title: Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Pasanen
authors.affiliation: Department of Pathology, University of Helsinki and HUSLAB, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Myllykangas
authors.affiliation: Department of Clinical Genetics, Helsinki University Central Hospital and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Pöyhönen
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Kiuru-Enari
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: P J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Laaksovirta
authors.affiliation: Department of Clinical Neurophysiology, HUS Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Toppila
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Ylikallio
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Tyynismaa
authors.affiliation: Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.|Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Auranen
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype
chemical_list: C554426:CHCHD10 protein, human; D024101:Mitochondrial Proteins
keywords: CHCHD10; clinical variability; proximal sensorimotor neuropathy; spinal muscular atrophy