Juvenile Amyotrophic Lateral Sclerosis

Mendelian MONDO:0017593 Pathograph 15 Show in embeddings browser Amyotrophic Lateral Sclerosis Motor Neuron Disease Neurodegenerative Disease

Juvenile amyotrophic lateral sclerosis (JALS) is a rare, genetically heterogeneous motor neuron disease defined by onset of combined upper and lower motor neuron degeneration before age 25, presenting with facial spasticity, dysarthria, pyramidal signs and gait disorder. It is not simply an early-onset presentation of adult ALS: roughly 40% of cases have an identifiable monogenic basis distributed across more than 20 loci, and the recurrent genes (ALS2/alsin, SETX, SPG11/spatacsin, SIGMAR1, SPTLC1, and FUS) are largely disjoint from the C9orf72/SOD1/TARDBP spectrum that dominates adult ALS. Autosomal recessive inheritance predominates for ALS2, SPG11 and SIGMAR1; SETX, FUS and SPTLC1 act dominantly, the latter two usually as de novo variants. Prognosis is subtype-determined rather than uniform — upper motor neuron-dominant forms follow an indolent course with survival into adulthood, whereas lower motor neuron-dominant forms with early bulbar involvement (paradigmatically FUS p.P525L) are rapidly fatal. This entry is deliberately a thin root: it records what is shared across JALS and what distinguishes it from adult ALS, and defers subtype-specific mechanism to the per-subtype entries.

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Pathophys.
2
Histopath.
10
Phenotypes
3
Gaps
15
Pathograph
6
Genes
3
Medical Actions
7
Subtypes
2
Differentials
3
References
1
Deep Research
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Classifications

Harrison's Part
NEUROLOGIC
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Subtypes

7
ALS2 / juvenile ALS type 2 (ALS2, alsin; autosomal recessive) MONDO:0008780
Autosomal recessive juvenile ALS caused by biallelic loss-of-function variants in ALS2, encoding alsin — a multidomain guanine nucleotide exchange factor for the Rab5 GTPase family. ALS2 sits at one end of an allelic spectrum with infantile-onset ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS), which share the upper motor neuron lesion but lack (JPLS) or differ in the timing of (IAHSP) lower motor neuron involvement. Onset is typically later and the course slower than in other JALS forms.
Show evidence (2 references)
PMID:35053075 SUPPORT Other
"Recessive mutations in the ALS2 gene are responsible for distinct MND conditions, namely Infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM:607225), Juvenile Primary Lateral Sclerosis (JPLS, OMIM:606353), and Juvenile Amyotrophic Lateral Sclerosis (JALS OMIM:205100)"
Establishes the recessive ALS2 allelic spectrum and confirms that JALS (OMIM 205100, the OMIM xref of MONDO:0008780) is one of its three conditions.
PMID:35053075 SUPPORT Other
"symptoms generally appear later for ALS2-induced JALS patients (median age 4, 5 years), and the clinical course is slower"
Supports the later onset and slower course that distinguish ALS2-related JALS from the other genetic subtypes.
ALS4 (SETX, senataxin; autosomal dominant) MONDO:0011223
Autosomal dominant juvenile ALS caused by missense variants in SETX, encoding senataxin, a DNA/RNA helicase implicated in R-loop resolution and RNA processing. Distal muscle weakness and atrophy with pyramidal signs and normal sensation, onset usually before 25 years, slow progression and a normal life span. Included here on the strength of the defining paper's explicit designation of ALS4 as a juvenile ALS with onset below 25 years, despite MONDO parenting MONDO:0011223 only under familial ALS (MONDO:0005144) — see the MONDO-gap discussion below.
Show evidence (2 references)
PMID:15106121 SUPPORT Human Clinical
"Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs."
Defines ALS4 as a dominant juvenile ALS and gives its distinguishing clinical triad.
PMID:15106121 SUPPORT Human Clinical
"Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
Establishes that ALS4 onset is definitionally within the juvenile window and that its course is indolent — the basis for listing it as a JALS subtype and for the slow-progression branch of `progression`.
ALS5 (SPG11, spatacsin; autosomal recessive) MONDO:0011196
Autosomal recessive juvenile ALS caused by biallelic loss-of-function variants in SPG11, encoding spatacsin — the same gene whose loss causes autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Ascertained in pedigrees selected for long-term survival, and associated with pseudobulbar affect and with chronic sensory axonal polyneuropathy on nerve conduction studies.
Show evidence (6 references)
PMID:20110243 SUPPORT Human Clinical
"12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival"
The paper's own quantitative result establishing biallelic SPG11 alterations as a cause of recessive juvenile ALS, and recording that the pedigrees were ascertained for long-term survival.
PMID:20110243 SUPPORT Human Clinical
"The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum."
Establishes the allelic relationship with AR-HSP/thin corpus callosum that makes SPG11 a shared locus rather than an ALS-specific one.
PMID:20301389 SUPPORT Human Clinical
"Onset occurs mainly during infancy or adolescence (range: age 1-31 years) and in rare cases as late as age 60 years."
GeneReviews CLINICAL CHARACTERISTICS. PARTIAL because the chapter describes the allelic SPG11-HSP phenotype rather than ALS5 itself; it supports the juvenile-onset window of SPG11-related disease, which is what places this locus in a juvenile-onset entry, but is not a direct observation of the ALS5 presentation.
+ 3 more references
ALS16 (SIGMAR1, sigma-1 receptor; autosomal recessive) MONDO:0013715
Autosomal recessive juvenile ALS caused by a homozygous SIGMAR1 variant in the transmembrane domain of the sigma-1 receptor, an endoplasmic reticulum chaperone. Described in a single consanguineous family; the mutant protein shows aberrant subcellular distribution and reduced resistance to ER-stress-induced apoptosis in a motor neuron-like cell line. SIGMAR1 is allelic with autosomal recessive distal hereditary motor neuronopathy (HMNR2), curated separately in Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive.yaml.
Show evidence (1 reference)
PMID:21842496 SUPPORT Human Clinical
"Here we describe a consanguineous family segregating juvenile ALS in an autosomal recessive pattern and describe the genetic variant responsible for the disorder."
Establishes the recessive juvenile ALS pedigree from which ALS16 was defined, and the single-family evidence base for this subtype.
FUS-related juvenile ALS (variant-level within ALS6; autosomal dominant, mostly de novo)
FUS-related juvenile ALS. Deliberately NOT bound to MONDO:0011951 (amyotrophic lateral sclerosis type 6): ALS6 is a gene-level concept covering FUS-ALS at any age, most of which is adult-onset, and MONDO parents it under familial ALS and FTD-MND rather than under JALS. The juvenile presentation is a variant-level phenomenon — the C-terminal nuclear-localisation-signal variants, paradigmatically p.P525L, are the ones consistently associated with juvenile onset, a severe rapidly progressive course, and a high proportion of de novo occurrence. This is the most prevalent monogenic JALS form globally, and its neuropathology (FUS-immunoreactive basophilic inclusions, TDP-43 negative) is what separates JALS pathology from the adult TDP-43 proteinopathy paradigm.
Show evidence (2 references)
PMID:21907581 SUPPORT Human Clinical
"this mutation is consistently associated with a specific phenotype characterized by juvenile onset, severe course and high proportion of de novo mutations in sporadic cases"
States the variant-level (p.P525L), not gene-level, basis for treating FUS-JALS as a distinct juvenile entity, and supports keeping this subtype unbound to the gene-level MONDO:0011951.
PMID:38540369 SUPPORT Other
"Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally."
Establishes FUS-related disease as the most prevalent monogenic JALS subtype worldwide.
ALS27 (SPTLC1, serine palmitoyltransferase; autosomal dominant, de novo) MONDO:0859529
Juvenile ALS caused by de novo, gain-of-function SPTLC1 variants in the transmembrane domain that escape ORMDL-mediated feedback inhibition of serine palmitoyltransferase, raising rather than lowering de novo sphingolipid synthesis. Distinguished from the other JALS subtypes by very early onset with failure to thrive, sparing of bulbar onset, and an exceptionally long course. Mechanism is curated in depth in the dedicated entry (Amyotrophic_Lateral_Sclerosis_27_Juvenile.yaml, PR #9067) and is summarised, not duplicated, here.
Show evidence (3 references)
PMID:34459874 SUPPORT Human Clinical
"De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."
The trio-exome result establishing de novo SPTLC1 variants as a juvenile ALS cause, together with the failure-to-thrive feature that flags this subtype clinically.
PMID:36801857 SUPPORT Human Clinical
"Notably, mutations in SPTLC1 occurred de novo in ten out of 16 JALS patients carrying SPTLC1 mutations,"
Quantifies the de novo predominance of SPTLC1 variants across the reported JALS series, supporting the de novo characterisation of this subtype.
PMID:36801857 SUPPORT Other
"Recently, SPTLC1 was identified as a disease-causative gene for JALS, and its mutations promoted enzymic activity, resulting in an increase in standard products."
States the gain-of-function direction of SPTLC1-JALS variants - increased enzyme activity producing more of the canonical sphingolipid products, as opposed to the altered substrate selectivity seen in HSAN1A.
Juvenile amyotrophic lateral sclerosis with dementia MONDO:0008781
A MONDO-asserted child of juvenile ALS (OMIM 205200) characterised as slowly progressive juvenile ALS with concomitantly progressive dementia. Listed for completeness of the MONDO hierarchy; no causal gene is recorded and the concept sits uneasily against the contemporary review position that cognitive compromise is not a hallmark of JALS and that FTD has not been directly correlated with it. Curated at name level only — no mechanism, phenotype or genetic claim is made here.
Show evidence (1 reference)
PMID:38540369 SUPPORT Other
"Significant cognitive compromise and autonomic disturbances are rare, and Frontotemporal Dementia (FTD) has not been directly correlated with JALS."
Cited as PARTIAL because it does not support the subtype; it records the contemporary review position that qualifies it, and is the reason this subtype is curated at name level only.
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Discussions and Knowledge Gaps

3
Should juvenile ALS be modelled as a TDP-43 proteinopathy, as adult ALS is?
INTERPRETATION OPEN jals_not_tdp43_proteinopathy
Attached to
pathophysiology#FUS Cytoplasmic Mislocalization and Basophilic Inclusion Formation pathophysiology#Combined Upper and Lower Motor Neuron Degeneration
The dismech entry for adult Amyotrophic Lateral Sclerosis carries a CANONICAL hypothesis in which TDP-43 cytoplasmic mislocalization and aggregation in the great majority of cases is the unifying pathology. Carrying that framing over to JALS would be wrong, and the error would be invisible because it would take the form of an omission rather than a false statement. The best-characterised JALS neuropathology is the basophilic-inclusion form seen with C-terminal FUS variants, and those inclusions are strongly FUS-positive and explicitly TDP-43 NEGATIVE; the authors conclude it should be classified as ALS-FUS. Reciprocally, spinal motor neurons in late-onset sporadic ALS show no abnormal FUS accumulation. The two entities therefore have different defining proteinopathies, not one shared one at different ages. This entry consequently declares no disease-level proteinopathy hypothesis: the FUS arm is a FUS proteinopathy, and the other genetic arms (endosomal, RNA-processing, lysosomal, ER-stress, sphingolipid) have no established aggregate pathology at all. Recorded as an explicit curated position rather than left implicit.
No claim is made here about the frequency of TDP-43 pathology in JALS generally — the point is that it has not been established as the unifying JALS pathology, not that it never occurs.
Show evidence (2 references)
PMID:20668261 SUPPORT Human Clinical
"Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
The direct immunohistochemical demonstration that the characteristic JALS inclusions are not TDP-43 pathology.
PMID:20579074 SUPPORT Human Clinical
"In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein."
The reciprocal observation: the juvenile proteinopathy is absent from adult sporadic ALS, so the two are distinct rather than age variants of one pathology.
Two juvenile-onset ALS concepts are not parented under MONDO:0017593; should MONDO add the is_a edges, and how should dismech model them meanwhile?
CURATION TODO OPEN jals_mondo_hierarchy_gaps
Verified against the local MONDO build on 2026-08-20. MONDO:0017593 (juvenile amyotrophic lateral sclerosis) has exactly four asserted children: MONDO:0008780 (ALS2), MONDO:0011196 (ALS5/SPG11), MONDO:0013715 (ALS16/SIGMAR1) and MONDO:0008781 (JALS with dementia). Two further concepts belong there on their own definitions but are parented only under MONDO:0005144 (familial ALS). Gap 1 - MONDO:0011223, amyotrophic lateral sclerosis type 4 (SETX). The defining publication states that ALS4 onset is usually below 25 years, which is the JALS criterion, and titles the disorder a form of juvenile ALS. This looks like a genuine missing is_a edge. This entry lists ALS4 as a subtype and binds MONDO:0011223 anyway, recording the divergence here rather than silently following the hierarchy. Gap 2 - MONDO:0859529, amyotrophic lateral sclerosis 27, juvenile (SPTLC1). Its own label contains the word juvenile and every reported case is juvenile-onset, yet it too hangs only off familial ALS. Note this partly resolves a stale claim in the triage of issue #8891 that no MONDO term existed for SPTLC1-juvenile ALS: the term does exist and is bound above. What is NOT resolved is the placement. Deliberately NOT proposed as a gap: MONDO:0011951 (ALS type 6, FUS). Its absence from the JALS hierarchy is arguably correct, because FUS-ALS is predominantly adult-onset and only specific C-terminal variants produce the juvenile phenotype. Equating ALS6 with juvenile ALS would be a gene-level-for-variant-level substitution. The FUS subtype above is therefore left unbound with that rationale stated on the subtype itself.
Show evidence (3 references)
PMID:15106121 SUPPORT Human Clinical
"Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
The onset criterion that makes ALS4 definitionally juvenile and supports Gap 1.
PMID:34459874 SUPPORT Human Clinical
"These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene."
Establishes SPTLC1-related disease as a juvenile ALS entity, supporting Gap 2.
PMID:21907581 SUPPORT Human Clinical
"Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years."
Supports treating juvenile FUS-ALS as variant-level, i.e. the reason ALS6 is NOT proposed as a third MONDO gap.
Should any JALS pathophysiology node declare conformance to the peripheral_axonal_degeneration module?
OPEN QUESTION OPEN jals_peripheral_axonal_degeneration_conformance
Attached to
pathophysiology#Combined Upper and Lower Motor Neuron Degeneration
Decision taken for this entry: NO conformance is declared at the root, and none is declared at subtype level either. The peripheral_axonal_degeneration module models a length-dependent distal axonopathy of peripheral neurons and Schwann cells converging on distal axonal degeneration and demyelination. JALS is defined by COMBINED upper and lower motor neuron degeneration — the upper motor neuron limb is a corticospinal central-tract lesion, which the module does not model at all. Conforming the convergent node would therefore assert a shape the disease does not have, and would misrepresent the entry to any tooling that reads conformance. Two subtype-level exceptions were considered and rejected for now. First, ALS4/SETX presents with distal weakness and normal sensation, which reads like the distal hereditary motor neuronopathy space — but the same defining sentence records pyramidal signs, so the corticospinal lesion is present and the phenotype is not a pure distal axonopathy. Second, for ALS2/alsin: infantile-onset ascending hereditary spastic paralysis, an ALS2 allelic disorder, shows elevated plasma neurofilament light suggesting axonal degeneration. That is evidence about IAHSP, not about ALS2-related JALS, and NfL elevation is a non-specific marker of axonal injury including central axonal injury; it does not establish a length-dependent peripheral axonopathy. Revisit if direct nerve-conduction or pathological evidence of a length-dependent distal axonopathy is published for a specific JALS subtype.
Show evidence (2 references)
PMID:15106121 REFUTE Human Clinical
"characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs"
REFUTE with respect to the proposal to conform ALS4: the same sentence that supplies the distal-axonopathy resemblance also records pyramidal signs, i.e. a corticospinal lesion the module does not cover.
PMID:40439044 SUPPORT Human Clinical
"Plasma NfL levels are elevated in IAHSP, suggesting axonal degeneration."
PARTIAL and about IAHSP, not JALS. Cited as the strongest available argument FOR an axonopathy framing of ALS2-related disease, and recorded here precisely so the decision against conformance can be re-examined against it.
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Pathophysiology

8
Alsin Loss of Function and Rab5 Endosomal Trafficking Failure
Biallelic ALS2 loss-of-function variants abolish or destabilise alsin, a 1657-residue multidomain protein whose MORN/VPS9 module acts as a guanine nucleotide exchange factor for the Rab5 GTPase family, and whose self-oligomerisation is required for that GEF activity. Disease-associated changes alter the native oligomeric state or the protein's capacity to interact with partners, disrupting Rab5-dependent endosome formation and endocytic trafficking in motor neurons.
ALS2 hgnc:443 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALS2 (hgnc:443). hgnc:443 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context ALS2 hgnc:443 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ALS2 (hgnc:443). hgnc:443 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic (homozygous or compound heterozygous) loss-of-function ALS2 variants; nonsense and frameshift changes predominate in reported pedigrees.
endosomal transport GO:0016197 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endosomal transport (GO:0016197). GO:0016197 is a biological process from the Gene Ontology. ↓ DECREASED
Rab5 guanine nucleotide exchange factor activity GO:0005085 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Rab5 guanine nucleotide exchange factor activity, annotated with guanyl-nucleotide exchange factor activity (GO:0005085). GO:0005085 is a molecular function from the Gene Ontology. ↓ DECREASED
early endosome GO:0005769 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves early endosome (GO:0005769). GO:0005769 is a cellular component from the Gene Ontology.
Downstream
Combined Upper and Lower Motor Neuron Degeneration ALS2 variation leads to degeneration of the corticospinal upper motor neurons; the steps connecting endosomal GEF failure to selective motor neuron loss are not established.
Show evidence (3 references)
PMID:35053075 SUPPORT Other
"Previous studies have demonstrated that Alsin preferentially targets the Rab5 GTPase family, which is involved in signal transduction, trafficking, and vesicle formation, suggesting that Alsin may play a key role in endocytosis and cytoskeletal reorganization in mammalian neuronal cells"
Establishes alsin as a Rab5-directed GEF acting on endocytosis, the molecular function this node asserts is lost.
PMID:35053075 SUPPORT Other
"mutations within Alsin's structured domains may be responsible for the alteration of Alsin's native oligomerization state or Alsin's propensity to interact with protein partners"
Supports disruption of oligomerisation and partner interaction as the proximal consequence of ALS2 mutation.
PMID:39424348 SUPPORT Human Clinical
"The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor."
Confirms the GEF function of the ALS2 gene product in a clinical cohort report.
Senataxin Helicase Dysfunction and RNA Processing Defect
Heterozygous missense variants in SETX alter senataxin, a 302.8-kD protein carrying a DNA/RNA helicase domain homologous to RENT1 and IGHMBP2. The proposed mechanism is neuronal degeneration through dysfunction of helicase activity or of other steps in RNA processing — including resolution of R-loops, the co-transcriptional RNA:DNA hybrids senataxin acts on.
SETX hgnc:445 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SETX (hgnc:445). hgnc:445 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SETX hgnc:445 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SETX (hgnc:445). hgnc:445 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS
Heterozygous missense SETX variants segregating in a dominant pedigree (T3I, L389S, R2136H in the defining study).
R-loop processing GO:0062176 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased R-loop processing (GO:0062176). GO:0062176 is a biological process from the Gene Ontology. ↓ DECREASED
RNA helicase activity GO:0003724 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RNA helicase activity (GO:0003724). GO:0003724 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Combined Upper and Lower Motor Neuron Degeneration Proposed route from helicase/RNA-processing dysfunction to motor neuron degeneration; the defining paper frames this as a suggestion, not a demonstrated chain.
Show evidence (2 references)
PMID:15106121 SUPPORT Human Clinical
"we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX)"
Identifies the dominant missense SETX variants underlying ALS4.
PMID:15106121 SUPPORT Human Clinical
"SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing."
Establishes the helicase/RNA-processing molecular function this node asserts is impaired.
Spatacsin Loss of Function and Lysosomal-Autophagic Dysfunction
Biallelic loss-of-function alterations in SPG11 remove spatacsin, whose loss is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and which functions in lysosome biogenesis and autophagic-lysosome reformation. The same lesion can produce a recessive juvenile ALS phenotype with long-term survival, making SPG11 a shared HSP/ALS locus rather than an ALS-specific one.
SPG11 hgnc:11226 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPG11 (hgnc:11226). hgnc:11226 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SPG11 hgnc:11226 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SPG11 (hgnc:11226). hgnc:11226 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
Biallelic SPG11 sequence alterations co-segregating with disease in consanguineous and non-consanguineous recessive JALS pedigrees.
lysosome organization GO:0007040 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased lysosome organization (GO:0007040). GO:0007040 is a biological process from the Gene Ontology. ↓ DECREASED autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Combined Upper and Lower Motor Neuron Degeneration SPG11 alterations co-segregate with clinically definite ALS by revised El Escorial criteria and, in one pedigree with available CNS tissue, with ALS neuropathology.
Show evidence (1 reference)
PMID:20110243 SUPPORT Human Clinical
"Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis."
The paper's own conclusion that SPG11 loss extends beyond HSP to recessive juvenile ALS. Quoted verbatim including the source's "spatascin" spelling.
Sigma-1 Receptor Mislocalization and ER Stress Vulnerability
A homozygous SIGMAR1 variant affecting a conserved residue in the transmembrane domain of the sigma-1 receptor, an endoplasmic reticulum chaperone, produces aberrant subcellular distribution of the protein and reduces cellular resistance to apoptosis induced by ER stress in an NSC34 motor neuron-like line.
SIGMAR1 hgnc:8157 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SIGMAR1 (hgnc:8157). hgnc:8157 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SIGMAR1 hgnc:8157 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SIGMAR1 (hgnc:8157). hgnc:8157 is a gene from the HUGO Gene Nomenclature Committee. zygosity: HOMOZYGOUS
Homozygous SIGMAR1 missense variant in a consanguineous pedigree, identified by homozygosity mapping to a ~120 kbp region on 9p13.3.
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress GO:0070059 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059). GO:0070059 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Combined Upper and Lower Motor Neuron Degeneration Proposed route from sigma-1 receptor dysfunction to motor neuron loss. Rests on a single consanguineous family plus cell-model data; no human neuropathology is available.
Show evidence (1 reference)
PMID:21842496 SUPPORT In Vitro
"The mutated protein showed an aberrant subcellular distribution in NSC34 cells. Furthermore, cells expressing the mutant protein were less resistant to apoptosis induced by endoplasmic reticulum stress."
The cell-model result establishing both the mislocalisation and the increased ER-stress apoptosis susceptibility this node asserts. IN_VITRO because the functional data come from a transfected motor neuron-like cell line, not from patients.
FUS Cytoplasmic Mislocalization and Basophilic Inclusion Formation
C-terminal nuclear-localisation-signal variants in FUS, paradigmatically p.P525L, drive the FUS protein out of the nucleus into the cytoplasm of motor neurons, where it forms basophilic inclusions containing abnormal FUS aggregates and disorganised organelles. These inclusions are strongly FUS-immunoreactive and negative for TDP-43, and are found in spinal motor neurons, in layers IV-V of cerebral cortex and in brainstem nuclei — a distribution matching the combined upper and lower motor neuron lesion.
spinal motor neuron CL:0011001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinal motor neuron, annotated with spinal cord motor neuron (CL:0011001). CL:0011001 is a cell type from the Cell Ontology.
FUS hgnc:4010 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves FUS (hgnc:4010). hgnc:4010 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context FUS hgnc:4010 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns FUS (hgnc:4010). hgnc:4010 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: DE_NOVO zygosity: HETEROZYGOUS
Heterozygous, usually de novo C-terminal FUS variants disrupting the nuclear localisation signal (p.P525L; also the frameshifting c.1554_1557delACAG).
protein import into nucleus GO:0006606 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein import into nucleus (GO:0006606). GO:0006606 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Combined Upper and Lower Motor Neuron Degeneration FUS-bearing basophilic inclusions coincide with severe loss of spinal motor neurons at autopsy in juvenile ALS.
Show evidence (3 references)
PMID:20579074 SUPPORT Human Clinical
"Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum."
Human autopsy evidence for FUS aggregation in basophilic inclusions in juvenile ALS spinal motor neurons.
PMID:20579074 SUPPORT Human Clinical
"In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei."
Establishes that the FUS pathology extends to cortical and brainstem neurons, matching the combined upper and lower motor neuron phenotype.
PMID:20668261 SUPPORT Human Clinical
"Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
The immunohistochemical result establishing these inclusions as TDP-43-negative — the specific finding behind the TDP-43 discussion below.
Serine Palmitoyltransferase Escape from ORMDL Inhibition
De novo SPTLC1 variants located within a single membrane-spanning domain impede the interaction of the serine palmitoyltransferase complex with its regulatory ORMDL subunit. Because ORMDL proteins mediate the homeostatic feedback that restrains SPT, the result is increased SPT activity and increased de novo sphingolipid synthesis — a gain of function, and the mechanistic mirror image of HSAN1A, where SPTLC1 variants near the active site instead redirect substrate selectivity toward neurotoxic deoxysphingoid bases.
SPTLC1 hgnc:11277 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPTLC1 (hgnc:11277). hgnc:11277 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context SPTLC1 hgnc:11277 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns SPTLC1 (hgnc:11277). hgnc:11277 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous de novo SPTLC1 missense variants in the transmembrane domain (p.Ala20Ser, p.Ser331Tyr, p.Leu38Arg; also the in-frame p.Leu39del).
sphingolipid biosynthetic process GO:0030148 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased sphingolipid biosynthetic process (GO:0030148). GO:0030148 is a biological process from the Gene Ontology. ↑ INCREASED
serine C-palmitoyltransferase activity GO:0004758 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves serine C-palmitoyltransferase activity (GO:0004758), qualified as gain of function. GO:0004758 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Combined Upper and Lower Motor Neuron Degeneration SPT dysregulation in this direction produces a motor neuron disease affecting both upper and lower motor neurons while sparing sensory neurons; the steps between excess sphingolipid synthesis and selective motor neuron loss are not established.
Show evidence (3 references)
PMID:37348646 SUPPORT In Vitro
"All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT."
Establishes the shared structural location of SPTLC1-ALS variants and the loss of ORMDL-mediated restraint that defines this node.
PMID:37348646 SUPPORT In Vitro
"An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells."
Direct functional confirmation of increased enzyme activity and increased sphingolipid synthesis, supporting the GAIN_OF_FUNCTION assignment.
PMID:38788085 SUPPORT Other
"In general, variants that cluster near the active site (PLP binding site), in SPTLC1 or SPTLC2, are usually associated with HSAN1 whereas those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP."
Establishes the position-dependent genotype-phenotype split between HSAN1 and juvenile ALS within the same gene — the two-failure-modes contrast this node records.
Combined Upper and Lower Motor Neuron Degeneration
The shared distal node of JALS and the feature that defines it clinically: degeneration of both corticospinal upper motor neurons and brainstem and spinal lower motor neurons, producing simultaneous pyramidal signs (spasticity, hyperreflexia, extensor plantar responses) and lower motor neuron signs (amyotrophy, weakness, fasciculation). Each of the upstream genetic arms converges here, but the balance between the two limbs of the lesion is subtype-determined and is what sets the rate of progression.
Betz upper motor neuron CL:4023052 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Betz upper motor neuron (CL:4023052). CL:4023052 is a cell type from the Cell Ontology. alpha motor neuron CL:0008038 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alpha motor neuron (CL:0008038). CL:0008038 is a cell type from the Cell Ontology.
motor neuron apoptotic process GO:0097049 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased motor neuron apoptotic process (GO:0097049). GO:0097049 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Motor Handicap and Respiratory Failure Progressive loss of motor units leads to loss of ambulation, bulbar failure and ultimately ventilatory failure; the rate is subtype-dependent.
Show evidence (3 references)
PMID:38540369 SUPPORT Other
"The clinical picture in typical JALS presentation is dominated by symmetric or asymmetric upper and lower motor neuron signs with variable rates of motor progression and bulbar compromise."
Establishes combined upper and lower motor neuron involvement as the defining clinical expression of this convergent node.
PMID:34946884 SUPPORT Other
"patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations"
Confirms that the combined upper and lower motor neuron lesion before age 25 is the operational definition of the JALS presentation.
PMID:35053075 SUPPORT Other
"Clinical manifestation reflects the degeneration of both upper motor neurons and lower motor neurons causing weakness of the lower limbs, spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction, sensory disturbances"
Ties the combined degeneration directly to the JALS clinical signs recorded as phenotypes below.
Progressive Motor Handicap and Respiratory Failure
The organism-level endpoint. In lower motor neuron-dominant and bulbar-onset forms, death from respiratory failure follows within months to a few years of onset; in upper motor neuron-dominant forms, motor handicap accumulates over decades with survival into adulthood and, for ALS4, a normal life span. There is no single JALS prognosis.
Show evidence (2 references)
PMID:35053075 SUPPORT Other
"Death usually occurs from respiratory failure between 7 and 84 months after onset"
PARTIAL: gives the fatal endpoint and its typical interval, but the figures are drawn from the reviewed JALS case literature and do not apply to the indolent upper motor neuron-dominant subtypes recorded in `progression`.
PMID:34946884 SUPPORT Other
"Disease prognosis varies from rapidly progressive to an indolent course."
Supports the explicit refusal to state a single disease-level prognosis for JALS.
✶

Histopathology

2
FUS-immunoreactive, TDP-43-negative basophilic inclusions
The defining neuropathology of FUS-related juvenile ALS. Remaining spinal motor neurons contain basophilic cytoplasmic inclusions that are strongly immunoreactive for FUS protein and negative for TDP-43. This is what separates juvenile from adult ALS at the level of pathology rather than genetics, and it is the evidential basis for the `jals_not_tdp43_proteinopathy` discussion: adult ALS is a TDP-43 proteinopathy in the great majority of cases, whereas these juvenile inclusions are not.
Show evidence (3 references)
PMID:20668261 SUPPORT Human Clinical
"Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
The immunohistochemical result itself - FUS-positive, TDP-43-negative - recorded here as a primary histopathological finding rather than only as support for a mechanistic node.
PMID:20579074 SUPPORT Human Clinical
"Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum."
Autopsy description pairing the inclusion pathology with severe spinal motor neuron loss and organelle disorganization in the surviving neurons.
PMID:20579074 SUPPORT Human Clinical
"In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein."
The reciprocal control observation within the same study: the FUS accumulation is absent from late-onset sporadic ALS, which is what makes this a juvenile-specific pathological signature rather than a shared one.
Extramotor FUS pathology in cerebral cortex and brainstem
The same FUS-positive inclusions are found beyond the spinal cord, in layers IV-V of cerebral cortex and in several brainstem nuclei. The anatomical distribution matches the combined upper and lower motor neuron phenotype that defines the disease clinically.
Show evidence (1 reference)
PMID:20579074 SUPPORT Human Clinical
"In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei."
Establishes the extramotor and upper-motor-neuron distribution of the FUS pathology, corroborating the combined UMN/LMN clinical picture.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Juvenile Amyotrophic Lateral Sclerosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Musculoskeletal 1
Spastic Paraparesis HP:0002313 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spastic paraparesis (HP:0002313). HP:0002313 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39424348 SUPPORT Human Clinical
"The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria."
Documents progressive spastic paraparesis in a clinical cohort of children with ALS2-related disease.
Nervous System 3
Dysarthria HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35053075 SUPPORT Other
"spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction"
Names dysarthria among the JALS clinical manifestations.
Fasciculations HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37348646 SUPPORT Human Clinical
"The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs."
Case-level documentation of fasciculation alongside pyramidal signs in a juvenile ALS patient.
Sensory Axonal Polyneuropathy Sensory neuropathy HP:0000763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory neuropathy (HP:0000763). HP:0000763 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"Nerve conduction studies may also demonstrate chronic sensory axonal polyneuropathy in cases of JALS associated with SPG11, VRK1, and SPTLC1 genes"
Restricts sensory involvement to named genetic subtypes rather than to JALS as a whole.
PMID:20301389 SUPPORT Human Clinical
"mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs"
GeneReviews CLINICAL CHARACTERISTICS. Independently places peripheral neuropathy at the SPG11 locus, corroborating one of the three loci named above. PARTIAL because the chapter describes the allelic SPG11-HSP presentation rather than ALS5 itself.
Respiratory 1
Respiratory Failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35053075 SUPPORT Other
"Death usually occurs from respiratory failure between 7 and 84 months after onset"
Establishes respiratory failure as the terminal event in JALS.
Growth 1
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34459874 SUPPORT Human Clinical
"De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive."
Ties failure to thrive specifically to SPTLC1-related juvenile ALS.
Other 4
Combined Upper and Lower Motor Neuron Signs Upper motor neuron dysfunction HP:0002493 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Upper motor neuron dysfunction (HP:0002493), qualified as juvenile onset, up to 25y. HP:0002493 is a phenotype from the Human Phenotype Ontology.
Onset: JUVENILE; up to 25y
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"The clinical picture in typical JALS presentation is dominated by symmetric or asymmetric upper and lower motor neuron signs with variable rates of motor progression and bulbar compromise."
Direct statement of the defining combined phenotype.
PMID:34946884 SUPPORT Other
"JALS is defined as onset before age 25."
States the defining age criterion recorded in the onset qualifier on this phenotype.
Spasticity of Facial Muscles HP:0002491 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity of facial muscles (HP:0002491). HP:0002491 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35053075 SUPPORT Other
"Clinical manifestation reflects the degeneration of both upper motor neurons and lower motor neurons causing weakness of the lower limbs, spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction, sensory disturbances"
Names facial spasticity among the JALS clinical manifestations.
Pseudobulbar Affect HP:0002193 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pseudobulbar affect (HP:0002193). HP:0002193 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"Pseudobulbar affect is most observed in ALS2 and SPG11 variants"
Attributes pseudobulbar affect specifically to the ALS2 and SPG11 subtypes rather than to JALS generally.
PMID:20301389 SUPPORT Human Clinical
"mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs"
GeneReviews CLINICAL CHARACTERISTICS. An independent authoritative source placing pseudobulbar involvement at the SPG11 locus, corroborating the second of the two loci named above and so supporting the decision to assert no single `subtype:` here. PARTIAL because the chapter describes the allelic SPG11-HSP presentation rather than ALS5 itself.
Distal Amyotrophy HP:0003693 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal amyotrophy (HP:0003693). HP:0003693 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15106121 SUPPORT Human Clinical
"characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs"
Establishes distal amyotrophy as the ALS4 presenting sign.
🧬

Genetic Associations

6
ALS2
Gene: ALS2 hgnc:443 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALS2 (hgnc:443). hgnc:443 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34946884 SUPPORT Other
"the most common gene mutations associated with JALS are FUS, SETX, and ALS2"
Establishes ALS2 among the most common JALS genes.
PMID:35053075 SUPPORT Other
"JALS is inherited in an autosomal-recessive pattern involving ALS2, SPG11, and SIGMAR1, while the SETX, UBQLN2, and FUS mutations are described as an underlying cause of an autosomal-dominant form of JALS"
Assigns the recessive/dominant split across the JALS genes, supporting the inheritance annotations on this and the following genetic records.
SETX
Gene: SETX hgnc:445 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SETX (hgnc:445). hgnc:445 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (3 references)
PMID:34946884 SUPPORT Other
"In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion."
Establishes SETX as the dominant exception within a predominantly recessive familial JALS gene set.
PMID:9497266 SUPPORT Human Clinical
"We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease."
The linkage study that established ALS4 as a dominant juvenile-onset motor neuron disease, before SETX was identified.
PMID:20301333 SUPPORT Human Clinical
"Identification of biallelic pathogenic variants in SETX by molecular genetic testing confirms the diagnosis."
Cited for the AOA2 half of the SETX allelic contrast ONLY - this GeneReviews chapter is about AOA2, not about ALS4 or JALS. It establishes that AOA2 requires biallelic SETX variants, which together with PMID:15106121 (dominant missense in ALS4) supports the two-failure-modes note above.
SPG11
Gene: SPG11 hgnc:11226 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPG11 (hgnc:11226). hgnc:11226 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20110243 SUPPORT Human Clinical
"The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees"
Co-segregation evidence for pathogenicity of the SPG11 alterations.
SIGMAR1
Gene: SIGMAR1 hgnc:8157 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SIGMAR1 (hgnc:8157). hgnc:8157 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:21842496 SUPPORT Human Clinical
"We identified a shared homozygosity region in affected individuals that spans ~120 kbp on chromosome 9p13.3 containing 9 RefSeq genes. Sequencing the SIGMAR1 gene revealed a mutation affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma-1 receptor."
The mapping and sequencing result establishing SIGMAR1 as the ALS16 gene.
FUS
Gene: FUS hgnc:4010 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FUS (hgnc:4010). hgnc:4010 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal dominant inheritance
Show evidence (3 references)
PMID:21907581 SUPPORT Human Clinical
"Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years."
Establishes that only some FUS variants produce the juvenile form, supporting the variant-level rather than gene-level treatment.
PMID:20668261 SUPPORT Human Clinical
"The FUS c.1574C>T (P525L) and c.1554_1557delACAG mutations are associated with this distinct phenotype."
Names the two specific C-terminal FUS variants associated with the juvenile basophilic-inclusion phenotype.
PMID:36801857 SUPPORT Human Clinical
"Mutations in FUS were described as the most common cause of the autosomal dominant form in JALS, and the majority was de novo."
Corroborates both the dominant inheritance and the de novo predominance recorded on this genetic record.
SPTLC1
Gene: SPTLC1 hgnc:11277 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPTLC1 (hgnc:11277). hgnc:11277 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Autosomal dominant inheritance
Show evidence (2 references)
PMID:37348646 SUPPORT Human Clinical
"Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS."
States the gain-of-function direction that distinguishes SPTLC1-JALS from the HSAN1A mechanism.
PMID:34459874 SUPPORT Human Clinical
"Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway."
Records the HSAN1A allelism from which the juvenile ALS phenotype was distinguished.
💊

