Autosomal recessive spastic paraplegia type 59

Summary

Autosomal recessive spastic paraplegia type 59 (MONDO:0018416) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 1
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	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:0001258	Spastic paraplegia	Very frequent (80-99%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002064	Spastic gait	Frequent (30-79%)
HP:0002169	Clonus	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002509	Limb hypertonia	Frequent (30-79%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001317	Abnormal cerebellum morphology	Excluded (0%)
HP:0002500	Abnormal cerebral white matter morphology	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive spastic paraplegia type 59
Mondo ID	MONDO:0018416
Orphanet	401795
UMLS	C4750857
MedGen	1669596
GARD	0021695
Is cancer (heuristic)	no

Also known as: SPG59

Data availability: 1 ClinVar variant · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › complex hereditary spastic paraplegia › autosomal recessive spastic paraplegia type 59

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 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 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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
704010	NM_005154.5(USP8):c.1330C>T (p.Arg444Cys)	USP8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
USP8	Moderate	Autosomal recessive	hereditary spastic paraplegia	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
USP8	Orphanet:401795	Autosomal recessive spastic paraplegia type 59
USP8	Orphanet:96253	Cushing disease

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
USP8	HGNC:12631	ENSG00000138592	P40818	Ubiquitin carboxyl-terminal hydrolase 8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
USP8	Ubiquitin carboxyl-terminal hydrolase 8	Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
USP8	Protease	yes	3.4.19.12	Peptidase_C19_UCH, Rhodanese-like_dom, USP8_dimer

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
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
USP8	284	ubiquitous	marker	calcaneal tendon, sural nerve, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
USP8	2,737

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
USP8	P40818	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Downregulation of ERBB2:ERBB3 signaling	1	815.7×	0.003	USP8
Regulation of FZD by ubiquitination	1	519.1×	0.003	USP8
Negative regulation of MET activity	1	519.1×	0.003	USP8
Ub-specific processing proteases	1	53.1×	0.019	USP8

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
regulation of protein catabolic process at postsynapse, modulating synaptic transmission	1	4213.0×	0.001	USP8
negative regulation of lysosomal protein catabolic process	1	3370.4×	0.001	USP8
positive regulation of amyloid fibril formation	1	3370.4×	0.001	USP8
protein K48-linked deubiquitination	1	648.1×	0.004	USP8
protein K63-linked deubiquitination	1	624.1×	0.004	USP8
cellular response to dexamethasone stimulus	1	581.1×	0.004	USP8
cellular response to nerve growth factor stimulus	1	468.1×	0.005	USP8
endosome organization	1	374.5×	0.005	USP8
mitotic cytokinesis	1	259.3×	0.006	USP8
Ras protein signal transduction	1	205.5×	0.007	USP8
regulation of protein localization	1	205.5×	0.007	USP8
protein deubiquitination	1	177.4×	0.007	USP8
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.007	USP8
regulation of protein stability	1	125.8×	0.009	USP8
proteolysis	1	34.2×	0.029	USP8

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
USP8	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
USP8	54	Binding:51, Functional:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
USP8	3.4.19.12	ubiquitinyl hydrolase 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	1	USP8
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
USP8	54	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.