Hereditary spastic paraplegia 62

Summary

Hereditary spastic paraplegia 62 (MONDO:0014302) is a disease caused by ERLIN1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ERLIN1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 110
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002061	Lower limb spasticity	Very frequent (80-99%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0030051	Tip-toe gait	Frequent (30-79%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Occasional (5-29%)
HP:0002064	Spastic gait	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0002943	Thoracic scoliosis	Occasional (5-29%)
HP:0003202	Skeletal muscle atrophy	Occasional (5-29%)
HP:0006380	Knee flexion contracture	Occasional (5-29%)
HP:0012514	Lower limb pain	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 62
Mondo ID	MONDO:0014302
OMIM	615681
Orphanet	401785
DOID	DOID:0110813
SNOMED CT	765045003
UMLS	C4284588
MedGen	924879
GARD	0017657
Is cancer (heuristic)	no

Also known as: autosomal recessive pure spastic paraplegia caused by mutation in ERLIN1 · autosomal recessive spastic paraplegia type 62 · ERLIN1 autosomal recessive pure spastic paraplegia · hereditary spastic paraplegia type 62 · spastic paraplegia 62, autosomal recessive · SPG62

Data availability: 110 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 › palsy › paraplegia › hereditary spastic paraplegia › pure hereditary spastic paraplegia › hereditary spastic paraplegia 62

Related subtypes (11): hereditary spastic paraplegia 34, hereditary spastic paraplegia 8, hereditary spastic paraplegia 12, hereditary spastic paraplegia 19, hereditary spastic paraplegia 28, hereditary spastic paraplegia 37, hereditary spastic paraplegia 42, hereditary spastic paraplegia 41, hereditary spastic paraplegia 72, hereditary spastic paraplegia 73, autosomal recessive spastic paraplegia type 71

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

110 retrieved; paginated sample, class counts are floors:

55 likely benign, 41 uncertain significance, 5 conflicting classifications of pathogenicity, 4 benign, 2 pathogenic, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
226427	NM_006459.4(ERLIN1):c.149G>T (p.Gly50Val)	ERLIN1	Pathogenic	no assertion criteria provided
2500861	NM_006459.4(ERLIN1):c.196-1G>A	ERLIN1	Pathogenic	criteria provided, single submitter
4537457	NM_006459.4(ERLIN1):c.273del (p.Ile91fs)	ERLIN1	Likely pathogenic	criteria provided, single submitter
1102035	NM_006459.4(ERLIN1):c.789A>G (p.Glu263=)	ERLIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344324	NM_006459.4(ERLIN1):c.315C>T (p.Ile105=)	ERLIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1344326	NM_006459.4(ERLIN1):c.762C>A (p.Ala254=)	ERLIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
226426	NM_006459.4(ERLIN1):c.763C>T (p.Arg255Ter)	ERLIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
596294	NM_006459.4(ERLIN1):c.195+3G>A	ERLIN1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000747	NM_006459.4(ERLIN1):c.162G>T (p.Met54Ile)	ERLIN1	Uncertain significance	criteria provided, single submitter
1042966	NM_006459.4(ERLIN1):c.1015A>G (p.Asn339Asp)	ERLIN1	Uncertain significance	criteria provided, single submitter
1305963	NM_006459.4(ERLIN1):c.430+3_430+6del	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1349898	NM_006459.4(ERLIN1):c.745+5A>G	ERLIN1	Uncertain significance	criteria provided, single submitter
1351159	NM_006459.4(ERLIN1):c.856A>C (p.Lys286Gln)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1373878	NM_006459.4(ERLIN1):c.653T>C (p.Ile218Thr)	ERLIN1	Uncertain significance	criteria provided, single submitter
1395987	NM_006459.4(ERLIN1):c.76C>G (p.His26Asp)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1402119	NM_006459.4(ERLIN1):c.728G>A (p.Arg243His)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1413885	NM_006459.4(ERLIN1):c.878C>A (p.Ser293Tyr)	ERLIN1	Uncertain significance	criteria provided, single submitter
1416413	NM_006459.4(ERLIN1):c.496A>G (p.Thr166Ala)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1425746	NM_006459.4(ERLIN1):c.799G>A (p.Ala267Thr)	ERLIN1	Uncertain significance	criteria provided, single submitter
1434738	NM_006459.4(ERLIN1):c.178A>G (p.Thr60Ala)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447973	NM_006459.4(ERLIN1):c.269G>T (p.Arg90Leu)	ERLIN1	Uncertain significance	criteria provided, single submitter
1473777	NM_006459.4(ERLIN1):c.1037G>A (p.Ser346Asn)	ERLIN1	Uncertain significance	criteria provided, single submitter
1491893	NM_006459.4(ERLIN1):c.284A>G (p.Asn95Ser)	ERLIN1	Uncertain significance	criteria provided, single submitter
1491903	NM_006459.4(ERLIN1):c.688C>T (p.Arg230Trp)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1500905	NM_006459.4(ERLIN1):c.689G>A (p.Arg230Gln)	ERLIN1	Uncertain significance	criteria provided, single submitter
1512248	NM_006459.4(ERLIN1):c.317T>C (p.Val106Ala)	ERLIN1	Uncertain significance	criteria provided, single submitter
1512511	NM_006459.4(ERLIN1):c.451A>G (p.Lys151Glu)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1896355	NM_006459.4(ERLIN1):c.874G>T (p.Ala292Ser)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2024548	NM_006459.4(ERLIN1):c.563+1G>A	ERLIN1	Uncertain significance	criteria provided, single submitter
2051439	NM_006459.4(ERLIN1):c.760G>T (p.Ala254Ser)	ERLIN1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
ERLIN1	Strong	Autosomal recessive	hereditary spastic paraplegia 62	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERLIN1	Orphanet:401785	Autosomal recessive spastic paraplegia type 62

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERLIN1	HGNC:16947	ENSG00000107566	O75477	Erlin-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERLIN1	Erlin-1	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs).

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERLIN1	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
esophagus squamous epithelium	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERLIN1	289	ubiquitous	marker	secondary oocyte, oocyte, esophagus squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERLIN1	1,560

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERLIN1	O75477	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CFTR causes cystic fibrosis	1	219.6×	0.008	ERLIN1
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	193.6×	0.008	ERLIN1
ABC-family protein mediated transport	1	121.5×	0.008	ERLIN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 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	2407.4×	0.001	ERLIN1
SREBP signaling pathway	1	1872.4×	0.001	ERLIN1
regulation of cholesterol biosynthetic process	1	1532.0×	0.001	ERLIN1
negative regulation of fatty acid biosynthetic process	1	887.0×	0.002	ERLIN1
cholesterol metabolic process	1	195.9×	0.006	ERLIN1
ERAD pathway	1	181.2×	0.006	ERLIN1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERLIN1	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
ERLIN1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	ERLIN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ERLIN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.