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Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant with de novo, familial and mosaic transmission HP:0000006

Heterozygous pathogenic SPTLC1 variants act dominantly. Six of seven families in the foundational study had de novo variants; another pedigree showed p.Leu39del transmission. A later p.Ala20Thr proband inherited the variant from an asymptomatic father with 17% mutant allele fraction in blood. Blood mosaicism does not determine neural or germline fractions or a safe threshold. Parental and family testing informs recurrence counseling; a non-mosaic heterozygous parent has a 50% transmission probability, with uncertain severity.

Autosomal dominant inheritance

Show evidence (3 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The variants occurred de novo in six of seven families."

Family ascertainment in the original study, not a population de novo rate.

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"mutant allele frequencies of 50% in the proband, 17% in the father, and 0% in the mother"

Blood ddPCR in one family; no nervous-system or germline threshold was measured.

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Discussions and Knowledge Gaps

4

Which lipid species and downstream processes connect SPT dysregulation to motor neuron injury?

KNOWLEDGE GAP OPEN als27-selective-neuronal-injury

Attached to

pathophysiology#Canonical Sphingolipid Accumulation pathophysiology#Lower Motor Neuron Degeneration

Human genetics and cell experiments establish altered regulation and synthesis, but the selective neuronal injury pathway remains unresolved. Plasma concentrations do not localize the relevant tissue exposure. Candidate mitochondrial and inflammatory signals in non-neural cells do not establish necessary mediators. Sensory-motor overlap also argues against a strict two-disease dichotomy.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Explicit unresolved mechanism.

Why does heterozygous exon-2 deletion fail to reproduce the tested ALS-like phenotype in mice?

HUMAN MODEL MISMATCH OPEN als27-mouse-human-mismatch

Attached to

animal_models#Sptlc1 exon 2 deletion mouse experimental_models#Engineered WTC11 motor neuron-like cells

The deletion models a real human splice consequence, so mismatch cannot be dismissed as an unrelated lesion. Homozygous lethality does not establish simple enzymatic loss of function. The mutant protein, complex incorporation and flux were not directly resolved. Human-cell evidence includes both monoallelic and compound engineered motor neuron-like cells; criticism of the compound line does not erase the monoallelic result.

Show evidence (2 references)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

"It remains unclear whether sufficient ΔE2 protein is available in vivo to incorporate into the SPT complex or interact with ORMDL proteins."

The key unmeasured molecular parameter.

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using CRISPR, we created one iPSC line heterozygous for p.(F40_S41del), akin to patient 3 and another line compound heterozygous for p.(F40_S41del) and a deletion of exon 2 (the consequence of the c.58 G > T variant), which would be predicted to further exacerbate the biochemical phenotype."

Both monoallelic and compound engineered lines were studied.

How do allele, cell type and assay conditions determine the effects of changing serine availability?

INTERPRETATION OPEN als27-serine-direction

Attached to

treatments#L-serine supplementation: unresolved clinical and biochemical effects biochemical#Variable 1-deoxysphingolipid profile

A HEK293FT assay and one compassionate-use case suggest possible biochemical or weight effects, while engineered neuronal lipid assays and mechanistic reviews raise concern about increasing canonical lipid production. Clinical neurological benefit and harm remain unproven. Serine restriction is also not an established therapy: low-serine cultures can increase deoxysphingolipids. The low-serine L39del carrier provides an association, not proof of diet-induced phenotype conversion.

Show evidence (2 references)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Clinical observation without control.

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Experimental countervailing concern for substrate restriction.

How do tissue-specific mosaicism and expression modify penetrance and biochemical findings?

KNOWLEDGE GAP OPEN als27-mosaic-expression

Attached to

inheritance#Autosomal dominant with de novo, familial and mosaic transmission

One clinically unaffected parent had 17% blood mosaicism, but brain and germline fractions were unmeasured and lipid levels were not a consistent intermediate phenotype. This does not define a safe threshold or predict the amount of therapeutic knockdown needed.

Show evidence (1 reference)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Further investigations are necessary to determine whether there is a threshold for the relative abundance of mutant alleles in the clinical presentation of ALS."

Authors explicitly leave the threshold unresolved.

⚙

Pathophysiology

10

Pathogenic SPTLC1 Variation

Dominant SPTLC1 variants associated with ALS include transmembrane-region missense and short deletions, as well as a splice-altering c.58G>T allele. Biochemical effects are allele-specific. S331 substitutions near the catalytic region can produce overlapping sensory-autonomic and motor disease and should not be treated as transmembrane-cluster alleles.

SPTLC1 hgnc:11277

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

Tested ALS-associated alleles can increase sphingolipid synthesis by escaping regulation; this does not assert identical functional effects for every variant or infer mouse enzymatic function from survival.

Experimental models

HEK293FT substrate preference and serine-response assays CELL LINE Engineered variant expression was compared with WT for substrate-associated and mitochondrial-probe readouts.

Patient lymphoblastoid proteomic model CELL LINE Proteomics characterized a patient-derived non-neural cell model, including lower SPTLC1 abundance.

Downstream

Abnormal SPTLC1 Splicing The c.58G>T allele can cause exon 2 skipping in sampled non-neural material.

Reduced ORMDL Association Several tested variants reduce association with regulatory ORMDL proteins; this is not universal across variants and assay systems.

Reduced Ceramide Responsiveness Tested variant-containing complexes can respond less to ceramide even with ORMDL retained.

Failure to Thrive and Growth Failure Reported in selected SPTLC1-related cases; the causal intermediary and contribution of systemic illness remain unresolved.

Cognitive Impairment Reported in selected SPTLC1-related cases; the causal intermediary and contribution of systemic illness remain unresolved.

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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:34059824 SUPPORT DIRECT PRIMARY RESULT 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.

Abnormal SPTLC1 Splicing

The c.58G>T allele predominantly skips exon 2 and deletes the transmembrane domain in sampled blood/cultured cells. In contrast, c.58G>A retained exon 2 in one patient lymphoblast line. Neural-tissue splicing was not measured, and the two nucleotide changes should not be assigned the same mechanism.

Experimental models

Patient c.58G>A lymphoblast splicing assay CELL LINE The c.58G>A lymphoblast sample did not show the exon skipping reported for c.58G>T.

Downstream

Reduced ORMDL Association The exon-deletion construct loses the transmembrane interface and showed impaired ORMDL association in engineered cells.

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Rather than the predicted amino acid substitution p.(A20S), this variant predominantly resulted in complete skipping of exon 2, which is predicted to result in in-frame deletion of amino acids 20–56 comprising the entire first transmembrane domain of the SPTLC1 protein18."

Primary non-neural transcript result.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No band corresponding to exon 2 skipping (266 bp) was detected"

Negative lymphoblast RT-PCR result for c.58G>A, not proof about every tissue.

Reduced ORMDL Association

Reduced association with ORMDL regulatory proteins was measured for several variants in engineered cells and for selected patient fibroblast preparations. Y23F retained association in the 2022 study; C133W also showed reduced association without the same canonical-lipid feedback defect. Purified ALS-variant complexes in the 2023 study retained ORMDL. Thus association loss is one possible route to dysregulation, not a necessary or sufficient explanation for every allele.

serine palmitoyltransferase complex GO:0017059

endoplasmic reticulum GO:0005783

Experimental models

Engineered HEK293 SPTLC1 variant systems CELL LINE Several variants showed lower ORMDL association, with variant-specific exceptions.

Downstream

Reduced SPT Feedback Inhibition Reduced regulatory association can contribute to impaired feedback, alongside alterations of sensing within assembled complexes.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Co-immunoprecipitation and native-complex experiments, with variant and system limits.

Reduced Ceramide Responsiveness

Recombinant human SPT-ORMDL complexes containing selected ALS-associated variants were less inhibited by short-chain ceramide despite ORMDL retention. Structural and engineered-mutant experiments support a ceramide-sensing site; the precise allosteric effect of each patient allele was not structurally resolved. Short-chain substrate assays and detergent-purified complexes do not reproduce all native membrane conditions.

endoplasmic reticulum GO:0005783

Experimental models

Purified human SPT-ORMDL and engineered membrane assays OTHER Selected SPTLC1 variant complexes had impaired ceramide sensing despite ORMDL retention.

Downstream

Reduced SPT Feedback Inhibition Reduced ceramide responsiveness weakens lipid-dependent suppression of SPT activity.

Show evidence (1 reference)

PMID:37308477 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is..."

Primary biochemical findings; the Y23A/Y23F discrepancy prevents equating all tested constructs with patient alleles.

Reduced SPT Feedback Inhibition

SPT normally undergoes homeostatic regulation by ORMDL proteins and ceramide. Several ALS-associated variants blunt that inhibition while retaining catalytic activity. The degree and route of escape depend on the allele and experimental system.

negative regulation of sphingolipid biosynthetic process GO:0090155 ↓ DECREASED

endoplasmic reticulum GO:0005783

Experimental models

Patient fibroblasts and allele-selective siRNA PRIMARY CELL CULTURE Variant-selective knockdown restored sensitivity to C6-ceramide.

Downstream

Increased De Novo Sphingolipid Synthesis Reduced feedback permits excess flux through the pathway in tested cells.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"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."

Primary cellular activity and lipid synthesis experiments.

Increased De Novo Sphingolipid Synthesis

Isotope-labeling experiments show increased formation of canonical sphingolipids in selected patient fibroblasts and engineered cells, including monoallelic F40_S41del motor neuron-like cells. This is distinct from a steady-state concentration assay and is not established for every tissue or allele.

sphingolipid biosynthetic process GO:0030148 ↑ INCREASED

serine C-palmitoyltransferase activity GO:0004758 ↑ INCREASED

endoplasmic reticulum GO:0005783

Experimental models

Engineered HEK293 SPTLC1 variant systems CELL LINE Isotope-labeling demonstrated increased synthesis in tested variant-expressing cells.

Patient fibroblasts and allele-selective siRNA PRIMARY CELL CULTURE Allele-selective siRNA reduced abnormal lipid synthesis in tested patient cultures.

Engineered WTC11 motor neuron-like cells IPSC DERIVED MODEL Stable-isotope labeling detected increased canonical lipid synthesis in both engineered genotypes.

Downstream

Canonical Sphingolipid Accumulation Increased synthesis can elevate canonical sphingoid bases and downstream lipid pools; their levels also depend on turnover and interconversion.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs."

Stable-isotope labeling of engineered WTC11-derived cells; monoallelic and compound lines were both studied.

Canonical Sphingolipid Accumulation

Selected patient plasma and cell samples show elevated canonical sphingoid bases, dihydrosphingolipids or ceramides. Species and lipid classes differ across individuals and experiments; not all complex lipids rise. A later family study compared one proband with two parents using repeated measurements, not independent patient replicates. The lipid-to-neuronal-injury bridge remains inferred.

Animal models

Sptlc1 exon 2 deletion mouse Mouse fails to recapitulate The measured tissue lipid pools were not significantly different at four months; this does not refute increased synthesis in human cells.

Downstream

Upper Motor Neuron Dysfunction Abnormal sphingolipid homeostasis is proposed to contribute to selective motor-system injury; the intermediate injury pathway is unresolved.

Lower Motor Neuron Degeneration Lipid dysregulation is proposed to contribute to lower motor neuron degeneration, without a demonstrated single toxic species or neuronal rescue endpoint.

Show evidence (2 references)

PMID:37348646 SUPPORT DIRECT PRIMARY RESULT 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:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The levels of complex ceramides, including lactosylceramide, hexosylceramide, and sphingomyelin, did not significantly differ across family members."

Negative lipid-class result limits any assertion of globally increased lipids.

Upper Motor Neuron Dysfunction

Spasticity, hyperreflexia and pyramidal signs establish upper motor neuron involvement in many reported patients. These signs can be absent in individual cases, and upper motor neuron dysfunction need not precede weakness. Human clinical signs do not provide direct counts of cortical neuron loss.

Downstream

Lower Limb Spasticity Upper motor pathway dysfunction contributes to lower-limb spasticity.

Hyperreflexia Upper motor pathway dysfunction can produce brisk reflexes.

Toe Walking (Tip-Toe Gait) Spastic motor dysfunction can cause a tip-toe gait.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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"

Clinical upper and lower motor neuron findings in six selected probands.

Lower Motor Neuron Degeneration

Clinical weakness, atrophy, fasciculations and multi-myotomal denervation support lower motor neuron disease. Sensory findings were normal in many transmembrane-variant cases, but mixed SPTLC1 phenotypes and intrafamilial variation prevent an absolute motor-only rule.

spinal cord motor neuron CL:0011001

Animal models

Sptlc1 exon 2 deletion mouse Mouse fails to recapitulate Overt tested motor, CMAP and late histological abnormalities were not reproduced in heterozygotes.

Downstream

Muscle Denervation Lower motor neuron degeneration reduces innervation of skeletal muscle.

Tongue Fasciculations Bulbar lower motor neuron involvement can produce tongue fasciculations.

Fasciculations Lower motor unit dysfunction can produce visible fasciculations.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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"

Clinical localization, rather than autopsy neuron counts.

Muscle Denervation

Denervated muscle shows neurogenic atrophy and acute or chronic electrodiagnostic changes. Limb, bulbar and respiratory muscle involvement produces variable disability; respiratory failure can develop while the patient is still ambulant. Mild inflammation in one muscle specimen does not establish a primary inflammatory myopathy or a causal inflammatory pathway.

Downstream

Progressive Muscle Weakness Loss of motor input impairs force generation.

Skeletal Muscle Atrophy Persistent denervation contributes to muscle wasting.

Diffuse Denervation on Electromyography Electrophysiology detects denervation across affected myotomes.

Dysarthria Bulbar motor involvement can impair articulation.

Dysphagia Bulbar motor involvement can impair swallowing.

Loss of Ambulation Progressive limb motor impairment can cause loss of walking.

Respiratory Insufficiency Respiratory muscle involvement can produce ventilatory insufficiency.

Scoliosis Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Joint Contractures Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Scapular Winging Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Pes Cavus Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Foot Drop Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Gowers Sign Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Tongue Atrophy Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes"

Four diagnostic biopsies showed neurogenic change.

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Histopathology

1

Neurogenic muscle atrophy

Diagnostic muscle biopsies showed acute/chronic neurogenic change and fiber-type grouping. One severe splice-variant case had mild focal inflammation and subsarcolemmal mitochondrial enrichment, without detectable protein or lipid aggregates by the reported microscopy. These findings do not establish a primary inflammatory myopathy or visible lipid-storage disorder.

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes"

Four selected biopsies.

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Microscopic investigations on the quadriceps muscle derived from our patient revealed a neurogenic atrophy characterized by fiber-type grouping and accompanied by unspecific subsarcolemmal enrichment of mitochondria and unravelled presence of mild inflammation."

Single-patient muscle specimen.

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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

21

Digestive 1

Dysphagia HP:0002015

Show evidence (2 references)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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.

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Because of the progressive bulbar dysfunction, nutrition via percutaneous endoscopic gastrostomy (PEG) tube was needed at the same time."

Bulbar feeding impairment in the exon-2 splice case, overlapping the foundational cohort.

Head and Neck 2

Tongue Fasciculations HP:0001308

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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 source describes progressive lower motor neuron involvement including tongue fasciculations; the wording does not provide a separate tongue-fasciculation numerator.

Tongue Atrophy HP:0012473

Show evidence (1 reference)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A neurological examination revealed symmetrical weakness, dominant muscular atrophy of the distal upper extremities, and tongue atrophy."

Direct examination in one patient.

Limbs 3

Scapular Winging HP:0003691

Show evidence (1 reference)

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed."

Clinical scapular winging.

Pes Cavus HP:0001761

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Foot deformities | Pes cavus | NA | Pes cavus/varus | NA |"

Table 1; unexamined/unreported cells are not negative findings.

Foot Drop Foot dorsiflexor weakness HP:0009027

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient walked abnormally owing to weakness and bilateral foot drop, and she had a positive Gower sign."

Direct gait examination.

Musculoskeletal 7

Lower Limb Spasticity HP:0002061

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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"

Clinical presentation of six selected index probands; this does not establish a disease-wide frequency.

Progressive Muscle Weakness HP:0003323

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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 HP:0003202

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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.

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

Show evidence (1 reference)

PMID:38788085 SUPPORT DIRECT REVIEW SYNTHESIS 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.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At the age of 13 years, scoliosis was noted during a medical checkup."

Individual c.58G>A case; source nonbreaking whitespace is normalized by validation.

Joint Contractures HP:0034392

Show evidence (1 reference)

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed."

Direct clinical observations in one patient.

