Progressive Axonal Neuropathy and Cerebellar Ataxia Associated with Homozygous Pathogenic POLG Mutation in a Patient of African Descent from Northern Minas Gerais/Jequitinhonha Valley, Brazil: A Case Report and Epidemiological Implications.

We report a 41-year-old man of African descent from the Northern Minas Gerais/Jequitinhonha Valley region of Brazil - historically characterized by geographic isolation, predominantly Afro-Indigenous ancestry, and structural consanguinity - born to first-degree cousin parents, who presented with progressive axonal sensorimotor neuropathy, cerebellar ataxia, dysarthria, and oculomotor abnormalities. His sister had died with a similar untreated neurological syndrome. Three serial electroneuromyographic studies demonstrated stable chronic axonal polyneuropathy with complete bilateral absence of sural, fibular, and plantar sensory potentials, and active distal denervation. Brain MRI, unchanged over a two-year interval, showed T2/FLAIR hyperintense foci in both cerebellar hemispheres and the right middle cerebellar peduncle with cerebellar atrophy, without diffusion restriction or contrast enhancement. Next-generation sequencing (NGS; Mendelics®; 101-gene hereditary neuropathy panel) identified a homozygous pathogenic variant in the POLG gene (c.2243G>C; p.Trp748Ser - ClinVar ID 13507), confirming the diagnosis of mitochondrial DNA depletion syndrome type 4B (OMIM #613662). The patient's paternal great-grandfather was from the state of Ceará, a region with documented European colonization, providing a plausible route for the introduction of this classically European founder allele into his Afro-Brazilian lineage, with homozygosity emerging through consanguinity. To our knowledge, this is the first report of p.Trp748Ser in a patient of African descent, directly challenging its presumed ethnic exclusivity. Clinical and electrophysiological stability over 2.5 years is consistent with the favorable course reported in p.W748S homozygotes. This case underscores the importance of POLG-related ataxia as a diagnostic consideration in patients of non-European ancestry presenting with axonal neuropathy and cerebellar signs, and highlights the consequences of underrepresentation of populations of African descent in genetic disease research.