ATP13A2 – Kufor-Rakeb syndrome

ATP13A2-related Kufor-Rakeb syndrome is an autosomal recessive juvenile-onset parkinsonism characterized by progressive extrapyramidal and pyramidal signs, cognitive decline, supranuclear gaze palsy and brain iron accumulation. Disease-causing biallelic ATP13A2 variants segregate with disease in multiple multiplex families, supporting a recessive inheritance model.

Genetic evidence includes compound heterozygous or homozygous ATP13A2 variants in at least 23 unrelated probands across 11 families, with segregation in consanguineous and non-consanguineous kindreds and absence of biallelic variants in healthy controls ([PMID:21060012], [PMID:20683840]). Segregation analysis identified 19 additional affected relatives carrying ATP13A2 pathogenic alleles.

The variant spectrum comprises truncating frameshift and nonsense mutations, splice-site alterations and rare missense changes. The recurrent founder allele c.3057del (p.Tyr1020fs) is reported in multiple pedigrees ([PMID:20310007]). Over 30 distinct ATP13A2 variants have been documented in Kufor-Rakeb syndrome.

Functional studies demonstrate loss-of-function as the principal mechanism: disease-associated mutants are retained in the endoplasmic reticulum, undergo proteasomal degradation and fail to localize to lysosomes, leading to reduced cathepsin D activity and fingerprint-like inclusions in patient cells and medaka fish models ([PMID:23499937]). Wild-type ATP13A2 protects against manganese‐induced cytotoxicity and regulates intracellular Zn²⁺ homeostasis, whereas pathogenic alleles abolish these effects ([PMID:21724849]).

Neuropathologic and animal model data show neuronal lipofuscin and sparse iron deposits without Lewy bodies, recapitulating features of neuronal ceroid lipofuscinosis and supporting overlap with neurodegeneration with brain iron accumulation ([PMID:22388936]). Concordant clinical, genetic and experimental findings confirm a definitive gene-disease relationship.

ATP13A2 sequencing is clinically indicated for early-onset parkinsonism with pyramidal signs and supranuclear gaze palsy, enabling accurate diagnosis, genetic counseling, and the exploration of cation-modulating therapies.

References

• Archives of neurology • 2010 • Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype PMID:21060012
• Movement disorders • 2010 • Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations PMID:20683840
• Movement disorders • 2010 • ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation PMID:20310007
• FEBS letters • 2013 • ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons PMID:23499937
• Journal of biological chemistry • 2011 • Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein PMID:21724849
• Human molecular genetics • 2012 • Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis PMID:22388936

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