Gowers Sign HP:0003391

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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"

Primary examination documents a positive Gower sign in a transmembrane-variant case.

Nervous System 6

Hyperreflexia HP:0001347

Show evidence (1 reference)

PMID:37497262 SUPPORT DIRECT PRIMARY RESULT 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."

The longitudinal L39del patient developed hyperreflexia; this avoids relying solely on the mixed S331Y case.

Fasciculations HP:0002380

Show evidence (1 reference)

PMID:37497262 SUPPORT DIRECT PRIMARY RESULT 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 HP:0001260

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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.

Cognitive Impairment HP:0100543

Severity: MILD

Show evidence (2 references)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Neuropsychological finding in one patient; Table 1 records executive dysfunction in patients 1 and 2.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Therefore, we are reluctant to conclude that this patient had cognitive decline."

The later low test score was uncertain and is not counted as a confirmed additional case.

Toe Walking (Tip-Toe Gait) HP:0030051

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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.

Loss of Ambulation HP:0002505

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Reported progressive ambulatory impairment in the selected original series.

PMID:36801857 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He could not walk and became wheelchair-dependent five years after onset."

New case with onset at seven years and wheelchair dependence approximately age 12.

Respiratory 1

Respiratory Insufficiency HP:0002093

Course: PROGRESSIVE

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Respiratory involvement in the original selected series, with variable severity and timing.

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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 HP:0001508

Show evidence (2 references)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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.

🧬

Genetic Associations

1

SPTLC1

Gene: SPTLC1 hgnc:11277 gene page relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT In Vitro

"Rather than the predicted amino acid substitution p.(A20S), this variant predominantly resulted in complete skipping of exon 2, which is predicted to result in in-frame deletion of amino acids 20–56 comprising the entire first transmembrane domain of the SPTLC1 protein18."

Splice consequence of c.58G>T.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No band corresponding to exon 2 skipping (266 bp) was detected"

Different c.58G>A transcript result.

+ 1 more reference

💊

Medical Actions

15

Multidisciplinary assessment and surveillance

Action: Multidisciplinary assessment and surveillance Ontology label: Supportive Care NCIT:C15747

Coordinate neurology, respiratory, nutrition, rehabilitation, communication, psychological and palliative services. Reassess swallowing, weight, strength, mobility, communication, respiratory function and care preferences as disease changes. The general guideline suggests coordinated review usually every three to six months, adjusted to progression and needs. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Provide coordinated care for people with ALS using a clinic‐based, specialist ALS MDT approach."

Strong general ALS recommendation; care organization is not a mutation-specific trial.

Noninvasive ventilatory support

Action: Noninvasive ventilatory support Ontology label: Mechanical Ventilation NCIT:C70909

Platform: Device

Offer noninvasive ventilation when symptoms, signs or respiratory testing support insufficiency; do not require a fixed FVC threshold or loss of ambulation first. Tolerance, interface, secretion management and patient preferences matter. Invasive ventilation requires advance shared decisions rather than an inevitable escalation. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.

Mechanism Target:

BYPASSES Respiratory Insufficiency — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency."

Strong general ALS recommendation.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency."

Strong general ALS recommendation.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Respiratory failure developed while she was still able to walk, requiring intermittent noninvasive positive pressure ventilation at the age of 18 years."

Documented ALS27 support, without a comparator efficacy estimate.

Cough augmentation and secretion clearance

Action: Cough augmentation and secretion clearance Ontology label: Supportive Care NCIT:C15747

Platform: Device

Assess cough effectiveness. Manual assistance or breath stacking can be followed by mechanical cough assistance when ineffective or judged necessary; suction is an adjunct. These measures support airway clearance rather than reverse motor neuron loss. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Offer cough augmentation techniques, such as manual assisted cough, to people with ALS who cannot cough effectively."

Strong recommendation, with technique choice individualized.

Nutrition and swallowing support

Action: Nutrition and swallowing support Ontology label: Nutritional Therapy NCIT:C65017

Assess weight change, hydration, swallowing, feeding effort and nutritional needs. Dietitian and swallowing-team input can guide food texture, liquid thickness, feeding aids and energy intake. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.

Mechanism Target:

MODULATES Failure to Thrive and Growth Failure — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration."

GeneReviews general ALS care.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration."

GeneReviews general ALS care.

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Identify causes for weight loss and reduced food and fluid intake (e.g., swallowing problems, respiratory insufficiency, depression, loss of appetite, muscle atrophy, upper limb weakness)."

Strong recommendation to investigate causes rather than assume all weight loss is one mechanism.

Gastrostomy when indicated

Action: Gastrostomy when indicated Ontology label: Nutritional Support NCIT:C15433

Platform: Surgery

Discuss gastrostomy early and revisit according to swallowing, weight, respiratory status, feeding burden and preferences. If respiratory insufficiency is present, establish NIV before and during the procedure as appropriate. Gastrostomy is not mandatory for every patient. A severe ALS27 splice-variant case required PEG because of bulbar dysfunction.

Mechanism Target:

BYPASSES Dysphagia — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking."

Strong recommendation for discussion and individualized timing.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking."

Strong recommendation for discussion and individualized timing.

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Because of the progressive bulbar dysfunction, nutrition via percutaneous endoscopic gastrostomy (PEG) tube was needed at the same time."

Documented use in ALS27, not a controlled outcome.

Physical and occupational therapy with mobility aids

Action: Physical and occupational therapy with mobility aids Ontology label: Physical Therapy NCIT:C15302

Individualize exercise, stretching, positioning and assistive devices to preserve joint movement, reduce stiffness and support daily activities. Consider fatigue and weakness when setting intensity. Walkers, wheelchairs, orthoses and transfer aids compensate for disability; prevention of contractures is an aim rather than established ALS27-specific efficacy.

Mechanism Target:

MODULATES Joint Contractures — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Maintain joint range of movementPrevent contracturesReduce stiffness and discomfortOptimise function and quality of life."

Goals of the guideline exercise recommendation; the cache joins adjacent list items.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Maintain joint range of movementPrevent contracturesReduce stiffness and discomfortOptimise function and quality of life."

Goals of the guideline exercise recommendation; the cache joins adjacent list items.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Assistive devices, such as walkers or wheelchairs, can aid mobility; and others, such as bathroom installments, hospital bed, and Hoyer lift, can aid in activities of daily living at home."

GeneReviews supportive care.

Symptomatic spasticity management

Action: Symptomatic spasticity management Ontology label: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Consider physical measures and, when appropriate, baclofen, tizanidine, gabapentin or other specialist-selected agents. Monitor sedation and increased weakness; focal botulinum toxin can be considered if other measures fail or are unsuitable. These are conditional general ALS recommendations, not evidence that every ALS27 patient has treatable spasticity.

Mechanism Target:

MODULATES Lower Limb Spasticity — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone."

Conditional general ALS recommendation.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone."

Conditional general ALS recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps; however, weakness and lethargy are common side effects."

GeneReviews balances symptom relief against adverse effects.

Speech and augmentative communication support

Action: Speech and augmentative communication support Ontology label: Supportive Care NCIT:C15747

Platform: Device

Assess communication early and provide appropriate low- or high-technology aids, including access methods that adapt to progressive motor impairment. Speech-language and occupational teams should review needs and train the patient and carers. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.

Mechanism Target:

BYPASSES Dysarthria — Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life."

Strong general ALS communication recommendation.

Show evidence (1 reference)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life."

Strong general ALS communication recommendation.

Riluzole within specialist ALS care

Action: Riluzole within specialist ALS care Ontology label: Pharmacotherapy NCIT:C15986

Agent: Riluzole CHEBI:8863

Platform: Small molecule

The 2024 EAN guideline recommends riluzole for people with ALS. Riluzole use is reported in an ALS27 patient, but that uncontrolled case cannot establish efficacy, and pediatric use requires individualized specialist assessment. This is general ALS treatment extrapolation, not a targeted correction of SPT feedback.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Offer lifelong riluzole to all people with ALS at diagnosis."

General ALS recommendation; no ALS27 subgroup result.

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She was diagnosed with juvenile ALS, and she has been taking riluzole since age 15 years."

Exposure in one patient, without an untreated comparator.

Psychological, caregiver and palliative support

Action: Psychological, caregiver and palliative support Ontology label: Supportive Care NCIT:C15747

Address emotional distress, care burden, symptom relief and changing priorities throughout the course. Discuss ventilation, feeding and advance care preferences in an age-appropriate manner with the patient and family. Cognitive or communication limitations require adapted support rather than an assumption of inability to participate.

Show evidence (2 references)

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"During MDT assessments and other appointments, discuss the psychological and emotional impact of ALS with the person and ask whether they have any psychological or support care needs."

General ALS recommendation; psychological care is not restricted to end-stage disease.

PMID:38470068 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"Provide support and advice on advance care planning for end of life."

General ALS recommendation, individualized for juvenile disease.

Genetic counseling and family evaluation

Action: Genetic counseling and family evaluation Ontology label: Genetic Counseling NCIT:C15240

Explain dominant inheritance, de novo occurrence, possible parental mosaicism and uncertain variable expression. Parental testing and counseling support recurrence-risk and reproductive decisions. Testing a symptomatic child is distinct from predictive testing for a strictly adult-onset condition. The unaffected father with 17% blood mosaicism does not establish a safe tissue threshold.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"In a family with an established diagnosis of ALS, it is appropriate to consider testing of symptomatic individuals regardless of age."

GeneReviews counseling guidance; the adult-onset predictive-testing discussion must not be indiscriminately applied to childhood ALS27.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT 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.

Allele-selective SPTLC1 siRNA: preclinical investigation

Action: Allele-selective SPTLC1 siRNA: preclinical investigation Ontology label: Pharmacotherapy NCIT:C15986

Platform: siRNA

Variant-selective siRNAs reduced abnormal lipid synthesis in fibroblasts carrying L39del or F40_S41del. This is biochemical rescue in cultured non-neuronal cells, not demonstrated rescue of neuron survival or patient disability. Each allele needs its own validated sequence; delivery, specificity and safe long-term lowering in the nervous system remain unresolved.

Mechanism Target:

INHIBITS Increased De Novo Sphingolipid Synthesis — Allele-selective lowering reduced excess lipid synthesis in tested patient fibroblast cultures.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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."

Primary fibroblast experiments; the study does not establish clinical safety or efficacy.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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."

Primary fibroblast experiments; the study does not establish clinical safety or efficacy.

LTX-002: investigational SPTLC1 antisense therapy

Action: LTX-002: investigational SPTLC1 antisense therapy Ontology label: Pharmacotherapy NCIT:C15986

Platform: Antisense oligonucleotide

An ongoing placebo-controlled phase 1/2 study evaluates intrathecal LTX-002 in adults with ALS. It is not restricted to SPTLC1-variant carriers and excludes children. Safety, pharmacokinetics and exploratory biomarkers are being studied; no results are posted and no juvenile ALS27 benefit is established. Registry-directed SPTLC1 lowering should not be conflated with the allele-selective siRNA fibroblast experiments.

Mechanism Target:

INHIBITS Increased De Novo Sphingolipid Synthesis — Intended reduction of SPTLC1-dependent synthesis; clinical target engagement and therapeutic benefit remain under investigation.

Show evidence (1 reference)

url:https://clinicaltrials.gov/api/v2/studies/NCT07660614 SUPPORT DIRECT BACKGROUND Human Clinical

"LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested."

Registry intervention rationale, not an outcome or proof of achieved target engagement.

Show evidence (1 reference)

url:https://clinicaltrials.gov/api/v2/studies/NCT07660614 SUPPORT DIRECT BACKGROUND Human Clinical

"LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested."

Registry intervention rationale, not an outcome or proof of achieved target engagement.

Partial SPT inhibition: investigational concept

Action: Partial SPT inhibition: investigational concept Ontology label: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Partial pharmacological suppression of SPT is proposed to reduce excess synthesis, but the available sources do not establish clinical efficacy in ALS27. Complete inhibition and nonspecific inhibitors can be toxic; changing basal output does not necessarily restore feedback regulation. This concept is distinct from the adult LTX-002 antisense study.

Mechanism Target:

INHIBITS Increased De Novo Sphingolipid Synthesis — Proposed inhibition of excess synthesis; the therapeutic window and patient benefit remain unproven.

Show evidence (1 reference)

PMID:38788085 SUPPORT INDIRECT REVIEW SYNTHESIS 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."

Review proposal, not a tested ALS27 clinical intervention.

Show evidence (1 reference)

PMID:38788085 SUPPORT INDIRECT REVIEW SYNTHESIS 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."

Review proposal, not a tested ALS27 clinical intervention.

L-serine supplementation: unresolved clinical and biochemical effects

Action: L-serine supplementation: unresolved clinical and biochemical effects Ontology label: Pharmacotherapy NCIT:C15986

Agent: L-serine CHEBI:17115

Platform: Small molecule

One compassionate-use patient gained weight without demonstrated neurological improvement. A HEK293FT study reported substrate-preference and mitochondrial-probe changes improved by serine, whereas isotope-labeled motor neuron-like cells showed increased canonical lipid production with serine availability. The substrate-preference result was not reproduced under another study's conditions. These are different assays and alleles; neither clinical benefit nor clinical worsening is established. Supplementation is not an established ALS27 treatment, and a theoretical risk of increasing lipid production warrants specialist caution.

Show evidence (4 references)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

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

Uncontrolled compassionate use; no proven neurological benefit.

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Her body weight increased during this off-label treatment, which was the first time she had gained weight in several years."

Weight change in one patient, not proof of neuronal benefit.

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Supplementation of 100 mM L-serine in the culture media for 48 hours rescued the mitochondrial abnormalities in the p.Ala20Ser and p.Cys133Trp lines."

MitoTracker size/intensity endpoints in HEK293 cells; not a neuron-survival rescue.

+ 1 more reference

🔬

Biochemical Markers

2

Plasma sphingolipid abnormalities

Show evidence (4 references)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Each sample underwent three to four independent measurements."

Repeated measurements within three people; no independent patient cohort is implied.

+ 1 more reference

Variable 1-deoxysphingolipid profile

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Culture perturbation, not a tested patient diet.

🔬

Diagnosis

3

Clinical and electrodiagnostic motor-neuron assessment

Assess upper and lower motor neuron findings across regions, nerve conduction and needle EMG, with evaluation for mimics. Sensory studies were normal in many cases, but mixed SPTLC1 phenotypes occur. An initial limb-girdle or spastic presentation does not exclude ALS27.

Show evidence (3 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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"

Clinical criteria in the original six probands.

PMID:38788085 SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

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

Review synthesis of the electrodiagnostic pattern.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/ SUPPORT DIRECT REVIEW SYNTHESIS Human Clinical

"The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations"

GeneReviews general diagnostic framework.

Molecular diagnosis and family testing

Identify a compatible heterozygous pathogenic or likely pathogenic SPTLC1 variant using an appropriate motor-neuron panel or broader sequencing, and interpret splice consequences when relevant. Parental testing distinguishes de novo, inherited and mosaic findings. An uncertain variant alone does not establish ALS27; a blood mosaic fraction does not measure neural or germline burden.

SPTLC1 and family testing NCIT:C15709

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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 DIRECT PRIMARY RESULT 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.

Supportive lipid and tissue investigations

Plasma lipid profiling and muscle biopsy can support mechanistic investigation or clarify mimics, but neither a validated lipid cutoff nor an obligatory biopsy pattern defines ALS27. Neurogenic muscle change supports denervation; absence of a lipid aggregate or an elevated lipid class does not exclude the molecular diagnosis.

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes"

Diagnostic biopsies in selected patients.

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The levels of complex ceramides, including lactosylceramide, hexosylceramide, and sphingomyelin, did not significantly differ across family members."

Not every lipid class is abnormal.

📈

Progression

2

Variable onset and localization

A 2023 literature-based comparison pooled 17 SPTLC1 cases, only one newly described, against 43 FUS cases. Mean onset in the selected SPTLC1 set was 7.9 years (SD 4.6), and all were categorized as spinal onset. The pooled set included overlapping publications and mixed sensory-motor phenotypes, so these are not population estimates or an independent replication cohort. A separate long-followed L39del patient first had documented weakness in early adulthood.

Show evidence (2 references)

PMID:36801857 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| AAO (years, mean ± SD) | 7.9 ± 4.6 | 18.1 ± 3.9 | 8.64 † | <0.01 |"

Table 2 of the pooled published cases.

PMID:36801857 SUPPORT DIRECT PRIMARY RESULT 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.

