• Martin Paucar, Daniel Nilsson, Martin Engvall, José Laffita-Mesa, Cilla Söderhäll, Mikael Skorpil, Christer Halldin, Patrik Fazio, Kristina Lagerstedt-Robinson, Göran Solders, Maria Angeria, Andrea Varrone, Mårten Risling, Hong Jiao, Inger Nennesmo, Anna Wedell, and Per Svenningsson.
• Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
• J. Intern. Med. 2024 Sep 1; 296 (3): 234248234-248.

BackgroundSpinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult-onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive.ObjectiveTo explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation.MethodsThree Swedish families with undiagnosed ataxia went through clinical, neurophysiological, and neuroimaging tests, including PET studies and genetic investigations. In four cases, neuropathological assessments of the neuroaxis were performed. Genetic testing included short read whole genome sequencing, short tandem repeat analysis with ExpansionHunter de novo, and long read sequencing.ResultsNovel features for SCA4 include dysautonomia, motor neuron affection, and abnormal eye movements. We found evidence of anticipation; neuroimaging demonstrated atrophy in the cerebellum, brainstem, and spinal cord. [18F]FDG-PET demonstrated brain hypometabolism and [11C]Flumazenil-PET reduced binding in several brain lobes, insula, thalamus, hypothalamus, and cerebellum. Moderate to severe loss of Purkinje cells in the cerebellum and of motor neurons in the anterior horns of the spinal cord along with pronounced degeneration of posterior tracts was also found. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A polyglycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 gene was identified segregating with disease and not found in 1000 controls.ConclusionsSCA4 is a neurodegenerative disease caused by a novel GGC expansion in the coding region of ZFHX3, and its spectrum is expanded to include dysautonomia and neuromuscular manifestations.© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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