Acute Vestibular Syndrome Unmasking an -Spectrum Disorder.

Objectives: Since the discovery of biallelic pentanucleotide expansions in as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome, a wide and growing clinical spectrum has emerged. In this article, we report a man with acute vestibular syndrome that likely unmasked a -spectrum disorder.

Methods: Detailed clinical evaluation, neuroimaging, nerve conduction studies, evaluation of vestibular function, and short-read whole-genome sequencing and targeted long-read adaptive sequencing were performed.

An X-Linked Ataxia Syndrome in a Family with Hearing Loss Associated with a Novel Variant in the BCAP31 Gene.

Objective: Pathogenic variants in B-cell receptor-associated protein (BCAP31) are associated with X-linked, deafness, dystonia and cerebral hypomyelination (DDCH) syndrome. DDCH is congenital and non-progressive, featuring severe intellectual disability (ID), variable dysmorphism, and sometimes associated with shortened survival. BCAP31 encodes one of the most abundant chaperones, with several functions including acting as a negative regulator of endoplasmic reticulum (ER) calcium ion (Ca) concentration.

The ZFHX3 GGC Repeat Expansion Underlying Spinocerebellar Ataxia Type 4 has a Common Ancestral Founder.

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.

ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model.

Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis.