Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and...

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Bibliographic Details
Published in:	Journal of neurology Vol. 271; no. 9; pp. 5804 - 5812
Main Authors:	Schaub, Annalisa, Erdmann, Hannes, Scholz, Veronika, Timmer, Manuela, Cordts, Isabell, Günther, Rene, Reilich, Peter, Abicht, Angela, Schöberl, Florian
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2024 Springer Nature B.V
Subjects:	Adult Aged Amyotrophic lateral sclerosis Ataxia Atrophy Autonomic nervous system Basal ganglia Central nervous system diseases Cerebellar ataxia Cerebellum Cohort Studies DNA Repeat Expansion Female Genotype & phenotype Germany Humans Male Medicine Medicine & Public Health Middle Aged Motor Neuron Disease - genetics Motor neuron diseases Motor neurone disease Movement disorders Neurology Neuropathy Neuroradiology Neurosciences Original Communication Phenotype Phenotypes Replication Protein C - genetics Vestibular system Germany Amyotrophic lateral sclerosis MND Oxford nanopore sequencing RFC1 Motor neuron disease Repeat analysis
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Summary:	Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1 , we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif ‘ACAAG’.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0340-5354 1432-1459 1432-1459
DOI:	10.1007/s00415-024-12519-6