Medical Actions

3
Multidisciplinary Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Coordinated non-pharmacological care by physical, speech and occupational therapists, nutritionists, psychologists and nurses. This is the core therapy for JALS; symptomatic management improves quality of life in more advanced disease.
Show evidence (3 references)
PMID:38540369 SUPPORT Other
"Non-pharmacological treatment based on a specialized multidisciplinary team approach, involving physical, speech, and occupational therapists, nutritionists, psychologists, and nurses, represents the core therapy of patients with JALS."
Establishes multidisciplinary supportive care as the core JALS therapy.
PMID:20301389 SUPPORT Human Clinical
"Care by a multidisciplinary team; physiotherapy to stretch spastic muscles; antispastic drugs such as baclofen; botulin toxin and intrathecal baclofen for severe and disabling spasticity when oral drugs are ineffective."
GeneReviews MANAGEMENT. Corroborates the multidisciplinary model and specifies the spasticity-directed measures for the SPG11 locus underlying the ALS5 subtype. PARTIAL because the recommendation is written for allelic SPG11-HSP, not for JALS as a whole.
PMID:20301389 SUPPORT Human Clinical
"Surveillance: Evaluation every six months to adjust physiotherapy and medications."
GeneReviews MANAGEMENT (surveillance). Supplies the review interval for ongoing supportive care at this locus; PARTIAL for the same allelic-entity reason.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling of the proband and at-risk relatives once a causal variant is known: recurrence-risk discussion appropriate to the subtype's inheritance mode, cascade carrier testing of relatives, and reproductive options including prenatal testing. The recurrence risk differs sharply across this entry's subtypes - 25% per pregnancy for the autosomal recessive loci (ALS2, SPG11, SIGMAR1) against a dominant or, for most FUS-related and SPTLC1 juvenile disease, de novo mechanism - so counseling is downstream of the molecular diagnosis rather than parallel to it. The testing strategy itself is curated under `diagnosis:`, not here.
Show evidence (1 reference)
PMID:20301389 SUPPORT Human Clinical
"Carrier testing for at-risk family members and prenatal testing for at-risk pregnancies are possible once the pathogenic variants in a family are known."
GeneReviews GENETIC COUNSELING. Establishes the two counseling actions that follow a molecular diagnosis - cascade carrier testing and prenatal testing - for the SPG11 locus underlying the ALS5 subtype. PARTIAL because the chapter is written for allelic SPG11-HSP rather than for JALS as a whole, and because the recurrence-risk arithmetic it states applies only to the recessive subtypes.
Oral L-Serine Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: L-serine CHEBI:17115 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses L-serine (CHEBI:17115). CHEBI:17115 is a therapeutic agent from Chemical Entities of Biological Interest.
Substrate-based therapy proposed for SPTLC1-related JALS. Subtype-restricted; there is no evidence base for its use in other JALS forms.
Mechanism Target:
INHIBITS Serine Palmitoyltransferase Escape from ORMDL Inhibition — Aimed at the SPTLC1 gain-of-function node. The review names it as a therapeutic option for SPTLC1-related JALS without reporting trial outcome data, so the target link is recorded as PARTIAL.
Show evidence (1 reference)
PMID:38540369 SUPPORT Other
"Other monogenic forms of therapeutic interest include SPTLC1-related JALS which is amenable to oral L-serine supplementation therapy"
PARTIAL: names L-serine as applicable to the SPTLC1 subtype but reports no efficacy data, and does not itself describe the molecular action on the SPT complex.
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"There are still very limited specific data regarding disease-modifying therapies for JALS."
Records the general absence of disease-modifying evidence in JALS, the context in which this subtype-restricted option sits.
PMID:34946884 SUPPORT Other
"although the utility of this approach is uncertain and may potentially worsen the overproduction of spingolipids"
A direct caution against the therapeutic rationale above, and a mechanistically pointed one: the SPTLC1 lesion curated in this entry is a gain-of-function escape from ORMDL inhibition causing excess canonical sphingolipid synthesis, so supplying more substrate to an already unrestrained enzyme could plausibly aggravate the primary defect rather than correct it. Recorded as PARTIAL because the source raises the concern without resolving it. The source's own spelling ("spingolipids") is preserved in the quote.
🔬

Diagnosis

2
Molecular genetic testing for a causal JALS gene
Whole-exome sequencing or a large next-generation-sequencing panel is recommended in both sporadic and familial juvenile-onset disease. Because JALS is genetically heterogeneous and the overall diagnostic yield is incomplete, a negative result does not exclude the diagnosis.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Identification of a causal variant assigns the genotypic subtype, which is what determines prognosis and trial eligibility in this entry.
Show evidence (1 reference)
PMID:38540369 SUPPORT Other
"Genetic testing is routinely recommended in JALS, both in sporadic and familial cases."
Establishes molecular testing as a routine diagnostic step in JALS rather than a purely counseling activity.
Biallelic SPG11 confirmation in the ALS5 subtype
Scoped to the ALS5 (SPG11) subtype. The molecular diagnosis at this locus rests on biallelic pathogenic variants together with the characteristic clinical and MRI findings - notably a thin corpus callosum, which is also the imaging feature that separates the allelic HSP presentation from ALS.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Two pathogenic SPG11 alleles in a proband with compatible clinical and MRI findings establish the diagnosis at this locus.
This section is a starting point, not a complete diagnostic workup for JALS. The clinical diagnostic criteria (El Escorial / Awaji), EMG, and the broader testing strategy are not yet curated here.
Show evidence (1 reference)
PMID:20301389 SUPPORT Human Clinical
"The diagnosis of SPG11 is established in a proband with characteristic clinical and MRI findings and biallelic pathogenic variants in SPG11 identified on molecular genetic testing."
GeneReviews DIAGNOSIS/TESTING. Defines the molecular-confirmation criterion for the SPG11 locus underlying ALS5.
📈

Progression

4
Indolent upper motor neuron-dominant course
ALS4
ALS4/SETX is the extreme of the indolent branch: slow progression with a normal life span. Recorded as a subtype-specific course, not a disease-level prognosis.
Show evidence (1 reference)
PMID:15106121 SUPPORT Human Clinical
"Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
The defining paper's statement of the ALS4 course.
Long-term survival with recessive SPG11 disease
ALS5
The SPG11 JALS pedigrees were explicitly ascertained for long-term survival, so this describes the ascertained population and may not generalise to all SPG11 juvenile ALS.
Show evidence (1 reference)
PMID:20110243 SUPPORT Human Clinical
"motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene"
PARTIAL: establishes long-term survival as the ascertainment criterion rather than as a demonstrated property of all SPG11 juvenile ALS.
Decades-long course with SPTLC1 disease
ALS27 Age: 22-52 years, single case with 30-year follow-up
Single-patient natural history; the longest documented follow-up of SPTLC1-related JALS.
Show evidence (2 references)
PMID:37497262 SUPPORT Human Clinical
"She lost independent ambulation at age 45 years."
Anchors the decades-long course: independent ambulation was retained for 23 years after presentation at age 22.
PMID:37497262 SUPPORT Human Clinical
"are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression"
States the slow-progression character of SPTLC1-related JALS.
Rapidly progressive lower motor neuron-dominant or bulbar-onset course
ALS6-JALS
The opposite pole from the indolent branch. In the index p.P525L case, tracheostomy was reached 14 months from onset in an 11-year-old.
Show evidence (2 references)
PMID:21907581 SUPPORT Human Clinical
"We report an 11-year-old girl affected by sporadic juvenile ALS with a rapid course resulting in tracheostomy after 14 months from the onset."
The case-level anchor for the rapidly fatal branch of JALS progression.
PMID:38540369 SUPPORT Other
"Rapidly progressive clinical course is more commonly observed in patients with specific pathogenic variants in FUS and SOD1 genes"
Attributes the rapid course to specific FUS and SOD1 variants rather than to JALS generally.
📊

Prevalence

2
Worldwide
Point Prevalence 0.008 per 100,000 <1 in 1,000,000
European multicentre estimate across 46 specialised ALS centres, restricted to onset before age 18, i.e. narrower than the age-25 JALS definition, so this understates JALS prevalence as defined here. Recorded as the only formal population estimate available.
Show evidence (1 reference)
PMID:38540369 SUPPORT Other
"A rare multicentric European study including data from 46 specialized ALS centers estimated a prevalence of 0.008 cases per 100,000 inhabitants with onset of symptoms before age 18, representing less than 0.1% of all ALS cases"
PARTIAL because the cited estimate uses an age-18 cutoff rather than the age-25 JALS definition.
United States, National ALS Registry 2015-2018, age-adjusted
Point Prevalence 0.24 per 100,000 (0.21–0.24) <1 in 1,000,000
Registry-based, and an undercount by construction: the Registry does not enrol patients under 18, and defines cases by age at diagnosis rather than age at symptom onset.
Show evidence (1 reference)
PMID:37789566 SUPPORT Human Clinical
"The crude and age adjusted prevalence rates remained steady from 2015 to 2018 with a slight increase in the age-adjusted prevalence from 0.21 to 0.24 per 100,000 persons during the interval"
Source of the registry-based age-adjusted prevalence range.
🌍

Epidemiology

2
Demographic distribution in the US National ALS Registry
Among 44 confirmed or likely juvenile ALS cases ascertained between 2010 and 2018, 79.5% were male and 54.5% were nonwhite — an inversion of the predominantly non-Hispanic White demographic of the Registry as a whole.
The authors flag this as unexpected and unexplained, and note that the cohort excludes patients under 18 and lacks genetic testing, so the demographic signal should not be over-read.
Show evidence (1 reference)
PMID:37789566 SUPPORT Human Clinical
"Of the 44 identified patients, 37.8% were diagnosed at age 24, were more likely to be nonwhite (54.5%), male (79.5%), and live in the Midwest or Northeast regions (54.5%) of the US."
Source of the sex and race distribution of registry-ascertained juvenile ALS.
Proportion with an identifiable monogenic basis
Approximately 40% of JALS cases have an identifiable monogenic cause, distributed across more than 20 genetic loci. A negative genetic test does not exclude the diagnosis.
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis"
Source of the 40% monogenic yield and the >20-locus figure.
PMID:34946884 SUPPORT Other
"Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases."
Independent statement of the same 40% figure from a separate review.
🔀

Differential Diagnoses

2

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

Hereditary Spastic Paraplegia
Overlapping Features Upper motor neuron-dominant JALS, particularly the ALS2 and SPG11 forms, mimics HSP; SPG11 is literally the same gene as AR-HSP with thin corpus callosum. Distinguishing features favouring HSP include a thin corpus callosum on imaging and a pure corticospinal phenotype with little clinically symptomatic motor neuronopathy.
Show evidence (1 reference)
PMID:38540369 SUPPORT Other
"Almost pure upper motor neuron compromise may also be observed, presenting with marked spasticity, brisk tendon reflexes, clonus, and extensor plantar responses"
Establishes the near-pure upper motor neuron presentation that creates the HSP differential.
Spinal Muscular Atrophy
Overlapping Features Lower motor neuron-dominant JALS mimics 5q and non-5q SMA and progressive muscular atrophy. In the 30-year SPTLC1 case the initial working diagnosis was late-onset SMA.
Show evidence (2 references)
PMID:38540369 SUPPORT Other
"Pure lower motor neuron involvement may also be identified, presenting with amyotrophy, weakness, fasciculation, hypotonia, and reduced or absent tendon reflexes"
Establishes the pure lower motor neuron presentation behind the SMA differential.
PMID:37497262 SUPPORT Human Clinical
"Based on these findings, she was given the presumptive diagnosis of late onset spinal muscular atrophy (SMA)."
A documented instance of JALS being misdiagnosed as SMA.
{ }

Source YAML

click to show 
name: Juvenile Amyotrophic Lateral Sclerosis
creation_date: "2026-08-20T00:00:00Z"
category: Mendelian
description: >
  Juvenile amyotrophic lateral sclerosis (JALS) is a rare, genetically
  heterogeneous motor neuron disease defined by onset of combined upper and
  lower motor neuron degeneration before age 25, presenting with facial
  spasticity, dysarthria, pyramidal signs and gait disorder. It is not simply
  an early-onset presentation of adult ALS: roughly 40% of cases have an
  identifiable monogenic basis distributed across more than 20 loci, and the
  recurrent genes (ALS2/alsin, SETX, SPG11/spatacsin, SIGMAR1, SPTLC1, and
  FUS) are largely disjoint from the C9orf72/SOD1/TARDBP spectrum that
  dominates adult ALS. Autosomal recessive inheritance predominates for ALS2,
  SPG11 and SIGMAR1; SETX, FUS and SPTLC1 act dominantly, the latter two
  usually as de novo variants. Prognosis is subtype-determined rather than
  uniform — upper motor neuron-dominant forms follow an indolent course with
  survival into adulthood, whereas lower motor neuron-dominant forms with
  early bulbar involvement (paradigmatically FUS p.P525L) are rapidly fatal.
  This entry is deliberately a thin root: it records what is shared across
  JALS and what distinguishes it from adult ALS, and defers subtype-specific
  mechanism to the per-subtype entries.
disease_term:
  preferred_term: juvenile amyotrophic lateral sclerosis
  term:
    id: MONDO:0017593
    label: juvenile amyotrophic lateral sclerosis
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
parents:
- Amyotrophic Lateral Sclerosis
- Motor Neuron Disease
- Neurodegenerative Disease
notes: >
  Scope and provenance. Curated from primary literature only; no deep-research
  provider pass was run for this entry (issue #8891). Orphanet ORPHA:300605 is
  the source of the MONDO:0017593 definition but could not be cited as
  structured evidence here: the Orphadata bulk XML that
  `just structured-rebuild-orphanet` reads is gitignored and
  `just refresh-orphadata` currently fails a pinned sha256 check against
  data/orphadata/MANIFEST.yaml, so no references_cache/ORPHA_300605.md exists.

  Cross-references rather than duplication. Adult-onset mechanism is curated in
  Amyotrophic_Lateral_Sclerosis.yaml and is deliberately not re-derived here.
  SPTLC1-related JALS (ALS27) is being curated as its own entry
  (Amyotrophic_Lateral_Sclerosis_27_Juvenile.yaml, PR #9067); the ALS27 subtype
  and genetic records below are intentionally summary-level and point at it.
  SIGMAR1 is also curated in
  Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive.yaml as HMNR2/dSMA2,
  the allelic lower-motor-neuron-only phenotype; ALS16 is retained here as a
  JALS subtype because MONDO parents MONDO:0013715 directly under
  MONDO:0017593.

