Mutations in alpha‐B‐crystallin cause autosomal dominant axonal Charcot–Marie–Tooth disease with congenital cataracts

European Journal of Neurology, vol. 31, pp. e16063

Abstract

BACKGROUND AND PURPOSE: Mutations 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. METHODS: Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. RESULTS: The 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. DISCUSSION: In 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.

Authors 16

1. Andrea Cortese corresponding

   University College London · University of Pavia · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

2. Riccardo Curró

   University College London · University of Pavia · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

3. Riccardo Ronco

   University College London · University of Pavia · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Brain and Behavioral Sciences University of Pavia Pavia Italy

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

4. Julian C. Blake

   University College London · UCL Queen Square Institute of Neurology · Norfolk and Norwich University Hospital

   Affiliation as printed

   Department of Clinical Neurophysiology Norfolk and Norwich University Hospital Norwich UK

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norwich, UK

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

5. Alexander Martin Rossor

   University College London · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

6. Enrico Bugiardini

   University College London · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

7. Matilde Laurá

   University College London · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

8. Tarek Ahmed Yousry

   University College London · UCL Queen Square Institute of Neurology

   Affiliation as printed

   Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

   Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

9. Roy Poh

   National Hospital for Neurology and Neurosurgery

   Affiliation as printed

   Neurogenetics Unit National Hospital for Neurology and Neurosurgery London UK

   Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK

10. James M. Polke

    National Hospital for Neurology and Neurosurgery

    Affiliation as printed

    Neurogenetics Unit National Hospital for Neurology and Neurosurgery London UK

    Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UK

11. Adriana P. Rebelo

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    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

    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

12. Maike Franziska Dohrn Aachen Department of Neurology, Medical Faculty

    RWTH Aachen University · Universitätsklinikum Aachen · University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    Department of Neurology Medical Faculty of the RWTH Aachen University Hospital Aachen Germany

    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

    Department of Neurology, Medical Faculty of the RWTH Aachen University Hospital, Aachen, Germany

    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

13. Mario Saporta

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    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

    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

14. Henry Houlden

    University College London · UCL Queen Square Institute of Neurology

    Affiliation as printed

    Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

    Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK

15. Stephan L. Zuchner

    University of Miami · Dr. John T. Macdonald Foundation

    Affiliation as printed

    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

    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

16. Mary M. Reilly corresponding

    University College London · UCL Queen Square Institute of Neurology

    Affiliation as printed

    Department of Neuromuscolar Diseases UCL Queen Square Institute of Neurology London UK

    Department of Neuromuscolar Diseases, UCL Queen Square Institute of Neurology, London, UK