Variable progression

The pooled paper reports a Kaplan-Meier mean disease-duration estimate of 512.0 months with 95% CI 416.7–607.3, not a median or interquartile range. Extensive censoring, small numbers and case selection prevent treating this estimate as individual life expectancy. One newly reported boy became wheelchair-dependent five years after onset; another L39del case lost independent walking at age 45. Respiratory failure can occur before loss of ambulation.

Show evidence (4 references)

PMID:36801857 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"| Disease duration (months, mean [95% CI]) | 512.0 (416.7–607.3) | 33.4 (21.6–45.1) | 26.32 ‡ | <0.01 |"

Table 2 defines the statistic and uncertainty; it is not median survival.

PMID:36801857 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He could not walk and became wheelchair-dependent five years after onset."

Severe childhood course.

PMID:37497262 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"She lost independent ambulation at age 45 years."

Long course in one patient.

+ 1 more reference

🔀

Differential Diagnoses

5

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

Hereditary Spastic Paraplegia

Overlapping Features Classic pure hereditary spastic paraplegia can resemble the initial spastic gait. Diffuse bulbar and limb lower motor neuron findings support ALS; complicated HSP can overlap, so lower motor neuron involvement is not an absolute exclusion of the whole HSP category.

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 DIRECT BACKGROUND 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.

🔬

Clinical Trials

1

NCT07660614 PHASE_I RECRUITING

First-in-human randomized placebo-controlled multiple-dose intrathecal LTX-002 study in adults with ALS. The ASO targets SPTLC1 mRNA. Planned enrollment is 56; the protocol includes three doses and primary safety assessment through day 169, with pharmacokinetic and exploratory biomarker/functional measures. It is a broader adult ALS study, not a juvenile ALS27 efficacy trial.

Show evidence (3 references)

clinicaltrials:NCT07660614 SUPPORT DIRECT BACKGROUND Human Clinical

"Specifically, the researchers will be looking at safety, tolerability (if someone has any side effects from the drug), pharmacokinetics (what the body does to the study drug) and pharmacodynamics (what the study drug does to the body)."

Registered study design, not outcomes.

url:https://clinicaltrials.gov/api/v2/studies/NCT07660614 SUPPORT DIRECT BACKGROUND Human Clinical

"LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested."

Intervention identity and target.

url:https://clinicaltrials.gov/api/v2/studies/NCT07660614 SUPPORT DIRECT BACKGROUND Human Clinical

"ALS symptom onset less than 36 months prior to Screening"

Eligibility restricts disease duration; the same registry specifies ages 18–75.

🧫

Experimental Models

7

Engineered HEK293 SPTLC1 variant systems CELL_LINE

HEK293-derived systems tested WT and variant SPTLC1 with SPT subunits/ORMDL, including SPTLC1-knockout reconstitution. Co-immunoprecipitation, native complexes, ceramide challenges and isotope labeling distinguish protein association, feedback and synthesis. COS-7 imaging assessed localization: most tested variants remained ER-associated, whereas exon-deleted SPTLC1 was mainly cytosolic with residual membrane-associated catalytic complex.

Pathograph links

Reduced ORMDL Association partially recapitulates fidelity: moderate Several variants showed lower ORMDL association, with variant-specific exceptions.

Limitations: Transformed non-neuronal cells, engineered expression and knockout/reconstitution can exaggerate effects relative to heterozygous tissues. Co-immunoprecipitation measures association, not a binding constant or causal neuron loss. Y23F and HSAN1 C133W show that association and feedback do not map one-to-one.

Readouts

ORMDL association in selected variant complexes

Direction: DECREASED

Interpretation: Several variants showed lower ORMDL association, with variant-specific exceptions.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Direct association readouts.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Direct association readouts.

Increased De Novo Sphingolipid Synthesis recapitulates fidelity: moderate Isotope-labeling demonstrated increased synthesis in tested variant-expressing cells.

Limitations: Transformed non-neuronal cells, engineered expression and knockout/reconstitution can exaggerate effects relative to heterozygous tissues. Co-immunoprecipitation measures association, not a binding constant or causal neuron loss. Y23F and HSAN1 C133W show that association and feedback do not map one-to-one.

Readouts

Newly synthesized sphingolipid abundance

Direction: INCREASED

Interpretation: Isotope-labeling demonstrated increased synthesis in tested variant-expressing cells.

Show evidence (1 reference)

PMID:37348646 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

The L38R source is available as an abstract; detailed methods are not inferred.

Show evidence (1 reference)

PMID:37348646 SUPPORT DIRECT PRIMARY RESULT In Vitro

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

The L38R source is available as an abstract; detailed methods are not inferred.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT 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."

Primary cellular complex studies.

Patient fibroblasts and allele-selective siRNA PRIMARY_CELL_CULTURE

Fibroblasts with L39del or F40_S41del showed altered lipid synthesis and ceramide feedback. Allele-selective siRNA lowered excess synthesis and restored ceramide responsiveness under the tested culture conditions. Primary cultures supplied several lipid assays; native-complex profiling additionally used immortalized derivatives.

Cell source

Patient skin-derived fibroblasts, with immortalized derivatives for native-complex assays

Pathograph links

Increased De Novo Sphingolipid Synthesis rescues fidelity: moderate Allele-selective siRNA reduced abnormal lipid synthesis in tested patient cultures.

Limitations: Non-neuronal patient skin fibroblasts reproduce biochemical defects but do not test selective motor neuron death or clinical efficacy. The native-gel complex experiment used immortalized fibroblast derivatives; it must not be described as an entirely primary-cell assay.

Readouts

Canonical lipid synthesis after variant-selective knockdown

Direction: RESTORED

Interpretation: Allele-selective siRNA reduced abnormal lipid synthesis in tested patient cultures.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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."

Primary rescue of a biochemical phenotype.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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."

Primary rescue of a biochemical phenotype.

Reduced SPT Feedback Inhibition rescues fidelity: moderate Variant-selective knockdown restored sensitivity to C6-ceramide.

Limitations: Non-neuronal patient skin fibroblasts reproduce biochemical defects but do not test selective motor neuron death or clinical efficacy. The native-gel complex experiment used immortalized fibroblast derivatives; it must not be described as an entirely primary-cell assay.

Readouts

C6-ceramide feedback response

Direction: RESTORED

Interpretation: Variant-selective knockdown restored sensitivity to C6-ceramide.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT In Vitro

"An attenuated C6-Cer response was also observed in fibroblasts derived from L39del and F40S41del patients, which could be restored after knockdown of the mutant mRNA transcripts (Figure 2G) using siRNAs that specifically silence the expression of the respective mutant alleles, as shown previously (4)."

Primary feedback-rescue result.

Show evidence (1 reference)

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT In Vitro

"An attenuated C6-Cer response was also observed in fibroblasts derived from L39del and F40S41del patients, which could be restored after knockdown of the mutant mRNA transcripts (Figure 2G) using siRNAs that specifically silence the expression of the respective mutant alleles, as shown previously (4)."

Primary feedback-rescue result.

Show evidence (2 references)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT 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."

Biochemical rescue in cultured patient fibroblasts.

PMID:35900868 SUPPORT DIRECT PRIMARY RESULT In Vitro

"For blue-native PAGE (BN-PAGE) analysis, control and patient fibroblasts were immortalized by transduction with retroviral vectors expressing the HPV-16 E7 gene and the catalytic component of human telomerase, as described previously (35)."

Important preparation difference for complex profiling.

Engineered WTC11 motor neuron-like cells IPSC_DERIVED_MODEL

Isogenic WTC11 iPSCs were differentiated using an inducible motor-neuron transcription-factor program. A monoallelic F40_S41del line and a separate F40_S41del/exon-2-deletion compound line both showed increased canonical lipid synthesis, with a larger effect in the compound line. It is incorrect to dismiss the entire study as compound-only or to describe these cells as patient-derived.

Cell source

Engineered WTC11 iPSCs with isogenic control

Pathograph links

Increased De Novo Sphingolipid Synthesis recapitulates fidelity: moderate Stable-isotope labeling detected increased canonical lipid synthesis in both engineered genotypes.

Limitations: Engineered WTC11 cells are not patient-derived. The monoallelic line approximates one patient genotype; the compound line does not represent reported dominant human genotypes. Short-term neuronal morphology and organelles appeared normal; these experiments establish lipid synthesis changes, not a rescued degeneration or long-term clinical phenotype.

Readouts

Labeled canonical sphingolipids

Direction: INCREASED

Interpretation: Stable-isotope labeling detected increased canonical lipid synthesis in both engineered genotypes.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs."

Primary caption describes both lines and their relative effects.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs."

Primary caption describes both lines and their relative effects.

Show evidence (1 reference)

PMID:34059824 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Using CRISPR, we created one iPSC line heterozygous for p.(F40_S41del), akin to patient 3 and another line compound heterozygous for p.(F40_S41del) and a deletion of exon 2 (the consequence of the c.58 G > T variant), which would be predicted to further exacerbate the biochemical phenotype."

Both monoallelic and compound engineered lines were studied.

Purified human SPT-ORMDL and engineered membrane assays OTHER

Human SPT-ORMDL complexes expressed in HEK293F cells were purified for cryo-EM and biochemical inhibition assays. Engineered ORMDL mutations tested the proposed ceramide-sensing site; related HeLa membrane assays tested feedback outside detergent-purified preparations. ALS-variant complexes retained ORMDL in this study while showing impaired ceramide response, providing a route distinct from universal dissociation.

Pathograph links

Reduced Ceramide Responsiveness partially recapitulates fidelity: moderate Selected SPTLC1 variant complexes had impaired ceramide sensing despite ORMDL retention.

Limitations: Recombinant proteins, detergent micelles and short-chain ceramide assays do not fully reproduce native neuronal membranes. ORMDL N13A/ΔN2 mutations are engineered probes rather than patient ALS27 alleles. The article labels one SPTLC1 construct Y23A, whereas patient reports identify Y23F. Binding-pocket occupancy and allosteric effects for every ALS allele remain unresolved.

Readouts

Ceramide-dependent inhibition of selected variant complexes

Direction: DECREASED

Interpretation: Selected SPTLC1 variant complexes had impaired ceramide sensing despite ORMDL retention.

Show evidence (1 reference)

PMID:37308477 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is..."

Primary recombinant-enzyme interpretation.

Show evidence (1 reference)

PMID:37308477 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is..."

Primary recombinant-enzyme interpretation.

Show evidence (1 reference)

PMID:37308477 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide."

Purified protein experiments, not a living-animal model.

HEK293FT substrate preference and serine-response assays CELL_LINE

Stable expression of A20S or C133W was tested with a CoA-release photometric assay and mitochondrial probe imaging. Serine supplementation restored the reported mitochondrial size/intensity phenotype. These findings motivated compassionate use but do not establish benefit for every ALS27 allele.

Pathograph links

Pathogenic SPTLC1 Variation perturbs fidelity: low Engineered variant expression was compared with WT for substrate-associated and mitochondrial-probe readouts.

Limitations: Overexpression in non-neuronal HEK293FT cells and a high-serine culture condition differ from physiological neuronal exposure. MitoTracker size/intensity are morphological/probe readouts, not direct neuron survival or a comprehensive mitochondrial flux assay. A later study did not reproduce the same A20S deoxylipid result under its conditions.

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The SPTLC1 enzyme complex activity was determined using a photometric assay measuring the release of free coenzyme A (coA) from the condensation reaction between palmitoyl-CoA and L-serine, L-alanine, and L-glycine."

Assay identifies the measured chemistry; no direct neuronal outcome.

Show evidence (1 reference)

PMID:34459874 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Supplementation of 100 mM L-serine in the culture media for 48 hours rescued the mitochondrial abnormalities in the p.Ala20Ser and p.Cys133Trp lines."

Measured probe phenotype in cultured cells.

Patient lymphoblastoid proteomic model CELL_LINE

EBV-immortalized lymphoblastoid cells from one c.58G>T case and two controls underwent proteomic and transcript profiling. SPTLC1 protein was lower while total transcript was not significantly changed; numerous candidate pathways were associated. The source uses the predicted A20S protein shorthand, but the allele primarily causes abnormal splicing.

Cell source

One affected donor and two control donors

Pathograph links

Pathogenic SPTLC1 Variation measures fidelity: low Proteomics characterized a patient-derived non-neural cell model, including lower SPTLC1 abundance.

Limitations: One patient and two control donors with culture replicates are not nine independent people. Immortalized lymphoblast expression changes do not establish motor-neuron mechanisms. Reduced protein with unchanged total RNA does not by itself prove a degradation pathway; the splice allele and predicted minor nonsense-mediated-decay product require separate interpretation.

Readouts

SPTLC1 protein abundance

Direction: DECREASED

Interpretation: Proteomics characterized a patient-derived non-neural cell model, including lower SPTLC1 abundance.

Show evidence (1 reference)

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Among the dysregulated proteins, SPTLC1 itself was identified with a significant decrease to 0.48-fold expression."

Protein abundance is not a direct SPT activity or stability assay.

Show evidence (1 reference)

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Among the dysregulated proteins, SPTLC1 itself was identified with a significant decrease to 0.48-fold expression."

Protein abundance is not a direct SPT activity or stability assay.

Show evidence (1 reference)

PMID:35627278 SUPPORT DIRECT PRIMARY RESULT In Vitro

"After the preparation of immortalized lymphoblastoid (see Section 2.1), samples were propagated (cell culture) to 2 × 3 samples for controls and 1 × 3 samples for the patient."

Replicates derive from three donors.

Patient c.58G>A lymphoblast splicing assay CELL_LINE

RT-PCR in patient-derived lymphoblasts showed exon-2 retention for c.58G>A, contrasting with the earlier c.58G>T splice result. This allele-specific negative splicing result does not exclude other functional abnormalities.

Pathograph links

Abnormal SPTLC1 Splicing fails to recapitulate fidelity: low The c.58G>A lymphoblast sample did not show the exon skipping reported for c.58G>T.

Limitations: Different nucleotide alleles were examined in non-neural cells; the negative result is specific to this splice event and sample.

Readouts

Exon-2 skipping in c.58G>A lymphoblasts

Direction: UNCHANGED

Interpretation: The c.58G>A lymphoblast sample did not show the exon skipping reported for c.58G>T.

Show evidence (2 references)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No band corresponding to exon 2 skipping (266 bp) was detected"

Measured negative splice result for c.58G>A.

+ 1 more reference

Show evidence (2 references)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No band corresponding to exon 2 skipping (266 bp) was detected"

Measured negative splice result for c.58G>A.

+ 1 more reference

Show evidence (1 reference)

PMID:39666121 SUPPORT DIRECT PRIMARY RESULT In Vitro

"No band corresponding to exon 2 skipping (266 bp) was detected"

Primary lymphoblast transcript assay.

🐁

Animal Models

1

Sptlc1 exon 2 deletion mouse GENETIC

The mouse exon deletion models the human c.58G>T splice consequence. Heterozygotes lacked overt motor deficits through 15 months, had tested CMAP measurements at 17 months and no overt neuronal-loss/gliosis findings at 18 months. Four-month tissue lipid concentrations were unchanged in the measured classes. Among 100 offspring only three homozygotes were found; those survivors failed to thrive and died at 6–8 weeks. Prenatal loss was inferred from under-representation, not demonstrated by staged embryonic observation. No direct SPT activity or synthesis-flux assay established whether the allele increases or decreases enzymatic function in vivo.

Species

Mouse

Genotype

Sptlc1ΔE2/+ and Sptlc1ΔE2/ΔE2; CRISPR 195-bp genomic deletion

Genes

SPTLC1 hgnc:11277

Publication

PMID:42392979

Pathograph links

Lower Motor Neuron Degeneration fails to recapitulate fidelity: low Overt tested motor, CMAP and late histological abnormalities were not reproduced in heterozygotes.

Limitations: The exon deletion models the splice consequence of human c.58G>T, but not every ALS27 allele. Steady-state lipid concentrations are not synthesis flux. Mutant-protein abundance, incorporation and SPT-ORMDL stoichiometry were unresolved; several partner antibodies were unusable. Homozygous under-representation and death do not prove enzymatic loss of function. Negative findings apply to the tested ages, assays and housing conditions.

Readouts

Tested heterozygous motor and neurodegenerative phenotype

Direction: UNCHANGED

Interpretation: Overt tested motor, CMAP and late histological abnormalities were not reproduced in heterozygotes.

Show evidence (1 reference)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

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

Primary negative heterozygous phenotype, distinct from homozygous viability.

Show evidence (1 reference)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

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

Primary negative heterozygous phenotype, distinct from homozygous viability.

Canonical Sphingolipid Accumulation fails to recapitulate fidelity: low The measured tissue lipid pools were not significantly different at four months; this does not refute increased synthesis in human cells.

Limitations: The exon deletion models the splice consequence of human c.58G>T, but not every ALS27 allele. Steady-state lipid concentrations are not synthesis flux. Mutant-protein abundance, incorporation and SPT-ORMDL stoichiometry were unresolved; several partner antibodies were unusable. Homozygous under-representation and death do not prove enzymatic loss of function. Negative findings apply to the tested ages, assays and housing conditions.

Readouts

Steady-state tissue sphingolipid concentrations

Direction: UNCHANGED

Interpretation: The measured tissue lipid pools were not significantly different at four months; this does not refute increased synthesis in human cells.

Show evidence (2 references)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Surprisingly, heterozygous Sptlc1ΔE2/+ mice did not exhibit any significant alterations in sphingolipid levels across multiple tissues, including the cortex, spinal cord, gastrocnemius muscle, and sciatic nerve (Fig 2A–C)."

Primary four-month tissue lipid concentration result.

+ 1 more reference

Show evidence (2 references)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Surprisingly, heterozygous Sptlc1ΔE2/+ mice did not exhibit any significant alterations in sphingolipid levels across multiple tissues, including the cortex, spinal cord, gastrocnemius muscle, and sciatic nerve (Fig 2A–C)."

Primary four-month tissue lipid concentration result.

+ 1 more reference

Show evidence (3 references)

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT 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."

Model construction.

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Among 100 offspring from 10 independent matings, only three homozygous mutant mice were identified, compared with 33 WT and 64 heterozygous littermates."

Observed genotype distribution, not a functional classification.

PMID:42392979 SUPPORT DIRECT PRIMARY RESULT Model Organism

"It remains unclear whether sufficient ΔE2 protein is available in vivo to incorporate into the SPT complex or interact with ORMDL proteins."

Unresolved molecular explanation for the mismatch.