  Named Entity Confusion guard. JALS sits in a numbered series (ALS1-ALS27+)
  and shares eponyms (Charcot, Lou Gehrig) with adult ALS, so every cited
  abstract was read to confirm it concerns juvenile-onset disease and the
  specific locus claimed. `just preflight-dr` was not applicable — no DR report
  was used, and MONDO:0017593 records no single causal gene, so the automated
  gene-frequency check would return SKIP; the manual gene/OMIM/synonym checks
  were done against `runoak -i sqlite:obo:mondo info` output instead.
references:
- reference: PMID:38540369
  title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
- reference: PMID:34946884
  title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
- reference: PMID:20301389
  title: "Spastic Paraplegia 11."
  tags:
  - GeneReviews
has_subtypes:
- name: ALS2
  display_name: ALS2 / juvenile ALS type 2 (ALS2, alsin; autosomal recessive)
  subtype_term:
    preferred_term: amyotrophic lateral sclerosis type 2, juvenile
    term:
      id: MONDO:0008780
      label: amyotrophic lateral sclerosis type 2, juvenile
  description: >
    Autosomal recessive juvenile ALS caused by biallelic loss-of-function
    variants in ALS2, encoding alsin — a multidomain guanine nucleotide
    exchange factor for the Rab5 GTPase family. ALS2 sits at one end of an
    allelic spectrum with infantile-onset ascending hereditary spastic
    paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS), which
    share the upper motor neuron lesion but lack (JPLS) or differ in the
    timing of (IAHSP) lower motor neuron involvement. Onset is typically later
    and the course slower than in other JALS forms.
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recessive mutations in the ALS2 gene are responsible for distinct MND conditions, namely Infantile-onset ascending hereditary spastic paralysis (IAHSP, OMIM:607225), Juvenile Primary Lateral Sclerosis (JPLS, OMIM:606353), and Juvenile Amyotrophic Lateral Sclerosis (JALS OMIM:205100)"
    explanation: >-
      Establishes the recessive ALS2 allelic spectrum and confirms that JALS
      (OMIM 205100, the OMIM xref of MONDO:0008780) is one of its three
      conditions.
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "symptoms generally appear later for ALS2-induced JALS patients (median age 4, 5 years), and the clinical course is slower"
    explanation: >-
      Supports the later onset and slower course that distinguish ALS2-related
      JALS from the other genetic subtypes.
- name: ALS4
  display_name: ALS4 (SETX, senataxin; autosomal dominant)
  subtype_term:
    preferred_term: amyotrophic lateral sclerosis type 4
    term:
      id: MONDO:0011223
      label: amyotrophic lateral sclerosis type 4
  description: >
    Autosomal dominant juvenile ALS caused by missense variants in SETX,
    encoding senataxin, a DNA/RNA helicase implicated in R-loop resolution and
    RNA processing. Distal muscle weakness and atrophy with pyramidal signs
    and normal sensation, onset usually before 25 years, slow progression and
    a normal life span. Included here on the strength of the defining paper's
    explicit designation of ALS4 as a juvenile ALS with onset below 25 years,
    despite MONDO parenting MONDO:0011223 only under familial ALS
    (MONDO:0005144) — see the MONDO-gap discussion below.
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs."
    explanation: >-
      Defines ALS4 as a dominant juvenile ALS and gives its distinguishing
      clinical triad.
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
    explanation: >-
      Establishes that ALS4 onset is definitionally within the juvenile window
      and that its course is indolent — the basis for listing it as a JALS
      subtype and for the slow-progression branch of `progression`.
- name: ALS5
  display_name: ALS5 (SPG11, spatacsin; autosomal recessive)
  subtype_term:
    preferred_term: amyotrophic lateral sclerosis type 5
    term:
      id: MONDO:0011196
      label: amyotrophic lateral sclerosis type 5
  description: >
    Autosomal recessive juvenile ALS caused by biallelic loss-of-function
    variants in SPG11, encoding spatacsin — the same gene whose loss causes
    autosomal recessive hereditary spastic paraplegia with thin corpus
    callosum. Ascertained in pedigrees selected for long-term survival, and
    associated with pseudobulbar affect and with chronic sensory axonal
    polyneuropathy on nerve conduction studies.
  evidence:
  - reference: PMID:20110243
    reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival"
    explanation: >-
      The paper's own quantitative result establishing biallelic SPG11
      alterations as a cause of recessive juvenile ALS, and recording that the
      pedigrees were ascertained for long-term survival.
  - reference: PMID:20110243
    reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum."
    explanation: >-
      Establishes the allelic relationship with AR-HSP/thin corpus callosum
      that makes SPG11 a shared locus rather than an ALS-specific one.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Onset occurs mainly during infancy or adolescence (range: age 1-31 years)
      and in rare cases as late as age 60 years.
    explanation: >-
      GeneReviews CLINICAL CHARACTERISTICS. PARTIAL because the chapter
      describes the allelic SPG11-HSP phenotype rather than ALS5 itself; it
      supports the juvenile-onset window of SPG11-related disease, which is
      what places this locus in a juvenile-onset entry, but is not a direct
      observation of the ALS5 presentation.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability with learning difficulties in childhood
      and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar
      involvement; and increased reflexes in the upper limbs
    explanation: >-
      GeneReviews CLINICAL CHARACTERISTICS. Independently corroborates the two
      features this subtype's description singles out - pseudobulbar
      involvement and peripheral neuropathy - as part of the SPG11 spectrum.
      PARTIAL for the same allelic-entity reason as above.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: SPG11 is inherited in an autosomal recessive manner.
    explanation: >-
      GeneReviews GENETIC COUNSELING. Authoritative-source confirmation of the
      autosomal recessive transmission asserted in this subtype's display_name
      and description.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carrier testing for at-risk family members and prenatal testing for
      at-risk pregnancies are possible once the pathogenic variants in a family
      are known.
    explanation: >-
      GeneReviews GENETIC COUNSELING. States the reproductive-counseling
      consequence of the biallelic SPG11 mechanism at this locus.
- name: ALS16
  display_name: ALS16 (SIGMAR1, sigma-1 receptor; autosomal recessive)
  subtype_term:
    preferred_term: amyotrophic lateral sclerosis type 16
    term:
      id: MONDO:0013715
      label: amyotrophic lateral sclerosis type 16
  description: >
    Autosomal recessive juvenile ALS caused by a homozygous SIGMAR1 variant in
    the transmembrane domain of the sigma-1 receptor, an endoplasmic reticulum
    chaperone. Described in a single consanguineous family; the mutant protein
    shows aberrant subcellular distribution and reduced resistance to
    ER-stress-induced apoptosis in a motor neuron-like cell line. SIGMAR1 is
    allelic with autosomal recessive distal hereditary motor neuronopathy
    (HMNR2), curated separately in
    Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive.yaml.
  evidence:
  - reference: PMID:21842496
    reference_title: "A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe a consanguineous family segregating juvenile ALS in an autosomal recessive pattern and describe the genetic variant responsible for the disorder."
    explanation: >-
      Establishes the recessive juvenile ALS pedigree from which ALS16 was
      defined, and the single-family evidence base for this subtype.
- name: ALS6-JALS
  display_name: FUS-related juvenile ALS (variant-level within ALS6; autosomal dominant, mostly de novo)
  description: >
    FUS-related juvenile ALS. Deliberately NOT bound to MONDO:0011951
    (amyotrophic lateral sclerosis type 6): ALS6 is a gene-level concept
    covering FUS-ALS at any age, most of which is adult-onset, and MONDO
    parents it under familial ALS and FTD-MND rather than under JALS. The
    juvenile presentation is a variant-level phenomenon — the C-terminal
    nuclear-localisation-signal variants, paradigmatically p.P525L, are the
    ones consistently associated with juvenile onset, a severe rapidly
    progressive course, and a high proportion of de novo occurrence. This is
    the most prevalent monogenic JALS form globally, and its neuropathology
    (FUS-immunoreactive basophilic inclusions, TDP-43 negative) is what
    separates JALS pathology from the adult TDP-43 proteinopathy paradigm.
  evidence:
  - reference: PMID:21907581
    reference_title: "P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this mutation is consistently associated with a specific phenotype characterized by juvenile onset, severe course and high proportion of de novo mutations in sporadic cases"
    explanation: >-
      States the variant-level (p.P525L), not gene-level, basis for treating
      FUS-JALS as a distinct juvenile entity, and supports keeping this
      subtype unbound to the gene-level MONDO:0011951.
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Currently, almost 40% of cases have an identifiable monogenic basis; type 6, associated with FUS gene variants, is the most prevalent globally."
    explanation: >-
      Establishes FUS-related disease as the most prevalent monogenic JALS
      subtype worldwide.
- name: ALS27
  display_name: ALS27 (SPTLC1, serine palmitoyltransferase; autosomal dominant, de novo)
  subtype_term:
    preferred_term: amyotrophic lateral sclerosis 27, juvenile
    term:
      id: MONDO:0859529
      label: amyotrophic lateral sclerosis 27, juvenile
  description: >
    Juvenile ALS caused by de novo, gain-of-function SPTLC1 variants in the
    transmembrane domain that escape ORMDL-mediated feedback inhibition of
    serine palmitoyltransferase, raising rather than lowering de novo
    sphingolipid synthesis. Distinguished from the other JALS subtypes by very
    early onset with failure to thrive, sparing of bulbar onset, and an
    exceptionally long course. Mechanism is curated in depth in the dedicated
    entry (Amyotrophic_Lateral_Sclerosis_27_Juvenile.yaml, PR #9067) and is
    summarised, not duplicated, here.
  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: >-
      The trio-exome result establishing de novo SPTLC1 variants as a juvenile
      ALS cause, together with the failure-to-thrive feature that flags this
      subtype clinically.
  - 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: "Notably, mutations in SPTLC1 occurred de novo in ten out of 16 JALS patients carrying SPTLC1 mutations,"
    explanation: >-
      Quantifies the de novo predominance of SPTLC1 variants across the
      reported JALS series, supporting the de novo characterisation of this
      subtype.
  - reference: PMID:36801857
    reference_title: "Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recently, SPTLC1 was identified as a disease-causative gene for JALS, and its mutations promoted enzymic activity, resulting in an increase in standard products."
    explanation: >-
      States the gain-of-function direction of SPTLC1-JALS variants - increased
      enzyme activity producing more of the canonical sphingolipid products,
      as opposed to the altered substrate selectivity seen in HSAN1A.
- name: JALS with dementia
  display_name: Juvenile amyotrophic lateral sclerosis with dementia
  subtype_term:
    preferred_term: juvenile amyotrophic lateral sclerosis with dementia
    term:
      id: MONDO:0008781
      label: juvenile amyotrophic lateral sclerosis with dementia
  description: >
    A MONDO-asserted child of juvenile ALS (OMIM 205200) characterised as
    slowly progressive juvenile ALS with concomitantly progressive dementia.
    Listed for completeness of the MONDO hierarchy; no causal gene is recorded
    and the concept sits uneasily against the contemporary review position
    that cognitive compromise is not a hallmark of JALS and that FTD has not
    been directly correlated with it. Curated at name level only — no
    mechanism, phenotype or genetic claim is made here.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Significant cognitive compromise and autonomic disturbances are rare, and Frontotemporal Dementia (FTD) has not been directly correlated with JALS."
    explanation: >-
      Cited as PARTIAL because it does not support the subtype; it records the
      contemporary review position that qualifies it, and is the reason this
      subtype is curated at name level only.
pathophysiology:
- name: Alsin Loss of Function and Rab5 Endosomal Trafficking Failure
  biological_scale: MOLECULAR
  role: Trigger
  description: >
    Biallelic ALS2 loss-of-function variants abolish or destabilise alsin, a
    1657-residue multidomain protein whose MORN/VPS9 module acts as a guanine
    nucleotide exchange factor for the Rab5 GTPase family, and whose
    self-oligomerisation is required for that GEF activity. Disease-associated
    changes alter the native oligomeric state or the protein's capacity to
    interact with partners, disrupting Rab5-dependent endosome formation and
    endocytic trafficking in motor neurons.
  genes:
  - preferred_term: ALS2
    term:
      id: hgnc:443
      label: ALS2
  molecular_functions:
  - preferred_term: Rab5 guanine nucleotide exchange factor activity
    modifier: DECREASED
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
  biological_processes:
  - preferred_term: endosomal transport
    modifier: DECREASED
    term:
      id: GO:0016197
      label: endosomal transport
  cellular_components:
  - preferred_term: early endosome
    term:
      id: GO:0005769
      label: early endosome
  genetic_context:
    gene:
      preferred_term: ALS2
      term:
        id: hgnc:443
        label: ALS2
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic (homozygous or compound heterozygous) loss-of-function ALS2
      variants; nonsense and frameshift changes predominate in reported
      pedigrees.
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Previous studies have demonstrated that Alsin preferentially targets the Rab5 GTPase family, which is involved in signal transduction, trafficking, and vesicle formation, suggesting that Alsin may play a key role in endocytosis and cytoskeletal reorganization in mammalian neuronal cells"
    explanation: >-
      Establishes alsin as a Rab5-directed GEF acting on endocytosis, the
      molecular function this node asserts is lost.
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "mutations within Alsin's structured domains may be responsible for the alteration of Alsin's native oligomerization state or Alsin's propensity to interact with protein partners"
    explanation: >-
      Supports disruption of oligomerisation and partner interaction as the
      proximal consequence of ALS2 mutation.
  - reference: PMID:39424348
    reference_title: "Phenotype and Genotype of Children with ALS2 gene-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The Alsin Rho Guanine Nucleotide Exchange Factor (ALS2) gene encodes a protein alsin that functions as a guanine nucleotide exchange factor."
    explanation: Confirms the GEF function of the ALS2 gene product in a clinical cohort report.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ALS2 variation leads to degeneration of the corticospinal upper motor
      neurons; the steps connecting endosomal GEF failure to selective motor
      neuron loss are not established.
    evidence:
    - reference: PMID:39424348
      reference_title: "Phenotype and Genotype of Children with ALS2 gene-Related Disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variations in ALS2 gene leads to degeneration of upper motor neurons of the corticospinal tract."
      explanation: >-
        Links the ALS2 lesion to corticospinal upper motor neuron degeneration.
        Supports the upper motor neuron half of the target node only; the lower
        motor neuron contribution in ALS2-related JALS is asserted from
        PMID:35053075 on the target node itself.
- name: Senataxin Helicase Dysfunction and RNA Processing Defect
  biological_scale: MOLECULAR
  role: Trigger
  description: >
    Heterozygous missense variants in SETX alter senataxin, a 302.8-kD protein
    carrying a DNA/RNA helicase domain homologous to RENT1 and IGHMBP2. The
    proposed mechanism is neuronal degeneration through dysfunction of helicase
    activity or of other steps in RNA processing — including resolution of
    R-loops, the co-transcriptional RNA:DNA hybrids senataxin acts on.
  genes:
  - preferred_term: SETX
    term:
      id: hgnc:445
      label: SETX
  molecular_functions:
  - preferred_term: RNA helicase activity
    modifier: DECREASED
    term:
      id: GO:0003724
      label: RNA helicase activity
  biological_processes:
  - preferred_term: R-loop processing
    modifier: DECREASED
    term:
      id: GO:0062176
      label: R-loop processing
  genetic_context:
    gene:
      preferred_term: SETX
      term:
        id: hgnc:445
        label: SETX
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
    allele_type: missense
    description: >-
      Heterozygous missense SETX variants segregating in a dominant pedigree
      (T3I, L389S, R2136H in the defining study).
  notes: >
    The R-loop processing annotation reflects senataxin's established
    molecular role; the cited ALS4 paper predates that characterisation and
    speaks instead of helicase activity or other steps in RNA processing.
    Replace with directly cited R-loop evidence if this node is elaborated.
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX)"
    explanation: Identifies the dominant missense SETX variants underlying ALS4.
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing."
    explanation: >-
      Establishes the helicase/RNA-processing molecular function this node
      asserts is impaired.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed route from helicase/RNA-processing dysfunction to motor neuron
      degeneration; the defining paper frames this as a suggestion, not a
      demonstrated chain.
    evidence:
    - reference: PMID:15106121
      reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing."
      explanation: >-
        PARTIAL because the source explicitly hedges - "suggest", "may cause";
        the edge is recorded as a proposed rather than established mechanism.
- name: Spatacsin Loss of Function and Lysosomal-Autophagic Dysfunction
  biological_scale: MOLECULAR
  role: Trigger
  description: >
    Biallelic loss-of-function alterations in SPG11 remove spatacsin, whose
    loss is the single most common cause of autosomal recessive hereditary
    spastic paraplegia with thin corpus callosum and which functions in
    lysosome biogenesis and autophagic-lysosome reformation. The same lesion
    can produce a recessive juvenile ALS phenotype with long-term survival,
    making SPG11 a shared HSP/ALS locus rather than an ALS-specific one.
  genes:
  - preferred_term: SPG11
    term:
      id: hgnc:11226
      label: SPG11
  biological_processes:
  - preferred_term: lysosome organization
    modifier: DECREASED
    term:
      id: GO:0007040
      label: lysosome organization
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  genetic_context:
    gene:
      preferred_term: SPG11
      term:
        id: hgnc:11226
        label: SPG11
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic SPG11 sequence alterations co-segregating with disease in
      consanguineous and non-consanguineous recessive JALS pedigrees.
  notes: >
    The GO annotations on this node describe spatacsin's established cellular
    role in lysosome/autophagy biology; they are not directly evidenced by the
    cited JALS papers, which establish the genetic lesion and the allelic HSP
    relationship. The lysosomal-autophagic mechanism is inferred from the
    SPG11-HSP literature and should be replaced with directly cited evidence
    if this node is elaborated.
  evidence:
  - reference: PMID:20110243
    reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study indicates that mutations in the spatascin gene could cause a much wider spectrum of clinical features than previously recognized, including autosomal recessive juvenile amyotrophic lateral sclerosis."
    explanation: >-
      The paper's own conclusion that SPG11 loss extends beyond HSP to
      recessive juvenile ALS. Quoted verbatim including the source's
      "spatascin" spelling.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      SPG11 alterations co-segregate with clinically definite ALS by revised
      El Escorial criteria and, in one pedigree with available CNS tissue, with
      ALS neuropathology.
    evidence:
    - reference: PMID:20110243
      reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were absent in controls and were associated with amyotrophic lateral sclerosis neuropathology in one member of one of these families for whom central nervous system tissue was available"
      explanation: >-
        The only neuropathological anchor in the defining study linking SPG11
        variants to motor neuron disease pathology rather than to HSP.
- name: Sigma-1 Receptor Mislocalization and ER Stress Vulnerability
  biological_scale: MOLECULAR
  role: Trigger
  description: >
    A homozygous SIGMAR1 variant affecting a conserved residue in the
    transmembrane domain of the sigma-1 receptor, an endoplasmic reticulum
    chaperone, produces aberrant subcellular distribution of the protein and
    reduces cellular resistance to apoptosis induced by ER stress in an NSC34
    motor neuron-like line.
  genes:
  - preferred_term: SIGMAR1
    term:
      id: hgnc:8157
      label: SIGMAR1
  biological_processes:
  - preferred_term: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0070059
      label: intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
  genetic_context:
    gene:
      preferred_term: SIGMAR1
      term:
        id: hgnc:8157
        label: SIGMAR1
    zygosity: HOMOZYGOUS
    description: >-
      Homozygous SIGMAR1 missense variant in a consanguineous pedigree,
      identified by homozygosity mapping to a ~120 kbp region on 9p13.3.
  evidence:
  - reference: PMID:21842496
    reference_title: "A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The mutated protein showed an aberrant subcellular distribution in NSC34 cells. Furthermore, cells expressing the mutant protein were less resistant to apoptosis induced by endoplasmic reticulum stress."
    explanation: >-
      The cell-model result establishing both the mislocalisation and the
      increased ER-stress apoptosis susceptibility this node asserts.
      IN_VITRO because the functional data come from a transfected motor
      neuron-like cell line, not from patients.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed route from sigma-1 receptor dysfunction to motor neuron loss.
      Rests on a single consanguineous family plus cell-model data; no human
      neuropathology is available.
    evidence:
    - reference: PMID:21842496
      reference_title: "A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Our findings emphasize the role of sigma-1 receptors in motor neuron function and disease."
      explanation: >-
        PARTIAL: the authors claim relevance to motor neuron function and
        disease but do not demonstrate the intervening steps in human tissue.
- name: FUS Cytoplasmic Mislocalization and Basophilic Inclusion Formation
  biological_scale: CELLULAR
  role: Trigger
  description: >
    C-terminal nuclear-localisation-signal variants in FUS, paradigmatically
    p.P525L, drive the FUS protein out of the nucleus into the cytoplasm of
    motor neurons, where it forms basophilic inclusions containing abnormal FUS
    aggregates and disorganised organelles. These inclusions are strongly
    FUS-immunoreactive and negative for TDP-43, and are found in spinal motor
    neurons, in layers IV-V of cerebral cortex and in brainstem nuclei — a
    distribution matching the combined upper and lower motor neuron lesion.
  genes:
  - preferred_term: FUS
    term:
      id: hgnc:4010
      label: FUS
  cell_types:
  - preferred_term: spinal motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  biological_processes:
  - preferred_term: protein import into nucleus
    modifier: DECREASED
    term:
      id: GO:0006606
      label: protein import into nucleus
  genetic_context:
    gene:
      preferred_term: FUS
      term:
        id: hgnc:4010
        label: FUS
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
    allele_type: missense
    description: >-
      Heterozygous, usually de novo C-terminal FUS variants disrupting the
      nuclear localisation signal (p.P525L; also the frameshifting
      c.1554_1557delACAG).
  evidence:
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum."
    explanation: >-
      Human autopsy evidence for FUS aggregation in basophilic inclusions in
      juvenile ALS spinal motor neurons.
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei."
    explanation: >-
      Establishes that the FUS pathology extends to cortical and brainstem
      neurons, matching the combined upper and lower motor neuron phenotype.
  - reference: PMID:20668261
    reference_title: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
    explanation: >-
      The immunohistochemical result establishing these inclusions as
      TDP-43-negative — the specific finding behind the TDP-43 discussion below.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: DIRECT
    description: >-
      FUS-bearing basophilic inclusions coincide with severe loss of spinal
      motor neurons at autopsy in juvenile ALS.
    evidence:
    - reference: PMID:20668261
      reference_title: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy and should be classified as ALS-FUS."
      explanation: >-
        Establishes the FUS proteinopathy as the defining molecular pathology
        of this juvenile ALS form.
- name: Serine Palmitoyltransferase Escape from ORMDL Inhibition
  biological_scale: MOLECULAR
  role: Trigger
  description: >
    De novo SPTLC1 variants located within a single membrane-spanning domain
    impede the interaction of the serine palmitoyltransferase complex with its
    regulatory ORMDL subunit. Because ORMDL proteins mediate the homeostatic
    feedback that restrains SPT, the result is increased SPT activity and
    increased de novo sphingolipid synthesis — a gain of function, and the
    mechanistic mirror image of HSAN1A, where SPTLC1 variants near the active
    site instead redirect substrate selectivity toward neurotoxic
    deoxysphingoid bases.
  genes:
  - preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  molecular_functions:
  - preferred_term: serine C-palmitoyltransferase activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004758
      label: serine C-palmitoyltransferase activity
  biological_processes:
  - preferred_term: sphingolipid biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0030148
      label: sphingolipid biosynthetic process
  genetic_context:
    gene:
      preferred_term: SPTLC1
      term:
        id: hgnc:11277
        label: SPTLC1
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
    allele_type: missense
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous de novo SPTLC1 missense variants in the transmembrane
      domain (p.Ala20Ser, p.Ser331Tyr, p.Leu38Arg; also the in-frame
      p.Leu39del).
  notes: >
    `modifier: GAIN_OF_FUNCTION` rather than `INCREASED` on the molecular
    function is deliberate and qualitative: the enzyme is not merely running
    faster but has escaped its ORMDL regulatory constraint. The downstream
    biosynthetic process is quantitative and therefore takes `INCREASED`.
    Detailed mechanism is curated in
    Amyotrophic_Lateral_Sclerosis_27_Juvenile.yaml.
  evidence:
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT."
    explanation: >-
      Establishes the shared structural location of SPTLC1-ALS variants and the
      loss of ORMDL-mediated restraint that defines this node.
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells."
    explanation: >-
      Direct functional confirmation of increased enzyme activity and increased
      sphingolipid synthesis, supporting the GAIN_OF_FUNCTION assignment.
  - reference: PMID:38788085
    reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In general, variants that cluster near the active site (PLP binding site), in SPTLC1 or SPTLC2, are usually associated with HSAN1 whereas those variants that affect the transmembrane domains of SPTLC1 or SPTSSA or intermembrane domain of SPTLC2 are more likely to cause jALS or cHSP."
    explanation: >-
      Establishes the position-dependent genotype-phenotype split between
      HSAN1 and juvenile ALS within the same gene — the two-failure-modes
      contrast this node records.
  downstream:
  - target: Combined Upper and Lower Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      SPT dysregulation in this direction produces a motor neuron disease
      affecting both upper and lower motor neurons while sparing sensory
      neurons; the steps between excess sphingolipid synthesis and selective
      motor neuron loss are not established.
    evidence:
    - reference: PMID:38788085
      reference_title: "Serine Palmitoyltransferase (SPT)-related Neurodegenerative and Neurodevelopmental Disorders."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "juvenile amyotrophic lateral sclerosis affecting the upper and lower motor neurons with sparing of sensory neurons"
      explanation: >-
        Links the SPT lesion to combined upper and lower motor neuron
        involvement with sensory sparing.
- name: Combined Upper and Lower Motor Neuron Degeneration
  biological_scale: CELLULAR
  role: Convergent effector
  description: >
    The shared distal node of JALS and the feature that defines it clinically:
    degeneration of both corticospinal upper motor neurons and brainstem and
    spinal lower motor neurons, producing simultaneous pyramidal signs
    (spasticity, hyperreflexia, extensor plantar responses) and lower motor
    neuron signs (amyotrophy, weakness, fasciculation). Each of the upstream
    genetic arms converges here, but the balance between the two limbs of the
    lesion is subtype-determined and is what sets the rate of progression.
  cell_types:
  - preferred_term: Betz upper motor neuron
    term:
      id: CL:4023052
      label: Betz upper motor neuron
  - preferred_term: alpha motor neuron
    term:
      id: CL:0008038
      label: alpha motor neuron
  biological_processes:
  - preferred_term: motor neuron apoptotic process
    modifier: INCREASED
    term:
      id: GO:0097049
      label: motor neuron apoptotic process
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical picture in typical JALS presentation is dominated by symmetric or asymmetric upper and lower motor neuron signs with variable rates of motor progression and bulbar compromise."
    explanation: >-
      Establishes combined upper and lower motor neuron involvement as the
      defining clinical expression of this convergent node.
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations"
    explanation: >-
      Confirms that the combined upper and lower motor neuron lesion before age
      25 is the operational definition of the JALS presentation.
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical manifestation reflects the degeneration of both upper motor neurons and lower motor neurons causing weakness of the lower limbs, spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction, sensory disturbances"
    explanation: >-
      Ties the combined degeneration directly to the JALS clinical signs
      recorded as phenotypes below.
  downstream:
  - target: Progressive Motor Handicap and Respiratory Failure
    causal_link_type: DIRECT
    description: >-
      Progressive loss of motor units leads to loss of ambulation, bulbar
      failure and ultimately ventilatory failure; the rate is subtype-dependent.
    evidence:
    - reference: PMID:38540369
      reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "certain subtypes with lower motor neuron-dominant features and early bulbar compromise lead to rapidly progressive motor handicap"
      explanation: >-
        Establishes progression to motor handicap as the organism-level
        consequence, and that the rate depends on which limb of the lesion
        dominates.
- name: Progressive Motor Handicap and Respiratory Failure
  biological_scale: ORGANISM
  role: Outcome
  description: >
    The organism-level endpoint. In lower motor neuron-dominant and
    bulbar-onset forms, death from respiratory failure follows within months to
    a few years of onset; in upper motor neuron-dominant forms, motor handicap
    accumulates over decades with survival into adulthood and, for ALS4,
    a normal life span. There is no single JALS prognosis.
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Death usually occurs from respiratory failure between 7 and 84 months after onset"
    explanation: >-
      PARTIAL: gives the fatal endpoint and its typical interval, but the
      figures are drawn from the reviewed JALS case literature and do not apply
      to the indolent upper motor neuron-dominant subtypes recorded in
      `progression`.
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Disease prognosis varies from rapidly progressive to an indolent course."
    explanation: >-
      Supports the explicit refusal to state a single disease-level prognosis
      for JALS.
phenotypes:
- category: Neurologic
  name: Combined Upper and Lower Motor Neuron Signs
  description: >
    Simultaneous pyramidal and lower motor neuron findings, symmetric or
    asymmetric, with variable bulbar compromise. This combination arising
    before age 25 years is the operational definition of JALS; the onset
    criterion is definitional, not merely characteristic.
  phenotype_term:
    preferred_term: Upper motor neuron dysfunction
    term:
      id: HP:0002493
      label: Upper motor neuron dysfunction
    onset:
      onset_category: JUVENILE
      max_age_years: 25
      notes: >-
        Onset before age 25 years is the criterion separating JALS from adult
        ALS. HP:0003621 (Juvenile onset) is a clinical-modifier term outside
        the PhenotypeTerm dynamic enum, so the criterion is recorded here as a
        structured onset qualifier rather than as a phenotype of its own.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The clinical picture in typical JALS presentation is dominated by symmetric or asymmetric upper and lower motor neuron signs with variable rates of motor progression and bulbar compromise."
    explanation: Direct statement of the defining combined phenotype.
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JALS is defined as onset before age 25."
    explanation: >-
      States the defining age criterion recorded in the onset qualifier on this
      phenotype.
- category: Neurologic
  name: Spasticity of Facial Muscles
  description: >
    Facial and pseudobulbar spasticity, named in the MONDO/Orphanet definition
    of JALS as one of its three cardinal features alongside dysarthria and gait
    disorder.
  phenotype_term:
    preferred_term: Spasticity of facial muscles
    term:
      id: HP:0002491
      label: Spasticity of facial muscles
