Juvenile primary lateral sclerosis

Summary

Juvenile primary lateral sclerosis (MONDO:0011663) is a disease caused by ALS2 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: ALS2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 32
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001285	Spastic tetraparesis	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002064	Spastic gait	Very frequent (80-99%)
HP:0002127	Abnormal upper motor neuron morphology	Very frequent (80-99%)
HP:0002141	Gait imbalance	Very frequent (80-99%)
HP:0002193	Pseudobulbar behavioral symptoms	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002371	Loss of speech	Frequent (30-79%)
HP:0002464	Spastic dysarthria	Frequent (30-79%)
HP:0000014	Abnormality of the bladder	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	juvenile primary lateral sclerosis
Mondo ID	MONDO:0011663
MeSH	C536416
OMIM	606353
Orphanet	247604
SNOMED CT	717964007
UMLS	C1853396
MedGen	342870
GARD	0004485
Is cancer (heuristic)	no

Also known as: JPLS · juvenile PLS · PLS juvenile · PLSJ · primary lateral sclerosis, juvenile

Data availability: 32 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › motor neuron disorder › hereditary motor neuron disease › lateral sclerosis › juvenile primary lateral sclerosis

Related subtypes (1): primary lateral sclerosis, adult, 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

32 retrieved; paginated sample, class counts are floors:

10 benign, 8 pathogenic, 4 likely pathogenic, 3 uncertain significance, 3 pathogenic/likely pathogenic, 2 benign/likely benign, 1 likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
393199	NM_020919.4(ALS2):c.3415C>T (p.Arg1139Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42137	NM_020919.4(ALS2):c.1619G>A (p.Gly540Glu)	ALS2	Pathogenic	no assertion criteria provided
425255	NM_020919.4(ALS2):c.3158G>A (p.Trp1053Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4406	NM_020919.4(ALS2):c.1867_1868del (p.Leu623fs)	ALS2	Pathogenic	criteria provided, single submitter
4407	NM_020919.4(ALS2):c.1427_1428del (p.Glu476fs)	ALS2	Pathogenic	criteria provided, single submitter
4414	NM_020919.4(ALS2):c.553del (p.Thr185fs)	ALS2	Pathogenic	criteria provided, single submitter
4416	NM_020919.4(ALS2):c.2980-2A>G	ALS2	Pathogenic	no assertion criteria provided
533743	NM_020919.4(ALS2):c.1233T>G (p.Tyr411Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
694322	NM_020919.4(ALS2):c.275_276del (p.Tyr92fs)	ALS2	Pathogenic	criteria provided, single submitter
804392	NM_020919.4(ALS2):c.601C>T (p.Arg201Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807368	NM_020919.4(ALS2):c.3583G>T (p.Gly1195Ter)	ALS2	Pathogenic	criteria provided, single submitter
1895403	NM_020919.4(ALS2):c.1321_1327del (p.Ile441fs)	ALS2	Likely pathogenic	criteria provided, single submitter
242457	NM_020919.4(ALS2):c.4261C>T (p.Arg1421Ter)	ALS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441678	NM_020919.4(ALS2):c.4064del (p.Gln1355fs)	ALS2	Likely pathogenic	criteria provided, single submitter
804391	NM_020919.4(ALS2):c.2104G>T (p.Glu702Ter)	ALS2	Likely pathogenic	criteria provided, single submitter
241307	NM_020919.4(ALS2):c.1115C>G (p.Pro372Arg)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029791	NM_020919.4(ALS2):c.2487G>A (p.Leu829=)	ALS2	Uncertain significance	criteria provided, single submitter
580658	NM_020919.4(ALS2):c.3134A>T (p.Lys1045Met)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
858653	NM_020919.4(ALS2):c.367T>C (p.Cys123Arg)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188874	NM_020919.4(ALS2):c.2171-62C>T	ALS2	Benign	criteria provided, multiple submitters, no conflicts
1188975	NM_020919.4(ALS2):c.4627-69T>A	ALS2	Benign	criteria provided, multiple submitters, no conflicts
1189020	NM_020919.4(ALS2):c.4123-64G>A	ALS2	Benign	criteria provided, multiple submitters, no conflicts
1219899	NM_020919.4(ALS2):c.2842-20C>T	ALS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1671695	NM_020919.4(ALS2):c.2170+19T>C	ALS2	Likely benign	criteria provided, multiple submitters, no conflicts
241312	NM_020919.4(ALS2):c.475G>A (p.Glu159Lys)	ALS2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
261364	NM_020919.4(ALS2):c.1102G>A (p.Val368Met)	ALS2	Benign	criteria provided, multiple submitters, no conflicts
261367	NM_020919.4(ALS2):c.20+7T>C	ALS2	Benign	criteria provided, multiple submitters, no conflicts
261368	NM_020919.4(ALS2):c.2466G>A (p.Val822=)	ALS2	Benign	criteria provided, multiple submitters, no conflicts
261375	NM_020919.4(ALS2):c.4004+25C>T	ALS2	Benign	criteria provided, multiple submitters, no conflicts
261377	NM_020919.4(ALS2):c.4015C>T (p.Leu1339=)	ALS2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 18 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALS2	Strong	Autosomal recessive	amyotrophic lateral sclerosis type 2, juvenile	10
ERLIN2	Supportive	Autosomal recessive	juvenile primary lateral sclerosis	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALS2	Orphanet:247604	Juvenile primary lateral sclerosis
ALS2	Orphanet:293168	Infantile-onset ascending hereditary spastic paralysis
ALS2	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
ERLIN2	Orphanet:209951	Autosomal spastic paraplegia type 18
ERLIN2	Orphanet:247604	Juvenile primary lateral sclerosis
ERLIN2	Orphanet:280384	Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALS2	HGNC:443	ENSG00000003393	Q96Q42	Alsin	gencc,clinvar
ERLIN2	HGNC:1356	ENSG00000147475	O94905	Erlin-2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALS2	Alsin	May act as a GTPase regulator.
ERLIN2	Erlin-2	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALS2	Other/Unknown	no		DH_dom, Reg_chr_condens, VPS9
ERLIN2	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
calcaneal tendon	1
choroid plexus epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALS2	254	ubiquitous	marker	cerebellum, cerebellar cortex, cerebellar hemisphere
ERLIN2	277	ubiquitous	marker	choroid plexus epithelium, renal medulla, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALS2	2,652
ERLIN2	2,170