{ }

Source YAML

click to show

name: Amyotrophic Lateral Sclerosis 27, Juvenile
creation_date: '2026-08-19T00:00:00Z'
category: Mendelian
description: Amyotrophic lateral sclerosis 27 (ALS27) is an SPTLC1-related, usually childhood-onset motor neuron disease with variable upper and lower motor neuron involvement, progressive weakness and atrophy, and possible bulbar and respiratory impairment. Heterozygous pathogenic variants can arise de novo, be transmitted within a family, or be inherited from a mosaic parent. Functional studies support excessive canonical sphingolipid synthesis through impaired regulation of serine palmitoyltransferase, with variant- and assay-dependent defects in ORMDL association and ceramide responsiveness. The steps linking lipid dysregulation to selective motor neuron degeneration remain unresolved. Some courses extend over decades, but severe childhood disability and early death also occur. Sensory sparing is common, with overlapping sensory-autonomic phenotypes in the wider SPTLC1 spectrum.
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 with de novo, familial and mosaic transmission
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: Heterozygous pathogenic SPTLC1 variants act dominantly. Six of seven families in the foundational study had de novo variants; another pedigree showed p.Leu39del transmission. A later p.Ala20Thr proband inherited the variant from an asymptomatic father with 17% mutant allele fraction in blood. Blood mosaicism does not determine neural or germline fractions or a safe threshold. Parental and family testing informs recurrence counseling; a non-mosaic heterozygous parent has a 50% transmission probability, with uncertain severity.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The variants occurred de novo in six of seven families.
explanation: Family ascertainment in the original study, not a population de novo rate.
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: mutant allele frequencies of 50% in the proband, 17% in the father, and 0% in the mother
explanation: Blood ddPCR in one family; no nervous-system or germline threshold was measured.
pathophysiology:
- name: Pathogenic SPTLC1 Variation
description: Dominant SPTLC1 variants associated with ALS include transmembrane-region missense and short deletions, as well as a splice-altering c.58G>T allele. Biochemical effects are allele-specific. S331 substitutions near the catalytic region can produce overlapping sensory-autonomic and motor disease and should not be treated as transmembrane-cluster alleles.
biological_scale: MOLECULAR
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
downstream:
- target: Abnormal SPTLC1 Splicing
description: The c.58G>T allele can cause exon 2 skipping in sampled non-neural material.
causal_link_type: DIRECT
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Rather than the predicted amino acid substitution p.(A20S), this variant predominantly resulted in complete skipping of exon 2, which is predicted to result in in-frame deletion of amino acids 20–56 comprising the entire first transmembrane domain of the SPTLC1 protein18.
explanation: Primary transcript analysis; not a demonstrated effect of every p.Ala20 substitution.
- target: Reduced ORMDL Association
description: Several tested variants reduce association with regulatory ORMDL proteins; this is not universal across variants and assay systems.
causal_link_type: DIRECT
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Cellular complex-association experiments; Y23F retained association under these conditions.
- target: Reduced Ceramide Responsiveness
description: Tested variant-containing complexes can respond less to ceramide even with ORMDL retained.
causal_link_type: DIRECT
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex.
explanation: Purified-complex assay separates sensing from physical association; the source labels one construct Y23A, unlike the clinical Y23F allele.
- target: Failure to Thrive and Growth Failure
description: Reported in selected SPTLC1-related cases; the causal intermediary and contribution of systemic illness remain unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Cognitive Impairment
description: Reported in selected SPTLC1-related cases; the causal intermediary and contribution of systemic illness remain unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Neuropsychological finding in one patient; Table 1 records executive dysfunction in patients 1 and 2.
quote_role: PRIMARY_RESULT
directness: INDIRECT
genes:
- preferred_term: SPTLC1
term:
id: hgnc:11277
label: SPTLC1
genetic_context:
gene:
preferred_term: SPTLC1
term:
id: hgnc:11277
label: SPTLC1
zygosity: HETEROZYGOUS
functional_impact_category: GAIN_OF_FUNCTION
description: Tested ALS-associated alleles can increase sphingolipid synthesis by escaping regulation; this does not assert identical functional effects for every variant or infer mouse enzymatic function from survival.
- name: Abnormal SPTLC1 Splicing
description: The c.58G>T allele predominantly skips exon 2 and deletes the transmembrane domain in sampled blood/cultured cells. In contrast, c.58G>A retained exon 2 in one patient lymphoblast line. Neural-tissue splicing was not measured, and the two nucleotide changes should not be assigned the same mechanism.
biological_scale: MOLECULAR
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Rather than the predicted amino acid substitution p.(A20S), this variant predominantly resulted in complete skipping of exon 2, which is predicted to result in in-frame deletion of amino acids 20–56 comprising the entire first transmembrane domain of the SPTLC1 protein18.
explanation: Primary non-neural transcript result.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: No band corresponding to exon 2 skipping (266 bp) was detected
explanation: Negative lymphoblast RT-PCR result for c.58G>A, not proof about every tissue.
downstream:
- target: Reduced ORMDL Association
description: The exon-deletion construct loses the transmembrane interface and showed impaired ORMDL association in engineered cells.
causal_link_type: DIRECT
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Includes the exon 2 deletion construct; human brain assembly was not assayed.
- name: Reduced ORMDL Association
description: Reduced association with ORMDL regulatory proteins was measured for several variants in engineered cells and for selected patient fibroblast preparations. Y23F retained association in the 2022 study; C133W also showed reduced association without the same canonical-lipid feedback defect. Purified ALS-variant complexes in the 2023 study retained ORMDL. Thus association loss is one possible route to dysregulation, not a necessary or sufficient explanation for every allele.
biological_scale: MOLECULAR
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Co-immunoprecipitation and native-complex experiments, with variant and system limits.
downstream:
- target: Reduced SPT Feedback Inhibition
description: Reduced regulatory association can contribute to impaired feedback, alongside alterations of sensing within assembled complexes.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
quote_role: PRIMARY_RESULT
directness: INDIRECT
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: The relation is qualified because binding and inhibition did not track uniformly across all variants.
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
- name: Reduced Ceramide Responsiveness
description: Recombinant human SPT-ORMDL complexes containing selected ALS-associated variants were less inhibited by short-chain ceramide despite ORMDL retention. Structural and engineered-mutant experiments support a ceramide-sensing site; the precise allosteric effect of each patient allele was not structurally resolved. Short-chain substrate assays and detergent-purified complexes do not reproduce all native membrane conditions.
biological_scale: MOLECULAR
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex.
explanation: Primary biochemical findings; the Y23A/Y23F discrepancy prevents equating all tested constructs with patient alleles.
downstream:
- target: Reduced SPT Feedback Inhibition
description: Reduced ceramide responsiveness weakens lipid-dependent suppression of SPT activity.
causal_link_type: DIRECT
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex.
explanation: Direct enzyme inhibition assays in recombinant complexes.
cellular_components:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
- name: Reduced SPT Feedback Inhibition
description: SPT normally undergoes homeostatic regulation by ORMDL proteins and ceramide. Several ALS-associated variants blunt that inhibition while retaining catalytic activity. The degree and route of escape depend on the allele and experimental system.
biological_scale: MOLECULAR
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary cellular activity and lipid synthesis experiments.
downstream:
- target: Increased De Novo Sphingolipid Synthesis
description: Reduced feedback permits excess flux through the pathway in tested cells.
causal_link_type: DIRECT
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Direct cellular perturbation supports increased synthesis.
biological_processes:
- preferred_term: negative regulation of sphingolipid biosynthetic process
term:
id: GO:0090155
label: negative regulation of sphingolipid biosynthetic process
modifier: DECREASED
cellular_components:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
- name: Increased De Novo Sphingolipid Synthesis
description: Isotope-labeling experiments show increased formation of canonical sphingolipids in selected patient fibroblasts and engineered cells, including monoallelic F40_S41del motor neuron-like cells. This is distinct from a steady-state concentration assay and is not established for every tissue or allele.
biological_scale: MOLECULAR
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs.
explanation: Stable-isotope labeling of engineered WTC11-derived cells; monoallelic and compound lines were both studied.
downstream:
- target: Canonical Sphingolipid Accumulation
description: Increased synthesis can elevate canonical sphingoid bases and downstream lipid pools; their levels also depend on turnover and interconversion.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: INDIRECT
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: Mechanistic interpretation supported by paired activity and lipid assays.
biological_processes:
- preferred_term: sphingolipid biosynthetic process
term:
id: GO:0030148
label: sphingolipid biosynthetic process
modifier: INCREASED
cellular_components:
- preferred_term: endoplasmic reticulum
term:
id: GO:0005783
label: endoplasmic reticulum
molecular_functions:
- preferred_term: serine C-palmitoyltransferase activity
term:
id: GO:0004758
label: serine C-palmitoyltransferase activity
modifier: INCREASED
- name: Canonical Sphingolipid Accumulation
description: Selected patient plasma and cell samples show elevated canonical sphingoid bases, dihydrosphingolipids or ceramides. Species and lipid classes differ across individuals and experiments; not all complex lipids rise. A later family study compared one proband with two parents using repeated measurements, not independent patient replicates. The lipid-to-neuronal-injury bridge remains inferred.
biological_scale: MOLECULAR
evidence:
- 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. # codespell:ignore particularily,signficantly
explanation: Identifies dihydrosphingolipids as the most raised species in patient plasma (quoted verbatim, including the source's typographical errors).
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The levels of complex ceramides, including lactosylceramide, hexosylceramide, and sphingomyelin, did not significantly differ across family members.
explanation: Negative lipid-class result limits any assertion of globally increased lipids.
downstream:
- target: Upper Motor Neuron Dysfunction
description: Abnormal sphingolipid homeostasis is proposed to contribute to selective motor-system injury; the intermediate injury pathway is unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
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: Clinical-genetic and cellular findings support a proposed disease mechanism; the selective injury intermediary remains unknown.
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: We do not yet understand why motor and sensory neurons show selective vulnerability to distinct biochemical changes in sphingolipid synthesis and homeostasis.
explanation: Authors explicitly state the unresolved cell-selectivity mechanism.
- target: Lower Motor Neuron Degeneration
description: Lipid dysregulation is proposed to contribute to lower motor neuron degeneration, without a demonstrated single toxic species or neuronal rescue endpoint.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
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: Clinical-genetic and cellular findings support a proposed disease mechanism; the selective injury intermediary remains unknown.
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: We do not yet understand why motor and sensory neurons show selective vulnerability to distinct biochemical changes in sphingolipid synthesis and homeostasis.
explanation: Clinical-genetic and cellular evidence motivates the link, but no direct patient-neuron death experiment proves it.
chemical_entities:
- preferred_term: sphingolipid
term:
id: CHEBI:26739
label: sphingolipid
modifier: INCREASED
- name: Upper Motor Neuron Dysfunction
description: Spasticity, hyperreflexia and pyramidal signs establish upper motor neuron involvement in many reported patients. These signs can be absent in individual cases, and upper motor neuron dysfunction need not precede weakness. Human clinical signs do not provide direct counts of cortical neuron loss.
biological_scale: CELLULAR
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Clinical upper and lower motor neuron findings in six selected probands.
downstream:
- target: Lower Limb Spasticity
description: Upper motor pathway dysfunction contributes to lower-limb spasticity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Clinical spastic motor presentation; no claim of a universal sequence.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Hyperreflexia
description: Upper motor pathway dysfunction can produce brisk reflexes.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: The longitudinal L39del case developed hyperreflexia as well as fasciculations.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Toe Walking (Tip-Toe Gait)
description: Spastic motor dysfunction can cause a tip-toe gait.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Observed spastic gait in the index probands.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- name: Lower Motor Neuron Degeneration
description: Clinical weakness, atrophy, fasciculations and multi-myotomal denervation support lower motor neuron disease. Sensory findings were normal in many transmembrane-variant cases, but mixed SPTLC1 phenotypes and intrafamilial variation prevent an absolute motor-only rule.
biological_scale: CELLULAR
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Clinical localization, rather than autopsy neuron counts.
downstream:
- target: Muscle Denervation
description: Lower motor neuron degeneration reduces innervation of skeletal muscle.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes
explanation: Neurogenic muscle biopsy changes support denervation.
- target: Tongue Fasciculations
description: Bulbar lower motor neuron involvement can produce tongue fasciculations.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Observed clinical lower motor neuron sign.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Fasciculations
description: Lower motor unit dysfunction can produce visible fasciculations.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Observed fasciculations in the longitudinal L39del case.
quote_role: PRIMARY_RESULT
directness: INDIRECT
cell_types:
- preferred_term: spinal cord motor neuron
term:
id: CL:0011001
label: spinal cord motor neuron
- name: Muscle Denervation
description: Denervated muscle shows neurogenic atrophy and acute or chronic electrodiagnostic changes. Limb, bulbar and respiratory muscle involvement produces variable disability; respiratory failure can develop while the patient is still ambulant. Mild inflammation in one muscle specimen does not establish a primary inflammatory myopathy or a causal inflammatory pathway.
biological_scale: TISSUE
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes
explanation: Four diagnostic biopsies showed neurogenic change.
downstream:
- target: Progressive Muscle Weakness
description: Loss of motor input impairs force generation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: followed by progressive lower motor neuron-mediated weakness without sensory symptoms or signs
explanation: Clinical lower motor neuron-mediated weakness.
- target: Skeletal Muscle Atrophy
description: Persistent denervation contributes to muscle wasting.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes
explanation: Neurogenic histology.
- target: Diffuse Denervation on Electromyography
description: Electrophysiology detects denervation across affected myotomes.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Review synthesis of electrodiagnostic findings.
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
- target: Dysarthria
description: Bulbar motor involvement can impair articulation.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Dysarthria documented in a primary case.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Dysphagia
description: Bulbar motor involvement can impair swallowing.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Dysphagia in a mixed S331Y case; an exon-2 splice case also required gastrostomy.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Loss of Ambulation
description: Progressive limb motor impairment can cause loss of walking.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: The disease was universally progressive and led to loss of independent ambulation and respiratory insufficiency of variable degrees.
explanation: Outcome in the selected original series; timing is variable.
- target: Respiratory Insufficiency
description: Respiratory muscle involvement can produce ventilatory insufficiency.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: Respiratory failure developed while she was still able to walk, requiring intermittent noninvasive positive pressure ventilation at the age of 18 years.
explanation: One patient demonstrates that respiratory and ambulatory milestones need not occur in a fixed order.
- target: Scoliosis
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: At the age of 13 years, scoliosis was noted during a medical checkup.
explanation: Individual c.58G>A case; source nonbreaking whitespace is normalized by validation.
- target: Joint Contractures
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed.
explanation: Direct clinical observations in one patient.
- target: Scapular Winging
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed.
explanation: Clinical scapular winging.
- target: Pes Cavus
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: '| Foot deformities | Pes cavus | NA | Pes cavus/varus | NA |'
explanation: Table 1; unexamined/unreported cells are not negative findings.
- target: Foot Drop
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: The patient walked abnormally owing to weakness and bilateral foot drop, and she had a positive Gower sign.
explanation: Direct gait examination.
- target: Gowers Sign
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Primary examination documents a positive Gower sign in a transmembrane-variant case.
quote_role: PRIMARY_RESULT
directness: INDIRECT
- target: Tongue Atrophy
description: Motor impairment and denervation can contribute to this clinical manifestation; the source documents the finding rather than experimentally isolating its intermediary.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: INDIRECT
snippet: A neurological examination revealed symmetrical weakness, dominant muscular atrophy of the distal upper extremities, and tongue atrophy.
explanation: Direct examination in one patient.
phenotypes:
- category: Neurologic
name: Lower Limb Spasticity
description: Lower-limb spasticity and toe walking were presenting findings in the six original unrelated probands, but some later patients presented predominantly with weakness or lacked classic pyramidal signs. No population frequency is inferred from selected cases.
phenotype_term:
preferred_term: Lower limb spasticity
term:
id: HP:0002061
label: Lower limb spasticity
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: Clinical presentation of six selected index probands; this does not establish a disease-wide frequency.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Neurologic
name: Progressive Muscle Weakness
description: Progressive weakness affects limb and sometimes bulbar or respiratory muscles. Proximal, distal and asymmetric presentations occur; lower motor neuron weakness does not invariably follow a prior spastic phase.
phenotype_term:
preferred_term: Progressive muscle weakness
term:
id: HP:0003323
label: Progressive muscle 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: Progressive lower motor neuron weakness in all six index-cohort probands.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Neurologic
name: Skeletal Muscle Atrophy
description: Generalized or regionally predominant neurogenic muscle wasting accompanies weakness. Proximal weakness can produce a Gowers sign or lordosis.
phenotype_term:
preferred_term: Skeletal muscle atrophy
term:
id: HP:0003202
label: Skeletal muscle atrophy
clinical_course: PROGRESSIVE
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Neurologic
name: Tongue Fasciculations
description: Tongue fasciculations are a reported bulbar lower motor neuron sign and can distinguish ALS from a classic pure spastic-paraplegia presentation; they are not documented in every case.
phenotype_term:
preferred_term: Tongue fasciculations
term:
id: HP:0001308
label: Tongue fasciculations
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 source describes progressive lower motor neuron involvement including tongue fasciculations; the wording does not provide a separate tongue-fasciculation numerator.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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: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: The longitudinal L39del patient developed hyperreflexia; this avoids relying solely on the mixed S331Y case.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Growth
name: Failure to Thrive and Growth Failure
description: Poor weight gain or low body mass was prominent in a growth-ascertained juvenile case series, including a mixed S331Y phenotype. Other patients had normal weight. Selected enrollment and incomplete assessment preclude a population frequency.
phenotype_term:
preferred_term: Failure to thrive
term:
id: HP:0001508
label: Failure to thrive
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Respiratory
name: Respiratory Insufficiency
description: Respiratory muscle involvement can require noninvasive or invasive ventilation. It may arise during childhood and while the patient remains ambulant; it is not invariably a late milestone.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
clinical_course: PROGRESSIVE
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 involvement in the original selected series, with variable severity and timing.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Neurologic
name: Dysphagia
description: Swallowing impairment can lead to gastrostomy, including in a patient with the c.58G>T splice-altering allele. The S331Y mixed sensory-motor case also had dysphagia. Other patients lacked swallowing problems at examination.
phenotype_term:
preferred_term: Dysphagia
term:
id: HP:0002015
label: Dysphagia
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Because of the progressive bulbar dysfunction, nutrition via percutaneous endoscopic gastrostomy (PEG) tube was needed at the same time.
explanation: Bulbar feeding impairment in the exon-2 splice case, overlapping the foundational cohort.
- category: Neurologic
name: Cognitive Impairment
description: Mild executive or attentional dysfunction was reported in two patients in the 2021 clinical series. This contradicts a later review statement that none had been reported. A low IQ score in the 2024 Japanese case was explicitly considered unreliable because of fatigue and discordant daily/academic functioning, and does not establish intellectual disability or cognitive decline. Hypoventilation was a possible explanation for later cognitive symptoms in another patient.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
severity: MILD
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: Neuropsychological finding in one patient; Table 1 records executive dysfunction in patients 1 and 2.
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Therefore, we are reluctant to conclude that this patient had cognitive decline.
explanation: The later low test score was uncertain and is not counted as a confirmed additional case.
- category: Neurologic
name: Toe Walking (Tip-Toe Gait)
description: A tip-toe gait was a presenting sign in the original spastic childhood cases. Other patients presented with proximal weakness or foot drop instead.
phenotype_term:
preferred_term: Toe walking (tip-toe gait)
term:
id: HP:0030051
label: Tip-toe gait
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- category: Neurologic
name: Diffuse Denervation on Electromyography
description: Electrodiagnostic testing can show chronic and active denervation across multiple myotomes, often with normal sensory conduction. This supports motor-system localization, but does not alone distinguish every complicated HSP or overlapping SPTLC1 phenotype.
phenotype_term:
preferred_term: Diffuse acute and chronic denervation on EMG
term:
id: HP:0003444
label: 'EMG: chronic denervation signs'
diagnostic: true
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- category: Neurologic
name: Loss of Ambulation
description: Progressive motor impairment can lead to loss of walking. Timing ranges from childhood in severe cases to the fifth decade in a long-followed L39del patient; wheelchair dependence is not restricted to adulthood.
phenotype_term:
preferred_term: Loss of ambulation
term:
id: HP:0002505
label: Loss of ambulation
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: Reported progressive ambulatory impairment in the selected original series.
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:36801857
reference_title: Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: He could not walk and became wheelchair-dependent five years after onset.
explanation: New case with onset at seven years and wheelchair dependence approximately age 12.
- name: Scoliosis
category: Musculoskeletal
description: Spinal curvature occurred in several individual cases and sometimes required surgery. No systematic frequency estimate is available.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: At the age of 13 years, scoliosis was noted during a medical checkup.
explanation: Individual c.58G>A case; source nonbreaking whitespace is normalized by validation.
- name: Joint Contractures
category: Musculoskeletal
description: Knee and ankle contractures were documented in a severe exon-2 splice case; the report does not specify every joint position.
phenotype_term:
preferred_term: Joint Contractures
term:
id: HP:0034392
label: Joint contracture
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed.
explanation: Direct clinical observations in one patient.
- name: Scapular Winging
category: Musculoskeletal
description: Scapulae alatae accompanied proximal weakness in the exon-2 splice case, which initially resembled a limb-girdle disorder.
phenotype_term:
preferred_term: Scapular Winging
term:
id: HP:0003691
label: Scapular winging
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: A generalized muscular atrophy and scapulae alatae, scoliosis, and contractures of both knees and ankles were diagnosed.
explanation: Clinical scapular winging.
- name: Pes Cavus
category: Musculoskeletal
description: High-arched feet were reported in the selected four-patient series, including one transmembrane and one mixed S331Y case.
phenotype_term:
preferred_term: Pes Cavus
term:
id: HP:0001761
label: Pes cavus
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: '| Foot deformities | Pes cavus | NA | Pes cavus/varus | NA |'
explanation: Table 1; unexamined/unreported cells are not negative findings.
- name: Foot Drop
category: Neurologic
description: Bilateral foot drop contributed to abnormal gait in the S331Y mixed sensory-motor case; this observation is not a frequency estimate for pure transmembrane-variant ALS27.
phenotype_term:
preferred_term: Foot Drop
term:
id: HP:0009027
label: Foot dorsiflexor weakness
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The patient walked abnormally owing to weakness and bilateral foot drop, and she had a positive Gower sign.
explanation: Direct gait examination.
- name: Gowers Sign
category: Neurologic
description: A Gowers sign reflects proximal weakness in reported cases and can initially suggest a muscle disorder.
phenotype_term:
preferred_term: Gowers Sign
term:
id: HP:0003391
label: Gowers sign
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: Primary examination documents a positive Gower sign in a transmembrane-variant case.
quote_role: PRIMARY_RESULT
directness: DIRECT
- name: Tongue Atrophy
category: Neurologic
description: Tongue wasting can accompany bulbar lower motor neuron disease, with or without documented fasciculations.
phenotype_term:
preferred_term: Tongue Atrophy
term:
id: HP:0012473
label: Tongue atrophy
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: A neurological examination revealed symmetrical weakness, dominant muscular atrophy of the distal upper extremities, and tongue atrophy.
explanation: Direct examination in one patient.