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Clinical manifestation reflects the degeneration of both upper motor neurons and lower motor neurons causing weakness of the lower limbs, spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction, sensory disturbances"
    explanation: Names facial spasticity among the JALS clinical manifestations.
- category: Neurologic
  name: Dysarthria
  description: Spastic and/or flaccid dysarthria from combined corticobulbar and bulbar involvement.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "spasticity of facial muscles, uncontrolled laughter, dysarthria, bladder dysfunction"
    explanation: Names dysarthria among the JALS clinical manifestations.
- category: Neurologic
  name: Pseudobulbar Affect
  description: >
    Emotional lability with uncontrolled laughing or crying, disproportionate
    to mood. Most observed in the ALS2 and SPG11 subtypes. No `subtype:`
    qualifier is asserted: the slot is single-valued and the feature is
    evidenced at two loci, so naming one of them would be less faithful than
    naming none.
  phenotype_term:
    preferred_term: Pseudobulbar affect
    term:
      id: HP:0002193
      label: Pseudobulbar affect
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pseudobulbar affect is most observed in ALS2 and SPG11 variants"
    explanation: >-
      Attributes pseudobulbar affect specifically to the ALS2 and SPG11
      subtypes rather than to JALS generally.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability with learning difficulties in childhood
      and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar
      involvement; and increased reflexes in the upper limbs
    explanation: >-
      GeneReviews CLINICAL CHARACTERISTICS. An independent authoritative source
      placing pseudobulbar involvement at the SPG11 locus, corroborating the
      second of the two loci named above and so supporting the decision to
      assert no single `subtype:` here. PARTIAL because the chapter describes
      the allelic SPG11-HSP presentation rather than ALS5 itself.
- category: Neurologic
  name: Distal Amyotrophy
  description: >
    Distal limb muscle wasting, the presenting lower motor neuron sign in the
    ALS4/SETX form, where it occurs with normal sensation and pyramidal signs.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  subtype: ALS4
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs"
    explanation: Establishes distal amyotrophy as the ALS4 presenting sign.
- category: Neurologic
  name: Fasciculations
  description: >
    Spontaneous motor unit discharges, including tongue fasciculation,
    reflecting lower motor neuron involvement.
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - 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: >-
      Case-level documentation of fasciculation alongside pyramidal signs in a
      juvenile ALS patient.
- category: Neurologic
  name: Spastic Paraparesis
  description: >
    Lower-limb spasticity and weakness, the usual presenting complaint in the
    upper motor neuron-dominant forms and the feature that makes JALS mimic
    hereditary spastic paraplegia.
  phenotype_term:
    preferred_term: Spastic paraparesis
    term:
      id: HP:0002313
      label: Spastic paraparesis
  evidence:
  - reference: PMID:39424348
    reference_title: "Phenotype and Genotype of Children with ALS2 gene-Related Disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical findings observed in our patients were insidious onset progressive spastic paraparesis, contractures, and dysarthria."
    explanation: >-
      Documents progressive spastic paraparesis in a clinical cohort of
      children with ALS2-related disease.
- category: Neurologic
  name: Respiratory Failure
  description: >
    Ventilatory failure from respiratory muscle denervation; the usual cause of
    death in the rapidly progressive subtypes, and a late complication in the
    indolent ones.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Death usually occurs from respiratory failure between 7 and 84 months after onset"
    explanation: Establishes respiratory failure as the terminal event in JALS.
- category: Neurologic
  name: Sensory Axonal Polyneuropathy
  description: >
    Chronic sensory axonal polyneuropathy on nerve conduction studies. Not a
    feature of JALS generally — restricted to the SPG11, VRK1 and SPTLC1
    subtypes, and its presence is a genotype clue rather than a diagnostic
    criterion. No `subtype:` qualifier is asserted: the slot is single-valued
    and the source names three loci, so naming one would misreport the scope.
  phenotype_term:
    preferred_term: Sensory neuropathy
    term:
      id: HP:0000763
      label: Sensory neuropathy
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nerve conduction studies may also demonstrate chronic sensory axonal polyneuropathy in cases of JALS associated with SPG11, VRK1, and SPTLC1 genes"
    explanation: >-
      Restricts sensory involvement to named genetic subtypes rather than to
      JALS as a whole.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild intellectual disability with learning difficulties in childhood
      and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar
      involvement; and increased reflexes in the upper limbs
    explanation: >-
      GeneReviews CLINICAL CHARACTERISTICS. Independently places peripheral
      neuropathy at the SPG11 locus, corroborating one of the three loci named
      above. PARTIAL because the chapter describes the allelic SPG11-HSP
      presentation rather than ALS5 itself.
- category: Growth
  name: Failure to Thrive
  description: >
    Severe growth retardation accompanying the SPTLC1/ALS27 subtype; it was the
    ascertainment feature in the trio-exome study that identified the gene.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  subtype: ALS27
  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: >-
      Ties failure to thrive specifically to SPTLC1-related juvenile ALS.
genetic:
- name: ALS2
  gene_term:
    preferred_term: ALS2
    term:
      id: hgnc:443
      label: ALS2
  relationship_type: CAUSATIVE
  subtype: ALS2
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: >-
      Biallelic ALS2 variants; recessive inheritance is more frequent in
      consanguineous families.
  notes: >
    ALS2 is one of the three or four most commonly implicated JALS genes.
    Biallelic ALS2 loss causes an allelic spectrum (IAHSP, JPLS, JALS) rather
    than a single phenotype, so an ALS2 genotype does not by itself predict the
    JALS presentation.
  evidence:
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the most common gene mutations associated with JALS are FUS, SETX, and ALS2"
    explanation: Establishes ALS2 among the most common JALS genes.
  - reference: PMID:35053075
    reference_title: "ALS2-Related Motor Neuron Diseases: From Symptoms to Molecules."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JALS is inherited in an autosomal-recessive pattern involving ALS2, SPG11, and SIGMAR1, while the SETX, UBQLN2, and FUS mutations are described as an underlying cause of an autosomal-dominant form of JALS"
    explanation: >-
      Assigns the recessive/dominant split across the JALS genes, supporting
      the inheritance annotations on this and the following genetic records.
- name: SETX
  gene_term:
    preferred_term: SETX
    term:
      id: hgnc:445
      label: SETX
  relationship_type: CAUSATIVE
  subtype: ALS4
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Heterozygous SETX missense variants; ALS4 is the one JALS form in which
      dominant inheritance was established from a large multigenerational
      pedigree rather than from de novo cases.
  notes: >
    SETX is allelic between two mechanistically distinct diseases with opposite
    inheritance: dominant missense variants cause ALS4 (juvenile ALS), whereas
    biallelic pathogenic variants cause ataxia with oculomotor apraxia type 2
    (AOA2). This is the SETX counterpart of the SPTLC1/HSAN1A contrast — one
    gene, two failure modes, two diseases.
  evidence:
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In familial cases, the gene mutations are mostly inherited in an autosomal recessive pattern and mutations in SETX are inherited in an autosomal dominant fashion."
    explanation: >-
      Establishes SETX as the dominant exception within a predominantly
      recessive familial JALS gene set.
  - reference: PMID:9497266
    reference_title: "Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed genetic mapping studies of an 11-generation pedigree with an autosomal dominant, juvenile-onset motor-systems disease."
    explanation: >-
      The linkage study that established ALS4 as a dominant juvenile-onset
      motor neuron disease, before SETX was identified.
  - reference: PMID:20301333
    reference_title: "Ataxia with Oculomotor Apraxia Type 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Identification of biallelic pathogenic variants in SETX by molecular genetic testing confirms the diagnosis."
    explanation: >-
      Cited for the AOA2 half of the SETX allelic contrast ONLY - this
      GeneReviews chapter is about AOA2, not about ALS4 or JALS. It establishes
      that AOA2 requires biallelic SETX variants, which together with
      PMID:15106121 (dominant missense in ALS4) supports the two-failure-modes
      note above.
- name: SPG11
  gene_term:
    preferred_term: SPG11
    term:
      id: hgnc:11226
      label: SPG11
  relationship_type: CAUSATIVE
  subtype: ALS5
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: Biallelic SPG11 sequence alterations co-segregating in recessive pedigrees.
  case_fractions:
  - population: 25 families with autosomal recessive juvenile ALS and long-term survival
    cohort_size: 25
    notes: >-
      10 of 25 ascertained pedigrees carried SPG11 alterations. Note the cohort
      was selected for long-term survival, so this fraction is not
      generalisable to unselected JALS.
    evidence:
    - reference: PMID:20110243
      reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "12 sequence alterations in the spatacsin gene (one of which is novel, IVS30 + 1 G > A) were identified in 10 unrelated pedigrees with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival"
      explanation: >-
        Reports 10 SPG11-positive pedigrees within the 25-family ascertained
        cohort described in the same abstract.
  evidence:
  - reference: PMID:20110243
    reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants seemed to be pathogenic since they co-segregated with the disease in all pedigrees"
    explanation: Co-segregation evidence for pathogenicity of the SPG11 alterations.
- name: SIGMAR1
  gene_term:
    preferred_term: SIGMAR1
    term:
      id: hgnc:8157
      label: SIGMAR1
  relationship_type: CAUSATIVE
  subtype: ALS16
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    description: Homozygous SIGMAR1 variant in a consanguineous pedigree.
  notes: >
    SIGMAR1 is allelic with autosomal recessive distal hereditary motor
    neuronopathy (HMNR2/dSMA2), which is curated in
    Distal_Hereditary_Motor_Neuronopathy_Autosomal_Recessive.yaml. The dHMN
    phenotype is lower-motor-neuron-only; ALS16 adds the upper motor neuron
    lesion. The evidence base for ALS16 is a single consanguineous family.
  evidence:
  - reference: PMID:21842496
    reference_title: "A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a shared homozygosity region in affected individuals that spans ~120 kbp on chromosome 9p13.3 containing 9 RefSeq genes. Sequencing the SIGMAR1 gene revealed a mutation affecting a highly conserved amino acid located in the transmembrane domain of the encoded protein, sigma-1 receptor."
    explanation: >-
      The mapping and sequencing result establishing SIGMAR1 as the ALS16 gene.
- name: FUS
  gene_term:
    preferred_term: FUS
    term:
      id: hgnc:4010
      label: FUS
  relationship_type: CAUSATIVE
  subtype: ALS6-JALS
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      Heterozygous dominant FUS variants, most arising de novo, so that
      apparently sporadic juvenile presentations are the rule.
  notes: >
    The juvenile phenotype is variant-level, not gene-level: FUS-ALS as a whole
    is mostly adult-onset, and it is specifically the C-terminal
    nuclear-localisation-signal variants (p.P525L and the frameshifting
    c.1554_1557delACAG) that produce the severe juvenile form. This is why the
    ALS6-JALS subtype above is left unbound to MONDO:0011951.
  evidence:
  - reference: PMID:21907581
    reference_title: "P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years."
    explanation: >-
      Establishes that only some FUS variants produce the juvenile form,
      supporting the variant-level rather than gene-level treatment.
  - reference: PMID:20668261
    reference_title: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FUS c.1574C>T (P525L) and c.1554_1557delACAG mutations are associated with this distinct phenotype."
    explanation: >-
      Names the two specific C-terminal FUS variants associated with the
      juvenile basophilic-inclusion phenotype.
  - 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 in FUS were described as the most common cause of the autosomal dominant form in JALS, and the majority was de novo."
    explanation: >-
      Corroborates both the dominant inheritance and the de novo predominance
      recorded on this genetic record.
- name: SPTLC1
  gene_term:
    preferred_term: SPTLC1
    term:
      id: hgnc:11277
      label: SPTLC1
  relationship_type: CAUSATIVE
  subtype: ALS27
  variant_origin: DE_NOVO
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: Heterozygous de novo SPTLC1 variants; no family history in reported probands.
  notes: >
    SPTLC1 causes two different diseases by two different molecular routes:
    transmembrane-domain variants escape ORMDL feedback and increase canonical
    sphingolipid synthesis, causing juvenile ALS (ALS27), while active-site
    variants alter substrate selectivity to generate deoxysphingoid bases,
    causing HSAN1A (MONDO:0008086). The juvenile ALS route is the
    gain-of-function one. Detail is curated in
    Amyotrophic_Lateral_Sclerosis_27_Juvenile.yaml.
  evidence:
  - reference: PMID:37348646
    reference_title: "SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS."
    explanation: >-
      States the gain-of-function direction that distinguishes SPTLC1-JALS from
      the HSAN1A mechanism.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway."
    explanation: >-
      Records the HSAN1A allelism from which the juvenile ALS phenotype was
      distinguished.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.008
  notes: >-
    European multicentre estimate across 46 specialised ALS centres, restricted
    to onset before age 18, i.e. narrower than the age-25 JALS definition, so
    this understates JALS prevalence as defined here. Recorded as the only
    formal population estimate available.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A rare multicentric European study including data from 46 specialized ALS centers estimated a prevalence of 0.008 cases per 100,000 inhabitants with onset of symptoms before age 18, representing less than 0.1% of all ALS cases"
    explanation: >-
      PARTIAL because the cited estimate uses an age-18 cutoff rather than the
      age-25 JALS definition.
- population: United States, National ALS Registry 2015-2018, age-adjusted
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_per_100000: 0.24
  rate_low: 0.21
  rate_high: 0.24
  notes: >-
    Registry-based, and an undercount by construction: the Registry does not
    enrol patients under 18, and defines cases by age at diagnosis rather than
    age at symptom onset.
  evidence:
  - reference: PMID:37789566
    reference_title: "A brief report on juvenile amyotrophic lateral sclerosis cases in the United States National ALS Registry: 2010-2018."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The crude and age adjusted prevalence rates remained steady from 2015 to 2018 with a slight increase in the age-adjusted prevalence from 0.21 to 0.24 per 100,000 persons during the interval"
    explanation: Source of the registry-based age-adjusted prevalence range.
epidemiology:
- name: Demographic distribution in the US National ALS Registry
  description: >
    Among 44 confirmed or likely juvenile ALS cases ascertained between 2010
    and 2018, 79.5% were male and 54.5% were nonwhite — an inversion of the
    predominantly non-Hispanic White demographic of the Registry as a whole.
  notes: >-
    The authors flag this as unexpected and unexplained, and note that the
    cohort excludes patients under 18 and lacks genetic testing, so the
    demographic signal should not be over-read.
  evidence:
  - reference: PMID:37789566
    reference_title: "A brief report on juvenile amyotrophic lateral sclerosis cases in the United States National ALS Registry: 2010-2018."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 44 identified patients, 37.8% were diagnosed at age 24, were more likely to be nonwhite (54.5%), male (79.5%), and live in the Midwest or Northeast regions (54.5%) of the US."
    explanation: Source of the sex and race distribution of registry-ascertained juvenile ALS.
- name: Proportion with an identifiable monogenic basis
  description: >
    Approximately 40% of JALS cases have an identifiable monogenic cause,
    distributed across more than 20 genetic loci. A negative genetic test does
    not exclude the diagnosis.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "More than 20 different genetic loci have been associated with both sporadic and familial juvenile Amyotrophic Lateral Sclerosis. Currently, almost 40% of cases have an identifiable monogenic basis"
    explanation: Source of the 40% monogenic yield and the >20-locus figure.
  - reference: PMID:34946884
    reference_title: "Juvenile Amyotrophic Lateral Sclerosis: A Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Juvenile amyotrophic lateral sclerosis (JALS) is a rare group of motor neuron disorders with gene association in 40% of cases."
    explanation: Independent statement of the same 40% figure from a separate review.
progression:
- phase: Indolent upper motor neuron-dominant course
  subtype: ALS4
  notes: >-
    ALS4/SETX is the extreme of the indolent branch: slow progression with a
    normal life span. Recorded as a subtype-specific course, not a
    disease-level prognosis.
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
    explanation: The defining paper's statement of the ALS4 course.
- phase: Long-term survival with recessive SPG11 disease
  subtype: ALS5
  notes: >-
    The SPG11 JALS pedigrees were explicitly ascertained for long-term
    survival, so this describes the ascertained population and may not
    generalise to all SPG11 juvenile ALS.
  evidence:
  - reference: PMID:20110243
    reference_title: "SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene"
    explanation: >-
      PARTIAL: establishes long-term survival as the ascertainment criterion
      rather than as a demonstrated property of all SPG11 juvenile ALS.
- phase: Decades-long course with SPTLC1 disease
  subtype: ALS27
  age_range: 22-52 years, single case with 30-year follow-up
  notes: >-
    Single-patient natural history; the longest documented follow-up of
    SPTLC1-related JALS.
  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 lost independent ambulation at age 45 years."
    explanation: >-
      Anchors the decades-long course: independent ambulation was retained for
      23 years after presentation at age 22.
  - 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: "are a recently identified cause of juvenile amyotrophic lateral sclerosis (JALS) with slow progression"
    explanation: States the slow-progression character of SPTLC1-related JALS.
- phase: Rapidly progressive lower motor neuron-dominant or bulbar-onset course
  subtype: ALS6-JALS
  notes: >-
    The opposite pole from the indolent branch. In the index p.P525L case,
    tracheostomy was reached 14 months from onset in an 11-year-old.
  evidence:
  - reference: PMID:21907581
    reference_title: "P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report an 11-year-old girl affected by sporadic juvenile ALS with a rapid course resulting in tracheostomy after 14 months from the onset."
    explanation: The case-level anchor for the rapidly fatal branch of JALS progression.
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Rapidly progressive clinical course is more commonly observed in patients with specific pathogenic variants in FUS and SOD1 genes"
    explanation: >-
      Attributes the rapid course to specific FUS and SOD1 variants rather than
      to JALS generally.
histopathology:
- name: FUS-immunoreactive, TDP-43-negative basophilic inclusions
  description: >-
    The defining neuropathology of FUS-related juvenile ALS. Remaining spinal
    motor neurons contain basophilic cytoplasmic inclusions that are strongly
    immunoreactive for FUS protein and negative for TDP-43. This is what
    separates juvenile from adult ALS at the level of pathology rather than
    genetics, and it is the evidential basis for the
    `jals_not_tdp43_proteinopathy` discussion: adult ALS is a TDP-43
    proteinopathy in the great majority of cases, whereas these juvenile
    inclusions are not.
  context: Postmortem spinal cord; two autopsy cases with FUS mutations.
  subtype: ALS6-JALS
  evidence:
  - reference: PMID:20668261
    reference_title: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
    explanation: >-
      The immunohistochemical result itself - FUS-positive, TDP-43-negative -
      recorded here as a primary histopathological finding rather than only as
      support for a mechanistic node.
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum."
    explanation: >-
      Autopsy description pairing the inclusion pathology with severe spinal
      motor neuron loss and organelle disorganization in the surviving neurons.
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein."
    explanation: >-
      The reciprocal control observation within the same study: the FUS
      accumulation is absent from late-onset sporadic ALS, which is what makes
      this a juvenile-specific pathological signature rather than a shared one.
  notes: >-
    Scoped to FUS-related juvenile ALS, and deliberately not generalized. The
    other subtypes have no comparably characterized aggregate pathology - the
    ALS2, SETX, SPG11, SIGMAR1 and SPTLC1 mechanisms are trafficking,
    RNA-processing, lysosomal, ER-stress and sphingolipid lesions respectively,
    and none has an established inclusion phenotype curated here. Do not read
    this section as the neuropathology of JALS as a whole. Evidence base is two
    autopsy cases.
- name: Extramotor FUS pathology in cerebral cortex and brainstem
  description: >-
    The same FUS-positive inclusions are found beyond the spinal cord, in
    layers IV-V of cerebral cortex and in several brainstem nuclei. The
    anatomical distribution matches the combined upper and lower motor neuron
    phenotype that defines the disease clinically.
  context: Postmortem cerebral cortex and brainstem; same two autopsy cases.
  subtype: ALS6-JALS
  evidence:
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei."
    explanation: >-
      Establishes the extramotor and upper-motor-neuron distribution of the FUS
      pathology, corroborating the combined UMN/LMN clinical picture.
diagnosis:
- name: Molecular genetic testing for a causal JALS gene
  description: >-
    Whole-exome sequencing or a large next-generation-sequencing panel is
    recommended in both sporadic and familial juvenile-onset disease. Because
    JALS is genetically heterogeneous and the overall diagnostic yield is
    incomplete, a negative result does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Identification of a causal variant assigns the genotypic subtype, which is
    what determines prognosis and trial eligibility in this entry.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Genetic testing is routinely recommended in JALS, both in sporadic and familial cases."
    explanation: >-
      Establishes molecular testing as a routine diagnostic step in JALS rather
      than a purely counseling activity.
- name: Biallelic SPG11 confirmation in the ALS5 subtype
  description: >-
    Scoped to the ALS5 (SPG11) subtype. The molecular diagnosis at this locus
    rests on biallelic pathogenic variants together with the characteristic
    clinical and MRI findings - notably a thin corpus callosum, which is also
    the imaging feature that separates the allelic HSP presentation from ALS.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Two pathogenic SPG11 alleles in a proband with compatible clinical and MRI
    findings establish the diagnosis at this locus.
  evidence:
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of SPG11 is established in a proband with characteristic
      clinical and MRI findings and biallelic pathogenic variants in SPG11
      identified on molecular genetic testing.
    explanation: >-
      GeneReviews DIAGNOSIS/TESTING. Defines the molecular-confirmation
      criterion for the SPG11 locus underlying ALS5.
  notes: >-
    This section is a starting point, not a complete diagnostic workup for
    JALS. The clinical diagnostic criteria (El Escorial / Awaji), EMG, and the
    broader testing strategy are not yet curated here.
treatments:
- name: Multidisciplinary Supportive Care
  description: >
    Coordinated non-pharmacological care by physical, speech and occupational
    therapists, nutritionists, psychologists and nurses. This is the core
    therapy for JALS; symptomatic management improves quality of life in more
    advanced disease.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Non-pharmacological treatment based on a specialized multidisciplinary team approach, involving physical, speech, and occupational therapists, nutritionists, psychologists, and nurses, represents the core therapy of patients with JALS."
    explanation: Establishes multidisciplinary supportive care as the core JALS therapy.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Care by a multidisciplinary team; physiotherapy to stretch spastic
      muscles; antispastic drugs such as baclofen; botulin toxin and intrathecal
      baclofen for severe and disabling spasticity when oral drugs are
      ineffective.
    explanation: >-
      GeneReviews MANAGEMENT. Corroborates the multidisciplinary model and
      specifies the spasticity-directed measures for the SPG11 locus underlying
      the ALS5 subtype. PARTIAL because the recommendation is written for
      allelic SPG11-HSP, not for JALS as a whole.
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surveillance: Evaluation every six months to adjust physiotherapy and
      medications.
    explanation: >-
      GeneReviews MANAGEMENT (surveillance). Supplies the review interval for
      ongoing supportive care at this locus; PARTIAL for the same
      allelic-entity reason.
- name: Genetic Counseling
  description: >
    Counseling of the proband and at-risk relatives once a causal variant is
    known: recurrence-risk discussion appropriate to the subtype's inheritance
    mode, cascade carrier testing of relatives, and reproductive options
    including prenatal testing. The recurrence risk differs sharply across this
    entry's subtypes - 25% per pregnancy for the autosomal recessive loci
    (ALS2, SPG11, SIGMAR1) against a dominant or, for most FUS-related and
    SPTLC1 juvenile disease, de novo mechanism - so counseling is downstream of
    the molecular diagnosis rather than parallel to it. The testing strategy
    itself is curated under `diagnosis:`, not here.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301389
    reference_title: Spastic Paraplegia 11.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Carrier testing for at-risk family members and prenatal testing for
      at-risk pregnancies are possible once the pathogenic variants in a family
      are known.
    explanation: >-
      GeneReviews GENETIC COUNSELING. Establishes the two counseling actions
      that follow a molecular diagnosis - cascade carrier testing and prenatal
      testing - for the SPG11 locus underlying the ALS5 subtype. PARTIAL
      because the chapter is written for allelic SPG11-HSP rather than for JALS
      as a whole, and because the recurrence-risk arithmetic it states applies
      only to the recessive subtypes.
- name: Oral L-Serine Supplementation
  description: >
    Substrate-based therapy proposed for SPTLC1-related JALS. Subtype-restricted;
    there is no evidence base for its use in other JALS forms.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: L-serine
      term:
        id: CHEBI:17115
        label: L-serine
  target_mechanisms:
  - target: Serine Palmitoyltransferase Escape from ORMDL Inhibition
    treatment_effect: INHIBITS
    description: >-
      Aimed at the SPTLC1 gain-of-function node. The review names it as a
      therapeutic option for SPTLC1-related JALS without reporting trial
      outcome data, so the target link is recorded as PARTIAL.
    evidence:
    - reference: PMID:38540369
      reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Other monogenic forms of therapeutic interest include SPTLC1-related JALS which is amenable to oral L-serine supplementation therapy"
      explanation: >-
        PARTIAL: names L-serine as applicable to the SPTLC1 subtype but reports
        no efficacy data, and does not itself describe the molecular action on
        the SPT complex.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There are still very limited specific data regarding disease-modifying therapies for JALS."
    explanation: >-
      Records the general absence of disease-modifying evidence in JALS, the
      context in which this subtype-restricted option sits.
  - reference: PMID:34946884
    reference_title: >-
      Juvenile amyotrophic lateral sclerosis: a review.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "although the utility of this approach is uncertain and may potentially worsen the overproduction of spingolipids"
    explanation: >-
      A direct caution against the therapeutic rationale above, and a
      mechanistically pointed one: the SPTLC1 lesion curated in this entry is a
      gain-of-function escape from ORMDL inhibition causing excess canonical
      sphingolipid synthesis, so supplying more substrate to an already
      unrestrained enzyme could plausibly aggravate the primary defect rather
      than correct it. Recorded as PARTIAL because the source raises the
      concern without resolving it. The source's own spelling
      ("spingolipids") is preserved in the quote.
  notes: >-
    The evidence here is a single reported patient who gained weight, set
    against an explicit published concern that the approach may worsen the
    underlying sphingolipid overproduction. This is a proposed option under
    active question, not an established therapy, and it should not be
    presented as one.
differential_diagnoses:
- name: Hereditary Spastic Paraplegia
  description: >
    Upper motor neuron-dominant JALS, particularly the ALS2 and SPG11 forms,
    mimics HSP; SPG11 is literally the same gene as AR-HSP with thin corpus
    callosum. Distinguishing features favouring HSP include a thin corpus
    callosum on imaging and a pure corticospinal phenotype with little
    clinically symptomatic motor neuronopathy.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Almost pure upper motor neuron compromise may also be observed, presenting with marked spasticity, brisk tendon reflexes, clonus, and extensor plantar responses"
    explanation: >-
      Establishes the near-pure upper motor neuron presentation that creates
      the HSP differential.
- name: Spinal Muscular Atrophy
  description: >
    Lower motor neuron-dominant JALS mimics 5q and non-5q SMA and progressive
    muscular atrophy. In the 30-year SPTLC1 case the initial working diagnosis
    was late-onset SMA.
  evidence:
  - reference: PMID:38540369
    reference_title: "Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pure lower motor neuron involvement may also be identified, presenting with amyotrophy, weakness, fasciculation, hypotonia, and reduced or absent tendon reflexes"
    explanation: >-
      Establishes the pure lower motor neuron presentation behind the SMA
      differential.
  - 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: "Based on these findings, she was given the presumptive diagnosis of late onset spinal muscular atrophy (SMA)."
    explanation: A documented instance of JALS being misdiagnosed as SMA.
discussions:
- discussion_id: jals_not_tdp43_proteinopathy
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Should juvenile ALS be modelled as a TDP-43 proteinopathy, as adult ALS is?
  attaches_to:
  - pathophysiology#FUS Cytoplasmic Mislocalization and Basophilic Inclusion Formation
  - pathophysiology#Combined Upper and Lower Motor Neuron Degeneration
  rationale: >
    The dismech entry for adult Amyotrophic Lateral Sclerosis carries a
    CANONICAL hypothesis in which TDP-43 cytoplasmic mislocalization and
    aggregation in the great majority of cases is the unifying pathology.
    Carrying that framing over to JALS would be wrong, and the error would be
    invisible because it would take the form of an omission rather than a
    false statement. The best-characterised JALS neuropathology is the
    basophilic-inclusion form seen with C-terminal FUS variants, and those
    inclusions are strongly FUS-positive and explicitly TDP-43 NEGATIVE; the
    authors conclude it should be classified as ALS-FUS. Reciprocally, spinal
    motor neurons in late-onset sporadic ALS show no abnormal FUS accumulation.
    The two entities therefore have different defining proteinopathies, not one
    shared one at different ages. This entry consequently declares no
    disease-level proteinopathy hypothesis: the FUS arm is a FUS proteinopathy,
    and the other genetic arms (endosomal, RNA-processing, lysosomal,
    ER-stress, sphingolipid) have no established aggregate pathology at all.
    Recorded as an explicit curated position rather than left implicit.
  evidence:
  - reference: PMID:20668261
    reference_title: "Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43)."
    explanation: >-
      The direct immunohistochemical demonstration that the characteristic JALS
      inclusions are not TDP-43 pathology.
  - reference: PMID:20579074
    reference_title: "Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein."
    explanation: >-
      The reciprocal observation: the juvenile proteinopathy is absent from
      adult sporadic ALS, so the two are distinct rather than age variants of
      one pathology.
  notes: >-
    No claim is made here about the frequency of TDP-43 pathology in JALS
    generally — the point is that it has not been established as the unifying
    JALS pathology, not that it never occurs.
- discussion_id: jals_mondo_hierarchy_gaps
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Two juvenile-onset ALS concepts are not parented under MONDO:0017593;
    should MONDO add the is_a edges, and how should dismech model them
    meanwhile?
  rationale: >
    Verified against the local MONDO build on 2026-08-20. MONDO:0017593
    (juvenile amyotrophic lateral sclerosis) has exactly four asserted
    children: MONDO:0008780 (ALS2), MONDO:0011196 (ALS5/SPG11),
    MONDO:0013715 (ALS16/SIGMAR1) and MONDO:0008781 (JALS with dementia).
    Two further concepts belong there on their own definitions but are
    parented only under MONDO:0005144 (familial ALS).

