title: Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients.
abstract: We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot-Marie-Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly <38 m/s in median or ulnar nerves in PMP22 duplication, >40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.
authors: S
authors: S
authors: Rudnik-Schöneborn
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.
authors: D
authors: D
authors: Tölle
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.|Friedrich-Baur-Institute, LMU Munich, Munich, Germany.
authors: J
authors: J
authors: Senderek
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.
authors: K
authors: K
authors: Eggermann
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.
authors: M
authors: M
authors: Elbracht
authors: Institute of Medical Genetics and Human Genetics, Charité-University Berlin, Berlin, Germany.
authors: U
authors: U
authors: Kornak
authors: Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors: M
authors: M
authors: von der Hagen
authors: Department of Neuropediatrics, University Hospital Freiburg, Freiburg, Germany.
authors: J
authors: J
authors: Kirschner
authors: Medical Faculty, Institute of Human Genetics and Anthropology, Heinrich-Heine University, Düsseldorf, Germany.
authors: B
authors: B
authors: Leube
authors: Dr. v. Hauner Childrens Hospital, University of Munich, Munich, Germany.
authors: W
authors: W
authors: Müller-Felber
authors: Department of Neuropediatrics, Developmental Neurology and Social Pediatrics, University Essen, Essen, Germany.
authors: U
authors: U
authors: Schara
authors: SPZ Pediatric Neurology, Charité University Berlin, Berlin, Germany.
authors: K
authors: K
authors: von Au
authors: Institute of Human Genetics, University Essen, Essen, Germany.
authors: D
authors: D
authors: Wieczorek
authors: Center for Children and Adolescent Medicine, University Clinic Heidelberg, Heidelberg, Germany.
authors: C
authors: C
authors: Bußmann
authors: Institute of Human Genetics, RWTH Aachen University Hospital, Aachen, Germany.
authors: K
authors: K
authors: Zerres
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D000483:Alleles; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D005838:Genotype; D005858:Germany; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D057188:Workflow; D055815:Young Adult
keywords: CMT disease; electrophysiological classification; genetic diagnosis; genotype-phenotype correlation