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Objectives: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia., Methods: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause., Results: Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8 . The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function., Discussion: Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NG., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin ( DMD ) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries., Methods: We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers., Results: We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations., Conclusions: Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility., (© 2020 American Academy of Neurology.)