    Gap 1 - MONDO:0011223, amyotrophic lateral sclerosis type 4 (SETX). The
    defining publication states that ALS4 onset is usually below 25 years,
    which is the JALS criterion, and titles the disorder a form of juvenile
    ALS. This looks like a genuine missing is_a edge. This entry lists ALS4 as
    a subtype and binds MONDO:0011223 anyway, recording the divergence here
    rather than silently following the hierarchy.

    Gap 2 - MONDO:0859529, amyotrophic lateral sclerosis 27, juvenile
    (SPTLC1). Its own label contains the word juvenile and every reported case
    is juvenile-onset, yet it too hangs only off familial ALS. Note this partly
    resolves a stale claim in the triage of issue #8891 that no MONDO term
    existed for SPTLC1-juvenile ALS: the term does exist and is bound above.
    What is NOT resolved is the placement.

    Deliberately NOT proposed as a gap: MONDO:0011951 (ALS type 6, FUS). Its
    absence from the JALS hierarchy is arguably correct, because FUS-ALS is
    predominantly adult-onset and only specific C-terminal variants produce the
    juvenile phenotype. Equating ALS6 with juvenile ALS would be a
    gene-level-for-variant-level substitution. The FUS subtype above is
    therefore left unbound with that rationale stated on the subtype itself.
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span."
    explanation: >-
      The onset criterion that makes ALS4 definitionally juvenile and supports
      Gap 1.
  - reference: PMID:34459874
    reference_title: "Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene."
    explanation: >-
      Establishes SPTLC1-related disease as a juvenile ALS entity, supporting
      Gap 2.
  - reference: PMID:21907581
    reference_title: "P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some FUS mutations have been observed in patients with the juvenile form of Amyotrophic Lateral Sclerosis starting before 25 years."
    explanation: >-
      Supports treating juvenile FUS-ALS as variant-level, i.e. the reason ALS6
      is NOT proposed as a third MONDO gap.
- discussion_id: jals_peripheral_axonal_degeneration_conformance
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Should any JALS pathophysiology node declare conformance to the
    peripheral_axonal_degeneration module?
  attaches_to:
  - pathophysiology#Combined Upper and Lower Motor Neuron Degeneration
  rationale: >
    Decision taken for this entry: NO conformance is declared at the root, and
    none is declared at subtype level either.

    The peripheral_axonal_degeneration module models a length-dependent distal
    axonopathy of peripheral neurons and Schwann cells converging on distal
    axonal degeneration and demyelination. JALS is defined by COMBINED upper
    and lower motor neuron degeneration — the upper motor neuron limb is a
    corticospinal central-tract lesion, which the module does not model at
    all. Conforming the convergent node would therefore assert a shape the
    disease does not have, and would misrepresent the entry to any tooling that
    reads conformance.

