Kufor-Rakeb syndrome

Summary

Kufor-Rakeb syndrome (MONDO:0011706) is a disease caused by ATP13A2 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ATP13A2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,003
• Phenotypes (HPO): 44
• Clinical trials: 1

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

Signs & symptoms

Clinical features (HPO)

44 HPO clinical features (Orphanet curated; top 44 by frequency):

HPO ID	Term	Frequency
HP:0000514	Slow saccadic eye movements	Very frequent (80-99%)
HP:0000605	Supranuclear gaze palsy	Very frequent (80-99%)
HP:0000726	Dementia	Very frequent (80-99%)
HP:0001300	Parkinsonism	Very frequent (80-99%)
HP:0002063	Rigidity	Very frequent (80-99%)
HP:0002395	Lower limb hyperreflexia	Very frequent (80-99%)
HP:0003487	Babinski sign	Very frequent (80-99%)
HP:0007256	Abnormal pyramidal sign	Very frequent (80-99%)
HP:0007350	Hyperreflexia in upper limbs	Very frequent (80-99%)
HP:0000020	Urinary incontinence	Frequent (30-79%)
HP:0000183	Tongue muscle weakness	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0000736	Short attention span	Frequent (30-79%)
HP:0001167	Abnormality of finger	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002367	Visual hallucinations	Frequent (30-79%)
HP:0002425	Anarthria	Frequent (30-79%)
HP:0008969	Leg muscle stiffness	Frequent (30-79%)
HP:0010553	Oculogyric crisis	Frequent (30-79%)
HP:0011446	Abnormality of higher mental function	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0000511	Vertical supranuclear gaze palsy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000643	Blepharospasm	Occasional (5-29%)
HP:0000658	Eyelid apraxia	Occasional (5-29%)
HP:0000741	Apathy	Occasional (5-29%)
HP:0001260	Dysarthria	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001760	Abnormal foot morphology	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002493	Upper motor neuron dysfunction	Occasional (5-29%)
HP:0002607	Bowel incontinence	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0007083	Hyperactive patellar reflex	Occasional (5-29%)
HP:0025403	Stooped posture	Occasional (5-29%)
HP:0031008	Lingual dystonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Kufor-Rakeb syndrome
Mondo ID	MONDO:0011706
MeSH	C537177
OMIM	606693
Orphanet	306674
DOID	DOID:0060556
UMLS	C1847640
MedGen	338281
GARD	0009174
NORD	1959
Is cancer (heuristic)	no

Also known as: KRPPD · KRS · Kufor Rakeb Syndrome · Kufor-Rakeb syndrome · Pallidopyramidal degeneration with supranuclear upgaze paresis, and dementia · park 9 · PARK9 · Parkinson disease type 9

Data availability: 1,003 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › basal ganglia disorder › parkinsonian disorder › Parkinson disease › young-onset Parkinson disease › juvenile-onset Parkinson disease › Kufor-Rakeb syndrome

Related subtypes (2): juvenile onset Parkinson disease 19A, Parkinson disease 19B, early-onset

Subtypes (1): parkinsonism due to ATP13A2 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

600 retrieved; paginated sample, class counts are floors:

252 likely benign, 239 uncertain significance, 47 conflicting classifications of pathogenicity, 24 pathogenic, 15 benign, 10 benign/likely benign, 9 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029840	NM_022089.4(ATP13A2):c.2529+1G>A	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075283	NM_022089.4(ATP13A2):c.3136G>T (p.Glu1046Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
1075284	NM_022089.4(ATP13A2):c.2146del (p.Asp715_Leu716insTer)	ATP13A2	Pathogenic	criteria provided, single submitter
1176183	NM_022089.4(ATP13A2):c.2116C>T (p.Gln706Ter)	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1219	NM_022089.4(ATP13A2):c.1306+5G>A	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1220	NM_022089.4(ATP13A2):c.1633_1654dup (p.Leu552fs)	ATP13A2	Pathogenic	no assertion criteria provided
1221	NM_022089.4(ATP13A2):c.1510G>C (p.Gly504Arg)	ATP13A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385899	NM_022089.4(ATP13A2):c.1113del (p.His372fs)	ATP13A2	Pathogenic	criteria provided, single submitter
1442231	NM_022089.4(ATP13A2):c.619C>T (p.Gln207Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
1456750	NC_000001.10:g.(?17316166)(17332293_?)del	ATP13A2	Pathogenic	criteria provided, single submitter
1458906	NC_000001.10:g.(?17330807)(17332293_?)del	ATP13A2	Pathogenic	criteria provided, single submitter
1751269	NM_022089.4(ATP13A2):c.604del (p.His202fs)	ATP13A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1968613	NM_022089.4(ATP13A2):c.3153dup (p.Ser1052fs)	ATP13A2	Pathogenic	criteria provided, single submitter
1996186	NM_022089.4(ATP13A2):c.2113C>T (p.Gln705Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
1999337	NM_022089.4(ATP13A2):c.1825G>T (p.Glu609Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
2013159	NM_022089.4(ATP13A2):c.1296dup (p.Ser433fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2021882	NM_022089.4(ATP13A2):c.965del (p.Gln322fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2022009	NM_022089.4(ATP13A2):c.2587del (p.Val863fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2039313	NM_022089.4(ATP13A2):c.572dup (p.Arg192fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2046647	NM_022089.4(ATP13A2):c.774G>A (p.Trp258Ter)	ATP13A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2064277	NM_022089.4(ATP13A2):c.533_536dup (p.Gln179fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2151865	NM_022089.4(ATP13A2):c.217dup (p.Val73fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2179757	NM_022089.4(ATP13A2):c.1378del (p.Arg460fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2419737	NM_022089.4(ATP13A2):c.213G>A (p.Trp71Ter)	ATP13A2	Pathogenic	criteria provided, single submitter
2572413	NM_022089.4(ATP13A2):c.2540_2550del (p.Gln847fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2629777	NM_022089.4(ATP13A2):c.1033_1034del (p.Leu345fs)	ATP13A2	Pathogenic	criteria provided, multiple submitters, no conflicts
2923611	NM_022089.4(ATP13A2):c.1932del (p.Ala646fs)	ATP13A2	Pathogenic	criteria provided, single submitter
2931003	NM_022089.4(ATP13A2):c.217del (p.Val73fs)	ATP13A2	Pathogenic	criteria provided, single submitter
1510691	NM_022089.4(ATP13A2):c.1846-2A>G	ATP13A2	Likely pathogenic	criteria provided, single submitter
1523588	NM_022089.4(ATP13A2):c.3083+2T>C	ATP13A2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
ATP13A2	Definitive	Autosomal recessive	Kufor-Rakeb syndrome	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP13A2	Orphanet:306674	Kufor-Rakeb syndrome
ATP13A2	Orphanet:314632	CLN12 disease
ATP13A2	Orphanet:513436	Autosomal recessive spastic paraplegia type 78

