Category: Parkinson's Disease: Genetics
Objective: To report a patient with juvenile-onset parkinsonism harboring a novel homozygous splice-site variant in ATP13A2.
Background: Kufor-Rakeb syndrome (KRS) is an ultra-rare form of autosomal-recessive hereditary parkinsonism with ~50 reported cases. Age of onset is typically 12-16 years, and the disease is characterized by rapid progression1. Clinical features include parkinsonism with postural instability, cognitive decline, pyramidal signs, supranuclear gaze palsy, dystonia, myoclonus, and dysphagia. Levodopa is beneficial but often induces disabling dyskinesias2.
Method: Genetic testing was performed using a customized NGS panel covering genes associated with genetic forms of parkinsonism and dystonia.
Results: A 23-year-old woman from Dagestan (a republic of the Russian Federation), born to a consanguineous family, presented with juvenile-onset parkinsonism. Her parents and two siblings are healthy; a maternal cousin reportedly had similar symptoms. Her motor development was normal. At age 18, she developed progressive bradykinesia, rigidity, and loss of fine motor skills. At age 19, dystonic trunk posturing with a lean to the right appeared. By the age 21, she started experiencing difficulties with chewing and swallowing food. At age 22, ambulation and speech became impaired, and a kinetic hand tremor appeared.
Examination revealed moderate bradykinesia, hypomimia, dysarthria, limb and axial rigidity, postural instability, and postural-kinetic hand tremor. Dystonic features included arm posturing and a lean of the body to the right during walking. She also displayed pyramidal signs, including hyperreflexia, spasticity in the lower limbs, and right foot clonus. She had mild cognitive impairment. Brain MRI was unremarkable. Treatment with levodopa/carbidopa 250/25 mg half a tablet three times daily and ropinirole 2 mg daily produced significant improvement.
A homozygous variant in the ATP13A2 gene (NM_022089.4:c.1039+1G>A), affecting the canonical splice site, was identified by molecular genetic testing. The variant is absent from population databases (gnomAD) and is predicted to be deleterious by SpliceAI (Δ-score = 1) 3,4. Based on these findings and the phenotype consistent with KRS, the variant was classified as likely pathogenic.
Conclusion: We describe the first Russian case of KRS, caused by a previously unreported variant in a splicing site of the ATP13A2 gene.
References: 1. Affronte L, Pini A, Pizzoli C et al. Case Report: Novel ATP13A2 pathogenic variants associated with early-onset parkinsonism and a mini-review. Front Genet. 2025 Jul 29;16:1588812. doi: 10.3389/fgene.2025.1588812. PMID: 40799219; PMCID: PMC12340552.
2. Croucher KM, Fleming SM. ATP13A2 (PARK9) and basal ganglia function. Front Neurol. 2024 Jan 5;14:1252400. doi: 10.3389/fneur.2023.1252400. PMID: 38249738; PMCID: PMC10796451.
3. Chen S, Francioli LC, Goodrich JK et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature. 2024 Jan;625(7993):92-100. doi: 10.1038/s41586-023-06045-0. Epub 2023 Dec 6. Erratum in: Nature. 2024 Feb;626(7997):E1. doi: 10.1038/s41586-024-07050-7. PMID: 38057664; PMCID: PMC11629659.
4. Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF et al. Predicting Splicing from Primary Sequence with Deep Learning. Cell. 2019 Jan 24;176(3):535-548.e24. doi: 10.1016/j.cell.2018.12.015. Epub 2019 Jan 17. PMID: 30661751.
To cite this abstract in AMA style:
L. Zaripova, M. Sadekova, E. Nuzhnyi, N. Abramycheva, E. Fedotova, S. Illarioshkin. Kufor-Rakeb Syndrome With a Novel Splice-Site Variant in the ATP13A2 Gene [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/kufor-rakeb-syndrome-with-a-novel-splice-site-variant-in-the-atp13a2-gene/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/kufor-rakeb-syndrome-with-a-novel-splice-site-variant-in-the-atp13a2-gene/