    Two subtype-level exceptions were considered and rejected for now.
    First, ALS4/SETX presents with distal weakness and normal sensation, which
    reads like the distal hereditary motor neuronopathy space — but the same
    defining sentence records pyramidal signs, so the corticospinal lesion is
    present and the phenotype is not a pure distal axonopathy.
    Second, for ALS2/alsin: infantile-onset ascending hereditary spastic
    paralysis, an ALS2 allelic disorder, shows elevated plasma neurofilament
    light suggesting axonal degeneration. That is evidence about IAHSP, not
    about ALS2-related JALS, and NfL elevation is a non-specific marker of
    axonal injury including central axonal injury; it does not establish a
    length-dependent peripheral axonopathy. Revisit if direct nerve-conduction
    or pathological evidence of a length-dependent distal axonopathy is
    published for a specific JALS subtype.
  evidence:
  - reference: PMID:15106121
    reference_title: "DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4)."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs"
    explanation: >-
      REFUTE with respect to the proposal to conform ALS4: the same sentence
      that supplies the distal-axonopathy resemblance also records pyramidal
      signs, i.e. a corticospinal lesion the module does not cover.
  - reference: PMID:40439044
    reference_title: "Elevated Plasma Neurofilament Light Chain Levels in Children with Infantile-Onset Ascending Hereditary Spastic Paralysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Plasma NfL levels are elevated in IAHSP, suggesting axonal degeneration."
    explanation: >-
      PARTIAL and about IAHSP, not JALS. Cited as the strongest available
      argument FOR an axonopathy framing of ALS2-related disease, and recorded
      here precisely so the decision against conformance can be re-examined
      against it.
📚

References & Deep Research

References

3
PMID:38540369
Clinical and Genetic Aspects of Juvenile Amyotrophic Lateral Sclerosis: A Promising Era Emerges.
No top-level findings curated for this source.
PMID:34946884
Juvenile Amyotrophic Lateral Sclerosis: A Review.
No top-level findings curated for this source.
PMID:20301389
Spastic Paraplegia 11.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
Juvenile Amyotrophic Lateral Sclerosis (JALS): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 53 citations 2026-08-20T13:53:31.472324

Juvenile Amyotrophic Lateral Sclerosis (JALS): Comprehensive Research Report

1. Disease Information

Overview

Juvenile amyotrophic lateral sclerosis (JALS) is a clinically and genetically heterogeneous group of motor neuron disorders defined operationally by symptom onset before age 25 years, involving progressive degeneration of both upper motor neurons (UMN, corticospinal tract) and lower motor neurons (LMN, anterior horn cells/bulbar nuclei). It is distinguished from adult-onset ALS (AO-ALS) by three major features, as summarized in the principal review of the field: 1. A markedly higher genetic yield — ~40% of JALS cases have an identifiable causative gene mutation, versus ~10% of AO-ALS cases 2. A highly variable disease course, "from very aggressive to a more indolent" trajectory, in contrast to the relatively uniform ~2–3 year mortality of typical AO-ALS 3. A greater propensity for syndromic, multi-system neurodegeneration extending beyond the motor system (cognitive, cerebellar, sensory, or movement-disorder features), whereas AO-ALS is comparatively restricted to motor pathways (Ghasemi & Brown/JALS review, Genes 2021, PMID: 34946884)

Key Identifiers

Resource Identifier
MONDO MONDO:0017593
Orphanet ORPHA:300605 (Juvenile amyotrophic lateral sclerosis); related: ORPHA:247604 (Juvenile primary lateral sclerosis); ORPHA:357043 (ALS type 4)
OMIM #205100 (ALS2, juvenile ALS due to ALS2/alsin); #602433 (ALS4, SETX); #105400 (ALS1 umbrella entry, SOD1)
GARD (NIH) GARD:11901

Synonyms / Alternative Names

  • Juvenile-onset amyotrophic lateral sclerosis (jALS)
  • Early-onset ALS
  • Pediatric ALS
  • Gene-specific eponymous forms: ALS2 (juvenile ALS-2), ALS4 (SETX/senataxin-related juvenile ALS), ALS16 (SIGMAR1-related)
  • Overlapping allelic disorders at the ALS2 locus: infantile-onset ascending hereditary spastic paralysis (IAHSP), juvenile primary lateral sclerosis (JPLS)

Data provenance

Nearly all quantitative epidemiologic data on JALS derive from aggregated, registry- or literature-level sources — principally the US CDC National ALS Registry (44 confirmed/likely juvenile cases identified 2010–2018) and pooled case-series/case-report literature reviews — rather than large prospective individual-patient cohorts, reflecting the disease's rarity (Larkin et al., Amyotroph Lateral Scler Frontotemporal Degener 2023, PMID: 37789566).

2. Etiology

Disease Causal Factors

JALS is primarily a monogenic/oligogenic disorder in the ~40% of cases with an identified mutation; the remainder are presumed sporadic/idiopathic or due to as-yet-unidentified genetic causes. Fifteen genes have been reported in association with JALS, though only three — FUS, SETX, and ALS2 — are recurrently implicated across multiple independent families, with the rest supported by single or few case reports (PMID: 34946884).

Genetic Risk/Causal Factors (by gene; see Section 4 for full detail)

  • FUS (fused in sarcoma) — most frequently implicated gene in JALS; predominantly de novo mutations
  • SETX (senataxin) — the only recurrent autosomal dominant JALS gene (ALS4)
  • ALS2 (alsin) — autosomal recessive; historically enriched in North African/Middle Eastern consanguineous families
  • SIGMAR1 (sigma-1 receptor) — autosomal recessive, very early (infantile) onset
  • SOD1 — rare in JALS (3 reported cases), typically de novo, distinct mutation spectrum from AO-ALS SOD1
  • SPTLC1 — mostly de novo; one autosomal dominant family
  • SPG11 — autosomal recessive
  • UBQLN2 — X-linked dominant
  • ERLIN1, GNE, TARDBP, VRK1, SYNE1, BICD2, DDHD1 — single-family/case reports (PMID: 34946884)

Environmental Risk Factors

No well-established environmental or occupational risk factors specific to JALS have been identified in the literature reviewed; environmental risk factor research in ALS overall (e.g., military service, heavy metal exposure, smoking, physical trauma) is concentrated in adult-onset, largely sporadic disease and has not been systematically studied in the pediatric/juvenile population. This is a notable evidence gap.

Protective Factors

No specific genetic or environmental protective factors for JALS are documented in the literature surveyed. General population variant-frequency data (e.g., gnomAD) for the causal genes have not been reported as conferring disease protection.

Gene–Environment Interactions

Not established for JALS specifically; the disease is modeled overwhelmingly as monogenic with variable expressivity/penetrance (e.g., SETX-ALS4 shows sex-dependent penetrance — see Section 9) rather than as a gene–environment interaction disorder.

3. Phenotypes

Core Motor Phenotype

  • Progressive muscle weakness and atrophy (LMN sign) — HPO: HP:0003324 (Generalized muscle weakness) / HP:0007358 (Progressive muscle weakness); HP:0003202 (Skeletal muscle atrophy)
  • Spasticity, hyperreflexia, extensor plantar responses (UMN signs) — HPO: HP:0001257 (Spasticity), HP:0001347 (Hyperreflexia), HP:0003487 (Babinski sign)
  • Fasciculations — HPO: HP:0002380
  • Dysarthria progressing to anarthria (especially ALS2) — HPO: HP:0001260 (Dysarthria)
  • Dysphagia — HPO: HP:0002015
  • Pseudobulbar affect (ALS2) — HPO: HP:0000749

Gene-Specific Phenotype Summary

Gene Onset pattern UMN/LMN balance Bulbar/respiratory Distinctive features
FUS Median 21 yrs; often bulbar onset Combined Frequent, early Myoclonic jerks, tremor, occasional cognitive/frontal decline
SETX (ALS4) Mean ~16 yrs, slow Balanced, distal-predominant LMN Spared Finger-to-nose dysmetria/ataxia in ~50%; sex-dependent penetrance
ALS2 Mean 4.9 yrs (1–20) UMN-prominent early Early, frequent (anarthria in 1st decade) Pseudobulbar affect, scoliosis, preserved cognition
SIGMAR1 1–2 yrs LMN (distal, forearm/hand) Spared Cognition preserved; overlaps distal HMN
SOD1 (JALS) Late 2nd–early 3rd decade Combined Variable Rapid, respiratory failure <2 yrs
SPTLC1 4–15 yrs Mixed Yes Elevated serum ceramide
SPG11 7–23 yrs (2nd decade typical) Balanced Early/common No cognitive impairment, no corpus callosum thinning (unlike HSP)
UBQLN2 16–24 yrs (rare juvenile cases) Variable Variable Frontotemporal dementia common
(All PMID: 34946884)

Onset, Severity, Progression, Frequency

  • Age of onset: ranges from infancy (SIGMAR1, ALS2) through the third decade (SOD1, TARDBP), with the operational upper bound at 25 years.
  • Severity/progression: bimodal — rapidly fatal (FUS, SOD1: death from respiratory failure within 1–2 years) vs. slowly progressive over decades (SETX, ALS2, SPG11 [27–40 yr duration], UBQLN2 [~4 decades]) (PMID: 34946884).
  • Frequency of specific signs: quantitative frequency data are limited to small case series; e.g., SETX-ALS4 penetrance is markedly sex-skewed (31% of males vs. 13% of females symptomatic) (PMID: 34946884; Grunseich et al., Ann Neurol 2020, 10.1002/ana.25681).

Quality of Life

Disease-specific QoL instruments (EQ-5D, SF-36, ALSFRS-R-based QoL substudies) have been applied in adult ALS but are not reported as validated or systematically applied in pediatric/juvenile ALS in the literature surveyed. The functional impact is inferable from the clinical course: progressive loss of ambulation, speech, swallowing, and (in FUS/SOD1 forms) respiratory independence, with earlier and longer-duration disability in indolent forms (SETX, ALS2, SPG11) due to decades-long disease courses beginning in childhood/adolescence — a distinct QoL burden (loss of developmental milestones, prolonged pediatric-to-adult disability) compared with AO-ALS.

4. Genetic/Molecular Information

Causal Genes (detailed)

FUS (Fused in Sarcoma; RNA-binding protein) - Most common JALS gene; predominantly de novo heterozygous mutations, often clustered in the C-terminal nuclear localization signal (NLS) domain - P525L mutation: consistently associated with the most severe/earliest-onset form (median onset 21 yrs), higher bulbar involvement, shortest survival (Waibel et al., Neurology 2010, PMID: 20668260; Bäumer et al., PMID: 20668260) - De novo R503fs frameshift reported in a 17-year-old female with sporadic JALS, rapid course, death 15 months from onset (PMID: 32501131) - Y526C novel C-terminal mutation strengthens FUS as "the most frequent genetic factor in aggressive juvenile ALS" (PMID: 28054830) - FUS-P525L reported with intellectual disability and expanded phenotype (Neurol Genet 2024, 10.1212/NXG.0000000000200009) - Neuropathology: cytoplasmic basophilic inclusions in Betz cells of motor cortex, with 12–15 nm tubulofilamentous ultrastructure — distinct from the TDP-43 pathology of sporadic ALS (PMID: 34946884)

SETX (Senataxin; DNA/RNA helicase, ALS4) - Autosomal dominant, gain-of-function heterozygous mutations (chr 9q34); the only recurrent AD gene in JALS - Series of 31 patients: mean onset 16 years, slowly progressive, normal life span (PMID: 34946884; Grunseich 2020) - Allele-specific silencing of a dominant SETX mutation as a therapeutic strategy is under preclinical investigation (bioRxiv 2024, 10.1101/2024.10.11.617871) - SETX also causes the allelic disorder ataxia with oculomotor apraxia type 2 (AOA2, recessive), with ALS4 mutations occurring at distinct SETX protein locations from AOA2 mutations (PMID: 34946884)

ALS2 (Alsin; Rho guanine nucleotide exchange factor, chr 2q33) - Autosomal recessive; loss-of-function (often nonsense/frameshift, premature stop codon) mutations distributed across the gene with no hotspot - Encodes a ~180–185 kDa multidomain protein with three GEF domains for Rab5 and other small GTPases (PMID: 34946884) - Allelic spectrum: infantile-onset ascending hereditary spastic paralysis (IAHSP) → juvenile primary lateral sclerosis (JPLS) → juvenile ALS2, representing a phenotypic continuum of severity (PMC: 4180207; PMC: 8721836) - Novel splice-site ALS2 mutation reported establishing diagnosis in a family with early anarthria and generalized dystonia (PMC: 4256290)

SIGMAR1 (Sigma-1 receptor; ER chaperone, ALS16) - Autosomal recessive; onset 1–2 years; distal (forearm/hand) LMN-predominant, spared bulbar/respiratory function, preserved cognition - Also causes a distinct allelic phenotype, distal hereditary motor neuropathy (dHMN), without the rapid progression/widespread neurogenic damage typical of ALS (ScienceDaily 2011, link; PMID: 34946884; PMC: 6060428; PMC: 12041004)

SOD1 (Cu/Zn superoxide dismutase 1) - Only 3 reported JALS cases; predominantly de novo, distinct mutation spectrum and inheritance pattern from typical AO-ALS SOD1 (usually AD, mean onset 5th decade) - Rapid progression, death from respiratory failure <2 years; neuropathology shows anterior horn degeneration with Bunina bodies and gliosis (PMID: 34946884)

SPTLC1 (Serine palmitoyltransferase long-chain base subunit 1) - Mostly de novo (one AD family); onset 4–15 years; catalyzes the rate-limiting step of de novo sphingolipid synthesis; elevated serum ceramide (distinct from the elevated deoxysphingolipids seen in SPTLC1-associated HSAN) - One patient trialed serine supplementation, which produced weight gain but uncertain disease benefit and theoretical risk of worsening sphingolipid overproduction (PMID: 34946884)

SPG11 (Spatacsin) - Autosomal recessive; onset 7–23 years (2nd decade typical); "SPG11-ARJALS" clinically distinguished from SPG11-hereditary spastic paraplegia (HSP) by absence of cognitive impairment and absence of corpus callosum thinning on MRI (Orhan et al., Neurol Genet 2016, 10.1212/NXG.0000000000000025; PMID: 34946884)

UBQLN2 (Ubiquilin 2) - X-linked dominant; mutations cluster in the PXX domain; regulates ubiquitinated protein degradation; frequently associated with frontotemporal dementia (PMID: 34946884)

Other single-case/single-family genes: ERLIN1 (Turkish family, homozygous, ER lipid-raft protein), GNE (sialic acid synthesis), TARDBP (p.Gly348Val, one JALS case), VRK1 (kinase, with sensory neuropathy and intellectual deterioration), SYNE1 (nuclear envelope–actin linker), BICD2 (motor adaptor protein), DDHD1 (mitochondrial phospholipase) (all PMID: 34946884).

Variant Classification & Population Frequency

Systematic gnomAD/ClinVar-level population-frequency and ACMG/AMP classification data specific to JALS-causing variants were not comprehensively retrieved in this search; individual variants (e.g., FUS P525L, SETX L389S/R2136H) are reported as pathogenic/likely pathogenic in the primary literature and ClinGen curations (see ClinGen Gene-Disease Validity records for SETX/ALS4).

Somatic vs. Germline

All reported JALS-causing variants are germline (constitutional), including de novo germline events in FUS, SOD1, and SPTLC1 forms.

Functional Consequences

  • FUS: gain-of-toxic-function via cytoplasmic mislocalization, aberrant U1 snRNA interaction, and stress granule incorporation (see Section 6)
  • SETX: gain-of-function affecting R-loop resolution and TGF-β pathway activation
  • ALS2: loss-of-function (GEF activity loss) affecting Rab5-dependent endosomal trafficking
  • SIGMAR1: loss-of-function affecting ER chaperone activity

Epigenetic / Chromosomal Information

No JALS-specific epigenetic (DNA methylation/histone) or large-scale chromosomal abnormality (aneuploidy/translocation) mechanisms were identified in the literature surveyed; JALS is modeled as point mutation/small indel-driven monogenic disease.

5. Environmental Information

No JALS-specific environmental toxin, occupational, lifestyle, or infectious-agent risk factors were identified in the literature surveyed. This contrasts with adult sporadic ALS, where environmental epidemiology (e.g., military deployment, heavy metals, pesticides, β-N-methylamino-L-alanine/BMAA) is more extensively studied but still not disease-defining. No infectious trigger has been established for JALS. This represents a clear knowledge gap suitable for flagging as KNOWLEDGE_GAP in a curated entry.

6. Mechanism / Pathophysiology

Causal Chains by Gene

FUS pathway: De novo NLS-domain mutation → impaired nuclear import of FUS protein → cytoplasmic mislocalization of FUS in motor neurons → incorporation into stress granules (co-localizing with TIAR) and aberrant trapping of U1 snRNP biogenesis intermediates via aberrant Sm-site zinc-finger interaction with U1 snRNA → disrupted RNA metabolism/splicing and pathological stress-granule dynamics (shift to unstructured, AU-rich transcriptome) → dose-dependent gain of toxic function, RBP insolubility → progressive motor neuron loss (in FUS-P525L knock-in mice, ~30% lumbar motor neuron loss by 12 months and 37% NMJ denervation by 1 year) without obligate cytoplasmic aggregate formation → denervation, weakness, bulbar dysfunction, respiratory failure. Sources: Vance et al. (PMID: 20699327); Sun et al. (PMC: 7733473); PMC: 7705167; ALZFORUM hFUS-P525L model summary.

SETX (ALS4) pathway: Heterozygous gain-of-function SETX mutation (helicase domain, e.g., L389S, R2136H) → impaired DNA/RNA helicase function and R-loop resolution → genomic instability (altered Rad51 recruitment), dysregulated transcriptional termination, and TGF-β pathway activation → downstream TDP-43 nuclear clearing and cytoplasmic mislocalization in spinal motor neurons (both in knock-in mouse models and human ALS4 postmortem tissue) → nucleocytoplasmic transport dysfunction (Ran/RanGAP1 nuclear-membrane abnormalities, delayed nuclear import) and enhanced stress granule formation → autophagy dysregulation → slowly progressive distal LMN degeneration with UMN signs, sparing bulbar/respiratory neurons. Source: Bennett et al., Acta Neuropathol 2018, PMID: 29725819; PMID: 34946884.

ALS2 (alsin) pathway: Biallelic loss-of-function ALS2 mutation → loss of alsin GEF activity for Rab5 → impaired Rab5-dependent endosome fusion and macropinocytosis-associated trafficking → disturbed endosomal transport of IGF1 and BDNF receptors, excessive Rab5-positive vesicle accumulation, reduced endosomal motility and increased endosome-to-lysosome conversion → impaired trophic signaling and microtubule/actin cytoskeletal remodeling defects in corticospinal and lower motor neurons → retrograde degeneration of upper motor neurons of the pyramidal tract (predominant early), later LMN involvement → progressive spasticity, dysarthria/anarthria, slow disease course. Sources: Devon et al., PNAS 2006, 10.1073/pnas.0510197103; Deng et al., PMC: 2842444; PMC: 2364715; Molecular Brain 2009, link.

SIGMAR1 pathway: Loss-of-function mutation in the ER chaperone sigma-1 receptor → failure to prevent misfolded protein accumulation, and dysregulated lipid transport/ion channel regulation, particularly in motor neurons of brainstem/spinal cord (high SIGMAR1 expression sites) → distal LMN-predominant degeneration sparing bulbar/respiratory and cognitive function.

SPTLC1 pathway: Gain-of-function/altered-specificity mutation in the rate-limiting sphingolipid biosynthesis enzyme → elevated serum ceramide → lipotoxic stress in motor neurons → mixed UMN/LMN degeneration with early spasticity.

SPG11 (spatacsin) pathway: Biallelic loss-of-function → impaired cytoskeletal stability and synaptic vesicle transport regulation → distal LMN + UMN degeneration, early bulbar involvement, without the corpus callosum thinning/cognitive impairment characteristic of SPG11-HSP.

Cellular Processes & Biological Processes (GO term suggestions)

  • Endosomal transport/protein trafficking (GO:0016197 endosomal transport) — ALS2
  • Stress granule assembly (GO:0034063 stress granule assembly) — FUS
  • mRNA processing / U1 snRNP biogenesis (GO:0006397 mRNA processing; GO:0000387 spliceosomal snRNP assembly) — FUS
  • DNA damage response / R-loop resolution (GO:0000724 double-strand break repair via homologous recombination; GO:0061077 chaperone-mediated protein folding) — SETX
  • Nucleocytoplasmic transport (GO:0006913 nucleocytoplasmic transport) — SETX
  • Autophagy (GO:0006914 autophagy) — SETX, ALS2
  • Sphingolipid biosynthetic process (GO:0030148 sphingolipid biosynthetic process) — SPTLC1
  • ER protein quality control / chaperone activity (GO:0034975 protein folding in endoplasmic reticulum) — SIGMAR1
  • Protein ubiquitination/proteasomal degradation (GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process) — UBQLN2

Protein Dysfunction Modes

  • FUS: cytoplasmic mislocalization + gain of toxic function (no obligate aggregation required for toxicity in knock-in models)
  • SOD1: misfolding/aggregation, loss of antioxidant enzymatic function
  • ALS2/alsin: complete loss of GEF function (LOF)
  • SIGMAR1: loss of chaperone function (LOF)

Tissue Damage / Neurodegeneration Mechanisms

Motor neuron death via a combination of proteostatic stress, impaired axonal/vesicular transport, glial activation (astrocytosis and microgliosis observed in FUS-P525L mouse spinal cord), oxidative stress (rationale for edaravone), and secondary denervation of neuromuscular junctions.

