Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs

• Published in: Journal of internal medicine Vol. 296; no. 3; pp. 234 - 248
• Main Authors: Paucar, Martin, Nilsson, Daniel, Engvall, Martin, Laffita‐Mesa, José, Söderhäll, Cilla, Skorpil, Mikael, Halldin, Christer, Fazio, Patrik, Lagerstedt‐Robinson, Kristina, Solders, Göran, Angeria, Maria, Varrone, Andrea, Risling, Mårten, Jiao, Hong, Nennesmo, Inger, Wedell, Anna, Svenningsson, Per
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2024
• Subjects: Abnormalities; Ataxia; Atrophy; Brain; Brain stem; Cerebellum; Degeneration; Disease control; Dysautonomia; Eye movements; Flumazenil; Gene sequencing; Genetic analysis; Genetic screening; Genomic analysis; Homeobox; Hypometabolism; Hypothalamus; Hypothalamus (anterior); Inclusion bodies; Inclusions; Medical imaging; Medicin och hälsovetenskap; Motor neurons; Mutation; Neural coding; Neuraxis; Neurodegeneration; Neurodegenerative diseases; Neuroimaging; Neuropathology; nucleotide expansion; Nucleotides; polyglycine; Polyneuropathy; Purkinje cells; Spinal cord; Spinocerebellar ataxia; Thalamus; Ubiquitin; Whole genome sequencing; ZFHX3; nucleotide expansion; ZFHX3; polyglycine; spinocerebellar ataxia
• ISSN: 0954-6820; 1365-2796; 1365-2796
• DOI: 10.1111/joim.13815

Background Spinocerebellar ataxia 4 (SCA4), characterized in 1996, features adult‐onset ataxia, polyneuropathy, and linkage to chromosome 16q22.1; its underlying mutation has remained elusive. Objective To explore the radiological and neuropathological abnormalities in the entire neuroaxis in SCA4 and search for its mutation. Methods Three 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. Results Novel 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. Conclusions SCA4 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.