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Background: The identification of a heterozygous exonic GGC repeat expansion in ZFHX3 underlying spinocerebellar ataxia type 4 (SCA4) has solved a 25-year diagnostic conundrum. We used adaptive long-read sequencing to decipher the pathogenic expansion in the index Utah family and an unrelated family from Iowa of Swedish ancestry. Contemporaneous to our discovery, other groups identified the same repeat expansion in affected individuals from Utah, Sweden, and Germany, highlighting the current pivotal time for detection of novel repeat expansion disorders., Methods: Given that the pathogenic repeat expansion is rare on a population level, we proposed a common ancestor across all families. Here, we employed targeted long-read sequencing through adaptive sampling, enriching for the chr16q22 region of interest., Results: Using phased sequencing results from individuals from Utah, Iowa, and Southern Sweden, we confirmed a common ~2000-year-old ancestral haplotype harbouring the repeat expansion., Conclusion: This study provides further insight into the genetic architecture of SCA4. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Several blood-based biomarkers offer the opportunity of in vivo detection of brain pathology and neurodegeneration in Alzheimer disease with high specificity and sensitivity, but the performance of amyloid-β (Aβ) measurements remains under evaluation. Autosomal dominant Alzheimer disease (ADAD) with mutations in PSEN1, PSEN2 and APP can be studied as a model for sporadic Alzheimer disease. However, clarifying the genetic effects on the Aβ-levels in different matrices such as cerebrospinal fluid or plasma is crucial for generalizability and utility of data. We aimed to explore plasma Aβ concentrations over the Alzheimer disease continuum in a longitudinal cohort of genetic Alzheimer disease., Methods: 92 plasma samples were collected from at-risk individuals (n = 47) in a Swedish cohort of ADAD, including 18 mutation carriers (13 APPswe (p.KM670/671NL) MC), 5 PSEN1 (p.H163Y) MC) and 29 non-carriers (NC) as the reference group. Concentrations of Aβ1-38, Aβ1-40 and Aβ1-42 were analyzed in plasma using immunoprecipitation coupled to tandem liquid chromatography mass spectrometry (IP-LC-MS/MS). Cross-sectional and repeated-measures data analyses were investigated family-wise, applying non-parametric tests as well as mixed-effects models., Results: Cross-sectional analysis at baseline showed more than a 3-fold increase in all plasma Aβ peptides in APPswe MC, regardless of clinical status, compared to controls (p < 0.01). PSEN1 (p.H163Y) presymptomatic MC had a decrease of plasma Aβ1-38 compared to controls (p < 0.05). There was no difference in Aβ1-42/1-40 ratio between APPswe MC (PMC and SMC), PSEN1 MC (PMC) and controls at baseline. Notably, both cross-sectional data and repeated-measures analysis suggested that APPswe MC have a stable Aβ1-42/1-40 ratio with increasing age, in contrast to the decrease seen with aging in both controls and PSEN1 (p.H163Y) MC., Conclusion: These data show very strong mutation-specific effects on Aβ profiles in blood, most likely due to a ubiquitous production outside of the CNS. Hence, analyses in an unselected clinical setting might unintentionally disclose genetic status. Furthermore, our findings suggest that the Aβ ratio might be a poor indicator of brain Aβ pathology in selected genetic cases. The very small sample size is a limitation that needs to be considered but reflects the scarcity of longitudinal in vivo data from genetic cohorts., (© 2024. The Author(s).)

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. [ 18 F]FDG-PET demonstrated brain hypometabolism and [ 11 C]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., (© 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.)