Objective: To describe the clinical, genetic, and phenotypic aspects of a patient with Kufor-Rakeb syndrome (KRS), an ultra-rare juvenile parkinsonism caused by ATP13A2 mutations.

Background: Kufor-Rakeb syndrome (PARK9) is an autosomal recessive neurodegenerative disorder associated with biallelic mutations in ATP13A2, a lysosomal P5-type ATPase involved in cation transport and lysosomal homeostasis: dysfunctional metal regulation, impaired lysosomal-mitochondrial integrity, and α-synuclein accumulation. KRS manifests with juvenile-onset parkinsonism combined with pyramidal signs, supranuclear gaze palsy, cerebellar features, cognitive and neuropsychiatric impairment. Fewer than 80 cases have been reported.

Method: We report the clinical, neurological, and genetic evaluation of a patient assessed at a national referral center. Neurological assessment included movement disorder examination using the MDS-UPDRS, Hoehn and Yahr staging, and cognitive screening with the MoCA. Neuropsychiatric symptoms were evaluated clinically. Genetic confirmation was obtained using next-generation sequencing through whole-exome analysis.

Results: A 40-year-old male with progressive parkinsonism presented with severe bradykinesia, rigidity, and gait impairment. Neurological examination revealed generalized hypokinesia, axial rigidity, impaired postural reflexes, and reduced arm swing. Oculomotor evaluation demonstrated limitation of upward gaze compatible with supranuclear gaze palsy. Pyramidal signs included lower-limb hyperreflexia and spasticity. The patient scored 61 on MDS-UPDRS part III, consistent with advanced motor impairment, and was classified as Hoehn and Yahr stage IV. Cognitive screening revealed mild impairment (MoCA 22/30). Neuropsychiatric manifestations included depressive symptoms and emotional lability. Genetic testing identified a homozygous ATP13A2 frameshift mutation c.379del (p.Asp127Metfs*29), predicted to produce a truncated protein causing lysosomal dysfunction and neuronal degeneration.

Conclusion: This case highlights the importance of recognizing Kufor-Rakeb syndrome in patients presenting with atypical parkinsonism and pyramidal-oculomotor abnormalities. A comprehensive neurological examination combined with genetic testing is essential for accurate diagnosis and differentiation from other causes of juvenile parkinsonism and neurodegeneration.

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OMIM – #606693 – KUFOR-RAKEB SYNDROME; KRS – OMIM – (OMIM.ORG). (n.d.). https://omim.org/entry/606693

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MDS Abstracts - https://www.mdsabstracts.org/abstract/homozygous-atp13a2-mutation-associated-kufor-rakeb-syndrome-expanding-the-spectrum-of-juvenile-parkinsonism/