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
ATP13A2	HGNC:30213	ENSG00000159363	Q9NQ11	Polyamine-transporting ATPase 13A2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP13A2	Polyamine-transporting ATPase 13A2	ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP13A2	Transcription factor	no		P_typ_ATPase, P-type_TPase_V, ATPase_P-typ_transduc_dom_A_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
prefrontal cortex	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP13A2	249	ubiquitous	marker	right frontal lobe, right hemisphere of cerebellum, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP13A2	2,267

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP13A2	Q9NQ11	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Ion transport by P-type ATPases	1	207.6×	0.014	ATP13A2
Ion channel transport	1	96.0×	0.016	ATP13A2
Transport of small molecules	1	25.1×	0.040	ATP13A2

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
spermine transmembrane transport	1	16852.0×	0.001	ATP13A2
extracellular exosome biogenesis	1	8426.0×	0.001	ATP13A2
regulation of autophagosome size	1	5617.3×	0.001	ATP13A2
regulation of lysosomal protein catabolic process	1	5617.3×	0.001	ATP13A2
polyamine transmembrane transport	1	4213.0×	0.001	ATP13A2
regulation of chaperone-mediated autophagy	1	3370.4×	0.001	ATP13A2
autophagosome organization	1	3370.4×	0.001	ATP13A2
negative regulation of lysosomal protein catabolic process	1	3370.4×	0.001	ATP13A2
regulation of intracellular protein transport	1	2808.7×	0.001	ATP13A2
regulation of autophagy of mitochondrion	1	2808.7×	0.001	ATP13A2
cellular response to manganese ion	1	2407.4×	0.001	ATP13A2
regulation of protein localization to nucleus	1	2106.5×	0.001	ATP13A2
autophagosome-lysosome fusion	1	1203.7×	0.002	ATP13A2
intracellular monoatomic cation homeostasis	1	1123.5×	0.002	ATP13A2
positive regulation of exosomal secretion	1	1123.5×	0.002	ATP13A2
protein localization to lysosome	1	1053.2×	0.002	ATP13A2
regulation of mitochondrion organization	1	842.6×	0.002	ATP13A2
lysosomal transport	1	702.2×	0.002	ATP13A2
regulation of neuron apoptotic process	1	702.2×	0.002	ATP13A2
cellular response to zinc ion	1	674.1×	0.002	ATP13A2
intracellular zinc ion homeostasis	1	481.5×	0.003	ATP13A2
positive regulation of protein secretion	1	343.9×	0.004	ATP13A2
lipid homeostasis	1	337.0×	0.004	ATP13A2
regulation of macroautophagy	1	295.6×	0.004	ATP13A2
intracellular iron ion homeostasis	1	244.2×	0.005	ATP13A2
monoatomic ion transmembrane transport	1	208.1×	0.006	ATP13A2
cellular response to oxidative stress	1	154.6×	0.007	ATP13A2
intracellular calcium ion homeostasis	1	145.3×	0.007	ATP13A2
autophagy	1	110.1×	0.009	ATP13A2
positive regulation of gene expression	1	38.7×	0.026	ATP13A2

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
ATP13A2	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	ATP13A2

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)
ATP13A2	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
NCT05522374	Not specified	RECRUITING	TIRCON International NBIA Registry