Molecular Profiling

Transcriptomic/proteomic profiling of stress-granule composition in ALS-FUS models shows a shift to a more unstructured, AU-rich RNA content (Oxford NAR 2024, 10.1093/nar/gkad739). Broader multi-omic (single-cell, spatial transcriptomic) characterization specific to JALS tissue was not identified in this search and likely represents a gap given tissue scarcity in pediatric cases.

Suggested Cell Types (CL terms)

  • Upper motor neuron / Betz cell (CL:0011005 corticospinal neuron / betz cell terminology varies)
  • Lower motor neuron / spinal cord motor neuron (CL:0000100 motor neuron; CL:0011012 alpha motor neuron)
  • Astrocyte (CL:0000127) — reactive astrocytosis
  • Microglial cell (CL:0000129) — microgliosis

7. Anatomical Structures Affected

Organ/System Level

  • Primary: central nervous system — motor cortex (Betz cells/UMN), corticospinal tract, brainstem motor nuclei, spinal cord anterior horn (LMN) (UBERON:0002298 brainstem; UBERON:0002240 spinal cord; UBERON:0002771 femoral motor neuron / generic UBERON:0000010 peripheral nervous system for LMN axons)
  • Secondary: skeletal muscle (denervation atrophy; UBERON:0001134 skeletal muscle tissue), neuromuscular junction (UBERON:0031594), respiratory musculature (diaphragm — UBERON:0001103) in aggressive forms (FUS, SOD1)
  • Body systems: nervous system (primary), musculoskeletal system (secondary — scoliosis in ALS2, contractures), respiratory system (bulbar/respiratory forms)

Tissue/Cell Level

  • Corticospinal (upper) motor neurons of the motor cortex
  • Spinal/bulbar (lower) motor neurons
  • Reactive astrocytes and microglia in affected spinal cord segments

Subcellular Level (GO Cellular Component)

  • Nucleus/nuclear pore complex (FUS mislocalization, SETX nucleocytoplasmic transport defect) — GO:0005634, GO:0005643
  • Cytoplasmic stress granules — GO:0010494
  • Endosomes/Rab5-positive vesicles (ALS2) — GO:0005768
  • Endoplasmic reticulum (SIGMAR1 chaperone) — GO:0005783
  • Mitochondria (DDHD1 phospholipase regulation) — GO:0005739

Localization/Lateralization

JALS motor neuron degeneration is typically symmetric/bilateral; asymmetric onset is reported in some SOD1-JALS cases. Imaging correlates: FUS shows T2/FLAIR pyramidal tract hyperintensity plus frontal atrophy/hypoperfusion; ALS2 shows mild cortical atrophy and corticospinal tract thinning; SYNE1 shows mild cerebellar atrophy (PMID: 34946884).

8. Temporal Development

Onset

  • Congenital/infantile: SIGMAR1 (1–2 yrs)
  • Early childhood: ALS2 (mean 4.9 yrs, range 1–20)
  • Childhood/adolescent (first–second decade): SETX (mean 16), SPTLC1 (4–15), SPG11 (7–23, typically 2nd decade), SYNE1 (11–12), ERLIN1 (before 24 in 6/12 family members)
  • Late second/third decade: FUS (median 21), SOD1 (late 2nd–early 3rd decade), GNE (mean 26, range 12–35), TARDBP (24), UBQLN2 (16–24) Onset is typically insidious, with symptom progression over months before diagnosis rather than acute presentation (PMID: 34946884).

Progression

  • Rapid (1–2 year mortality): FUS, SOD1
  • Intermediate (1–2 decades): GNE (mean 13.4 yrs), SYNE1 (death ~age 39)
  • Slow (multiple decades, near-normal lifespan possible): SETX/ALS4 ("normal life span" per OMIM #602433), ALS2, SIGMAR1, SPTLC1, SPG11 (27–40 yr disease duration), UBQLN2 (~4 decades), ERLIN1 (death 5th–6th decade) (PMID: 34946884)

Patterns

No spontaneous remission is described for JALS. "Critical periods" are not formally defined, though the operational <25-year onset window itself demarcates the diagnostic category. Disease course is generally monophasic progressive rather than relapsing-remitting, distinguishing JALS from its phenocopies (e.g., HSP, which can show more static/slowly progressive UMN-only courses).

9. Inheritance and Population

Epidemiology

  • US National ALS Registry (2010–2018): 44 confirmed/likely juvenile ALS cases (onset <25 yrs) identified nationally; age-adjusted prevalence rose from 0.21/100,000 (2015) to 0.24/100,000 (2018) (Larkin et al. 2023, PMID: 37789566)
  • Overall ALS prevalence (all ages, US) is ~9.9 per 100,000 for context; only ~5% of all ALS cases have onset before age 30, and ~13% before age 40 (Target ALS summary; general ALS epidemiology literature)
  • Demographics from the registry: 79.5% male / 20.5% female (>3:1 male predominance); 54.5% non-white / 45.5% non-Hispanic white — an "inverse" pattern relative to general ALS demographics (which skew white); geographic distribution: Northeast 29.5%, Midwest 25%, South/West 15.9% each (PMID: 37789566)

Inheritance Patterns (genetic forms)

Gene Inheritance
ALS2, SIGMAR1, SPG11, ERLIN1, GNE, VRK1 Autosomal recessive
SETX Autosomal dominant (only recurrent AD gene)
FUS, SOD1, SPTLC1 (most) De novo (dominant, non-inherited)
UBQLN2 X-linked dominant
(PMID: 34946884)

Penetrance / Expressivity

SETX-ALS4 shows incomplete, sex-dependent penetrance — males symptomatic 31% vs. females 13%, with males also showing greater disease burden and higher serum creatine kinase (PMID: 34946884; Grunseich 2020, 10.1002/ana.25681). Variable expressivity is evident across the phenotypic continuum of ALS2 mutations (IAHSP–JPLS–JALS2).

Genetic Anticipation, Mosaicism, Founder Effects

Not systematically documented for JALS in the literature surveyed. ALS2 was historically over-represented in consanguineous North African and Middle Eastern families, consistent with a founder/consanguinity effect for autosomal recessive disease, though the gene is now recognized globally (PMID: 34946884).

Consanguinity

Elevated relevance for the autosomal recessive forms (ALS2, SIGMAR1, SPG11) given their original ascertainment in consanguineous pedigrees.

Carrier Frequency

Population carrier-frequency data (gnomAD-derived) specific to JALS-causing recessive alleles were not retrieved in this search and would need dedicated gnomAD querying per gene/variant.

10. Diagnostics

Clinical Criteria

JALS diagnosis rests on: (1) age of onset <25 years, and (2) evidence of combined UMN + LMN degeneration, applying the same clinical framework used for AO-ALS (revised El Escorial / Awaji criteria), which have recognized limitations in sensitivity, particularly in atypical/pediatric presentations (search results on El Escorial criteria, 2024–2025 literature). The principal JALS review states: "Patients presenting with combined upper and lower motor neuron disorders before age 25 should be carefully examined for genetic mutations" (PMID: 34946884).

Electrodiagnostics (EMG/NCS)

Pattern across JALS genes: active denervation with chronic neurogenic changes and no sensory abnormalities on nerve conduction studies (consistent with a pure motor neuronopathy), though it "confirms LMN involvement but [is] not useful in distinguishing the different gene mutations." SETX is a partial exception, showing low/absent motor NCS amplitudes with normal sensory studies (PMID: 34946884).

Imaging

  • MRI often normal or shows only mild abnormality
  • FUS: pyramidal tract T2/FLAIR hyperintensity, frontal atrophy/hypoperfusion
  • ALS2: mild cortical atrophy, corticospinal tract thinning
  • SETX: muscle MRI shows distal lower-extremity fatty infiltration
  • SYNE1: mild cerebellar atrophy (PMID: 34946884)

Genetic Testing

Given the 40% genetic yield, multigene panel testing (or WES) covering ALS2, SETX, FUS, SIGMAR1, SOD1, SPTLC1, SPG11, UBQLN2, and the rarer genes is the recommended diagnostic approach once combined UMN/LMN signs with onset <25 years are established. Single-gene testing may be prioritized by phenotype (e.g., SETX first for AD family history with distal, bulbar-sparing disease; ALS2 for AR consanguineous families with very early anarthria/spasticity).

Differential Diagnosis ("JALS mimics")

  • Juvenile Primary Lateral Sclerosis (JPLS): UMN-only, ALS2-associated
  • Hereditary Spastic Paraplegia (HSP): UMN-predominant, sensory neuropathy, no bulbar involvement typically; SPG11, ALS2, ERLIN1, DDHD1-associated; MRI corpus callosum thinning (contrasting with SPG11-ARJALS)
  • Spinal muscular atrophy (SMA): pure LMN, no UMN signs — the key discriminator per differential-diagnosis literature
  • Distal hereditary motor neuropathy (dHMN): LMN-only (SIGMAR1 allelic overlap)
  • NBIA (neurodegeneration with brain iron accumulation): reported mimicking JALS initially in one case (10-year-old girl) before basal ganglia iron deposition emerged (PMID: 34946884)

11. Outcome/Prognosis

Survival/Mortality

Prognosis is strongly gene-dependent rather than uniform: - Poor prognosis / rapid mortality: FUS (death from respiratory failure within 1–2 years, especially P525L), SOD1-JALS (documented deaths <2 years) - Favorable/near-normal prognosis: SETX/ALS4 (OMIM: "normal life span"), ALS2 (slow progression despite early onset), SPG11 (27–40 year disease duration), UBQLN2 (~4-decade course) (PMID: 34946884)

Morbidity/Functional Outcomes

Long-duration forms (ALS2, SETX, SPG11) accrue substantial cumulative disability (progressive spasticity, anarthria, loss of ambulation) over a period spanning childhood through adulthood — a distinct morbidity profile from AO-ALS's shorter but more uniformly fatal course.

Prognostic Factors

The causative gene is itself the dominant prognostic factor; the review states, "hereditary patterns and coexisting features may be useful in determining prognosis," and that gene identification "allows for a better prediction of prognosis and early diagnostic testing in other affected family members" (PMID: 34946884). No validated biomarker-based prognostic score specific to JALS was identified (contrast with AO-ALS, where plasma neurofilament light chain (NfL) is an emerging prognostic/pharmacodynamic biomarker, notably used in tofersen trials).

12. Treatment

Pharmacotherapy

  • Riluzole — the only agent broadly used across ALS with proven (modest) survival benefit in adults (2–3 month prolongation of tracheostomy-free survival); pediatric/juvenile use is described in the literature as "less established," used at some centers on a case-by-case basis (Healthline; NCBI Bookshelf review; PMID search results)
  • Edaravone — FDA-approved 2017 for AO-ALS (antioxidant, reduces oxidative/free-radical injury); pediatric investigation described as ongoing/limited, with regional variation in approval status
  • Tofersen (antisense oligonucleotide) — FDA accelerated approval April 2023, specifically for SOD1-mutant ALS; intrathecally administered, binds SOD1 mRNA to reduce toxic SOD1 protein and CSF SOD1 levels; reduces plasma neurofilament light chain, though ALSFRS-R functional benefit has been variable across trials (NEJM 2022, PMID: [35379992]; systematic review PMC: 12003547). Given SOD1's rarity as a JALS cause (3 reported cases) but its druggability, this is the clearest example of a genotype-matched precision therapy potentially applicable to a JALS subgroup, though pediatric/juvenile-specific trial data were not identified in this search.
  • Serine supplementation (SPTLC1) — trialed in one SPTLC1-JALS patient, produced weight gain; "utility... is uncertain and may potentially worsen the overproduction of sphingolipids" (PMID: 34946884)

Advanced/Experimental Therapeutics

  • Antisense oligonucleotide silencing approaches are in preclinical development for FUS (PMC: 8799464) and for the dominant SETX ALS4 mutation via allele-specific silencing (bioRxiv 2024)
  • Gene therapy trials (e.g., NCT04632225, "Engensis"/VM202) are registered for ALS broadly but not JALS-specific

Supportive/Rehabilitative Care

Multidisciplinary clinic management (neurology, pulmonology, PT/OT, speech-language pathology, nutrition, social work, ALS association support) is standard of care; respiratory support ranges from noninvasive to invasive mechanical ventilation as disease progresses (search results, general ALS management literature; NCIT:C15302 Physical Therapy, NCIT:C15315 Rehabilitation, NCIT:C15747 Supportive Care).

Treatment Algorithm Notes

No JALS-specific clinical practice guideline algorithm was identified; management is extrapolated from AO-ALS guidelines with genotype-informed personalization emphasized as the field's stated future direction: "With the future of personalized medicine, the identification of a disease-causing gene mutation may lead to treatment" (PMID: 34946884).

Suggested NCIT terms: NCIT:C15986 (Pharmacotherapy) for riluzole/edaravone; NCIT:C15238 (Gene Therapy) for ASO approaches (tofersen, investigational FUS/SETX ASOs); NCIT:C15240 (Genetic Counseling); NCIT:C15315 (Rehabilitation); NCIT:C15313 not applicable (no radiotherapy role).

13. Prevention

Primary/Secondary Prevention

No primary prevention strategy exists (genetic, non-modifiable causal factors dominate). Secondary prevention centers on genetic counseling and cascade family testing once a proband's causative variant is identified, given that gene identification "allows for... early diagnostic testing in other affected family members" (PMID: 34946884).

Screening

  • No population-based newborn or carrier screening program specific to JALS genes was identified.
  • For autosomal recessive forms (ALS2, SIGMAR1, SPG11) in populations with known consanguinity/founder variants, targeted carrier screening and prenatal/preimplantation genetic testing would be a plausible clinical application, though not documented as an established program in the literature surveyed.

Genetic Counseling

Recommended for families with a confirmed pathogenic variant, particularly for the autosomal dominant (SETX) and X-linked (UBQLN2) forms where risk to relatives is high and predictable, and for autosomal recessive forms where carrier status and reproductive risk counseling is relevant.

Public Health / Prophylaxis

Not applicable — no infectious or environmentally preventable component has been established for JALS.

14. Other Species / Natural Disease

No naturally occurring juvenile-onset ALS phenocopy in non-human species was identified in this search. (Note: dismech's existing Amyotrophic_Lateral_Sclerosis entry documents naturally occurring canine degenerative myelopathy [SOD1 E40K homozygous dogs] as an adult/older-onset model informative for general ALS motor neuron degeneration — PMID:19188595 — but this is not described as a juvenile-onset natural disease analog and would need independent verification before being cited under a JALS-specific entry.) Comparative/orthologous gene information (ALS2, SETX, FUS, SOD1 orthologs) is well established across model organisms per Alliance of Genome Resources/MGI/RGD but was not separately queried here.

15. Model Organisms

Mouse Models

  • Als2−/− (alsin knockout) mice: Decreased locomotor activity, small but significant decrease in cortical motor neuron size; "four ALS2-deficient mouse models have been generated by different groups... though these mouse models largely fail to recapitulate hallmarks of motor neuron disease" — i.e., fidelity is LOW/MODERATE and should be flagged as a HUMAN_MODEL_MISMATCH in curation. Mechanistically, Als2−/− neurons show disturbed Rab5-dependent endosomal transport of IGF1/BDNF receptors, excess Rab5-positive vesicle accumulation, reduced endosomal motility (Devon et al., PNAS 2006, 10.1073/pnas.0510197103; PMC: 2364715). Als2 loss also exacerbates motor dysfunction when crossed onto a SOD1-H46R AO-ALS mouse background, via disturbed endolysosomal trafficking (Deng et al., PMC: 2842444) — a genetic-modifier/epistasis model rather than a standalone JALS model.
  • SETX knock-in mice (L389S and R2136H): Both transgenic and knock-in approaches yield mice with neuromuscular phenotypes and motor neuron degeneration; critically, they recapitulate TDP-43 nuclear clearing and cytoplasmic mislocalization, matching human ALS4 postmortem spinal cord pathology — a relatively high-fidelity model for the TDP-43 pathology arm, with additional readouts of nucleocytoplasmic transport dysfunction (Ran/RanGAP1 abnormalities) and enhanced stress granule formation (Bennett et al., Acta Neuropathol 2018, PMID: 29725819).
  • FUS-P525L humanized knock-in mice ("hFUS-P525L"): Progressive, age-dependent lumbar motor neuron loss (~30% by 12 months), NMJ denervation (37% loss of tibialis NMJs by 1 year), astrocytosis/microgliosis, occurring via a dose-dependent gain-of-toxic-function mechanism without obligate cytoplasmic aggregation — an important negative/nuanced finding: "the ALS FUS knock-in model... showed neuronal dysfunction and degeneration in the absence of cytoplasmic FUS protein accumulation, suggesting aggregates may not be the initial drivers of neuronal dysfunction" (ALZFORUM hFUS-P525L summary; related "FUSΔ14" knock-in model, PMC: 5841203).

Other Model Systems

  • C. elegans FUS knock-in models show disrupted autophagy and neuronal dysfunction (bioRxiv, 10.1101/799932)
  • A separate TDP-43 knock-in mouse model (independent of SETX) is described as "a robust TDP-43 knock-in mouse model of ALS" relevant to the broader TDP-43 proteinopathy shared across ALS subtypes (PMC: 6975031)
  • iPSC-derived motor neurons: a human iPSC line carrying a de novo pathogenic FUS mutation identified in a juvenile ALS patient was differentiated into motor neurons showing pathological characteristics recapitulating patient disease features (PMC: 7507938) — a patient-derived cellular model with inherently high genotype fidelity.

Model Limitations Summary

Across all mouse models, a recurring limitation is that rodent lifespan/physiology compresses or alters the decades-long human juvenile disease course, and that Als2 knockout mice in particular fail to fully recapitulate the human motor neuron disease phenotype despite the biochemical (endosomal trafficking) defect being conserved — an explicit candidate for a HUMAN_MODEL_MISMATCH discussion node in any curated pathophysiology entry.

Summary of Key Evidence Gaps

  1. Environmental risk/protective factors for JALS are essentially unstudied as a distinct question from AO-ALS.
  2. Population genetics (gnomAD carrier frequencies, penetrance estimates) for most JALS genes beyond SETX are not well quantified.
  3. JALS-specific treatment trial data (riluzole/edaravone/tofersen efficacy in patients <25 years) are sparse; most evidence is extrapolated from adult trials or single case reports.
  4. Quality-of-life instruments validated specifically for pediatric/juvenile ALS were not identified.
  5. Als2 mouse models' translational fidelity is explicitly reported as poor, an important caveat for any pathophysiology narrative built on this model.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 37
Resolved 37
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 4
Quoted claims not found in source 3
References weighed for topical relevance 37
On topic 23
Off topic 0

Quotes not found in the cited source

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

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

  • PMID:28054830 (abstract only): "the most frequent genetic factor in aggressive juvenile ALS"
  • closest text in source: "Although amyotrophic lateral sclerosis (ALS) typically occurs around 60 years, numerous publications report an onset of ALS before the age of 25 years that define juvenile ALS (jALS)"
  • PMID:34946884: "utility... is uncertain and may potentially worsen the overproduction of sphingolipids"
  • closest text in source: "Treatment with serine was initiated in one patient and resulted in weight gain, [57] although the utility of this approach is uncertain and may potentially worsen the overproduction of spingolipids [58]"
  • PMC:PMC5841203 (abstract only): "the ALS FUS knock-in model... showed neuronal dysfunction and degeneration in the absence of cytoplasmic FUS protein accumulation, suggesting aggregates may not be the initial drivers of neuronal dysfunction"
  • closest text in source: "Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation"