Affiliation:
1. Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK
2. Department of Brain and Behavioral Sciences University of Pavia Pavia Italy
3. Department of Clinical Neurophysiology Norfolk and Norwich University Hospital Norwich UK
4. Neurogenetics Unit National Hospital for Neurology and Neurosurgery London UK
5. Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics University of Miami Miller School of Medicine Miami Florida USA
6. Department of Neurology Medical Faculty of the RWTH Aachen University Hospital Aachen Germany
Abstract
AbstractBackground and purposeMutations in the alpha‐B‐crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB.MethodsWhole‐exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot–Marie–Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features.ResultsThe pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination.DiscussionIn cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone‐assisted autophagy.
Funder
Deutsche Forschungsgemeinschaft
European Academy of Neurology
Fondazione Cariplo
Fondazione Regionale per la Ricerca Biomedica
Medical Research Council
Muscular Dystrophy Association
National Center for Advancing Translational Sciences
National Institute of Neurological Disorders and Stroke
Rare Diseases Clinical Research Network
UCLH Biomedical Research Centre
Subject
Neurology (clinical),Neurology