PMID- 30415211 OWN - NLM STAT- MEDLINE DCOM- 20191114 LR - 20191114 IS - 1468-6244 (Electronic) IS - 0022-2593 (Linking) VI - 55 IP - 12 DP - 2018 Dec TI - Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations. PG - 814-823 LID - 10.1136/jmedgenet-2018-105650 [doi] AB - BACKGROUND: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. RESULTS: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. CONCLUSION: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling. CI - (c) Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Lupo, Vincenzo AU - Lupo V AUID- ORCID: 0000-0002-3774-9854 AD - Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. AD - Rare Diseases Joint Units, INCLIVA & IIS La Fe-CIPF, Valencia, Spain. AD - Department of Genomics and Traslational Genetics, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. FAU - Frasquet, Marina AU - Frasquet M AD - Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain. AD - Neuromuscular and Ataxias Research Group, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain. FAU - Sanchez-Monteagudo, Ana AU - Sanchez-Monteagudo A AD - Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. AD - Rare Diseases Joint Units, INCLIVA & IIS La Fe-CIPF, Valencia, Spain. AD - Department of Genomics and Traslational Genetics, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. FAU - Pelayo-Negro, Ana Lara AU - Pelayo-Negro AL AD - University Hospital 'Marques de Valdecilla (IDIVAL)' and 'Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED)', Santander, Spain. FAU - Garcia-Sobrino, Tania AU - Garcia-Sobrino T AD - Neurology Department, Hospital Clinico Universitario, Santiago de Compostela, Spain. FAU - Sedano, Maria Jose AU - Sedano MJ AD - University Hospital 'Marques de Valdecilla (IDIVAL)' and 'Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas (CIBERNED)', Santander, Spain. FAU - Pardo, Julio AU - Pardo J AD - Neurology Department, Hospital Clinico Universitario, Santiago de Compostela, Spain. FAU - Misiego, Mercedes AU - Misiego M AD - Neurology Department, Hospital Sierrallana, Torrelavega, Spain. FAU - Garcia-Garcia, Jorge AU - Garcia-Garcia J AD - Neurology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. FAU - Sobrido, Maria Jesus AU - Sobrido MJ AD - Neurogenetics Research Group, Instituto de Investigaciones Sanitarias (IDIS), and Fundacion Publica Galega de Medicina Xenomica, Santiago de Compostela, Spain. FAU - Martinez-Rubio, Maria Dolores AU - Martinez-Rubio MD AD - Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. AD - Rare Diseases Joint Units, INCLIVA & IIS La Fe-CIPF, Valencia, Spain. AD - Department of Genomics and Traslational Genetics, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. FAU - Chumillas, Maria Jose AU - Chumillas MJ AD - Department of Clinical Neurophysiology, Hospital Universitari i Politecnic La Fe, Valencia, Spain. AD - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain. FAU - Vilchez, Juan Jesus AU - Vilchez JJ AD - Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain. AD - Neuromuscular and Ataxias Research Group, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain. AD - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain. AD - Department of Medicine, Universitat de Valencia, Valencia, Spain. FAU - Vazquez-Costa, Juan Francisco AU - Vazquez-Costa JF AD - Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain. AD - Neuromuscular and Ataxias Research Group, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain. AD - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain. FAU - Espinos, Carmen AU - Espinos C AD - Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. AD - Rare Diseases Joint Units, INCLIVA & IIS La Fe-CIPF, Valencia, Spain. AD - Department of Genomics and Traslational Genetics, Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain. FAU - Sevilla, Teresa AU - Sevilla T AD - Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe, Valencia, Spain. AD - Neuromuscular and Ataxias Research Group, Instituto de Investigacion Sanitaria La Fe, Valencia, Spain. AD - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Spain. AD - Department of Medicine, Universitat de Valencia, Valencia, Spain. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181110 PL - England TA - J Med Genet JT - Journal of medical genetics JID - 2985087R RN - EC 3.4.24.- (Metalloendopeptidases) RN - Inherited Peripheral Neuropathy SB - IM MH - Adult MH - Aged MH - Alleles MH - Amino Acid Substitution MH - Electromyography MH - Electrophysiological Phenomena MH - Female MH - Gene Frequency MH - Genes, Recessive MH - *Genetic Association Studies MH - Genotype MH - Humans MH - *Inheritance Patterns MH - Magnetic Resonance Imaging MH - Male MH - Metalloendopeptidases/*genetics/metabolism MH - Middle Aged MH - *Mutation MH - Pedigree MH - Peripheral Nervous System Diseases/*diagnosis/*genetics MH - *Phenotype OTO - NOTNLM OT - clinical genetics OT - diagnostics OT - genetic screening/counselling OT - neuromuscular disease OT - peripheral nerve disease COIS- Competing interests: None declared. EDAT- 2018/11/12 06:00 MHDA- 2019/11/15 06:00 CRDT- 2018/11/12 06:00 PHST- 2018/07/31 00:00 [received] PHST- 2018/09/19 00:00 [revised] PHST- 2018/10/07 00:00 [accepted] PHST- 2018/11/12 06:00 [pubmed] PHST- 2019/11/15 06:00 [medline] PHST- 2018/11/12 06:00 [entrez] AID - jmedgenet-2018-105650 [pii] AID - 10.1136/jmedgenet-2018-105650 [doi] PST - ppublish SO - J Med Genet. 2018 Dec;55(12):814-823. doi: 10.1136/jmedgenet-2018-105650. Epub 2018 Nov 10.