Infantile-onset ascending hereditary spastic paralysis

Summary

Infantile-onset ascending hereditary spastic paralysis (MONDO:0011797) is a disease caused by ALS2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ALS2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 815
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001257	Spasticity	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002425	Anarthria	Very frequent (80-99%)
HP:0002445	Tetraplegia	Very frequent (80-99%)
HP:0002510	Spastic tetraplegia	Very frequent (80-99%)
HP:0005216	Impaired mastication	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0002193	Pseudobulbar behavioral symptoms	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile-onset ascending hereditary spastic paralysis
Mondo ID	MONDO:0011797
MeSH	C537217
OMIM	607225
Orphanet	293168
SNOMED CT	703543005
UMLS	C2931441
MedGen	419413
GARD	0004914
Is cancer (heuristic)	no

Also known as: IAHSP · spastic paralysis, infantile onset ascending · spastic paralysis, infantile-onset ascending

Data availability: 815 ClinVar variants · 3 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 › ALS2-related motor neuron disease › infantile-onset ascending hereditary spastic paralysis

Related subtypes (2): amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis

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

600 retrieved; paginated sample, class counts are floors:

262 likely benign, 216 uncertain significance, 32 benign, 31 pathogenic, 27 conflicting classifications of pathogenicity, 19 likely pathogenic, 9 benign/likely benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217879	NM_020919.3(ALS2):c.[1911C>A;4261C>T]		Pathogenic	no assertion criteria provided
100653	NM_020919.4(ALS2):c.2761C>T (p.Arg921Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1066545	NM_020919.4(ALS2):c.3624+1G>A	ALS2	Pathogenic	criteria provided, single submitter
1180678	NM_020919.4(ALS2):c.1640+1G>A	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1443530	NM_020919.4(ALS2):c.1622del (p.His541fs)	ALS2	Pathogenic	criteria provided, single submitter
1446510	NM_020919.4(ALS2):c.4528C>T (p.Arg1510Ter)	ALS2	Pathogenic	criteria provided, single submitter
1454451	NM_020919.4(ALS2):c.4368del (p.Lys1457fs)	ALS2	Pathogenic	criteria provided, single submitter
1455318	NM_020919.4(ALS2):c.864del (p.Val289fs)	ALS2	Pathogenic	criteria provided, single submitter
1460001	NC_000002.11:g.(?202587756)(202589192_?)del	ALS2	Pathogenic	criteria provided, single submitter
1482490	NM_020919.4(ALS2):c.3703-2A>G	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1679834	NM_020919.4(ALS2):c.4270C>T (p.Gln1424Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693001	NM_020919.4(ALS2):c.347G>A (p.Gly116Glu)	ALS2	Pathogenic	criteria provided, single submitter
1693002	NM_020919.4(ALS2):c.2580+2T>C	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1693003	NM_020919.4(ALS2):c.2417+1G>C	ALS2	Pathogenic	criteria provided, single submitter
1693004	NM_020919.4(ALS2):c.2713-2A>C	ALS2	Pathogenic	criteria provided, single submitter
1693005	NM_020919.4(ALS2):c.158_160del (p.Gly53del)	ALS2	Pathogenic	criteria provided, single submitter
1693006	NM_020919.4(ALS2):c.3517delG	ALS2	Pathogenic	criteria provided, single submitter
1805070	NM_020919.4(ALS2):c.3829A>T (p.Lys1277Ter)	ALS2	Pathogenic	criteria provided, single submitter
183240	NM_020919.4(ALS2):c.4573dup (p.Val1525fs)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2007382	NM_020919.4(ALS2):c.977del (p.Gly326fs)	ALS2	Pathogenic	criteria provided, single submitter
2115520	NM_020919.4(ALS2):c.3070C>T (p.Gln1024Ter)	ALS2	Pathogenic	criteria provided, single submitter
2155448	NM_020919.4(ALS2):c.2839C>T (p.Gln947Ter)	ALS2	Pathogenic	criteria provided, single submitter
2184611	NM_020919.4(ALS2):c.2527C>T (p.Arg843Ter)	ALS2	Pathogenic	criteria provided, single submitter
241308	NM_020919.4(ALS2):c.1425_1428del (p.Gly477fs)	ALS2	Pathogenic	criteria provided, single submitter
2503048	NM_020919.4(ALS2):c.3703-2A>C	ALS2	Pathogenic	criteria provided, single submitter
2796368	NM_020919.4(ALS2):c.114G>A (p.Trp38Ter)	ALS2	Pathogenic	criteria provided, single submitter
2808755	NM_020919.4(ALS2):c.460C>T (p.Gln154Ter)	ALS2	Pathogenic	criteria provided, single submitter
2822022	NM_020919.4(ALS2):c.641T>G (p.Leu214Ter)	ALS2	Pathogenic	criteria provided, single submitter
2856462	NM_020919.4(ALS2):c.3799dup (p.Ser1267fs)	ALS2	Pathogenic	criteria provided, single submitter
2866395	NM_020919.4(ALS2):c.2880G>A (p.Trp960Ter)	ALS2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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	infantile-onset ascending hereditary spastic paralysis	10

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

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALS2	HGNC:443	ENSG00000003393	Q96Q42	Alsin	gencc,clinvar
MPP4	HGNC:13680	ENSG00000082126	Q96JB8	MAGUK p55 subfamily member 4	clinvar
ILF3	HGNC:6038	ENSG00000129351	Q12906	Interleukin enhancer-binding factor 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALS2	Alsin	May act as a GTPase regulator.
MPP4	MAGUK p55 subfamily member 4	May play a role in retinal photoreceptors development.
ILF3	Interleukin enhancer-binding factor 3	RNA-binding protein that plays an essential role in the biogenesis of circular RNAs (circRNAs) which are produced by back-splicing circularization of pre-mRNAs.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALS2	Other/Unknown	no		DH_dom, Reg_chr_condens, VPS9
MPP4	Kinase	yes		SH3_domain, PDZ, L27_dom
ILF3	Other/Unknown	no		DZF_dom, dsRBD_dom, DSRM1_ILF3

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
cerebellar cortex	1
cerebellum	1
oocyte	1
secondary oocyte	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALS2	254	ubiquitous	marker	cerebellum, cerebellar cortex, cerebellar hemisphere
MPP4	122	broad	marker	secondary oocyte, oocyte, cerebellar hemisphere
ILF3	303	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ILF3	4,787
ALS2	2,652
MPP4	1,139

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ILF3	Q12906	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MPP4	Q96JB8	76.39
ALS2	Q96Q42	74.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 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
Regulation of CDH11 gene transcription	1	519.1×	0.021	ILF3
Rab regulation of trafficking	1	184.2×	0.030	ALS2
PKR-mediated signaling	1	70.5×	0.044	ILF3
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.044	ALS2
RAC1 GTPase cycle	1	30.5×	0.060	ALS2
RHO GTPase cycle	1	30.1×	0.060	ALS2
Membrane Trafficking	1	18.5×	0.065	ALS2
Vesicle-mediated transport	1	17.4×	0.065	ALS2
Signaling by Rho GTPases	1	17.1×	0.065	ALS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.065	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
spliceosome-depend formation of circular RNA	1	1123.5×	0.016	ILF3
regulation of endosome size	1	510.7×	0.016	ALS2
receptor recycling	1	432.1×	0.016	ALS2
protein localization to synapse	1	255.3×	0.016	MPP4
lysosomal transport	1	234.1×	0.016	ALS2
positive regulation of protein kinase activity	1	224.7×	0.016	ALS2
positive regulation of Rac protein signal transduction	1	216.1×	0.016	ALS2
neuromuscular junction development	1	175.5×	0.016	ALS2
regulation of postsynaptic membrane neurotransmitter receptor levels	1	165.2×	0.016	ALS2
behavioral fear response	1	144.0×	0.016	ALS2
endosome organization	1	124.8×	0.016	ALS2
negative regulation of viral genome replication	1	124.8×	0.016	ILF3
synaptic transmission, glutamatergic	1	119.5×	0.016	ALS2
positive regulation of GTPase activity	1	92.1×	0.018	ALS2
neuron projection morphogenesis	1	92.1×	0.018	ALS2
endosomal transport	1	81.4×	0.019	ALS2
negative regulation of translation	1	65.3×	0.022	ILF3
locomotory behavior	1	59.8×	0.023	ALS2
response to oxidative stress	1	43.5×	0.030	ALS2
protein homooligomerization	1	40.7×	0.030	ALS2
intracellular protein localization	1	34.9×	0.034	ALS2
defense response to virus	1	23.1×	0.047	ILF3
protein phosphorylation	1	22.6×	0.047	ILF3
negative regulation of DNA-templated transcription	1	10.5×	0.096	ILF3
positive regulation of DNA-templated transcription	1	9.3×	0.104	ILF3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ILF3	1	2
ALS2	0	0
MPP4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SEPANTRONIUM BROMIDE	2	ILF3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ILF3	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
SEPANTRONIUM BROMIDE	2	ILF3

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	1	ILF3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MPP4
E	Difficult family or no structure, no drug	1	ALS2

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	—
MPP4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.