biochemical:
- name: Plasma sphingolipid abnormalities
notes: Selected patients have increased sphinganine, sphingosine, dihydrosphingolipids or ceramide species. Patterns vary across alleles and assays; normal or unchanged classes also occur. The Japanese family analysis compared one proband with two parents and used three to four repeat measurements per sample, not a multi-patient replication cohort. No validated diagnostic cutoff or universal plasma signature is established.
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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. # codespell:ignore particularily,signficantly
explanation: Identifies dihydrosphingolipids as the most raised species in patient plasma (quoted verbatim, including the source's typographical errors).
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Each sample underwent three to four independent measurements.
explanation: Repeated measurements within three people; no independent patient cohort is implied.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The levels of complex ceramides, including lactosylceramide, hexosylceramide, and sphingomyelin, did not significantly differ across family members.
explanation: Limits the claim to affected lipid classes.
- name: Variable 1-deoxysphingolipid profile
notes: 'Normal deoxysphingolipids were reported in the foundational ALS cases, contrasting with many HSAN1 alleles. This is not an absolute exon-2 rule: S331 mixed phenotypes and a L39del carrier with low serine had elevated deoxy species. Low-serine culture can increase deoxy lipids in both wild-type and mutant cells. Diet-induced conversion of human ALS into HSAN1 was not demonstrated.'
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Culture perturbation, not a tested patient diet.
progression:
- phase: Variable onset and localization
notes: A 2023 literature-based comparison pooled 17 SPTLC1 cases, only one newly described, against 43 FUS cases. Mean onset in the selected SPTLC1 set was 7.9 years (SD 4.6), and all were categorized as spinal onset. The pooled set included overlapping publications and mixed sensory-motor phenotypes, so these are not population estimates or an independent replication cohort. A separate long-followed L39del patient first had documented weakness in early adulthood.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: '| AAO (years, mean ± SD) | 7.9 ± 4.6 | 18.1 ± 3.9 | 8.64 † | <0.01 |'
explanation: Table 2 of the pooled published cases.
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- phase: Variable progression
notes: The pooled paper reports a Kaplan-Meier mean disease-duration estimate of 512.0 months with 95% CI 416.7–607.3, not a median or interquartile range. Extensive censoring, small numbers and case selection prevent treating this estimate as individual life expectancy. One newly reported boy became wheelchair-dependent five years after onset; another L39del case lost independent walking at age 45. Respiratory failure can occur before loss of ambulation.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: '| Disease duration (months, mean [95% CI]) | 512.0 (416.7–607.3) | 33.4 (21.6–45.1) | 26.32 ‡ | <0.01 |'
explanation: Table 2 defines the statistic and uncertainty; it is not median survival.
- reference: PMID:36801857
reference_title: Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: He could not walk and became wheelchair-dependent five years after onset.
explanation: Severe childhood course.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: She lost independent ambulation at age 45 years.
explanation: Long course in one patient.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Respiratory failure developed while she was still able to walk, requiring intermittent noninvasive positive pressure ventilation at the age of 18 years.
explanation: Variable milestone order.
differential_diagnoses:
- name: Hereditary Spastic Paraplegia
description: Classic pure hereditary spastic paraplegia can resemble the initial spastic gait. Diffuse bulbar and limb lower motor neuron findings support ALS; complicated HSP can overlap, so lower motor neuron involvement is not an absolute exclusion of the whole HSP category.
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.
quote_role: BACKGROUND
directness: DIRECT
- name: Hereditary Sensory and Autonomic Neuropathy Type 1 (SPTLC1-related)
description: SPTLC1-related HSAN1 often features sensory-autonomic neuropathy and increased deoxysphingolipid production from altered substrate usage. Mixed alleles and intrafamilial variation prevent a strict biochemical or neuronal dichotomy.
disease_term:
preferred_term: hereditary sensory and autonomic neuropathy
term:
id: MONDO:0015364
label: hereditary sensory and autonomic neuropathy
distinguishing_features:
- Prominent sensory-autonomic impairment and deoxy lipid elevation support HSAN1, but overlapping S331 and L39del presentations require integrated clinical and molecular interpretation.
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- name: SPTLC2-Related Juvenile Amyotrophic Lateral Sclerosis
description: SPTLC2 variants can also impair SPT regulation and cause motor neuron disease. Molecular testing distinguishes the gene. Cognitive findings have been reported in both SPTLC1 and SPTLC2 series and are not a categorical discriminator.
distinguishing_features:
- Causal gene and variant interpretation; clinical and biochemical overlap is substantial.
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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- 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.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- name: FUS-Related Juvenile Amyotrophic Lateral Sclerosis
description: FUS is an important alternative juvenile ALS gene. A small literature-based comparison found more bulbar onset and shorter estimated duration in FUS cases, but selected group differences do not predict every individual course.
distinguishing_features:
- Molecular testing establishes the gene; age, onset site and speed of progression provide clues rather than exclusion rules.
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.
quote_role: BACKGROUND
directness: DIRECT
genetic:
- name: SPTLC1
gene_term:
preferred_term: SPTLC1
term:
id: hgnc:11277
label: SPTLC1
relationship_type: CAUSATIVE
notes: SPTLC1 encodes an SPT subunit. Heterozygous transmembrane-region variants include Y23F, L38R, L39del and F40_S41del. c.58G>T predominantly alters splicing, whereas c.58G>A retained exon 2 in one non-neural assay despite sharing codon 20. Sequence, transcript and protein-level interpretations must be distinguished. The p.Leu38Arg case-report title has discordant nucleotide/protein notation, so only the protein designation is used here. S331 substitutions can produce mixed sensory-autonomic and motor disease. Neither variant position alone nor a single plasma lipid result determines clinical classification.
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Rather than the predicted amino acid substitution p.(A20S), this variant predominantly resulted in complete skipping of exon 2, which is predicted to result in in-frame deletion of amino acids 20–56 comprising the entire first transmembrane domain of the SPTLC1 protein18.
explanation: Splice consequence of c.58G>T.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: No band corresponding to exon 2 skipping (266 bp) was detected
explanation: Different c.58G>A transcript result.
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
treatments:
- name: Multidisciplinary assessment and surveillance
description: Coordinate neurology, respiratory, nutrition, rehabilitation, communication, psychological and palliative services. Reassess swallowing, weight, strength, mobility, communication, respiratory function and care preferences as disease changes. The general guideline suggests coordinated review usually every three to six months, adjusted to progression and needs. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.
treatment_term:
preferred_term: Multidisciplinary assessment and surveillance
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Provide coordinated care for people with ALS using a clinic‐based, specialist ALS MDT approach.
explanation: Strong general ALS recommendation; care organization is not a mutation-specific trial.
- name: Noninvasive ventilatory support
description: Offer noninvasive ventilation when symptoms, signs or respiratory testing support insufficiency; do not require a fixed FVC threshold or loss of ambulation first. Tolerance, interface, secretion management and patient preferences matter. Invasive ventilation requires advance shared decisions rather than an inevitable escalation. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.
treatment_term:
preferred_term: Noninvasive ventilatory support
term:
id: NCIT:C70909
label: Mechanical Ventilation
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency.
explanation: Strong general ALS recommendation.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Respiratory failure developed while she was still able to walk, requiring intermittent noninvasive positive pressure ventilation at the age of 18 years.
explanation: Documented ALS27 support, without a comparator efficacy estimate.
therapeutic_modality: DEVICE
target_mechanisms:
- target: Respiratory Insufficiency
treatment_effect: BYPASSES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: NIV should be offered to all patients with ALS with either symptoms, signs, or laboratory investigations supportive of respiratory insufficiency.
explanation: Strong general ALS recommendation.
- name: Cough augmentation and secretion clearance
description: Assess cough effectiveness. Manual assistance or breath stacking can be followed by mechanical cough assistance when ineffective or judged necessary; suction is an adjunct. These measures support airway clearance rather than reverse motor neuron loss. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.
treatment_term:
preferred_term: Cough augmentation and secretion clearance
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Offer cough augmentation techniques, such as manual assisted cough, to people with ALS who cannot cough effectively.
explanation: Strong recommendation, with technique choice individualized.
therapeutic_modality: DEVICE
- name: Nutrition and swallowing support
description: Assess weight change, hydration, swallowing, feeding effort and nutritional needs. Dietitian and swallowing-team input can guide food texture, liquid thickness, feeding aids and energy intake. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.
treatment_term:
preferred_term: Nutrition and swallowing support
term:
id: NCIT:C65017
label: Nutritional Therapy
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration.
explanation: GeneReviews general ALS care.
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Identify causes for weight loss and reduced food and fluid intake (e.g., swallowing problems, respiratory insufficiency, depression, loss of appetite, muscle atrophy, upper limb weakness).
explanation: Strong recommendation to investigate causes rather than assume all weight loss is one mechanism.
target_mechanisms:
- target: Failure to Thrive and Growth Failure
treatment_effect: MODULATES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration.
explanation: GeneReviews general ALS care.
- name: Gastrostomy when indicated
description: Discuss gastrostomy early and revisit according to swallowing, weight, respiratory status, feeding burden and preferences. If respiratory insufficiency is present, establish NIV before and during the procedure as appropriate. Gastrostomy is not mandatory for every patient. A severe ALS27 splice-variant case required PEG because of bulbar dysfunction.
treatment_term:
preferred_term: Gastrostomy when indicated
term:
id: NCIT:C15433
label: Nutritional Support
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking.
explanation: Strong recommendation for discussion and individualized timing.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Because of the progressive bulbar dysfunction, nutrition via percutaneous endoscopic gastrostomy (PEG) tube was needed at the same time.
explanation: Documented use in ALS27, not a controlled outcome.
therapeutic_modality: SURGERY
target_mechanisms:
- target: Dysphagia
treatment_effect: BYPASSES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Discuss gastrostomy at an early stage, and at regular intervals as ALS progresses, taking into account the person's preferences and issues, such as ability to swallow, weight loss, respiratory function, effort of feeding and drinking, and risk of choking.
explanation: Strong recommendation for discussion and individualized timing.
- name: Physical and occupational therapy with mobility aids
description: Individualize exercise, stretching, positioning and assistive devices to preserve joint movement, reduce stiffness and support daily activities. Consider fatigue and weakness when setting intensity. Walkers, wheelchairs, orthoses and transfer aids compensate for disability; prevention of contractures is an aim rather than established ALS27-specific efficacy.
treatment_term:
preferred_term: Physical and occupational therapy with mobility aids
term:
id: NCIT:C15302
label: Physical Therapy
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Maintain joint range of movementPrevent contracturesReduce stiffness and discomfortOptimise function and quality of life.
explanation: Goals of the guideline exercise recommendation; the cache joins adjacent list items.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Assistive devices, such as walkers or wheelchairs, can aid mobility; and others, such as bathroom installments, hospital bed, and Hoyer lift, can aid in activities of daily living at home.
explanation: GeneReviews supportive care.
target_mechanisms:
- target: Joint Contractures
treatment_effect: MODULATES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Maintain joint range of movementPrevent contracturesReduce stiffness and discomfortOptimise function and quality of life.
explanation: Goals of the guideline exercise recommendation; the cache joins adjacent list items.
- name: Symptomatic spasticity management
description: Consider physical measures and, when appropriate, baclofen, tizanidine, gabapentin or other specialist-selected agents. Monitor sedation and increased weakness; focal botulinum toxin can be considered if other measures fail or are unsuitable. These are conditional general ALS recommendations, not evidence that every ALS27 patient has treatable spasticity.
treatment_term:
preferred_term: Symptomatic spasticity management
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone.
explanation: Conditional general ALS recommendation.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps; however, weakness and lethargy are common side effects.
explanation: GeneReviews balances symptom relief against adverse effects.
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Lower Limb Spasticity
treatment_effect: MODULATES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Consider cannabinoids, baclofen, tizanidine, or gabapentin to treat muscle stiffness, spasticity, or increased tone.
explanation: Conditional general ALS recommendation.
- name: Speech and augmentative communication support
description: Assess communication early and provide appropriate low- or high-technology aids, including access methods that adapt to progressive motor impairment. Speech-language and occupational teams should review needs and train the patient and carers. General ALS guidance is extrapolated to ALS27 with age-appropriate specialist judgment; it is not evidence of genotype-specific pediatric efficacy.
treatment_term:
preferred_term: Speech and augmentative communication support
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life.
explanation: Strong general ALS communication recommendation.
therapeutic_modality: DEVICE
target_mechanisms:
- target: Dysarthria
treatment_effect: BYPASSES
description: Symptom-directed care; no correction of the underlying SPTLC1 variant is claimed.
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Provide AAC equipment that meets the needs of the person without delay to maximise participation in activities of daily living and maintain quality of life.
explanation: Strong general ALS communication recommendation.
- name: Riluzole within specialist ALS care
description: The 2024 EAN guideline recommends riluzole for people with ALS. Riluzole use is reported in an ALS27 patient, but that uncontrolled case cannot establish efficacy, and pediatric use requires individualized specialist assessment. This is general ALS treatment extrapolation, not a targeted correction of SPT feedback.
treatment_term:
preferred_term: Riluzole within specialist ALS care
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Riluzole
term:
id: CHEBI:8863
label: Riluzole
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Offer lifelong riluzole to all people with ALS at diagnosis.
explanation: General ALS recommendation; no ALS27 subgroup result.
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: She was diagnosed with juvenile ALS, and she has been taking riluzole since age 15 years.
explanation: Exposure in one patient, without an untreated comparator.
therapeutic_modality: SMALL_MOLECULE
- name: Psychological, caregiver and palliative support
description: Address emotional distress, care burden, symptom relief and changing priorities throughout the course. Discuss ventilation, feeding and advance care preferences in an age-appropriate manner with the patient and family. Cognitive or communication limitations require adapted support rather than an assumption of inability to participate.
treatment_term:
preferred_term: Psychological, caregiver and palliative support
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: During MDT assessments and other appointments, discuss the psychological and emotional impact of ALS with the person and ask whether they have any psychological or support care needs.
explanation: General ALS recommendation; psychological care is not restricted to end-stage disease.
- reference: PMID:38470068
reference_title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: Provide support and advice on advance care planning for end of life.
explanation: General ALS recommendation, individualized for juvenile disease.
- name: Genetic counseling and family evaluation
description: Explain dominant inheritance, de novo occurrence, possible parental mosaicism and uncertain variable expression. Parental testing and counseling support recurrence-risk and reproductive decisions. Testing a symptomatic child is distinct from predictive testing for a strictly adult-onset condition. The unaffected father with 17% blood mosaicism does not establish a safe tissue threshold.
treatment_term:
preferred_term: Genetic counseling and family evaluation
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: In a family with an established diagnosis of ALS, it is appropriate to consider testing of symptomatic individuals regardless of age.
explanation: GeneReviews counseling guidance; the adult-onset predictive-testing discussion must not be indiscriminately applied to childhood ALS27.
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- name: 'Allele-selective SPTLC1 siRNA: preclinical investigation'
description: Variant-selective siRNAs reduced abnormal lipid synthesis in fibroblasts carrying L39del or F40_S41del. This is biochemical rescue in cultured non-neuronal cells, not demonstrated rescue of neuron survival or patient disability. Each allele needs its own validated sequence; delivery, specificity and safe long-term lowering in the nervous system remain unresolved.
treatment_term:
preferred_term: 'Allele-selective SPTLC1 siRNA: preclinical investigation'
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary fibroblast experiments; the study does not establish clinical safety or efficacy.
therapeutic_modality: SIRNA
target_mechanisms:
- target: Increased De Novo Sphingolipid Synthesis
treatment_effect: INHIBITS
description: Allele-selective lowering reduced excess lipid synthesis in tested patient fibroblast cultures.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary fibroblast experiments; the study does not establish clinical safety or efficacy.
- name: 'LTX-002: investigational SPTLC1 antisense therapy'
description: An ongoing placebo-controlled phase 1/2 study evaluates intrathecal LTX-002 in adults with ALS. It is not restricted to SPTLC1-variant carriers and excludes children. Safety, pharmacokinetics and exploratory biomarkers are being studied; no results are posted and no juvenile ALS27 benefit is established. Registry-directed SPTLC1 lowering should not be conflated with the allele-selective siRNA fibroblast experiments.
treatment_term:
preferred_term: 'LTX-002: investigational SPTLC1 antisense therapy'
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07660614
reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07660614
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested.
explanation: Registry intervention rationale, not an outcome or proof of achieved target engagement.
therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
target_mechanisms:
- target: Increased De Novo Sphingolipid Synthesis
treatment_effect: INHIBITS
description: Intended reduction of SPTLC1-dependent synthesis; clinical target engagement and therapeutic benefit remain under investigation.
evidence:
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07660614
reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07660614
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested.
explanation: Registry intervention rationale, not an outcome or proof of achieved target engagement.
- name: 'Partial SPT inhibition: investigational concept'
description: Partial pharmacological suppression of SPT is proposed to reduce excess synthesis, but the available sources do not establish clinical efficacy in ALS27. Complete inhibition and nonspecific inhibitors can be toxic; changing basal output does not necessarily restore feedback regulation. This concept is distinct from the adult LTX-002 antisense study.
treatment_term:
preferred_term: 'Partial SPT inhibition: investigational concept'
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:38788085
reference_title: Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
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: Review proposal, not a tested ALS27 clinical intervention.
therapeutic_modality: SMALL_MOLECULE
target_mechanisms:
- target: Increased De Novo Sphingolipid Synthesis
treatment_effect: INHIBITS
description: Proposed inhibition of excess synthesis; the therapeutic window and patient benefit remain unproven.
evidence:
- reference: PMID:38788085
reference_title: Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
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: Review proposal, not a tested ALS27 clinical intervention.
- name: 'L-serine supplementation: unresolved clinical and biochemical effects'
description: One compassionate-use patient gained weight without demonstrated neurological improvement. A HEK293FT study reported substrate-preference and mitochondrial-probe changes improved by serine, whereas isotope-labeled motor neuron-like cells showed increased canonical lipid production with serine availability. The substrate-preference result was not reproduced under another study's conditions. These are different assays and alleles; neither clinical benefit nor clinical worsening is established. Supplementation is not an established ALS27 treatment, and a theoretical risk of increasing lipid production warrants specialist caution.
treatment_term:
preferred_term: 'L-serine supplementation: unresolved clinical and biochemical effects'
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: L-serine
term:
id: CHEBI:17115
label: L-serine
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We did not observe evidence of neurological improvement, although prolonged therapy would be required to detect such an effect.
explanation: Uncontrolled compassionate use; no proven 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Her body weight increased during this off-label treatment, which was the first time she had gained weight in several years.
explanation: Weight change in one patient, not proof of neuronal benefit.
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Supplementation of 100 mM L-serine in the culture media for 48 hours rescued the mitochondrial abnormalities in the p.Ala20Ser and p.Cys133Trp lines.
explanation: MitoTracker size/intensity endpoints in HEK293 cells; not a neuron-survival rescue.
- reference: PMID:38788085
reference_title: Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
supports: SUPPORT
evidence_source: OTHER
quote_role: REVIEW_SYNTHESIS
directness: INDIRECT
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: Review prediction; patient harm has not been demonstrated here.
therapeutic_modality: SMALL_MOLECULE
animal_models:
- name: Sptlc1 exon 2 deletion mouse
species: Mouse
genotype: Sptlc1ΔE2/+ and Sptlc1ΔE2/ΔE2; CRISPR 195-bp genomic deletion
category: GENETIC
publication: PMID:42392979
description: The mouse exon deletion models the human c.58G>T splice consequence. Heterozygotes lacked overt motor deficits through 15 months, had tested CMAP measurements at 17 months and no overt neuronal-loss/gliosis findings at 18 months. Four-month tissue lipid concentrations were unchanged in the measured classes. Among 100 offspring only three homozygotes were found; those survivors failed to thrive and died at 6–8 weeks. Prenatal loss was inferred from under-representation, not demonstrated by staged embryonic observation. No direct SPT activity or synthesis-flux assay established whether the allele increases or decreases enzymatic function in vivo.
genes:
- preferred_term: SPTLC1
term:
id: hgnc:11277
label: SPTLC1
modeled_mechanisms:
- target: Lower Motor Neuron Degeneration
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: Overt tested motor, CMAP and late histological abnormalities were not reproduced in heterozygotes.
limitations: The exon deletion models the splice consequence of human c.58G>T, but not every ALS27 allele. Steady-state lipid concentrations are not synthesis flux. Mutant-protein abundance, incorporation and SPT-ORMDL stoichiometry were unresolved; several partner antibodies were unusable. Homozygous under-representation and death do not prove enzymatic loss of function. Negative findings apply to the tested ages, assays and housing conditions.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely.
explanation: Primary negative heterozygous phenotype, distinct from homozygous viability.
readouts:
- name: Tested heterozygous motor and neurodegenerative phenotype
target: Lower Motor Neuron Degeneration
direction: UNCHANGED
interpretation: Overt tested motor, CMAP and late histological abnormalities were not reproduced in heterozygotes.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Although heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely.
explanation: Primary negative heterozygous phenotype, distinct from homozygous viability.
- target: Canonical Sphingolipid Accumulation
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: The measured tissue lipid pools were not significantly different at four months; this does not refute increased synthesis in human cells.
limitations: The exon deletion models the splice consequence of human c.58G>T, but not every ALS27 allele. Steady-state lipid concentrations are not synthesis flux. Mutant-protein abundance, incorporation and SPT-ORMDL stoichiometry were unresolved; several partner antibodies were unusable. Homozygous under-representation and death do not prove enzymatic loss of function. Negative findings apply to the tested ages, assays and housing conditions.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Surprisingly, heterozygous Sptlc1ΔE2/+ mice did not exhibit any significant alterations in sphingolipid levels across multiple tissues, including the cortex, spinal cord, gastrocnemius muscle, and sciatic nerve (Fig 2A–C).
explanation: Primary four-month tissue lipid concentration result.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our in vivo data reflect steady-state metabolic outcomes rather than direct enzymatic activity.
explanation: Authors explicitly distinguish lipid pools from flux.
readouts:
- name: Steady-state tissue sphingolipid concentrations
target: Canonical Sphingolipid Accumulation
direction: UNCHANGED
interpretation: The measured tissue lipid pools were not significantly different at four months; this does not refute increased synthesis in human cells.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Surprisingly, heterozygous Sptlc1ΔE2/+ mice did not exhibit any significant alterations in sphingolipid levels across multiple tissues, including the cortex, spinal cord, gastrocnemius muscle, and sciatic nerve (Fig 2A–C).
explanation: Primary four-month tissue lipid concentration result.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our in vivo data reflect steady-state metabolic outcomes rather than direct enzymatic activity.
explanation: Authors explicitly distinguish lipid pools from flux.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Model construction.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Among 100 offspring from 10 independent matings, only three homozygous mutant mice were identified, compared with 33 WT and 64 heterozygous littermates.
explanation: Observed genotype distribution, not a functional classification.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: It remains unclear whether sufficient ΔE2 protein is available in vivo to incorporate into the SPT complex or interact with ORMDL proteins.
explanation: Unresolved molecular explanation for the mismatch.
experimental_models:
- name: Engineered HEK293 SPTLC1 variant systems
experimental_model_type: CELL_LINE
description: 'HEK293-derived systems tested WT and variant SPTLC1 with SPT subunits/ORMDL, including SPTLC1-knockout reconstitution. Co-immunoprecipitation, native complexes, ceramide challenges and isotope labeling distinguish protein association, feedback and synthesis. COS-7 imaging assessed localization: most tested variants remained ER-associated, whereas exon-deleted SPTLC1 was mainly cytosolic with residual membrane-associated catalytic complex.'
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary cellular complex studies.
modeled_mechanisms:
- target: Reduced ORMDL Association
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Several variants showed lower ORMDL association, with variant-specific exceptions.
limitations: Transformed non-neuronal cells, engineered expression and knockout/reconstitution can exaggerate effects relative to heterozygous tissues. Co-immunoprecipitation measures association, not a binding constant or causal neuron loss. Y23F and HSAN1 C133W show that association and feedback do not map one-to-one.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Direct association readouts.
readouts:
- name: ORMDL association in selected variant complexes
target: Reduced ORMDL Association
direction: DECREASED
interpretation: Several variants showed lower ORMDL association, with variant-specific exceptions.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Direct association readouts.
- target: Increased De Novo Sphingolipid Synthesis
relationship: RECAPITULATES
fidelity: MODERATE
description: Isotope-labeling demonstrated increased synthesis in tested variant-expressing cells.
limitations: Transformed non-neuronal cells, engineered expression and knockout/reconstitution can exaggerate effects relative to heterozygous tissues. Co-immunoprecipitation measures association, not a binding constant or causal neuron loss. Y23F and HSAN1 C133W show that association and feedback do not map one-to-one.
evidence:
- reference: PMID:37348646
reference_title: SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells.
explanation: The L38R source is available as an abstract; detailed methods are not inferred.
readouts:
- name: Newly synthesized sphingolipid abundance
target: Increased De Novo Sphingolipid Synthesis
direction: INCREASED
interpretation: Isotope-labeling demonstrated increased synthesis in tested variant-expressing cells.
evidence:
- reference: PMID:37348646
reference_title: SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells.
explanation: The L38R source is available as an abstract; detailed methods are not inferred.
- name: Patient fibroblasts and allele-selective siRNA
experimental_model_type: PRIMARY_CELL_CULTURE
description: Fibroblasts with L39del or F40_S41del showed altered lipid synthesis and ceramide feedback. Allele-selective siRNA lowered excess synthesis and restored ceramide responsiveness under the tested culture conditions. Primary cultures supplied several lipid assays; native-complex profiling additionally used immortalized derivatives.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Biochemical rescue in cultured patient fibroblasts.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: For blue-native PAGE (BN-PAGE) analysis, control and patient fibroblasts were immortalized by transduction with retroviral vectors expressing the HPV-16 E7 gene and the catalytic component of human telomerase, as described previously (35).
explanation: Important preparation difference for complex profiling.
modeled_mechanisms:
- target: Increased De Novo Sphingolipid Synthesis
relationship: RESCUES
fidelity: MODERATE
description: Allele-selective siRNA reduced abnormal lipid synthesis in tested patient cultures.
limitations: Non-neuronal patient skin fibroblasts reproduce biochemical defects but do not test selective motor neuron death or clinical efficacy. The native-gel complex experiment used immortalized fibroblast derivatives; it must not be described as an entirely primary-cell assay.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary rescue of a biochemical phenotype.
readouts:
- name: Canonical lipid synthesis after variant-selective knockdown
target: Increased De Novo Sphingolipid Synthesis
direction: RESTORED
interpretation: Allele-selective siRNA reduced abnormal lipid synthesis in tested patient cultures.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Primary rescue of a biochemical phenotype.
- target: Reduced SPT Feedback Inhibition
relationship: RESCUES
fidelity: MODERATE
description: Variant-selective knockdown restored sensitivity to C6-ceramide.
limitations: Non-neuronal patient skin fibroblasts reproduce biochemical defects but do not test selective motor neuron death or clinical efficacy. The native-gel complex experiment used immortalized fibroblast derivatives; it must not be described as an entirely primary-cell assay.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: An attenuated C6-Cer response was also observed in fibroblasts derived from L39del and F40S41del patients, which could be restored after knockdown of the mutant mRNA transcripts (Figure 2G) using siRNAs that specifically silence the expression of the respective mutant alleles, as shown previously (4).
explanation: Primary feedback-rescue result.
readouts:
- name: C6-ceramide feedback response
target: Reduced SPT Feedback Inhibition
direction: RESTORED
interpretation: Variant-selective knockdown restored sensitivity to C6-ceramide.
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: An attenuated C6-Cer response was also observed in fibroblasts derived from L39del and F40S41del patients, which could be restored after knockdown of the mutant mRNA transcripts (Figure 2G) using siRNAs that specifically silence the expression of the respective mutant alleles, as shown previously (4).
explanation: Primary feedback-rescue result.
cell_source: Patient skin-derived fibroblasts, with immortalized derivatives for native-complex assays
- name: Engineered WTC11 motor neuron-like cells
experimental_model_type: IPSC_DERIVED_MODEL
description: Isogenic WTC11 iPSCs were differentiated using an inducible motor-neuron transcription-factor program. A monoallelic F40_S41del line and a separate F40_S41del/exon-2-deletion compound line both showed increased canonical lipid synthesis, with a larger effect in the compound line. It is incorrect to dismiss the entire study as compound-only or to describe these cells as patient-derived.
evidence:
- &id001
reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Using CRISPR, we created one iPSC line heterozygous for p.(F40_S41del), akin to patient 3 and another line compound heterozygous for p.(F40_S41del) and a deletion of exon 2 (the consequence of the c.58 G > T variant), which would be predicted to further exacerbate the biochemical phenotype.
explanation: Both monoallelic and compound engineered lines were studied.
modeled_mechanisms:
- target: Increased De Novo Sphingolipid Synthesis
relationship: RECAPITULATES
fidelity: MODERATE
description: Stable-isotope labeling detected increased canonical lipid synthesis in both engineered genotypes.
limitations: Engineered WTC11 cells are not patient-derived. The monoallelic line approximates one patient genotype; the compound line does not represent reported dominant human genotypes. Short-term neuronal morphology and organelles appeared normal; these experiments establish lipid synthesis changes, not a rescued degeneration or long-term clinical phenotype.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs.
explanation: Primary caption describes both lines and their relative effects.
readouts:
- name: Labeled canonical sphingolipids
target: Increased De Novo Sphingolipid Synthesis
direction: INCREASED
interpretation: Stable-isotope labeling detected increased canonical lipid synthesis in both engineered genotypes.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Canonical sphingolipids ceramides and glucosyl ceramides (glucCer) are increased in p.F40_S41del iPSC-hMNs compared to their isogenic control and increase further in the double mutant iPSC-hMNs.
explanation: Primary caption describes both lines and their relative effects.
cell_source: Engineered WTC11 iPSCs with isogenic control
- name: Purified human SPT-ORMDL and engineered membrane assays
experimental_model_type: OTHER
description: Human SPT-ORMDL complexes expressed in HEK293F cells were purified for cryo-EM and biochemical inhibition assays. Engineered ORMDL mutations tested the proposed ceramide-sensing site; related HeLa membrane assays tested feedback outside detergent-purified preparations. ALS-variant complexes retained ORMDL in this study while showing impaired ceramide response, providing a route distinct from universal dissociation.
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Here we show that purified human SPT-ORMDL complexes are inhibited by the central sphingolipid metabolite ceramide.
explanation: Purified protein experiments, not a living-animal model.
modeled_mechanisms:
- target: Reduced Ceramide Responsiveness
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: Selected SPTLC1 variant complexes had impaired ceramide sensing despite ORMDL retention.
limitations: Recombinant proteins, detergent micelles and short-chain ceramide assays do not fully reproduce native neuronal membranes. ORMDL N13A/ΔN2 mutations are engineered probes rather than patient ALS27 alleles. The article labels one SPTLC1 construct Y23A, whereas patient reports identify Y23F. Binding-pocket occupancy and allosteric effects for every ALS allele remain unresolved.
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex.
explanation: Primary recombinant-enzyme interpretation.
readouts:
- name: Ceramide-dependent inhibition of selected variant complexes
target: Reduced Ceramide Responsiveness
direction: DECREASED
interpretation: Selected SPTLC1 variant complexes had impaired ceramide sensing despite ORMDL retention.
evidence:
- reference: PMID:37308477
reference_title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Our results, in which ORMDL3 is apparently associated with the complexes containing the SPTLC1 variants, demonstrate that the unrestrained sphingolipid biosynthesis caused by SPTLC1 ALS variants is associated, at least in part, with impaired ceramide sensing of these variants when ORMDL is contained within the SPT complex.
explanation: Primary recombinant-enzyme interpretation.
- name: HEK293FT substrate preference and serine-response assays
experimental_model_type: CELL_LINE
description: Stable expression of A20S or C133W was tested with a CoA-release photometric assay and mitochondrial probe imaging. Serine supplementation restored the reported mitochondrial size/intensity phenotype. These findings motivated compassionate use but do not establish benefit for every ALS27 allele.
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Supplementation of 100 mM L-serine in the culture media for 48 hours rescued the mitochondrial abnormalities in the p.Ala20Ser and p.Cys133Trp lines.
explanation: Measured probe phenotype in cultured cells.
modeled_mechanisms:
- target: Pathogenic SPTLC1 Variation
relationship: PERTURBS
fidelity: LOW
description: Engineered variant expression was compared with WT for substrate-associated and mitochondrial-probe readouts.
limitations: Overexpression in non-neuronal HEK293FT cells and a high-serine culture condition differ from physiological neuronal exposure. MitoTracker size/intensity are morphological/probe readouts, not direct neuron survival or a comprehensive mitochondrial flux assay. A later study did not reproduce the same A20S deoxylipid result under its conditions.
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The SPTLC1 enzyme complex activity was determined using a photometric assay measuring the release of free coenzyme A (coA) from the condensation reaction between palmitoyl-CoA and L-serine, L-alanine, and L-glycine.
explanation: Assay identifies the measured chemistry; no direct neuronal outcome.
- name: Patient lymphoblastoid proteomic model
experimental_model_type: CELL_LINE
description: EBV-immortalized lymphoblastoid cells from one c.58G>T case and two controls underwent proteomic and transcript profiling. SPTLC1 protein was lower while total transcript was not significantly changed; numerous candidate pathways were associated. The source uses the predicted A20S protein shorthand, but the allele primarily causes abnormal splicing.
evidence:
- reference: PMID:35627278
reference_title: New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: After the preparation of immortalized lymphoblastoid (see Section 2.1), samples were propagated (cell culture) to 2 × 3 samples for controls and 1 × 3 samples for the patient.
explanation: Replicates derive from three donors.
modeled_mechanisms:
- target: Pathogenic SPTLC1 Variation
relationship: MEASURES
fidelity: LOW
description: Proteomics characterized a patient-derived non-neural cell model, including lower SPTLC1 abundance.
limitations: One patient and two control donors with culture replicates are not nine independent people. Immortalized lymphoblast expression changes do not establish motor-neuron mechanisms. Reduced protein with unchanged total RNA does not by itself prove a degradation pathway; the splice allele and predicted minor nonsense-mediated-decay product require separate interpretation.
evidence:
- reference: PMID:35627278
reference_title: New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Among the dysregulated proteins, SPTLC1 itself was identified with a significant decrease to 0.48-fold expression.
explanation: Protein abundance is not a direct SPT activity or stability assay.
readouts:
- name: SPTLC1 protein abundance
target: Pathogenic SPTLC1 Variation
direction: DECREASED
interpretation: Proteomics characterized a patient-derived non-neural cell model, including lower SPTLC1 abundance.
evidence:
- reference: PMID:35627278
reference_title: New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Among the dysregulated proteins, SPTLC1 itself was identified with a significant decrease to 0.48-fold expression.
explanation: Protein abundance is not a direct SPT activity or stability assay.
cell_source: One affected donor and two control donors
- name: Patient c.58G>A lymphoblast splicing assay
experimental_model_type: CELL_LINE
description: RT-PCR in patient-derived lymphoblasts showed exon-2 retention for c.58G>A, contrasting with the earlier c.58G>T splice result. This allele-specific negative splicing result does not exclude other functional abnormalities.
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: No band corresponding to exon 2 skipping (266 bp) was detected
explanation: Primary lymphoblast transcript assay.
modeled_mechanisms:
- target: Abnormal SPTLC1 Splicing
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: The c.58G>A lymphoblast sample did not show the exon skipping reported for c.58G>T.
limitations: Different nucleotide alleles were examined in non-neural cells; the negative result is specific to this splice event and sample.
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: No band corresponding to exon 2 skipping (266 bp) was detected
explanation: Measured negative splice result for c.58G>A.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: were conducted with non-neural tissue, and may not reflect the actual splicing of transcripts in neural tissue.
explanation: Source explicitly limits tissue extrapolation.
readouts:
- name: Exon-2 skipping in c.58G>A lymphoblasts
target: Abnormal SPTLC1 Splicing
direction: UNCHANGED
interpretation: The c.58G>A lymphoblast sample did not show the exon skipping reported for c.58G>T.
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: No band corresponding to exon 2 skipping (266 bp) was detected
explanation: Measured negative splice result for c.58G>A.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: IN_VITRO
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: were conducted with non-neural tissue, and may not reflect the actual splicing of transcripts in neural tissue.
explanation: Source explicitly limits tissue extrapolation.
discussions:
- discussion_id: als27-selective-neuronal-injury
kind: KNOWLEDGE_GAP
status: OPEN
prompt: Which lipid species and downstream processes connect SPT dysregulation to motor neuron injury?
rationale: Human genetics and cell experiments establish altered regulation and synthesis, but the selective neuronal injury pathway remains unresolved. Plasma concentrations do not localize the relevant tissue exposure. Candidate mitochondrial and inflammatory signals in non-neural cells do not establish necessary mediators. Sensory-motor overlap also argues against a strict two-disease dichotomy.
attaches_to:
- pathophysiology#Canonical Sphingolipid Accumulation
- pathophysiology#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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We do not yet understand why motor and sensory neurons show selective vulnerability to distinct biochemical changes in sphingolipid synthesis and homeostasis.
explanation: Explicit unresolved mechanism.
- discussion_id: als27-mouse-human-mismatch
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: Why does heterozygous exon-2 deletion fail to reproduce the tested ALS-like phenotype in mice?
rationale: The deletion models a real human splice consequence, so mismatch cannot be dismissed as an unrelated lesion. Homozygous lethality does not establish simple enzymatic loss of function. The mutant protein, complex incorporation and flux were not directly resolved. Human-cell evidence includes both monoallelic and compound engineered motor neuron-like cells; criticism of the compound line does not erase the monoallelic result.
attaches_to:
- animal_models#Sptlc1 exon 2 deletion mouse
- experimental_models#Engineered WTC11 motor neuron-like cells
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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: It remains unclear whether sufficient ΔE2 protein is available in vivo to incorporate into the SPT complex or interact with ORMDL proteins.
explanation: The key unmeasured molecular parameter.
- *id001
- discussion_id: als27-serine-direction
kind: INTERPRETATION
status: OPEN
prompt: How do allele, cell type and assay conditions determine the effects of changing serine availability?
rationale: 'A HEK293FT assay and one compassionate-use case suggest possible biochemical or weight effects, while engineered neuronal lipid assays and mechanistic reviews raise concern about increasing canonical lipid production. Clinical neurological benefit and harm remain unproven. Serine restriction is also not an established therapy: low-serine cultures can increase deoxysphingolipids. The low-serine L39del carrier provides an association, not proof of diet-induced phenotype conversion.'
attaches_to:
- 'treatments#L-serine supplementation: unresolved clinical and biochemical effects'
- biochemical#Variable 1-deoxysphingolipid profile
evidence:
- reference: PMID:34459874
reference_title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: We did not observe evidence of neurological improvement, although prolonged therapy would be required to detect such an effect.
explanation: Clinical observation without control.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Experimental countervailing concern for substrate restriction.
- discussion_id: als27-mosaic-expression
kind: KNOWLEDGE_GAP
status: OPEN
prompt: How do tissue-specific mosaicism and expression modify penetrance and biochemical findings?
rationale: One clinically unaffected parent had 17% blood mosaicism, but brain and germline fractions were unmeasured and lipid levels were not a consistent intermediate phenotype. This does not define a safe threshold or predict the amount of therapeutic knockdown needed.
attaches_to:
- inheritance#Autosomal dominant with de novo, familial and mosaic transmission
evidence:
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Further investigations are necessary to determine whether there is a threshold for the relative abundance of mutant alleles in the clinical presentation of ALS.
explanation: Authors explicitly leave the threshold unresolved.
notes: This entry covers SPTLC1-related ALS27, distinguishing its predominant motor phenotype from SPTLC1-related hereditary sensory and autonomic neuropathy and mixed phenotypes. Small, selected and overlapping case series do not establish population phenotype frequencies or a universal disease course. The matched deep-research report was checked against primary full texts. The complete ALS GeneReviews chapter includes SPTLC1; its diagnosis, multidisciplinary care and counseling provide a general ALS baseline, not genotype-specific pediatric efficacy estimates.
diagnosis:
- name: Clinical and electrodiagnostic motor-neuron assessment
description: Assess upper and lower motor neuron findings across regions, nerve conduction and needle EMG, with evaluation for mimics. Sensory studies were normal in many cases, but mixed SPTLC1 phenotypes occur. An initial limb-girdle or spastic presentation does not exclude ALS27.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
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: Clinical criteria in the original six probands.
- 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: Review synthesis of the electrodiagnostic pattern.
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
reference_title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: REVIEW_SYNTHESIS
directness: DIRECT
snippet: The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations
explanation: GeneReviews general diagnostic framework.
- name: Molecular diagnosis and family testing
description: Identify a compatible heterozygous pathogenic or likely pathogenic SPTLC1 variant using an appropriate motor-neuron panel or broader sequencing, and interpret splice consequences when relevant. Parental testing distinguishes de novo, inherited and mosaic findings. An uncertain variant alone does not establish ALS27; a blood mosaic fraction does not measure neural or germline burden.
diagnosis_term:
preferred_term: SPTLC1 and family testing
term:
id: NCIT:C15709
label: Genetic Testing
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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- 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.
quote_role: PRIMARY_RESULT
directness: DIRECT
- name: Supportive lipid and tissue investigations
description: Plasma lipid profiling and muscle biopsy can support mechanistic investigation or clarify mimics, but neither a validated lipid cutoff nor an obligatory biopsy pattern defines ALS27. Neurogenic muscle change supports denervation; absence of a lipid aggregate or an elevated lipid class does not exclude the molecular diagnosis.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes
explanation: Diagnostic biopsies in selected patients.
- reference: PMID:39666121
reference_title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: The levels of complex ceramides, including lactosylceramide, hexosylceramide, and sphingomyelin, did not significantly differ across family members.
explanation: Not every lipid class is abnormal.
histopathology:
- name: Neurogenic muscle atrophy
description: Diagnostic muscle biopsies showed acute/chronic neurogenic change and fiber-type grouping. One severe splice-variant case had mild focal inflammation and subsarcolemmal mitochondrial enrichment, without detectable protein or lipid aggregates by the reported microscopy. These findings do not establish a primary inflammatory myopathy or visible lipid-storage disorder.
evidence:
- reference: PMID:34059824
reference_title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Four patients had undergone a muscle biopsy, which demonstrated acute and chronic neurogenic changes
explanation: Four selected biopsies.
- 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
quote_role: PRIMARY_RESULT
directness: DIRECT
snippet: Microscopic investigations on the quadriceps muscle derived from our patient revealed a neurogenic atrophy characterized by fiber-type grouping and accompanied by unspecific subsarcolemmal enrichment of mitochondria and unravelled presence of mild inflammation.
explanation: Single-patient muscle specimen.
clinical_trials:
- name: NCT07660614
description: First-in-human randomized placebo-controlled multiple-dose intrathecal LTX-002 study in adults with ALS. The ASO targets SPTLC1 mRNA. Planned enrollment is 56; the protocol includes three doses and primary safety assessment through day 169, with pharmacokinetic and exploratory biomarker/functional measures. It is a broader adult ALS study, not a juvenile ALS27 efficacy trial.
phase: PHASE_I
status: RECRUITING
notes: Registry API checked 2026-09-21; last posted update 2026-08-18. Ages 18–75, recent symptom onset and respiratory eligibility limits apply; a pathogenic SPTLC1 variant is not required. No results are posted. Registration and recruiting status do not establish efficacy or successful target engagement. The schema has no combined phase I/II value; PHASE_I records the earliest phase and the description preserves both.
evidence:
- reference: clinicaltrials:NCT07660614
reference_title: A First-in-Human, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of Intrathecally Administered LTX-002 in Adult Participants With Amyotrophic Lateral Sclerosis
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: Specifically, the researchers will be looking at safety, tolerability (if someone has any side effects from the drug), pharmacokinetics (what the body does to the study drug) and pharmacodynamics (what the study drug does to the body).
explanation: Registered study design, not outcomes.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07660614
reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07660614
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: LTX-002 is an antisense oligonucleotide (ASO) targeting SPTLC1 messenger RNA (mRNA). Several dose levels will be tested.
explanation: Intervention identity and target.
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07660614
reference_title: https://clinicaltrials.gov/api/v2/studies/NCT07660614
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
quote_role: BACKGROUND
directness: DIRECT
snippet: ALS symptom onset less than 36 months prior to Screening
explanation: Eligibility restricts disease duration; the same registry specifies ages 18–75.
review_notes: Comprehensive review checked the full original YAML, matching deep-research narrative and original references. Actual scientific bodies were read in full for PMID34059824, 34459874, 35900868, 36801857, 37497262, 35627278, 38788085 and 37308477; an independent source peer read the complete 39666121 and 42392979 bodies, methods, supplied tables and captions, with claim-local passages checked here. Generated caches for 34459874 and 36801857 were refreshed to recover omitted tables; no cache was hand-edited. PMID36204986 and 37348646 remain abstract-supported. The complete ALS GeneReviews chapter was read through clinical characteristics, diagnosis, management and counseling; it explicitly includes SPTLC1 and is applicable as a general baseline. The complete EAN 2024 recommendations and methodology were consumed; general ALS evidence and consensus are not presented as genotype-specific pediatric trials. Small and overlapping selected reports do not justify pooled phenotype-frequency bands. The 2023 survival table labels 512 months as a mean with 95% confidence interval, not a median with IQR; censoring and literature selection limit interpretation. Cognitive findings in the
primary 2021 series take precedence over the later review assertion of none, while the uncertain IQ assessment in 2024 is not converted to intellectual disability. c.58G>T splice skipping is distinct from c.58G>A exon retention. Human monoallelic and compound WTC11 lines were both present; they were engineered, not patient-derived. The mouse deletion models a real human splice consequence, but negative steady-state lipids are not a flux assay and homozygous lethality does not prove loss of enzymatic function. ORMDL association and ceramide sensing are separate, assay-dependent readouts. The structural source labels one construct Y23A instead of clinical Y23F; this discrepancy is retained as a limitation. The L38R case title has nucleotide/protein discordance; unsupported nucleotide notation is not reproduced. A single mosaic parent does not establish a safe neural threshold. Serine-associated weight change, cell-probe rescue and hypothesized clinical harm are distinguished. The current NCT07660614 full API was read and has no posted results; it recruits adults with broader ALS rather than children or a required SPTLC1 genotype. No disease-specific prevalence estimate or faithful progressive
animal model is established by these sources.
references:
- reference: PMID:34059824
title: Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.
- reference: PMID:34459874
title: Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.
- reference: PMID:35627278
title: New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1.
- reference: PMID:35900868
title: SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.
- reference: PMID:36801857
title: Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.
- reference: PMID:37308477
title: Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
- reference: PMID:37348646
title: SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.
- reference: PMID:37497262
title: Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.
- reference: PMID:38470068
title: European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).
- reference: PMID:38788085
title: Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.
- reference: PMID:39666121
title: Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.
- reference: PMID:42392979
title: Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.
- reference: clinicaltrials:NCT07660614
title: A First-in-Human, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of Intrathecally Administered LTX-002 in Adult Participants With Amyotrophic Lateral Sclerosis
- reference: url:https://clinicaltrials.gov/api/v2/studies/NCT07660614
title: https://clinicaltrials.gov/api/v2/studies/NCT07660614
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/
title: Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf
tags:
- GeneReviews

