Ataxia - oculomotor apraxia type 4

Summary

Ataxia - oculomotor apraxia type 4 (MONDO:0014557) is a disease caused by PNKP (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PNKP (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 47
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0001251	Ataxia	Obligate (100%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0000657	Oculomotor apraxia	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Occasional (5-29%)
HP:0003560	Muscular dystrophy	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0009053	Distal lower limb muscle weakness	Occasional (5-29%)
HP:0002442	Dyscalculia	Occasional (5-29%)
HP:0010522	Dyslexia	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0007141	Sensorimotor neuropathy	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0000570	Abnormal saccadic eye movements	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0001780	Abnormality of toe	Occasional (5-29%)
HP:0008955	Progressive distal muscular atrophy	Occasional (5-29%)
HP:0001009	Telangiectasia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	ataxia - oculomotor apraxia type 4
Mondo ID	MONDO:0014557
OMIM	616267
Orphanet	459033
DOID	DOID:0081383
UMLS	C4225397
MedGen	902323
GARD	0013111
Is cancer (heuristic)	no

Also known as: AOA4 · ataxia - oculomotor apraxia type 4 · ataxia-oculomotor apraxia 4 · ataxia-oculomotor apraxia-4 · oculomotor apraxia or related oculomotor disease caused by mutation in PNKP · PNKP oculomotor apraxia or related oculomotor disease

Data availability: 47 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive cerebellar ataxia › autosomal recessive syndromic cerebellar ataxia › ataxia - oculomotor apraxia type 4

Related subtypes (6): autosomal recessive cerebellar ataxia-saccadic intrusion syndrome, autosomal recessive spinocerebellar ataxia 11, peroxisome biogenesis disorder 4B, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, Gemignani syndrome, cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

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

47 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 9 conflicting classifications of pathogenicity, 7 pathogenic, 5 pathogenic/likely pathogenic, 3 benign/likely benign, 2 likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1033198	NM_007254.4(PNKP):c.1227_1228del (p.Cys409_Glu410delinsTer)	PNKP	Pathogenic	criteria provided, single submitter
1453676	NM_007254.4(PNKP):c.721G>T (p.Glu241Ter)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187766	NM_007254.4(PNKP):c.1123G>T (p.Gly375Trp)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
187767	NM_007254.4(PNKP):c.1322_1323insAGCCG (p.Gly442fs)	PNKP	Pathogenic	no assertion criteria provided
187768	NM_007254.4(PNKP):c.1549_1550insTGTACTGC (p.Gln517fs)	PNKP	Pathogenic	no assertion criteria provided
190219	NM_007254.4(PNKP):c.1221_1223del (p.Thr408del)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2086105	NM_007254.4(PNKP):c.394_395del (p.Asp132fs)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
383110	NM_007254.4(PNKP):c.1207C>T (p.Gln403Ter)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688919	NM_007254.4(PNKP):c.1116_1123del (p.Phe373fs)	PNKP	Pathogenic	criteria provided, single submitter
4847	NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs)	PNKP	Pathogenic	criteria provided, multiple submitters, no conflicts
692103	NM_007254.4(PNKP):c.148C>G (p.Gln50Glu)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
817332	NM_007254.4(PNKP):c.1288_1294del (p.Ser430fs)	PNKP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3336665	NM_007254.4(PNKP):c.1298+2T>A	PNKP	Likely pathogenic	criteria provided, single submitter
4845667	NM_007254.4(PNKP):c.1485dup (p.Ser496fs)	PNKP	Likely pathogenic	criteria provided, single submitter
138721	NM_007254.4(PNKP):c.1298+6G>A	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159794	NM_007254.4(PNKP):c.416G>A (p.Arg139His)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
159803	NM_007254.4(PNKP):c.968C>T (p.Thr323Met)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
206401	NM_007254.4(PNKP):c.1029+2T>C	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
206404	NM_007254.4(PNKP):c.1129G>A (p.Gly377Arg)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
391407	NM_007254.4(PNKP):c.1009G>C (p.Glu337Gln)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
538898	NM_007254.4(PNKP):c.1510del (p.Arg504fs)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95478	NM_007254.4(PNKP):c.1360C>A (p.Leu454Met)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95491	NM_007254.4(PNKP):c.901C>T (p.Arg301Trp)	PNKP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1027736	NM_007254.4(PNKP):c.896C>T (p.Pro299Leu)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
194242	NM_007254.4(PNKP):c.1177C>T (p.His393Tyr)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
197287	NM_007254.4(PNKP):c.290A>G (p.Asn97Ser)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
198198	NM_007254.4(PNKP):c.625G>A (p.Glu209Lys)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
206391	NM_007254.4(PNKP):c.670C>T (p.Arg224Cys)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
206399	NM_007254.4(PNKP):c.1003G>T (p.Gly335Cys)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts
206415	NM_007254.4(PNKP):c.1391G>C (p.Arg464Pro)	PNKP	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
PNKP	Definitive	Autosomal recessive	ataxia - oculomotor apraxia type 4	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PNKP	Orphanet:101101	Charcot-Marie-Tooth disease type 2B2
PNKP	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
PNKP	Orphanet:459033	Ataxia-oculomotor apraxia type 4

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
PNKP	HGNC:9154	ENSG00000039650	Q96T60	Bifunctional polynucleotide phosphatase/kinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PNKP	Bifunctional polynucleotide phosphatase/kinase	Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways.

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PNKP	Phosphatase	yes	2.7.1.78	HAD-SF_hydro_IIIA, PNKP, Polynucleotide_phosphatase

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
granulocyte	1
right adrenal gland cortex	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PNKP	259	ubiquitous	marker	right uterine tube, granulocyte, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PNKP	2,445

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PNKP	Q96T60	2

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
APEX1-Independent Resolution of AP Sites via the Single Nucleotide Replacement Pathway	1	1631.4×	6e-04	PNKP

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
response to radiation	1	1203.7×	0.003	PNKP
base-excision repair, gap-filling	1	1123.5×	0.003	PNKP
positive regulation of double-strand break repair via nonhomologous end joining	1	991.3×	0.003	PNKP
DNA-templated DNA replication	1	561.7×	0.003	PNKP
positive regulation of telomere maintenance	1	510.7×	0.003	PNKP
double-strand break repair via nonhomologous end joining	1	421.3×	0.003	PNKP
nucleotide-excision repair	1	383.0×	0.003	PNKP
response to oxidative stress	1	130.6×	0.009	PNKP
DNA repair	1	63.8×	0.016	PNKP

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
PNKP	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
PNKP	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PNKP	2.7.1.78, 3.1.3.32	polynucleotide 5’-hydroxyl-kinase, polynucleotide 3’-phosphatase

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	PNKP
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)
PNKP	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.