Spastic paraplegia 83, autosomal recessive

Summary

Spastic paraplegia 83, autosomal recessive (MONDO:0033614) is a disease caused by HPDL (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HPDL (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 83, autosomal recessive
Mondo ID	MONDO:0033614
OMIM	619027
Orphanet	631076
DOID	DOID:0112346
UMLS	C5436637
MedGen	1759445
GARD	0025812
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic paraplegia type 83 · SPG83

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

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 › spastic paraplegia 83, autosomal recessive

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

10 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 likely pathogenic, 1 pathogenic/likely pathogenic, 1 likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
979212	NM_032756.4(HPDL):c.149G>A (p.Gly50Asp)	HPDL	Pathogenic	criteria provided, multiple submitters, no conflicts
1344850	NM_032756.4(HPDL):c.859T>C (p.Tyr287His)	LOC129930440	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3076081	NM_032756.4(HPDL):c.862T>C (p.Tyr288His)	HPDL	Likely pathogenic	criteria provided, single submitter
3256610	NM_032756.4(HPDL):c.1066G>C (p.Ala356Pro)	HPDL	Likely pathogenic	criteria provided, single submitter
4537461	NM_032756.4(HPDL):c.727C>T (p.Gln243Ter)	HPDL	Likely pathogenic	criteria provided, single submitter
1344851	NM_032756.4(HPDL):c.847C>T (p.Pro283Ser)	HPDL	Uncertain significance	criteria provided, single submitter
3891347	NM_032756.4(HPDL):c.815G>C (p.Gly272Ala)	HPDL	Uncertain significance	criteria provided, single submitter
4291094	NM_032756.4(HPDL):c.128G>C (p.Arg43Pro)	HPDL	Uncertain significance	criteria provided, single submitter
4292415	NM_032756.4(HPDL):c.2T>A (p.Met1Lys)	HPDL	Uncertain significance	criteria provided, single submitter
1694510	NM_032756.4(HPDL):c.1017G>A (p.Glu339=)	HPDL	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
HPDL	Strong	Autosomal recessive	spastic paraplegia 83, autosomal recessive	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPDL	Orphanet:528084	Non-specific syndromic intellectual disability
HPDL	Orphanet:631076	Autosomal recessive spastic paraplegia type 83
HPDL	Orphanet:641353	Infantile neurodegeneration-progressive spasticity-intellectual disability-white matter lesions 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
HPDL	HGNC:28242	ENSG00000186603	Q96IR7	4-hydroxyphenylpyruvate dioxygenase-like protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPDL	4-hydroxyphenylpyruvate dioxygenase-like protein	Iron-dependent dioxygenase that catalyzes the conversion of 4-hydroxyphenylpyruvate (4-HPPA) to 4-hydroxymandelate (4-HMA) in the mitochondria, one of the steps in the biosynthesis of coenzyme Q10 from tyrosine.

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)
HPDL	Other/Unknown	no		4OHPhenylPyrv_dOase, Glyas_Bleomycin-R_OHBP_Dase, VOC_core

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
ileal mucosa	1
mucosa of transverse colon	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPDL	152	broad	marker	primordial germ cell in gonad, mucosa of transverse colon, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HPDL	1,149

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HPDL	Q96IR7	91.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Ubiquinol biosynthesis	1	878.5×	0.001	HPDL

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
aromatic amino acid metabolic process	1	8426.0×	1e-04	HPDL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPDL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	HPDL

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)
HPDL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.