P Pasanen1, L Myllykangas2, M Pöyhönen3, S Kiuru-Enari4, P J Tienari4,5, H Laaksovirta4,5, J Toppila6, E Ylikallio5, H Tyynismaa5, M Auranen4,5. 1. Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland. 2. Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland. 3. Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland. 4. Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 5. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland. 6. Department of Clinical Neurophysiology, HUS Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
Abstract
OBJECTIVES: Mutations in the CHCHD10 gene, which encodes a mitochondrially targeted protein, have emerged as an important cause of motor neuron disease and frontotemporal lobar degeneration. The aim of this study was to assess the clinical variability in a large family carrying the p.Gly66Val mutation of the CHCHD10 gene. This mutation has recently been reported to cause late-onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot-Marie-Tooth neuropathy (CMT2) in the Finnish population. MATERIALS AND METHODS: Nine affected members of an extended Finnish pedigree were included in the study. Detailed clinical and neurophysiological examinations were performed. The CHCHD10 p.Gly66Val mutation was examined by Sanger sequencing. RESULTS: The heterozygous p.Gly66Val mutation was present in all affected individuals from whom a DNA sample was available. The clinical phenotype varied from proximal sensorimotor neuropathy to spinal muscular atrophy and in one case resembled motor neuron disease ALS at its early stages. The age of onset varied from 30 to 73 years. CONCLUSIONS: Our data demonstrate that even within the same family, the p.Gly66Val variant can cause variable phenotypes ranging from CMT2-type axonal neuropathy to spinal muscular atrophy, which may also present as an ALS-like disease. The spectrum of CHCHD10-related neuromuscular disease has widened rapidly, and we recommend keeping the threshold for genetic testing low particularly when dominant inheritance or mitochondrial pathology is present.
OBJECTIVES: Mutations in the CHCHD10 gene, which encodes a mitochondrially targeted protein, have emerged as an important cause of motor neuron disease and frontotemporal lobar degeneration. The aim of this study was to assess the clinical variability in a large family carrying the p.Gly66Val mutation of the CHCHD10 gene. This mutation has recently been reported to cause late-onset spinal muscular atrophy (SMAJ) or sensorimotor axonal Charcot-Marie-Tooth neuropathy (CMT2) in the Finnish population. MATERIALS AND METHODS: Nine affected members of an extended Finnish pedigree were included in the study. Detailed clinical and neurophysiological examinations were performed. The CHCHD10p.Gly66Val mutation was examined by Sanger sequencing. RESULTS: The heterozygous p.Gly66Val mutation was present in all affected individuals from whom a DNA sample was available. The clinical phenotype varied from proximal sensorimotor neuropathy to spinal muscular atrophy and in one case resembled motor neuron diseaseALS at its early stages. The age of onset varied from 30 to 73 years. CONCLUSIONS: Our data demonstrate that even within the same family, the p.Gly66Val variant can cause variable phenotypes ranging from CMT2-type axonal neuropathy to spinal muscular atrophy, which may also present as an ALS-like disease. The spectrum of CHCHD10-related neuromuscular disease has widened rapidly, and we recommend keeping the threshold for genetic testing low particularly when dominant inheritance or mitochondrial pathology is present.
Authors: S R Burstein; F Valsecchi; H Kawamata; M Bourens; R Zeng; A Zuberi; T A Milner; S M Cloonan; C Lutz; A Barrientos; G Manfredi Journal: Hum Mol Genet Date: 2018-01-01 Impact factor: 6.150