Objective: To describe Kufor-Rakeb Syndrome (KRS) due to a novel ATP13A2 1459 C>T mutation in two Chinese siblings.

Background: Kufor-Rakeb Syndrome is a rare autosomal recessive juvenile-onset progressive form of Parkinson’s disease (PARK9), first described in 1994, and associated with spasticity, dementia, and supranuclear gaze palsy. Mutations in the ATP13A2, associated with the Park9 locus (chromosome 1p36) have been identified in 11 different kindreds to date (Park et al 2015). Loss of function mutations in ATP13A2 result in impairment in zinc intracellular transport, which perturbs lysosomal function. ATP13A2 contributes to dopaminergic neuron survival through changes in iron homeostasis. Treatment response to standard Parkinson’s medications is limited.

Methods: Subjects were recruited in 2016 at the Weill Cornell Medical Center Movement Disorders clinic. An extended neurological, family, and medical history was performed and a neurological exam, with detailed motor evaluation was video-recorded. 

Results: Two brothers of Chinese descent, aged 27 (subject 1) and 30 years old (subject 2), presented with parkinsonism in childhood, marked by significant rigidity, bradykinesia, and gait instability. MRI of the brain showed cerebellar atrophy in the subject 1 and mild dysplasia of the corpus callosum in the subject 2. Whole exome sequencing in both brothers revealed homozygosity for a novel ATP13A2 mutation c.1459 C>T, a nonsense mutation that is thought to be pathogenic and the likely cause of their KRS. This mutation within exon 14 of the E1-E2 ATPase domain leads to the substitution of a stop codon for an arginine residue, resulting in the premature interruption of ATP13A2 translation and subsequent loss of function. The brothers described in this series were treated with carbidopa-levodopa and physical therapy. Within four weeks, they showed improvement of their Unified Parkinson Disease Rating Scale, Part III motor subscale, from 33 to 30 (subject 1) and 43 to 31 (subject 2), including improvements in rigidity, leg agility and gait.

Conclusions: This report highlights the presence of a novel mutation leading to the development of Kufor-Rakeb Syndrome in a Chinese family and adds to our knowledge of this rare syndrome. Long term follow up and further investigation into treatments that target cell signaling pathways downstream of ATP13A2 mutations may prove beneficial in targeting the metabolic derangements present in this syndrome. 

References: Park, J.-S., Blair, N. F. and Sue, C. M. (2015), The role of ATP13A2 in Parkinson’s disease: Clinical phenotypes and molecular mechanisms. Mov Disord., 30: 770–779. doi:10.1002/mds.26243

Park, J.-S., Mehta, P., Cooper, A. A., Veivers, D., Heimbach, A., Stiller, B., Kubisch, C., Fung, V. S., Krainc, D., Mackay-Sim, A. and Sue, C. M. (2011), Pathogenic effects of novel mutations in the P-type ATPase ATP13A2 (PARK9) causing Kufor-Rakeb syndrome, a form of early-onset parkinsonism. Hum. Mutat., 32: 956–964. doi:10.1002/humu.21527

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MDS Abstracts - https://www.mdsabstracts.org/abstract/kufor-rakeb-syndrome-due-to-a-novel-atp13a2-mutation-in-two-chinese-brothers/