📚

References & Deep Research

References

15

PMID:34059824

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis.

No top-level findings curated for this source.

PMID:34459874

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

No top-level findings curated for this source.

PMID:35627278

New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1.

No top-level findings curated for this source.

PMID:35900868

SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.

No top-level findings curated for this source.

PMID:36801857

Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations.

No top-level findings curated for this source.

PMID:37308477

Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.

No top-level findings curated for this source.

PMID:37348646

SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS.

No top-level findings curated for this source.

PMID:37497262

Thirty-Year Follow-Up of Early Onset Amyotrophic Lateral Sclerosis with a Pathogenic Variant in SPTLC1.

No top-level findings curated for this source.

PMID:38470068

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

No top-level findings curated for this source.

PMID:38788085

Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders.

No top-level findings curated for this source.

PMID:39666121

Genetic and functional analyses of SPTLC1 in juvenile amyotrophic lateral sclerosis.

No top-level findings curated for this source.

PMID:42392979

Deletion of exon 2 in ALS-linked Sptlc1 causes lethality in homozygous mice but not in heterozygotes.

No top-level findings curated for this source.

clinicaltrials:NCT07660614

A First-in-Human, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of Intrathecally Administered LTX-002 in Adult Participants With Amyotrophic Lateral Sclerosis

No top-level findings curated for this source.

url:https://clinicaltrials.gov/api/v2/studies/NCT07660614

https://clinicaltrials.gov/api/v2/studies/NCT07660614

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1450/

Amyotrophic Lateral Sclerosis Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record review notes

Comprehensive review checked the full original YAML, matching deep-research narrative and original references. Actual scientific bodies were read in full for PMID34059824, 34459874, 35900868, 36801857, 37497262, 35627278, 38788085 and 37308477; an independent source peer read the complete 39666121 and 42392979 bodies, methods, supplied tables and captions, with claim-local passages checked here. Generated caches for 34459874 and 36801857 were refreshed to recover omitted tables; no cache was hand-edited. PMID36204986 and 37348646 remain abstract-supported. The complete ALS GeneReviews chapter was read through clinical characteristics, diagnosis, management and counseling; it explicitly includes SPTLC1 and is applicable as a general baseline. The complete EAN 2024 recommendations and methodology were consumed; general ALS evidence and consensus are not presented as genotype-specific pediatric trials. Small and overlapping selected reports do not justify pooled phenotype-frequency bands. The 2023 survival table labels 512 months as a mean with 95% confidence interval, not a median with IQR; censoring and literature selection limit interpretation. Cognitive findings in the primary 2021 series take precedence over the later review assertion of none, while the uncertain IQ assessment in 2024 is not converted to intellectual disability. c.58G>T splice skipping is distinct from c.58G>A exon retention. Human monoallelic and compound WTC11 lines were both present; they were engineered, not patient-derived. The mouse deletion models a real human splice consequence, but negative steady-state lipids are not a flux assay and homozygous lethality does not prove loss of enzymatic function. ORMDL association and ceramide sensing are separate, assay-dependent readouts. The structural source labels one construct Y23A instead of clinical Y23F; this discrepancy is retained as a limitation. The L38R case title has nucleotide/protein discordance; unsupported nucleotide notation is not reproduced. A single mosaic parent does not establish a safe neural threshold. Serine-associated weight change, cell-probe rescue and hypothesized clinical harm are distinguished. The current NCT07660614 full API was read and has no posted results; it recruits adults with broader ALS rather than children or a required SPTLC1 genotype. No disease-specific prevalence estimate or faithful progressive animal model is established by these sources.

Record notes

This entry covers SPTLC1-related ALS27, distinguishing its predominant motor phenotype from SPTLC1-related hereditary sensory and autonomic neuropathy and mixed phenotypes. Small, selected and overlapping case series do not establish population phenotype frequencies or a universal disease course. The matched deep-research report was checked against primary full texts. The complete ALS GeneReviews chapter includes SPTLC1; its diagnosis, multidisciplinary care and counseling provide a general ALS baseline, not genotype-specific pediatric efficacy estimates.

Create: Amyotrophic Lateral Sclerosis 27, Juvenile (SPTLC1/ALS27) · 2026-08-20T04:33:33Z · View source

De novo curation of ALS27 (MONDO:0859529, OMIM 620285, causal gene SPTLC1/hgnc:11277) from primary literature plus one falcon deep-research report. Identity anchoring (NEC risk is high for the numbered ALS1..ALS27 series): MONDO looked up with OAK, confirming RO:0004003 SPTLC1 and OMIM:620285. `just preflight-dr research/Amyotrophic_Lateral_Sclerosis_27_Juvenile-deep-research-falcon.md MONDO:0859529` returned PASS (SPTLC1 mentioned 41 times; nearest rival SPTLC2 at 5). Deep research: falcon (Edison), 712 s, 11 citations. Its own reference-validation block reported needs_review: true with one unresolved identifier, "DOI:10.3233/JND-240014-current". I re-checked that identifier: the failure was a formatting artifact (an em-dash and the word "current" concatenated onto the DOI in the report text). The clean DOI 10.3233/JND-240014 resolves via the PMC ID converter to PMID:38788085 (Mohassel, Abdullah, Eichler, J Neuromuscul Dis 2024), which was fetched with `just fetch-reference` and cited. No other report identifier was unresolved. The report was used as leads only; every cited PMID was fetched independently and every snippet checked against its own cache file. Key correction the deep research surfaced, and the most safety-relevant content in the entry: the JAMA Neurology index paper (PMID:34459874) describes an ALS27 patient given high-dose oral L-serine on a compassionate basis. Read alone that looks like a candidate therapy. The 2024 authoritative review (PMID:38788085) states that in SPT-related motor neuron disease, which is caused by unrestrained SPT activity, serine supplementation is predicted to EXACERBATE sphingolipid overproduction, and that serine supplementation of iPSC-derived motor neurons carrying SPTLC1 p.Phe40_Ser41del accentuated the consequences of SPT overactivity. The treatment entry is therefore titled "predicted harmful", carries REFUTE evidence, and records both the observed weight gain and the absence of neurological improvement so the n-of-1 exposure is neither hidden nor overstated. The HSAN1 rationale (where L-serine IS therapeutic) is explicitly marked as not transferable. Mechanistic model curated as a chained pathograph: SPTLC1 transmembrane-domain gain-of-function variant -> impaired ORMDL-mediated feedback inhibition of serine palmitoyltransferase (GO:0004758 GAIN_OF_FUNCTION and GO:0090155 LOSS_OF_FUNCTION on the same node, plus GO:0017059 SPT complex and GO:0005783 ER) -> unrestrained de novo sphingolipid synthesis (GO:0030148 INCREASED; CHEBI sphingolipid/sphinganine/ceramide INCREASED) -> upper and lower motor neuron degeneration -> progressive denervation and neurogenic muscle atrophy -> loss of ambulation and respiratory insufficiency. The step from lipid excess to motor neuron death is marked INDIRECT_UNKNOWN_INTERMEDIATES with PARTIAL evidence, because it is genuinely not established. Three discussions recorded rather than papered over: a KNOWLEDGE_GAP on why motor and sensory neurons are selectively vulnerable to different sphingolipid abnormalities (stated as unresolved by both the 2021 Nature Medicine paper and the 2024 review); a HUMAN_MODEL_MISMATCH noting that no faithful in vivo ALS27 model exists (the 2026 Sptlc1 exon-2-deletion knock-in is curated as FAILS_TO_RECAPITULATE, since heterozygotes show neither motor deficits nor ALS-like neuropathology while homozygotes die, i.e. the allele behaves as loss-of-function in mouse rather than the human gain-of-function); and an OPEN_QUESTION on whether SPTLC1-related ALS and HSAN1 are discrete entities or a continuum, given the p.Ser331 hybrid cases and the serine-limitation experiment that shifted an ALS lipid signature toward an HSAN1-like one within one pedigree. Cognitive impairment is curated with the disagreement visible: the 2024 review says cognitive dysfunction has not been reported in SPTLC1-ALS, while the JAMA Neurology cohort documented mild cognitive dysfunction in one patient and measured attentional/executive impairment in another. Neither side was suppressed. Scope: SPTLC2-related juvenile ALS (ALS28) and SPTSSA-related complicated HSP are recorded as differential diagnoses only, not curated here. Deliberately NOT curated: datasets (no relevant repository accession identified; dataset search keyed on a causal gene is a known Named Entity Confusion route for an ultra-rare disease and was not worth the risk), prevalence (no reliable population estimate exists in the literature), and clinical_trials (no ALS27-specific registered trial found). GeneReviews baseline: PubMed searched for a GeneReviews chapter on ALS27 / SPTLC1-related ALS on 2026-08-19; none exists, so that step does not apply. Recorded in the entry notes. Relationship to the existing broad kb/disorders/Amyotrophic_Lateral_Sclerosis.yaml entry: that entry is a Complex-category entity whose curated mechanism is TDP-43 proteinopathy and convergent proteostatic failure, and it contains no SPTLC1 content at all. ALS27 is a Mendelian primary metabolic disease with a disjoint mechanism, its own MONDO term, and distinct treatment logic, so it is curated as a standalone entry with parents: Amyotrophic Lateral Sclerosis rather than as a has_subtypes entry on the broad file. Validation actually run and read: `just validate` (schema + terms + references) passed; `just count-verified-snippets` reported 83/83 verified against cached references; `just validate-disorders` (the batched --no-full-text sweep CI runs) passed; `just check-duplicate-keys` OK; `just check-title-snippets` reported no new title-quoting snippets; `just compliance` 96.7% global / 97.2% weighted.

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.

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

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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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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

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Pleiotropy and genotype–phenotype distinction

5. Environmental and lifestyle information

6. Mechanism and pathophysiology

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7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

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11. Outcome and prognosis

12. Treatment and current implementation

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