Hereditary spastic paraplegia 64

Summary

Hereditary spastic paraplegia 64 (MONDO:0014303) is a disease caused by ENTPD1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ENTPD1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 168
• Phenotypes (HPO): 9

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		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

9 HPO clinical features (Orphanet curated; top 9 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0006889	Intellectual disability, borderline	Frequent (30-79%)
HP:0001284	Areflexia	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary spastic paraplegia 64
Mondo ID	MONDO:0014303
OMIM	615683
Orphanet	401810
DOID	DOID:0110815
SNOMED CT	726609005
UMLS	C3810289
MedGen	816619
GARD	0017659
Is cancer (heuristic)	no

Also known as: autosomal recessive complex spastic paraplegia caused by mutation in ENTPD1 · autosomal recessive spastic paraplegia type 64 · ENTPD1 autosomal recessive complex spastic paraplegia · hereditary spastic paraplegia type 64 · spastic paraplegia 64, autosomal recessive · SPG64

Data availability: 168 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › hereditary spastic paraplegia 64

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 18, 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 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

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

168 retrieved; paginated sample, class counts are floors:

77 likely benign, 58 uncertain significance, 9 pathogenic, 9 conflicting classifications of pathogenicity, 7 benign, 6 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
101076	NM_001776.6(ENTPD1):c.628G>A (p.Gly210Arg)	ENTPD1	Pathogenic	no assertion criteria provided
101077	NM_001776.6(ENTPD1):c.520G>T (p.Glu174Ter)	ENTPD1	Pathogenic	no assertion criteria provided
2129367	NM_001776.6(ENTPD1):c.1020C>G (p.Tyr340Ter)	ENTPD1	Pathogenic	criteria provided, single submitter
2443792	NM_001776.6(ENTPD1):c.1109T>A (p.Leu370Ter)	ENTPD1	Pathogenic	criteria provided, single submitter
2443794	NM_001776.6(ENTPD1):c.640del (p.Gly216fs)	ENTPD1	Pathogenic	no assertion criteria provided
2784423	NM_001776.6(ENTPD1):c.861T>A (p.Tyr287Ter)	ENTPD1	Pathogenic	criteria provided, multiple submitters, no conflicts
3775363	NM_001776.6(ENTPD1):c.967C>T (p.Gln323Ter)	ENTPD1	Pathogenic	criteria provided, single submitter
802625	NM_001776.6(ENTPD1):c.770_771del (p.Gly257fs)	ENTPD1	Pathogenic	criteria provided, single submitter
3237367	NM_001776.6(ENTPD1):c.1174C>T (p.Gln392Ter)	ENTPD1-AS1	Pathogenic	no assertion criteria provided
3638856	NM_001776.6(ENTPD1):c.813+2C>G	ENTPD1	Likely pathogenic	criteria provided, single submitter
3775912	NM_001776.6(ENTPD1):c.262+1G>T	ENTPD1	Likely pathogenic	criteria provided, single submitter
3776000	NM_001776.6(ENTPD1):c.144+1G>A	ENTPD1	Likely pathogenic	criteria provided, single submitter
3779615	NM_001776.6(ENTPD1):c.17-2A>G	ENTPD1	Likely pathogenic	criteria provided, single submitter
802624	NM_001776.6(ENTPD1):c.574-6_574-3del	ENTPD1	Likely pathogenic	criteria provided, single submitter
3336673	NM_001776.6(ENTPD1):c.457del (p.Glu153fs)	ENTPD1-AS1	Likely pathogenic	criteria provided, single submitter
2085110	NM_001776.6(ENTPD1):c.871G>A (p.Val291Met)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2150484	NM_001776.6(ENTPD1):c.740A>G (p.Asn247Ser)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2663477	NM_001776.6(ENTPD1):c.536G>A (p.Trp179Ter)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374088	NM_001776.6(ENTPD1):c.25G>A (p.Val9Met)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547899	NM_001164178.1(ENTPD1):c.52G>A (p.Glu18Lys)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
704012	NM_001776.6(ENTPD1):c.1338C>T (p.Ser446=)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
705302	NM_001776.6(ENTPD1):c.834C>T (p.Leu278=)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
965980	NM_001776.6(ENTPD1):c.920T>A (p.Met307Lys)	ENTPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498850	NM_001776.6(ENTPD1):c.1479C>G (p.Ile493Met)	ENTPD1-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1003440	NM_001776.6(ENTPD1):c.229G>A (p.Val77Met)	ENTPD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1022844	NM_001776.6(ENTPD1):c.1342G>A (p.Ala448Thr)	ENTPD1	Uncertain significance	criteria provided, single submitter
1030478	NM_001776.6(ENTPD1):c.*7C>T	ENTPD1	Uncertain significance	criteria provided, single submitter
1040141	NM_001776.6(ENTPD1):c.454G>T (p.Val152Leu)	ENTPD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1052295	NM_001776.6(ENTPD1):c.284T>C (p.Val95Ala)	ENTPD1	Uncertain significance	criteria provided, single submitter
1053783	NM_001776.6(ENTPD1):c.1339G>A (p.Asp447Asn)	ENTPD1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ENTPD1	Definitive	Autosomal recessive	complex hereditary spastic paraplegia	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ENTPD1	Orphanet:401810	Autosomal recessive spastic paraplegia type 64

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ENTPD1	HGNC:3363	ENSG00000138185	P49961	Ectonucleoside triphosphate diphosphohydrolase 1	gencc,clinvar
ENTPD1-AS1	HGNC:45203	ENSG00000226688		ENTPD1 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ENTPD1	Ectonucleoside triphosphate diphosphohydrolase 1	Catalyzes the hydrolysis of nucleoside triphosphates (NTPs) and diphosphates (NDPs).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ENTPD1	Enzyme (other)	yes	3.6.1.5	GDA1_CD39_NTPase
ENTPD1-AS1	Other/Unknown	no

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
monocyte	1
mononuclear cell	1
saphenous vein	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ENTPD1	274	broad	marker	saphenous vein, monocyte, mononuclear cell
ENTPD1-AS1	234	ubiquitous	marker	tendon of biceps brachii, male germ line stem cell (sensu Vertebrata) in testis, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENTPD1	2,623
ENTPD1-AS1	0

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ENTPD1	P49961	90.85

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Phosphate bond hydrolysis by NTPDase proteins	1	1427.5×	0.001	ENTPD1
Purinergic signaling in leishmaniasis infection	1	423.0×	0.002	ENTPD1

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
nucleoside diphosphate catabolic process	1	4213.0×	8e-04	ENTPD1
ADP catabolic process	1	4213.0×	8e-04	ENTPD1
AMP catabolic process	1	2407.4×	1e-03	ENTPD1
platelet aggregation	1	337.0×	0.005	ENTPD1
blood coagulation	1	173.7×	0.008	ENTPD1
cell adhesion	1	37.5×	0.028	ENTPD1
G protein-coupled receptor signaling pathway	1	36.2×	0.028	ENTPD1

Therapeutics

Drug target analysis

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

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
ENTPD1	1	3
ENTPD1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENTPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENTPD1	32	Binding:27, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENTPD1	3.6.1.5	apyrase

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

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)
SURAMIN	3	ENTPD1

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	ENTPD1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ENTPD1-AS1

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)
ENTPD1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.