Spastic ataxia 4

Summary

Spastic ataxia 4 (MONDO:0013354) is a disease caused by MTPAP (GenCC Strong), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTPAP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 14
• Phenotypes (HPO): 16
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002313	Spastic paraparesis	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0000182	Movement abnormality of the tongue	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002359	Frequent falls	Frequent (30-79%)
HP:0006895	Lower limb hypertonia	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0200049	Upper limb hypertonia	Frequent (30-79%)
HP:0000712	Emotional lability	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic ataxia 4
Mondo ID	MONDO:0013354
OMIM	613672
Orphanet	254343
DOID	DOID:0050943
UMLS	C3150925
MedGen	462275
GARD	0010992
Is cancer (heuristic)	no

Also known as: autosomal recessive spastic ataxia - optic atrophy - dysarthria · autosomal recessive spastic ataxia 4 · autosomal recessive spastic ataxia caused by mutation in MTPAP · autosomal recessive spastic ataxia type 4 · MTPAP autosomal recessive spastic ataxia · spastic ataxia 4, autosomal recessive · spastic ataxia type 4 · SPAX4

Data availability: 14 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › spastic ataxia 4

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

14 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
18391	NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)	MTPAP	Pathogenic	criteria provided, single submitter
1494230	NM_018109.4(MTPAP):c.1550C>T (p.Pro517Leu)	MTPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2182204	NM_018109.4(MTPAP):c.1624A>G (p.Thr542Ala)	MTPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418340	NM_018109.4(MTPAP):c.1072C>T (p.Arg358Trp)	MTPAP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028088	NM_018109.4(MTPAP):c.1673T>C (p.Leu558Pro)	MTPAP	Uncertain significance	criteria provided, single submitter
1029511	NM_018109.4(MTPAP):c.842C>G (p.Thr281Ser)	MTPAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805661	NM_018109.4(MTPAP):c.1283T>C (p.Ile428Thr)	MTPAP	Uncertain significance	criteria provided, single submitter
1805662	NM_018109.4(MTPAP):c.1567C>T (p.Arg523Trp)	MTPAP	Uncertain significance	criteria provided, single submitter
374341	NM_018109.4(MTPAP):c.1468G>T (p.Val490Leu)	MTPAP	Uncertain significance	no assertion criteria provided
447743	NM_018109.4(MTPAP):c.346G>A (p.Val116Ile)	MTPAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
805055	NM_018109.4(MTPAP):c.468G>C (p.Gln156His)	MTPAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
138280	NM_018109.4(MTPAP):c.157+20C>T	LOC130003597	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
129624	NM_018109.4(MTPAP):c.484C>T (p.Arg162Cys)	MTPAP	Benign	criteria provided, multiple submitters, no conflicts
138281	NM_018109.4(MTPAP):c.555+19C>T	MTPAP	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
MTPAP	Strong	Autosomal recessive	spastic ataxia 4	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTPAP	Orphanet:254343	Autosomal recessive spastic ataxia-optic atrophy-dysarthria 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
MTPAP	HGNC:25532	ENSG00000107951	Q9NVV4	Poly(A) RNA polymerase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTPAP	Poly(A) RNA polymerase, mitochondrial	Polymerase that creates the 3’ poly(A) tail of mitochondrial transcripts.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTPAP	Enzyme (other)	yes	2.7.7.19	PAP_assoc, RL, NT_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
gingival epithelium	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTPAP	276	ubiquitous	marker	oocyte, secondary oocyte, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTPAP	1,414

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTPAP	Q9NVV4	1

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
Mitochondrial mRNA modification	1	1038.2×	1e-03	MTPAP

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
mitochondrial RNA 3’-end processing	1	5617.3×	6e-04	MTPAP
mitochondrial mRNA polyadenylation	1	4213.0×	6e-04	MTPAP
histone mRNA catabolic process	1	1685.2×	1e-03	MTPAP
RNA 3’-end processing	1	1296.3×	1e-03	MTPAP
mRNA processing	1	78.8×	0.013	MTPAP

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
MTPAP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTPAP	2.7.7.19	polynucleotide adenylyltransferase

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	MTPAP
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)
MTPAP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford