Objective: To describe a genetically proven case of Kufor-Rakeb syndrome (KRS) in a young portuguese patient with juvenile parkinsonism.

Background: Mutations in the ATP13A2 gene (PARK9) cause autosomal recessive KRS characterized by juvenile or young-onset levodopa-responsive parkinsonism associated with spasticity, progressive supranuclear palsy and dementia. ATP13A2 has a role of lysosomal pump and is a cation transporter (Mn2+, Zn2+). Loss of function leads to lysosomal dysfunction, iron accumulation in brain and impairment of zinc transport. Brain MRIs of KRS’ patients may reveal putaminal and caudate iron accumulation.

Methods: Case report. A five years longitudinal video-recorded follow-up of a genetically confirmed patient, with neurological, motor, and cognitive evaluation.

Results: A 20-year old portuguese female with no significant family history presented with mild gait disorder, hand tremor and dysarthria progressing for two years. She had bilateral, symmetric akineto-rigid syndrome, pyramidal signs, dysarthria, swallowing disorders, and dysexecutive mild cognitive impairment (MMSE 25/30). Parkinsonism responded to 300 mg/day of levodopa (UPDRS-3 reduced from 19 to 8). Brain MRI revealed diffuse moderate atrophy. A 123I-FP-CIT SPECT confirmed bilateral dopaminergic denervation. Iron and copper metabolism were normal. Recording of eye movements showed vertical and horizontal hypometric saccades and inhibition failure. Next Generation Sequencing panel revealed a homozygous variant Gly504Arg of ATP13A2 gene. During follow-up, dyskinesia developed at age 22. Parkinsonism slowly increased, with a preserved autonomy for most activities of daily living. Dysexecutive syndrome was stable between 20 and 24 y.o., but now the patient has apraxia and language disorders.

Conclusions: We report a rare homozygous variant G504R of ATP13A2 gene (PARK9) that was previously described in a single brazilian patient (Di Fonzo et al., Neurology 2007) with juvenile Parkinson’s disease and no KRS. In the present case, the same mutation lead to a slowly progressive KRS. In the hypothesis that the pathophysiology involves iron accumulation in the striatum we empirically started a treatment with deferiprone (30 mg/kg/d), an iron chelator.

References: ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease. Di Fonzo et al., Neurology. 2007 May 8;68(19):1557-62.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/kufor-rakeb-syndrome-and-a-rare-atp13a2-missense-mutation-in-a-portuguese-patient/