Hereditary spastic paraplegia 18

Summary

Hereditary spastic paraplegia 18 (MONDO:0012639) is a disease caused by ERLIN2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ERLIN2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 13
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0001371	Flexion contracture	Very frequent (80-99%)
HP:0002460	Distal muscle weakness	Very frequent (80-99%)
HP:0002540	Inability to walk	Very frequent (80-99%)
HP:0002987	Elbow flexion contracture	Very frequent (80-99%)
HP:0006380	Knee flexion contracture	Very frequent (80-99%)
HP:0006466	Ankle flexion contracture	Very frequent (80-99%)
HP:0007350	Hyperreflexia in upper limbs	Very frequent (80-99%)
HP:0012453	Bilateral wrist flexion contracture	Very frequent (80-99%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0002079	Hypoplasia of the corpus callosum	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000322	Short philtrum	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000574	Thick eyebrow	Occasional (5-29%)
HP:0000664	Synophrys	Occasional (5-29%)
HP:0000666	Horizontal nystagmus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001583	Rotary nystagmus	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002166	Impaired vibration sensation in the lower limbs	Occasional (5-29%)
HP:0002378	Hand tremor	Occasional (5-29%)
HP:0003273	Hip contracture	Occasional (5-29%)
HP:0003306	Spinal rigidity	Occasional (5-29%)
HP:0005830	Flexion contracture of toe	Occasional (5-29%)
HP:0005997	Restricted neck movement due to contractures	Occasional (5-29%)
HP:0011448	Ankle clonus	Occasional (5-29%)
HP:0100712	Abnormal lumbar spine morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 18
Mondo ID	MONDO:0012639
MeSH	C567628
Orphanet	209951
DOID	DOID:0110771
SNOMED CT	732932004
UMLS	C2749936
MedGen	442343
GARD	0004922
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in ERLIN2 · autosomal recessive spastic paraplegia 18 · autosomal recessive spastic paraplegia type 18 · ERLIN2 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 18 · intellectual disability, motor dysfunction and joint contractures · spastic paraplegia 18 · spastic paraplegia 18, autosomal recessive · SPG18

Data availability: 13 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 18

Related subtypes (49): hereditary sensory and autonomic neuropathy with spastic paraplegia, hereditary spastic paraplegia 15, hereditary spastic paraplegia 23, spastic paraplegia-glaucoma-intellectual disability syndrome, Troyer syndrome, MASA syndrome, hereditary spastic paraplegia 11, hereditary spastic paraplegia 24, hereditary spastic paraplegia 25, hereditary spastic paraplegia 27, hereditary spastic paraplegia 26, spastic paraplegia, optic atropy, and neuropathy, hereditary spastic paraplegia 32, spastic ataxia 2, hereditary spastic paraplegia 39, hereditary spastic paraplegia 45, hereditary spastic paraplegia 44, hereditary spastic paraplegia 46, hereditary spastic paraplegia 53, hereditary spastic paraplegia 49, hereditary spastic paraplegia 54, hereditary spastic paraplegia 55, hereditary spastic paraplegia 43, hereditary spastic paraplegia 57, hereditary spastic paraplegia 64, hereditary spastic paraplegia 61, hereditary spastic paraplegia 63, glutamate pyruvate transaminase 2 deficiency, hereditary spastic paraplegia 74, autosomal recessive complex spastic paraplegia type 9B, hereditary spastic paraplegia 75, spastic paraplegia-severe developmental delay-epilepsy syndrome, autosomal recessive spastic paraplegia type 76, autosomal recessive spastic paraplegia type 78, autosomal dominant complex spastic paraplegia, maternally-inherited spastic paraplegia, fatty acid hydroxylase-associated neurodegeneration, autosomal recessive spastic paraplegia type 59, autosomal recessive spastic paraplegia type 60, autosomal recessive spastic paraplegia type 66, autosomal recessive spastic paraplegia type 67, autosomal recessive spastic paraplegia type 68, autosomal recessive spastic paraplegia type 69, autosomal recessive spastic paraplegia type 70, spastic paraplegia 84, autosomal recessive, spastic paraplegia 85, autosomal recessive, spastic paraplegia 86, autosomal recessive, kyphoscoliosis-lateral tongue atrophy-hereditary spastic paraplegia syndrome, autosomal recessive complex spastic paraplegia due to kennedy pathway dysfunction

Subtypes (2): spastic paraplegia 18b, autosomal recessive, spastic paraplegia 18a, autosomal dominant

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

13 retrieved; paginated sample, class counts are floors:

7 pathogenic, 3 uncertain significance, 2 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579114	NM_007175.8(ERLIN2):c.47_48delinsAA (p.Cys16Ter)	ERLIN2	Pathogenic	criteria provided, single submitter
2663863	NM_007175.8(ERLIN2):c.660del (p.Val221fs)	ERLIN2	Pathogenic	criteria provided, single submitter
30913	NM_007175.8(ERLIN2):c.812_813insAC (p.Asn272fs)	ERLIN2	Pathogenic	no assertion criteria provided
92113	NM_007175.8(ERLIN2):c.499-1G>T	ERLIN2	Pathogenic	no assertion criteria provided
989004	NM_007175.8(ERLIN2):c.799A>G (p.Lys267Glu)	ERLIN2	Pathogenic	criteria provided, single submitter
989005	NM_007175.8(ERLIN2):c.819G>A (p.Lys273=)	ERLIN2	Pathogenic	criteria provided, single submitter
989006	NM_007175.8(ERLIN2):c.877A>G (p.Ser293Gly)	ERLIN2	Pathogenic	criteria provided, single submitter
3779628	NM_007175.8(ERLIN2):c.107+2T>C	ERLIN2	Likely pathogenic	criteria provided, single submitter
435090	NM_007175.8(ERLIN2):c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA	ERLIN2	Likely pathogenic	criteria provided, single submitter
1032526	NM_007175.8(ERLIN2):c.356A>G (p.Lys119Arg)	ERLIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1710198	NM_007175.8(ERLIN2):c.538C>T (p.Arg180Cys)	ERLIN2	Uncertain significance	no assertion criteria provided
2663843	NM_007175.8(ERLIN2):c.869C>T (p.Ala290Val)	ERLIN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3775641	NM_007175.8(ERLIN2):c.557+4A>C	ERLIN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
ERLIN2	Strong	Autosomal recessive	hereditary spastic paraplegia 18	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERLIN2	HGNC:1356	ENSG00000147475	O94905	Erlin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 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)
ERLIN2	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
calcaneal tendon	1
choroid plexus epithelium	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
ERLIN2	2,170

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERLIN2	O94905	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Signaling by plasma membrane FGFR1 fusions	1	2855.0×	0.002	ERLIN2
Signaling by FGFR1 in disease	1	292.8×	0.006	ERLIN2
Defective CFTR causes cystic fibrosis	1	219.6×	0.006	ERLIN2
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	1	193.6×	0.006	ERLIN2
ABC-family protein mediated transport	1	121.5×	0.008	ERLIN2

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	ERLIN2
SREBP signaling pathway	1	1872.4×	0.001	ERLIN2
regulation of cholesterol biosynthetic process	1	1532.0×	0.001	ERLIN2
negative regulation of fatty acid biosynthetic process	1	887.0×	0.002	ERLIN2
cholesterol metabolic process	1	195.9×	0.006	ERLIN2
ERAD pathway	1	181.2×	0.006	ERLIN2

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
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: 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	ERLIN2

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)
ERLIN2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.