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERLIN2	O94905	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALS2	Q96Q42	74.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by plasma membrane FGFR1 fusions	1	1427.5×	0.010	ERLIN2
Rab regulation of trafficking	1	184.2×	0.029	ALS2
Signaling by FGFR1 in disease	1	146.4×	0.029	ERLIN2
Defective CFTR causes cystic fibrosis	1	109.8×	0.029	ERLIN2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	96.8×	0.029	ERLIN2
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.033	ALS2
ABC-family protein mediated transport	1	60.7×	0.033	ERLIN2
RAC1 GTPase cycle	1	30.5×	0.051	ALS2
RHO GTPase cycle	1	30.1×	0.051	ALS2
Membrane Trafficking	1	18.5×	0.063	ALS2
Vesicle-mediated transport	1	17.4×	0.063	ALS2
Signaling by Rho GTPases	1	17.1×	0.063	ALS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.063	ALS2
Signal Transduction	1	5.1×	0.187	ALS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cholesterol biosynthetic process	1	1203.7×	0.007	ERLIN2
SREBP signaling pathway	1	936.2×	0.007	ERLIN2
regulation of cholesterol biosynthetic process	1	766.0×	0.007	ERLIN2
regulation of endosome size	1	766.0×	0.007	ALS2
receptor recycling	1	648.1×	0.007	ALS2
negative regulation of fatty acid biosynthetic process	1	443.5×	0.008	ERLIN2
lysosomal transport	1	351.1×	0.008	ALS2
positive regulation of protein kinase activity	1	337.0×	0.008	ALS2
positive regulation of Rac protein signal transduction	1	324.1×	0.008	ALS2
neuromuscular junction development	1	263.3×	0.008	ALS2
regulation of postsynaptic membrane neurotransmitter receptor levels	1	247.8×	0.008	ALS2
behavioral fear response	1	216.1×	0.009	ALS2
endosome organization	1	187.2×	0.009	ALS2
synaptic transmission, glutamatergic	1	179.3×	0.009	ALS2
positive regulation of GTPase activity	1	138.1×	0.010	ALS2
neuron projection morphogenesis	1	138.1×	0.010	ALS2
endosomal transport	1	122.1×	0.011	ALS2
cholesterol metabolic process	1	98.0×	0.013	ERLIN2
ERAD pathway	1	90.6×	0.013	ERLIN2
locomotory behavior	1	89.6×	0.013	ALS2
response to oxidative stress	1	65.3×	0.017	ALS2
protein homooligomerization	1	61.1×	0.017	ALS2
intracellular protein localization	1	52.3×	0.019	ALS2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALS2	0	0
ERLIN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ERLIN2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ALS2, ERLIN2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALS2	0	—
ERLIN2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.