.Leu39del allele and its transmission within a pedigree.
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the sporadic occurrence of the disease, SPTLC1 variants occurred de novo (that is, were absent in the unaffected parents"
    explanation: Establishes the predominantly de novo origin of ALS27 variants.
  - reference: PMID:42392979
    reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All known ALS-linked SPTLC1 mutations cluster within exon 2, and a specific variant, c.58G>T, results in exon 2 skipping."
    explanation: States the exon 2 clustering of ALS-linked SPTLC1 variants and the splicing consequence of c.58G>T.
treatments:
- name: Allele-Selective SPTLC1 siRNA (investigational)
  description: >-
    Custom small interfering RNAs designed to degrade the mutant SPTLC1 allele while
    sparing the wild-type allele normalized sphingolipid levels in patient-derived cells.
    This is a proof-of-concept in vitro result only — no in vivo or clinical data exist,
    and the negative heterozygous mouse model means there is currently no animal system
    in which to test efficacy.
  therapeutic_modality: SIRNA
  treatment_term:
    preferred_term: Gene Silencing Therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    treatment_effect: INHIBITS
    description: >-
      Selective knockdown of the mutant transcript removes the unregulated SPT subunit
      and restores normal sphingolipid levels.
    evidence:
    - reference: PMID:34059824
      reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro."
      explanation: Demonstrates allele-selective knockdown normalizing sphingolipid levels, establishing the mechanistic target.
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro."
    explanation: The only reported disease-modifying strategy for ALS27, at in vitro proof-of-concept stage.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While effective, and imposing little chance for over-inhibition of SPT, this approach has limited generalizability and needs to be custom-designed and validated for each disease-causing SPT variant."
    explanation: Records the translational limitation - each ALS27 allele needs its own bespoke siRNA - which is why this has not scaled beyond proof of concept.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPT genes are thought to be haplosufficient; that is, loss of function or deletion of one gene copy does not cause a phenotype. Thus, allele-specific knockdown is a feasible approach in correcting the dominant gain of function in all SPT-related diseases."
    explanation: Establishes the genetic precondition (haplosufficiency) that makes allele-specific knockdown a safe strategy in principle.
- name: High-Dose Oral L-Serine Supplementation (compassionate use; predicted harmful)
  description: >-
    NOT a recommended ALS27 therapy, and recorded here as a safety caution. High-dose
    (10 g/day) oral L-serine was given on a compassionate basis to one ALS27 patient;
    body weight increased for the first time in years, ceramide levels stayed within the
    normal range, and no neurological improvement was observed.

    The rationale was not simply borrowed from HSAN1. The JAMA Neurology authors ran
    their own assay and found the p.Ala20Ser complex had an altered L-alanine and glycine
    preference over L-serine, and that serine supplementation reversed those defects
    toward wild-type in culture — an HSAN1-like biochemistry in an exon-2 allele, pointing
    opposite to the harm prediction.

    The prevailing view is nevertheless that supplementation is harmful here: in
    SPT-related motor neuron disease the enzyme is unrestrained rather than
    substrate-promiscuous, L-serine is the substrate it is consuming, and serine
    supplementation of iPSC-derived motor neurons carrying SPTLC1 p.Phe40_Ser41del
    accentuated the consequences of SPT overactivity. Both sides are curated below rather
    than only the one that supports the caution; the unresolved direction of effect is
    tracked in the open_als27_serine_direction_of_effect discussion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: REFUTE
    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: Authoritative review states that serine supplementation is predicted to be harmful, not helpful, in SPT-related motor neuron disease including ALS27.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "serine supplementation in iPSC-derived motor neurons with the SPTLC1del40 - 41 variant accentuated the consequences of SPT overactivity"
    explanation: Experimental corroboration in an ALS27-genotype iPSC motor neuron model that serine makes the biochemical defect worse.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We did not observe evidence of neurological improvement, although prolonged therapy would be required to detect such an effect."
    explanation: The only clinical exposure of an ALS27 patient to L-serine produced no demonstrated neurological benefit.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her body weight increased during this off-label treatment, which was the first time she had gained weight in several years."
    explanation: Records the one positive observation (weight gain) from that compassionate-use exposure, so the entry neither hides nor overstates it.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "the p.Ala20Ser variant SPTLC1 complex had an altered L-alanine and glycine preference over the canonical L-serine compared with the wild-type SPTLC1 complex"
    explanation: Contradicts the harm prediction at its premise - this exon-2 ALS allele showed the HSAN1-like altered substrate preference that serine supplementation is meant to correct.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "These defects were reversed to the wild-type phenotype on serine supplementation in the culture"
    explanation: A direct in vitro rescue by serine in an ALS27 allele, pointing opposite to the iPSC result that underpins the harm caution. Recorded because a safety-relevant claim must show its contradicting evidence.
- name: Partial Serine Palmitoyltransferase Inhibition (investigational concept)
  description: >-
    The mechanistically rational counter to unrestrained SPT is to inhibit the enzyme
    partially. No agent has reached clinical evaluation for ALS27. Myriocin is a potent
    suicide inhibitor but is too toxic for clinical development; L-cycloserine and other
    inhibitors show dose-related toxicity; D-cycloserine (an approved second-line
    antitubercular) is the one tolerable exception but has never been systematically
    tested for SPT overactivity. Two caveats are load-bearing: complete SPT inhibition is
    systemically toxic, and inhibition does not restore the lost dynamic regulation — it
    only lowers the setpoint.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    treatment_effect: INHIBITS
    description: >-
      Partial pharmacological inhibition of SPT would lower flux through the de novo
      pathway without abolishing it.
    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 the therapeutic target and the dose-window caution.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "All of these inhibitors show dose-related toxicity or off-target activity that have hampered their clinical development"
    explanation: Explains why no SPT inhibitor is clinically available for ALS27 despite a clear target.
- name: Dietary Serine and Glycine Restriction (theoretical)
  description: >-
    Because SPT overproduction depends on L-serine availability, restricting dietary
    serine and glycine (glycine is readily converted to serine) is a theoretically
    feasible way to reduce substrate supply. It is the exact inverse of HSAN1 management
    and has not been tested clinically in ALS27. Note the countervailing risk documented
    in the mechanistic literature: severe serine limitation shifts SPTLC1-ALS cells
    toward the neurotoxic 1-deoxysphingolipid (HSAN1-like) signature, so this is a
    two-sided intervention rather than a simple substrate-reduction strategy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Dietary Intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since overproduction of canonical sphingolipids relies on availability of L-serine as a substrate, in addition to SPT inhibition, serine depletion is another theoretically feasible approach to ameliorate SPT overactivity."
    explanation: States the substrate-restriction rationale and marks it as theoretical.
  - reference: PMID:35900868
    reference_title: "SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Limiting L-serine availability in SPTLC1-ALS-expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature."
    explanation: Documents the countervailing hazard of serine restriction, which is why this remains theoretical rather than recommended.
- name: Respiratory Support
  description: >-
    Non-invasive ventilation progressing to tracheostomy and long-term ventilation as
    forced vital capacity declines. Supportive rather than disease-modifying.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "respiratory failure requiring tracheostomy and ventilation"
    explanation: Documents ventilatory support as the required intervention for ALS27 respiratory failure.
animal_models:
- name: Sptlc1 exon 2 deletion knock-in mouse
  species: Mouse
  genotype: Sptlc1 exon 2 deletion (CRISPR/Cas9 knock-in), heterozygous and homozygous
  category: GENETIC
  publication: PMID:42392979
  description: >-
    A CRISPR/Cas9 knock-in mouse deleting exon 2 of the endogenous murine Sptlc1 locus,
    modelling the consequence of the human c.58G>T variant that causes exon 2 skipping.
    Heterozygous mice — the genotype matching the human dominant disease — developed
    neither motor deficits nor ALS-like neuropathology; homozygotes died prematurely.
    There is therefore currently no faithful in vivo model of ALS27; as of the 2024
    authoritative review none had been reported at all, and this first attempt does not
    reproduce the phenotype.
  genes:
  - preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  modeled_mechanisms:
  - target: Upper and Lower Motor Neuron Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Heterozygous exon-2-deletion mice, the genotype corresponding to the human dominant
      disease, showed no motor defects and no ALS-like neuropathology.
    limitations: >-
      Exon 2 deletion is not the same lesion as a heterozygous missense/in-frame-deletion
      allele: the human ALS27 mechanism requires a full-length SPTLC1 protein that still
      assembles into SPT but escapes ORMDL restraint, whereas deleting the exon removes
      the transmembrane segment entirely. Homozygous lethality also indicates the allele
      behaves as a severe loss-of-function in mice rather than the human gain-of-function.
      Species differences in sphingolipid handling and the short murine lifespan relative
      to the decades-long human course are further confounds.
    evidence:
    - reference: PMID:42392979
      reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely."
      explanation: Explicit negative result — the heterozygous model does not reproduce the human ALS27 phenotype.
  evidence:
  - reference: PMID:42392979
    reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel knock-in mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus."
    explanation: Describes construction of the model.
experimental_models:
- name: SPTLC1 variant-expressing HEK293 cells
  experimental_model_type: CELL_LINE
  description: >-
    HEK293 (and SPTLC1-knockout HEK293) cells stably expressing wild-type or ALS27-variant
    SPTLC1 are the workhorse system for ALS27. They reproduce the core biochemical
    phenotype — increased SPT activity, increased de novo sphingolipid synthesis, raised
    dihydrosphingolipids, and impaired ORMDL binding — and were the system in which
    allele-selective siRNA rescue was demonstrated.
  modeled_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Variant-expressing cells show increased SPT activity and increased de novo
      sphingolipid synthesis, matching the patient plasma lipid signature.
    limitations: >-
      HEK293 is a non-neuronal, transformed embryonic kidney line. It reproduces the
      enzymology and the lipid signature but says nothing about why motor neurons in
      particular die, and expression is typically supraphysiological.
    evidence:
    - reference: PMID:37348646
      reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells."
      explanation: Confirms the cell model reproduces increased SPT activity and de novo sphingolipid synthesis.
  evidence:
  - reference: PMID:35900868
    reference_title: "SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature."
    explanation: Cell models establish the impaired ORMDL binding and the distinct ALS lipid signature.
- name: Patient-derived fibroblasts carrying SPTLC1-ALS variants
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary fibroblasts from ALS27 patients show the unrestrained SPT activity and the
    canonical-sphingolipid excess seen in patient serum, and were the system in which
    allele-specific siRNA knockdown rescued the enzyme overactivity.
  cell_source: Patient skin biopsy
  modeled_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Patient fibroblasts reproduce the enzyme overactivity and were used to demonstrate
      allele-specific rescue.
    limitations: >-
      Fibroblasts are not motor neurons; they capture the enzymology and the lipid
      signature but cannot report on the selective neuronal vulnerability that defines the
      disease.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "siRNA mediated allele-specific knockdown of SPTLC1-related ALS variants rescued the enzyme overactivity in patient derived fibroblasts"
      explanation: Documents the rescue experiment performed in this model system.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Studies of cell models (transfected HEK293 cells), patient-derived fibroblasts, and serum samples have been invaluable in understanding the primary effects of these mutations on SPT."
    explanation: Establishes patient-derived fibroblasts as an informative model system for the primary enzymatic defect in SPT-related disease.
- name: iPSC-derived lower motor neuron-like cells (compound-heterozygous SPTLC1 delF40_S41/delExon2)
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    iPSC-derived lower motor neuron-like cells carrying an ALS27 allele reproduce the
    biochemical phenotype (elevated canonical sphingolipids) but notably show no effect on
    differentiation, morphology, or survival — so the model does NOT yet reproduce the
    neurodegeneration itself. Serine supplementation of these cells accentuated the
    consequences of SPT overactivity, which is the experimental basis for the L-serine
    safety caution.
  cell_source: Patient-derived induced pluripotent stem cells
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  modeled_mechanisms:
  - target: Unrestrained De Novo Sphingolipid Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Elevated canonical sphingolipids in an ALS27-genotype motor neuron-like cell.
    limitations: >-
      Reproduces the lipid abnormality only. Differentiation, morphology, and survival
      were unaffected, so the model does not capture motor neuron death, and detailed
      characterization has not been reported. A published genotype objection also applies:
      the line is compound heterozygous (SPTLC1 delF40_S41 / delExon2), whereas no
      reported ALS27 patient carries compound-heterozygous variants, so the sphingolipid
      rise in this model may be driven by a different mechanism than the human disease.
      This matters because the same model supplies the experimental leg of the L-serine
      safety caution.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Studies of iPSC-derived lower motor neuron-like cells harboring the SPTLC1-related ALS variant (p.F40_S41del) have shown elevated canonical sphingolipids without an effect on differentiation, morphology, and survival in these cells"
      explanation: Reports the lipid phenotype together with the explicit absence of a cellular degeneration phenotype.
    - reference: PMID:42392979
      reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "However, ALS patients reported to date do not carry compound-heterozygous mutations. Therefore, an increase in sphingolipids in this model might be driven by a different mechanism."
      explanation: Published objection to the genotype of this iPSC line, which qualifies every conclusion drawn from it including the serine result.
  - target: Upper and Lower Motor Neuron Degeneration
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      No effect on differentiation, morphology, or survival was observed in these
      ALS27-genotype motor neuron-like cells.
    limitations: >-
      iPSC-derived motor neuron-like cells are developmentally immature and were assessed
      over a short culture period, against a human disease that takes years to decades to
      kill motor neurons; the absence of a survival phenotype may reflect the model's time
      course rather than the absence of a cell-autonomous mechanism. Detailed
      characterization of these cells has not been reported.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: REFUTE
      evidence_source: IN_VITRO
      snippet: "elevated canonical sphingolipids without an effect on differentiation, morphology, and survival in these cells"
      explanation: Explicit negative result for a degeneration phenotype in the iPSC motor neuron model.
  evidence:
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "however, more detailed characterization of these cells has not been reported yet."
    explanation: Marks the iPSC motor neuron model as informative but only shallowly characterized, so conclusions drawn from it should stay provisional.
discussions:
- discussion_id: gap_als27_motor_neuron_selective_vulnerability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why are motor neurons selectively vulnerable to SPT overactivity while sensory neurons
    are selectively vulnerable to deoxysphingolipid accumulation, when both phenotypes
    arise from variants in the same gene?
  rationale: >-
    ALS27 and HSAN1 are both SPTLC1 diseases, but they hit opposite neuronal populations
    according to which lipid species accumulates. Nothing in the current model explains the
    cell-type selectivity; the pathway from excess canonical sphingolipid to motor neuron
    death is entirely uncharacterized, which is also why no rational neuroprotective target
    exists downstream of SPT itself.
  attaches_to:
  - pathophysiology#Unrestrained De Novo Sphingolipid Synthesis
  - pathophysiology#Upper and Lower Motor Neuron Degeneration
  evidence:
  - reference: PMID:34059824
    reference_title: "Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We do not yet understand why motor and sensory neurons show selective vulnerability to distinct biochemical changes in sphingolipid synthesis and homeostasis."
    explanation: The authors state the gap explicitly.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "future fundamental studies to establish the downstream cellular consequences of abnormal SPT activity, the selective vulnerability of sensory and motor neurons to distinct biochemical changes in SPT function"
    explanation: The 2024 review restates the same gap as an outstanding research priority, three years after it was first flagged.
- discussion_id: mismatch_als27_no_faithful_in_vivo_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does any existing animal model reproduce human ALS27, given that heterozygous Sptlc1
    exon-2-deletion mice show neither motor deficits nor ALS-like neuropathology?
  rationale: >-
    The human disease is a dominant gain-of-function requiring an assembled but
    unrestrained SPT complex. The available mouse deletes exon 2 outright, which behaves
    as a loss-of-function (homozygous lethal) and leaves heterozygotes unaffected. Until a
    knock-in carrying an actual ALS27 missense or in-frame-deletion allele is
    characterized, therapeutic candidates such as allele-selective siRNA cannot be tested
    in vivo, and the in vitro rescue result stands alone.
  attaches_to:
  - pathophysiology#Upper and Lower Motor Neuron Degeneration
  proposed_experiments:
  - experiment_id: exp_als27_missense_knockin_mouse
    name: Knock-in mouse carrying a human ALS27 missense allele
    description: >-
      Generate heterozygous knock-in mice carrying Sptlc1 p.Ala20Ser or p.Leu39del (rather
      than an exon deletion) and phenotype for motor behaviour, spinal motor neuron counts,
      neuromuscular junction integrity, and CNS/plasma sphingolipidomics.
  evidence:
  - reference: PMID:42392979
    reference_title: "Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely."
    explanation: The negative in vivo result that defines the mismatch.
  - 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: As of the 2024 review no murine ALS27 model existed; the 2026 exon-2-deletion mouse is the first attempt and it fails to recapitulate, so the gap remains open.
- discussion_id: open_als27_hsan1_continuum_vs_discrete_entities
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Are SPTLC1-related motor and sensory phenotypes two discrete diseases or a continuum?
  rationale: >-
    The classical dichotomy (exon 2 / transmembrane variants cause ALS27; C-terminal
    variants cause HSAN1) is complicated by patients with mixed sensorimotor features
    (p.Ser331Tyr "juvenile ALS-Plus") and by the demonstration that L-serine availability
    can shift an ALS lipid signature toward an HSAN1-like one within a single pedigree.
    How dismech splits these entities affects whether ALS27 should remain a standalone
    entry or be modeled as one pole of an SPTLC1 spectrum.
  attaches_to:
  - pathophysiology#Unrestrained De Novo Sphingolipid Synthesis
  evidence:
  - reference: PMID:35900868
    reference_title: "SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency."
    explanation: Shows an ALS27 genotype producing an HSAN1 phenotype under serine limitation, blurring the entity boundary.
  - reference: PMID:35627278
    reference_title: "New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It was postulated that the phenotypes associated with dominant variants in SPTLC1 may represent a continuum between neuropathy and ALS in some cases, complicated by additional symptoms such as cognitive impairment."
    explanation: States the continuum hypothesis explicitly.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that SPTLC1-related HSAN1 and ALS phenotypes are not mutually exclusive, and aspects of both phenotypes may co-occur."
    explanation: The p.Ser331 hybrid cases show concurrent 1-deoxysphingolipid and canonical-sphingolipid excess, so the two SPTLC1 entities are not cleanly disjoint.
notes: >-
  Scope: this entry covers SPTLC1-related juvenile ALS (ALS27, MONDO:0859529, OMIM 620285)
  only. The mechanistically parallel SPTLC2-related childhood-onset ALS (ALS28) is a
  separate entity and is not curated here. No GeneReviews chapter exists for ALS27 or for
  SPTLC1-related ALS (PubMed searched 2026-08-19); the GeneReviews baseline step therefore
  does not apply.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 11 citations 2026-08-19T21:12:29.613521

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Amyotrophic Lateral Sclerosis 27, Juvenile
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Amyotrophic Lateral Sclerosis 27, Juvenile covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Amyotrophic Lateral Sclerosis 27, Juvenile (SPTLC1-Associated)

Executive summary

Amyotrophic lateral sclerosis 27, juvenile (ALS27) is an exceptionally rare, Mendelian motor-neuron disease caused by heterozygous gain-of-function variants in SPTLC1, encoding a core subunit of serine palmitoyltransferase (SPT). It usually begins in childhood with lower-limb spasticity, toe walking, gait disturbance, distal weakness, and later diffuse upper- and lower-motor-neuron involvement. Sensory function is characteristically preserved. Unlike typical adult ALS, progression is often measured in decades, although bulbar and respiratory dysfunction can eventually occur. The central mechanism is failure of ORMDL-mediated feedback inhibition of SPT, causing excessive synthesis of canonical sphingolipids rather than the abnormal 1-deoxysphingolipids characteristic of SPTLC1-related hereditary sensory and autonomic neuropathy type 1 (HSAN1). (wang2023clinicalfeaturedifference pages 5-6, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

The most immediately actionable disease-specific points are: (1) include SPTLC1 in genetic testing for childhood motor-neuron/HSP-like presentations; (2) use EMG and sensory studies to distinguish ALS27 from pure hereditary spastic paraplegia and HSAN1; (3) consider sphingolipid profiling as a research-level supportive biomarker; and (4) avoid empiric L-serine supplementation, because it may increase pathogenic canonical sphingolipid production. No targeted therapy or disease-specific clinical trial has established efficacy. (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 7-9, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Table: This compact table summarizes the most actionable disease-specific facts for SPTLC1-associated juvenile ALS (ALS27), including identity, variants, phenotype, mechanism, diagnostics, and treatment caveats. It is designed for direct reuse in a knowledge-base entry while clearly flagging evidence limitations and unknowns.

1. Disease information

Definition and classification

ALS27 is a genetic form of juvenile ALS affecting upper and lower motor neurons, generally with onset before age 25 and commonly in early childhood. It should not be conflated with all juvenile ALS, a genetically heterogeneous group that also includes FUS-, ALS2-, SETX-, SIGMAR1-, SPG11-, and other gene-associated disorders. The defining gene–disease association is SPTLC1–ALS27. Open Targets records one associated target, SPTLC1, supported by five evidence records and literature including PMIDs 34059824, 34459874, 35900868, 36204986, and 40027730. (OpenTargets Search: Amyotrophic lateral sclerosis 27, juvenile-SPTLC1)

Identifiers and names

MONDO: MONDO:0859529.
Gene: SPTLC1, serine palmitoyltransferase long-chain base subunit 1; Ensembl ENSG00000090054. (OpenTargets Search: Amyotrophic lateral sclerosis 27, juvenile-SPTLC1)
Common synonyms: amyotrophic lateral sclerosis type 27; ALS27; juvenile ALS 27; SPTLC1-associated juvenile ALS; SPTLC1-related childhood-onset ALS; SPT-related motor-neuron disease.
OMIM: commonly catalogued as an ALS27/juvenile ALS entry linked to SPTLC1; the exact OMIM accession was not independently recoverable from the retrieved evidence and should be verified directly in OMIM before database loading.
Orphanet: no disease-specific ORPHA identifier was established from the retrieved evidence.
ICD-10: no subtype-specific code; operational coding generally falls under G12.21 Amyotrophic lateral sclerosis in ICD-10-CM or the relevant G12 motor-neuron-disease category.
MeSH: Amyotrophic Lateral Sclerosis; no separate ALS27 descriptor was identified.

The available evidence is principally aggregated disease-level literature, small case series, pedigrees, and mechanistic studies—not individual-patient EHR data.

Key primary and recent publications

Mohassel et al., Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis, 2021, PMID 34059824—foundational human genetic/mechanistic study.
Johnson et al., Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis, JAMA Neurology, 2021, PMID 34459874, DOI: https://doi.org/10.1001/jamaneurol.2021.2598.
Lone et al., SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins, Journal of Clinical Investigation, July 2022, PMID 35900868, DOI: https://doi.org/10.1172/JCI161908. Its abstract states: “ORMDL binding to the holoenzyme complex is impaired…resulting in increased SL synthesis and a distinct lipid signature.” (lone2022sptlc1variantsassociated pages 6-8, lone2022sptlc1variantsassociated pages 1-3)
Wang et al., Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations, Chinese Medical Journal, February 2023, DOI: https://doi.org/10.1097/CM9.0000000000002495. (wang2023clinicalfeaturedifference pages 5-6)
Mohassel et al., Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders, Journal of Neuromuscular Diseases, May 2024, DOI: https://doi.org/10.3233/JND-240014—current authoritative synthesis. (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Syeda et al., Recurrent de novo SPTLC2 variant causes childhood-onset ALS by excess sphingolipid synthesis, JNNP 95:103–113, online 2023/issue 2024, DOI: https://doi.org/10.1136/jnnp-2023-332132. This is not ALS27, but independently corroborates excess SPT activity as a juvenile motor-neuron-disease mechanism. (syeda2024recurrentdenovo pages 1-2)

2. Etiology, risk, and protective factors

Causal factor

ALS27 is caused by germline heterozygous SPTLC1 variants that confer a biochemical gain of function. Most reported patients carry de novo variants, although vertical transmission and autosomal-dominant pedigrees—particularly involving p.Leu39del—are documented. The variants cluster in exon 2/N-terminal transmembrane sequences involved in binding ORMDL negative regulators. (wang2023clinicalfeaturedifference pages 5-6, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

This is not a conventional multifactorial ALS susceptibility association: rare, high-effect variants are sufficient to cause a Mendelian syndrome. No infectious cause has been implicated.

Genetic risk and modifiers

A pathogenic allele is the principal risk factor. Penetrance has not been quantified reliably; the ascertainment of affected transmitting relatives suggests substantial penetrance, but unaffected-carrier studies are insufficient. The literature provides no validated modifier gene, polygenic score, anticipation, or germline-mosaicism frequency. Parental mosaicism remains biologically possible in apparently de novo disease and should be considered in recurrence counseling.

Environment and substrate availability

No conventional ALS environmental exposure—smoking, pesticides, metals, military service, strenuous exercise, or trauma—has been shown to cause or modify ALS27 specifically. The best-supported gene–environment/metabolic interaction is amino-acid substrate availability. Limiting L-serine relative to L-alanine shifted mutant SPTLC1 lipid production toward 1-deoxysphingolipids and an HSAN1-like phenotype; a p.Leu39del family member with sensory disease had an elevated alanine/serine ratio and L-serine deficiency. Thus diet and systemic amino-acid metabolism may modify biochemical phenotype, but clinical effect sizes remain unknown. (lone2022sptlc1variantsassociated pages 6-8, lone2022sptlc1variantsassociated pages 8-9, mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)

No genetic or environmental protective factor has been validated. L-serine is not protective in ALS27 and may be harmful.

3. Phenotypes

Core phenotype and frequency

In a 2023 analysis of 17 SPTLC1-JALS cases, mean onset was 7.9 ± 4.6 years; all 17 had spinal onset, versus 62.8% among 43 FUS-JALS cases. Bulbar onset was 0%, although bulbar involvement can emerge later. Mean estimated disease duration was 512.0 months (95% CI 416.7–607.3; approximately 42.7 years), versus 33.4 months for FUS-JALS. These estimates derive from a literature-assembled, small cohort and are susceptible to survival and publication bias. (wang2023clinicalfeaturedifference pages 5-6)

Phenotype	Character/course	Suggested HPO term
Childhood onset	Usually insidious; reported from age 3–4 years, occasionally second/third decade	HP:0011463 Childhood onset; HP:0003581 Adult onset where applicable
Lower-limb spasticity/hyperreflexia	Often an early UMN manifestation; progressive	HP:0001257 Spasticity; HP:0001347 Hyperreflexia
Toe walking/abnormal gait	Common presenting manifestation before age 10	HP:0040083 Toe walking; HP:0001288 Gait disturbance
Distal leg weakness and atrophy	Progressive LMN involvement; may spread to multiple myotomes	HP:0009053 Distal lower-limb muscle weakness; HP:0003202 Skeletal muscle atrophy
Diffuse denervation	Acute and chronic neurogenic changes on EMG	HP:0003457 EMG abnormality; HP:0003448 Decreased motor nerve conduction amplitude
Pes cavus/scoliosis	Secondary to longstanding asymmetric or distal weakness	HP:0001761 Pes cavus; HP:0002650 Scoliosis
Bulbar dysfunction	Not typical at onset; may occur in later disease	HP:0001283 Bulbar palsy; HP:0002015 Dysphagia; HP:0002167 Dysarthria
Respiratory dysfunction	Late complication in some patients	HP:0002878 Respiratory insufficiency
Sensory sparing	Normal sensory examination/NCS is characteristic	encode as absence of HP:0000763 Sensory neuropathy
Cognitive function	Usually preserved; not systematically tested	absence of HP:0100543 Cognitive impairment, with caution

A newly reported de novo p.Ala20Thr patient developed lower-limb spasticity and weakness at age seven, followed by progressive spread over 12.3 years, severe distal weakness, scoliosis, and pes cavus, without sensory or cognitive impairment. (wang2023clinicalfeaturedifference pages 5-6)

Quality-of-life impact

No ALS27-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was identified. Expected impacts include progressive loss of ambulation and self-care, orthopedic deformity, communication/swallowing difficulty, and eventual ventilatory dependence. These impacts should be recorded as clinically plausible consequences, not disease-specific quantified outcomes.

4. Genetic and molecular information

Gene and variant spectrum

SPTLC1 encodes the long-chain base subunit 1 of SPT. Reported ALS-associated variants include p.Ala20Ser, p.Tyr23Phe, p.Leu38Arg, p.Leu39del, p.Phe40_Ser41del, and exon-2 skipping caused by an Ala20-associated splice effect; p.Ala20Thr was reported in 2023. The 2023 compilation included 17 patients, many de novo and several familial p.Leu39del cases. (wang2023clinicalfeaturedifference pages 5-6, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

These are missense, in-frame deletion, or splice-altering alleles—not a simple haploinsufficiency series. They are germline, not somatic. Population frequencies were not provided in the retrieved studies, but pathogenic de novo variants underlying such an ultra-rare dominant pediatric disorder are expected to be absent or extremely rare in reference populations; each variant nevertheless requires direct gnomAD and ClinVar review before clinical classification.

The functional consequence is best classified as toxic/dysregulated gain of function: mutant complexes retain or increase sphingolipid synthesis while escaping ORMDL feedback. Complete SPTLC1 loss would not be mechanistically equivalent. No large recurrent chromosomal abnormality has been established.

Pleiotropy and genotype–phenotype distinction

C-terminal/cytoplasmic SPTLC1 variants, especially around Cys133 and Ser331, classically cause HSAN1 through altered substrate use and increased 1-deoxysphingolipids. Ser331 substitutions can produce mixed sensory/motor phenotypes and early cataracts. Therefore, “SPTLC1-related disorder” is broader than ALS27, and variant position plus lipid biochemistry are important for interpretation. (lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 4-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

No validated ALS27-specific modifier gene or epigenetic signature has been reported.

5. Environmental and lifestyle information

There is no evidence that toxins, radiation, pollution, infection, smoking, alcohol, or exercise initiate ALS27. Dietary amino-acid balance is a plausible biochemical modifier, but no preventive diet has been validated. The absence of evidence should not be interpreted as proof that systemic metabolism cannot influence severity. The p.Leu39del biochemical observations specifically motivate measurement of serine, alanine, and sphingolipids in atypical mixed motor-sensory cases. (lone2022sptlc1variantsassociated pages 6-8, mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)

6. Mechanism and pathophysiology

Upstream causal chain

Heterozygous SPTLC1 variant affects the N-terminal transmembrane/ORMDL-interaction region.
Mutant SPTLC1 is incorporated into the ER-resident SPT holoenzyme, although exon-2 deletion can impair ER integration and partially destabilize SPTLC2.
Binding or regulatory communication with ORMDL1–3 is weakened.
Ceramide-dependent feedback inhibition fails.
SPT excessively condenses L-serine and palmitoyl-CoA, increasing de novo long-chain bases, ceramides, and complex canonical sphingolipids.
Lipid-membrane composition, organelle homeostasis, signaling, and axonal maintenance are presumed to become toxic to corticospinal and lower motor neurons.
Progressive motor-neuron/axon dysfunction produces spasticity, denervation, muscle atrophy, orthopedic deformity, and eventually bulbar/respiratory disease. Steps 1–5 are strongly supported; the precise molecular bridge from lipid excess to selective motor-neuron death remains unresolved. (lone2022sptlc1variantsassociated pages 6-8, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

SPT occupies the endoplasmic-reticulum membrane and ER–mitochondrial contact sites. The complex includes SPTLC1/SPTLC2 catalytic components, SPTSSA/SPTSSB activating subunits, and ORMDL inhibitors. Relevant suggested terms include GO:0005783 endoplasmic reticulum; GO:0005789 ER membrane; GO:0006665 sphingolipid metabolic process; GO:0030148 sphingolipid biosynthetic process; GO:0046513 ceramide biosynthetic process; and GO:0045768 positive regulation of anti-apoptotic signaling only if demonstrated in future disease-specific work. (syeda2024recurrentdenovo pages 1-2, lone2022sptlc1variantsassociated pages 1-3)

Lipidomics and molecular profiling

Patient serum, fibroblasts, and engineered cells show excessive canonical sphingolipid synthesis. Particularly informative species include sphingolipids bearing C18:0, C20:0, and C22:0 acyl chains, which are normally minor. In contrast, 1-deoxysphingolipids are generally not the dominant ALS27 signature. L-serine restriction can increase 1-deoxysphingolipids, demonstrating substrate-dependent biochemical plasticity. (lone2022sptlc1variantsassociated pages 6-8, lone2022sptlc1variantsassociated pages 12-14)

No robust disease-specific transcriptomic, proteomic, spatial-transcriptomic, single-cell, epigenomic, or metabolomic signature beyond targeted/untargeted sphingolipidomics has been validated. iPSC-derived lower-motor-neuron-like cells carrying p.Phe40_Ser41del showed increased canonical sphingolipids but, in the limited reported characterization, no clear differentiation, morphology, or survival defect. (mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Cell Ontology suggestions: CL:0000127 astrocyte, CL:0000129 microglial cell, CL:0000236 B cell should not be asserted as primary disease cells without direct evidence; the supported targets are motor neurons, especially CL:0000100 motor neuron and CL:0000104 lower motor neuron. Skeletal myofibers are downstream denervation targets.

7. Anatomical structures affected

Primary disease sites are the motor system: corticospinal upper motor neurons, anterior-horn/lower motor neurons, brainstem motor nuclei in later disease, motor roots/axons, neuromuscular junctions, and secondarily skeletal muscle. Suggested anatomy terms include UBERON:0002240 spinal cord; UBERON:0000955 brain; UBERON:0002298 brainstem; UBERON:0002439 myotome; UBERON:0001134 skeletal muscle tissue; and UBERON:0001021 nerve. ER and ER–mitochondrial contact regions are the principal subcellular sites. (lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Onset is often bilateral lower-limb/spinal rather than bulbar. Individual asymmetry can occur, but consistent lateralization has not been established.

8. Temporal development

Onset is usually chronic and insidious in early childhood. An HSP-like phase—spastic gait or toe walking—may precede recognizable diffuse LMN disease. The course is relentlessly progressive rather than episodic or relapsing-remitting, but often much slower than FUS-JALS or adult ALS. Late stages may include bulbar and respiratory compromise. No spontaneous remission is documented. (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

The optimal intervention window is unknown. Mechanistically, treatment before extensive denervation would be preferable, but no presymptomatic biomarker threshold or trial evidence defines such a window.

9. Inheritance and population

Inheritance is autosomal dominant, with many cases arising de novo and some transmitted through affected families. Recurrence risk for an affected heterozygous individual is theoretically 50% per pregnancy. For parents of an apparently de novo case, recurrence is low but not zero because parental germline mosaicism has not been excluded systematically.

No ALS27-specific incidence, prevalence, carrier frequency, sex ratio, founder effect, or geographic concentration is established. The 2023 compilation contained 6 males and 11 females, but 6:11 is not a reliable population sex ratio because of the tiny, literature-ascertained sample. Cases have been reported in multiple ancestries and countries, arguing against restriction to one population. (wang2023clinicalfeaturedifference pages 5-6)

There is no evidence for anticipation. Expressivity is variable in onset, rate of progression, and late bulbar/respiratory involvement.

10. Diagnostics

Clinical and electrophysiologic diagnosis

ALS27 should be considered in a child or young adult with progressive spastic paraparesis plus distal weakness/atrophy, diffuse denervation, and preserved sensation. EMG typically shows diffuse acute and chronic denervation across multiple myotomes; nerve-conduction studies show normal sensory responses and no primary demyelinating process. A sural-nerve biopsy in at least one patient showed sensory preservation, but biopsy is not routinely required. (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

There is no ALS27-specific MRI pattern. MRI is mainly used to exclude structural brain/spinal-cord disease. Pulmonary function, swallowing assessment, nutrition, speech, and serial motor-functional measures are required for staging and management.

Genetic testing strategy

Use a comprehensive juvenile motor-neuron disease/ALS/HSP panel that includes SPTLC1, or trio WES/WGS.
Trio analysis is particularly useful for demonstrating de novo status.
Inspect exon-level sequence and splice effects; routine filtering should retain in-frame deletions and splice-altering variants, not only missense/nonsense variants.
Confirm by an orthogonal method and test parents/relatives.
Interpret variants using phenotype, domain location, segregation, absence/rarity in population data, and functional/lipidomic evidence.

CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion assays do not directly diagnose ALS27, although broader testing may be needed when the phenotype is unresolved. WGS may detect intronic/splice or structural lesions missed by panels/WES.

Biomarkers

Plasma/serum or fibroblast sphingolipidomics may demonstrate elevated canonical ceramides and unusual acyl-chain species and can support pathogenicity, but no certified cutoff, sensitivity, specificity, or regulatory-qualified assay exists. Neurofilament light may be useful in ALS generally, but it is not validated specifically in slowly progressive ALS27.

Differential diagnosis

Major alternatives are hereditary spastic paraplegia, FUS-JALS, ALS2-related disease, SETX-associated ALS4, SPG11, SIGMAR1 disease, spinal muscular atrophy, distal hereditary motor neuropathy, primary lateral sclerosis, structural myelopathy, leukodystrophy, and metabolic motor-neuron disorders. ALS27 is favored over pure HSP by widespread LMN denervation; over HSAN1 by sensory sparing and canonical rather than deoxy-sphingolipid excess. (wang2023clinicalfeaturedifference pages 5-6, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Cascade testing is appropriate after a familial variant is identified. Population or newborn screening is not currently recommended.

11. Outcome and prognosis

ALS27 is severely disabling but often slower than other ALS forms. Long survival into the fifth or sixth decade has been reported, and cognition may remain preserved; nevertheless, progression is described as universal and relentless, and bulbar/respiratory failure can occur. Disease-specific 5- or 10-year survival, mortality rates, median life expectancy, validated prognostic scores, and treatment-adjusted outcomes are unavailable. (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Important morbidity includes gait loss, contractures, scoliosis, pes cavus, weakness, communication/swallowing impairment, malnutrition, secretion problems, and respiratory insufficiency. Recovery of lost motor neurons is not expected with current care.

12. Treatment and current implementation

Disease-specific therapy

No approved SPTLC1-targeted treatment and no relevant disease-specific interventional trial were identified. Proposed approaches remain experimental:

Partial SPT inhibition: mechanistically rational, but systemic SPT is essential. Myriocin and L-/D-cycloserine inhibit SPT; toxicity, off-target effects, dosing, and CNS delivery prevent clinical recommendation. D-cycloserine is approved for tuberculosis, not ALS27. (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)
RNA-directed reduction of mutant SPTLC1: allele-selective ASO/siRNA strategies are conceptually attractive for a dominant gain-of-function disorder but lack ALS27 clinical evidence.
Substrate manipulation: serine depletion has theoretical risks, and no safe therapeutic regimen is established.
Critical contraindication/caution: avoid L-serine supplementation outside specialist research oversight. Serine enhanced consequences of SPT overactivity in p.Phe40_Ser41del iPSC-derived motor neurons and is predicted to worsen canonical sphingolipid overproduction. (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)

Suggested NCIt concepts include Antisense Oligonucleotide Therapy, Gene Silencing Therapy, Physical Therapy, Occupational Therapy, Speech Therapy, Noninvasive Ventilation, Gastrostomy, and Palliative Care; precise NCIt identifiers should be resolved against the current NCIt release.

Supportive real-world management

Until targeted therapy exists, management should follow a multidisciplinary pediatric/young-adult motor-neuron-disease pathway: physical and occupational therapy, stretching and contracture prevention, orthoses and mobility aids, scoliosis surveillance, spasticity treatment, speech/augmentative communication, swallowing and nutritional monitoring, cough augmentation, noninvasive ventilation when indicated, secretion management, psychosocial support, and advance-care planning. Riluzole and edaravone have not been studied specifically in ALS27; use is an individualized specialist decision rather than evidence-based genotype-specific therapy.

13. Prevention

Primary prevention through lifestyle modification or vaccination is not applicable. Secondary prevention consists of identifying at-risk relatives and recognizing early motor signs. Tertiary prevention aims to limit contractures, falls, malnutrition, aspiration, respiratory complications, and communication loss.

Genetic counseling should cover dominant transmission, frequent de novo occurrence, parental testing, possible germline mosaicism, cascade testing, and reproductive options—including prenatal diagnosis and preimplantation genetic testing when a familial pathogenic variant is known. There is no population screening program or prophylactic medication.

14. Other species and natural disease

No naturally occurring veterinary analogue of SPTLC1-ALS27, breed predisposition, zoonotic transmission, or cross-species infectious susceptibility was identified. Orthologous Sptlc1 genes are widely conserved in vertebrates, reflecting the essential role of sphingolipid synthesis. This is a noncommunicable genetic disease with no zoonotic potential.

15. Models and research resources

Disease-specific cellular models: COS-7 and HEK293/SPTLC1-knockout complementation systems, patient fibroblasts, serum lipidomics, and p.Phe40_Ser41del iPSC-derived lower-motor-neuron-like cells. These reproduce impaired ORMDL regulation and lipid excess but have not yet robustly reproduced progressive motor-neuron death. (lone2022sptlc1variantsassociated pages 12-14, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Animal evidence: as of the 2024 review, no published mouse carrying an ALS27-specific SPTLC1 allele had been established; knock-in models were under development. Indirect models support the pathway: loss of two Ormdl isoforms causes neurodegeneration, and conditional expression of constitutively active fusion-SPT causes high sphingolipids, progressive hindlimb paralysis, and sciatic-nerve pathology. The spontaneous Sptssb “stellar” mouse develops early ataxia and premature death, but none is a faithful ALS27 model. (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Relevant resources include MGI/IMSR for future mouse alleles, ZFIN for zebrafish, FlyBase for Drosophila SPT-pathway models, Cellosaurus for cell lines, and GEO/SRA for future transcriptomic datasets.

Expert interpretation and principal knowledge gaps

The strongest current interpretation is that ALS27 is a metabolic motor-neuron disease caused by dysregulated sphingolipid flux, not merely another protein-aggregation ALS. The convergence of SPTLC1 and SPTLC2 juvenile ALS supports causality, while the contrast with HSAN1 demonstrates that the type of lipid produced—not simply increased SPT activity—helps determine neuronal selectivity. Nevertheless, why canonical sphingolipid excess preferentially injures motor neurons remains unanswered. (syeda2024recurrentdenovo pages 1-2, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

Priority gaps are: prospective natural-history cohorts; penetrance and prevalence estimates; standardized plasma/CSF lipid biomarkers; motor-neuron-specific lipidomics and single-cell studies; faithful knock-in animal models; allele-selective silencing; and safe, partial, nervous-system-targeted SPT inhibition. Epidemiology, formal quality-of-life statistics, validated prognostic biomarkers, and controlled treatment-response rates should be entered in a knowledge base as not established, rather than extrapolated from common adult ALS.

References

(wang2023clinicalfeaturedifference pages 5-6): Pei-Shan Wang, Qiao Wei, Hongfu Li, and Zhi-Ying Wu. Clinical feature difference between juvenile amyotrophic lateral sclerosis with sptlc1 and fus mutations. Chinese Medical Journal, Feb 2023. URL: https://doi.org/10.1097/cm9.0000000000002495, doi:10.1097/cm9.0000000000002495. This article has 4 citations and is from a peer-reviewed journal.
(lone2022sptlc1variantsassociated pages 1-3): Museer A. Lone, Mari J. Aaltonen, Aliza Zidell, Helio F. Pedro, Jonas Alex Morales Saute, Shalett Mathew, Payam Mohassel, Carsten Bonnemann, Eric A. Shoubridge, and Thorsten Hornemann. Sptlc1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ormdl proteins. BioRxiv, Apr 2022. URL: https://doi.org/10.1101/2022.04.29.490031, doi:10.1101/2022.04.29.490031. This article has 0 citations.
(mohassel2024serinepalmitoyltransferase(spt)related pages 6-7): Payam Mohassel, Meher Abdullah, Florian S. Eichler, and Teresa M. Dunn. Serine palmitoyltransferase (spt)-related neurodegenerative and neurodevelopmental disorders. Journal of Neuromuscular Diseases, 11:735-747, May 2024. URL: https://doi.org/10.3233/jnd-240014, doi:10.3233/jnd-240014. This article has 10 citations and is from a peer-reviewed journal.
(mohassel2024serinepalmitoyltransferase(spt)related pages 7-9): Payam Mohassel, Meher Abdullah, Florian S. Eichler, and Teresa M. Dunn. Serine palmitoyltransferase (spt)-related neurodegenerative and neurodevelopmental disorders. Journal of Neuromuscular Diseases, 11:735-747, May 2024. URL: https://doi.org/10.3233/jnd-240014, doi:10.3233/jnd-240014. This article has 10 citations and is from a peer-reviewed journal.
(OpenTargets Search: Amyotrophic lateral sclerosis 27, juvenile-SPTLC1): Open Targets Query (Amyotrophic lateral sclerosis 27, juvenile-SPTLC1, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(mohassel2024serinepalmitoyltransferase(spt)related pages 4-6): Payam Mohassel, Meher Abdullah, Florian S. Eichler, and Teresa M. Dunn. Serine palmitoyltransferase (spt)-related neurodegenerative and neurodevelopmental disorders. Journal of Neuromuscular Diseases, 11:735-747, May 2024. URL: https://doi.org/10.3233/jnd-240014, doi:10.3233/jnd-240014. This article has 10 citations and is from a peer-reviewed journal.
(lone2022sptlc1variantsassociated pages 6-8): Museer A. Lone, Mari J. Aaltonen, Aliza Zidell, Helio F. Pedro, Jonas Alex Morales Saute, Shalett Mathew, Payam Mohassel, Carsten Bonnemann, Eric A. Shoubridge, and Thorsten Hornemann. Sptlc1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ormdl proteins. BioRxiv, Apr 2022. URL: https://doi.org/10.1101/2022.04.29.490031, doi:10.1101/2022.04.29.490031. This article has 0 citations.
(syeda2024recurrentdenovo pages 1-2): Safoora B Syeda, Museer A Lone, Payam Mohassel, Sandra Donkervoort, Pinki Munot, Marcondes C França, Juan Eli Galarza-Brito, Matthias Eckenweiler, Alexander Asamoah, Kenneth Gable, Anirban Majumdar, Anke Schumann, Sita D Gupta, Arpita Lakhotia, Perry B Shieh, A Reghan Foley, Kelly E Jackson, Katherine R Chao, Thomas L Winder, Francesco Catapano, Lucy Feng, Janbernd Kirschner, Francesco Muntoni, Teresa M Dunn, Thorsten Hornemann, and Carsten G Bönnemann. Recurrent de novo sptlc2 variant causes childhood-onset amyotrophic lateral sclerosis (als) by excess sphingolipid synthesis. Journal of Neurology, Neurosurgery, and Psychiatry, 95:103-113, Nov 2024. URL: https://doi.org/10.1136/jnnp-2023-332132, doi:10.1136/jnnp-2023-332132. This article has 23 citations.
(lone2022sptlc1variantsassociated pages 8-9): Museer A. Lone, Mari J. Aaltonen, Aliza Zidell, Helio F. Pedro, Jonas Alex Morales Saute, Shalett Mathew, Payam Mohassel, Carsten Bonnemann, Eric A. Shoubridge, and Thorsten Hornemann. Sptlc1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ormdl proteins. BioRxiv, Apr 2022. URL: https://doi.org/10.1101/2022.04.29.490031, doi:10.1101/2022.04.29.490031. This article has 0 citations.
(lone2022sptlc1variantsassociated pages 12-14): Museer A. Lone, Mari J. Aaltonen, Aliza Zidell, Helio F. Pedro, Jonas Alex Morales Saute, Shalett Mathew, Payam Mohassel, Carsten Bonnemann, Eric A. Shoubridge, and Thorsten Hornemann. Sptlc1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ormdl proteins. BioRxiv, Apr 2022. URL: https://doi.org/10.1101/2022.04.29.490031, doi:10.1101/2022.04.29.490031. This article has 0 citations.

Artifacts

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Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	7
Unresolved (possible confabulation)	1
Unverifiable	0
References weighed for topical relevance	7
On topic	5
Off topic	0

Unresolved references

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DOI:10.3233/JND-240014—current (2 mentions) - Identifier did not resolve to a record

domain	disease-specific finding	quantitative/detail	evidence type/limitations
Disease identity	Amyotrophic lateral sclerosis 27, juvenile; Mendelian juvenile ALS subtype linked to SPTLC1	MONDO:0859529; target association SPTLC1 / ENSG00000090054 (OpenTargets Search: Amyotrophic lateral sclerosis 27, juvenile-SPTLC1)	Disease-level ontology and target-association resource; does not provide full clinical detail (OpenTargets Search: Amyotrophic lateral sclerosis 27, juvenile-SPTLC1)
Causal gene / mechanism class	SPTLC1 pathogenic variants cause a dominant gain-of-function disorder of sphingolipid biosynthesis	Pathogenic effect is increased/unrestrained SPT activity via impaired ORMDL regulation rather than classic loss of function (lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Primary mechanistic human/cell studies and review synthesis; selective motor-neuron vulnerability remains incompletely explained (lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Inheritance	Usually autosomal dominant, commonly de novo	2023 compilation table lists many cases as de novo; AD familial cases also reported, including multiple p.Leu39del relatives (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Derived largely from case reports/small pedigrees; penetrance not well quantified (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Established disease variants	Recurrently implicated ALS27 variants cluster in SPTLC1 exon 2 / N-terminal transmembrane domain	Five established variants emphasized in reviews/comparative data: p.A20S, p.Y23F, p.L38R, p.Leu39del, p.Phe40_Ser41del; p.A20T reported as a novel case in 2023 (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Variant set based on early case series/reviews through 2024; later expansion possible (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Age at onset / natural history	Very early childhood onset with unusually slow course relative to FUS-JALS	In 17-patient SPTLC1 JALS comparison: AAO 7.9 ± 4.6 years, 100% spinal onset, disease duration 512.0 months (95% CI 416.7–607.3) vs FUS-JALS 33.4 months (95% CI 21.6–45.1) (wang2023clinicalfeaturedifference pages 5-6)	Cohort assembled from literature plus new cases; small numbers and publication bias likely (wang2023clinicalfeaturedifference pages 5-6)
Core phenotype	Combined upper and lower motor neuron disease, often beginning in legs	Early lower-limb spasticity, toe walking/gait abnormality, weakness/atrophy; symptoms may start as early as 3–4 years; bulbar/respiratory involvement can occur later (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Mostly retrospective case data; severity varies across variants/families (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Sensory / cognitive profile	Sensory system usually spared; cognition usually preserved	No sensory neuropathy is typical even late; normal sensory studies and at least one normal sural biopsy reported; cognitive dysfunction generally not reported in SPTLC1-ALS, unlike some SPTLC2 cases (mohassel2024serinepalmitoyltransferase(spt)related pages 4-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Important disease discriminator, but systematic neuropsychology is limited (mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Electrophysiology / pathology	Motor neuron disorder pattern supports ALS over HSP	EMG/NCS: normal sensory studies with diffuse acute and chronic denervation in multiple myotomes and no demyelinating features; extensive neurogenic damage helps distinguish from HSP (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Disease-specific but based on relatively few deeply phenotyped patients (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Molecular mechanism	Variants disrupt ORMDL-SPTLC1 interaction at the ER SPT complex	SPT resides in ER/ER-mitochondrial contact sites; ALS variants in the N-terminal TMD impair ORMDL binding and feedback inhibition, causing excess canonical sphingolipid synthesis (lone2022sptlc1variantsassociated pages 1-3, lone2022sptlc1variantsassociated pages 6-8, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Strong cell-biochemical evidence; downstream pathway from lipid excess to motor-neuron death remains partly unresolved (lone2022sptlc1variantsassociated pages 6-8, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Biomarker signature	Distinct canonical sphingolipid / ceramide signature rather than HSAN1-like deoxySL excess	Elevated canonical sphingolipids, including unusual C18:0, C20:0, C22:0 acyl-chain species; generally not 1-deoxysphingolipid-driven unless substrate conditions shift (lone2022sptlc1variantsassociated pages 6-8, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Promising biochemical biomarker from serum/fibroblast/cell studies; no standardized clinical cutoff/assay yet (lone2022sptlc1variantsassociated pages 6-8, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Diagnostic approach	Suspect in children with slowly progressive spastic-paraparetic/motor neuron syndrome and no sensory loss	Recommended work-up from disease-specific evidence: broad genetic testing (WES/WGS or ALS/HSP panels including SPTLC1) + EMG/NCS + clinical exclusion of HSP/HSAN1; lipidomics may support mechanism where available (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	No dedicated formal diagnostic criteria for ALS27; practice extrapolated from juvenile ALS genetics literature (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Differential diagnosis	Often confused early with hereditary spastic paraplegia; biochemically distinct from HSAN1	HSP mimic: early spastic gait; ALS27 favored by LMN involvement/EMG denervation. HSAN1 differs by sensory neuropathy and deoxysphingolipid excess (wang2023clinicalfeaturedifference pages 5-6, lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Differential framework is strong, but based on expert synthesis more than prospective studies (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Treatment caveat	Avoid L-serine supplementation in SPT-related motor-neuron disease	Reviews and mechanistic studies predict serine may exacerbate canonical sphingolipid overproduction; iPSC-derived motor neurons with p.F40_S41del reportedly worsened with serine supplementation (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Key actionable caution; not based on controlled clinical trials in ALS27 (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Current treatment status	No disease-specific approved therapy or registered disease-specific trial identified	Standard care remains supportive/ALS multidisciplinary management; partial SPT inhibition is proposed conceptually but not established clinically for ALS27 (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)	No disease-specific interventional trial retrieved; evidence for therapy is preclinical/expert-opinion level (mohassel2024serinepalmitoyltransferase(spt)related pages 7-9)
Models	Human cell systems provide main mechanistic evidence	Evidence includes HEK293/COS-7 systems, patient fibroblasts, and iPSC-derived lower motor neuron-like cells with elevated canonical sphingolipids; no murine SPT-related ALS model reported so far in 2024 review (lone2022sptlc1variantsassociated pages 1-3, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Major translational gap: limited in vivo disease modeling for ALS27 specifically (mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)
Evidence gaps	Major unknowns remain despite strong gene-mechanism link	Missing/limited: prevalence and incidence, penetrance, validated prognosis markers, standardized lipid biomarker thresholds, controlled treatment data, and explanation for selective motor-neuron vulnerability (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)	Knowledge base should mark many epidemiology/outcome fields as not established rather than infer from general ALS (wang2023clinicalfeaturedifference pages 5-6, mohassel2024serinepalmitoyltransferase(spt)related pages 6-7)

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2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

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Amyotrophic Lateral Sclerosis 27, Juvenile (SPTLC1-Associated)

Executive summary

1. Disease information

Definition and classification

Key primary and recent publications

2. Etiology, risk, and protective factors

Causal factor

Genetic risk and modifiers

Environment and substrate availability

3. Phenotypes

Core phenotype and frequency

Quality-of-life impact

4. Genetic and molecular information

Gene and variant spectrum

Pleiotropy and genotype–phenotype distinction

5. Environmental and lifestyle information

6. Mechanism and pathophysiology

Upstream causal chain

Lipidomics and molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and electrophysiologic diagnosis

Genetic testing strategy

Biomarkers

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11. Outcome and prognosis

12. Treatment and current implementation

Disease-specific therapy

Supportive real-world management

13. Prevention

14. Other species and natural disease

15. Models and research resources

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