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Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations
  1. Vincenzo Lupo1,2,3,
  2. Marina Frasquet4,5,
  3. Ana Sánchez-Monteagudo1,2,3,
  4. Ana Lara Pelayo-Negro6,
  5. Tania García-Sobrino7,
  6. María José Sedano6,
  7. Julio Pardo7,
  8. Mercedes Misiego8,
  9. Jorge García-García9,
  10. María Jesús Sobrido10,
  11. María Dolores Martínez-Rubio1,2,3,
  12. María José Chumillas11,12,
  13. Juan Jesús Vílchez4,5,12,13,
  14. Juan Francisco Vázquez-Costa4,5,12,
  15. Carmen Espinós1,2,3,
  16. Teresa Sevilla4,5,12,13
  1. 1 Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
  2. 2 Rare Diseases Joint Units, INCLIVA & IIS La Fe-CIPF, Valencia, Spain
  3. 3 Department of Genomics and Traslational Genetics, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
  4. 4 Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain
  5. 5 Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
  6. 6 University Hospital ‘Marqués de Valdecilla (IDIVAL)’ and ‘Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)’, Santander, Spain
  7. 7 Neurology Department, Hospital Clínico Universitario, Santiago de Compostela, Spain
  8. 8 Neurology Department, Hospital Sierrallana, Torrelavega, Spain
  9. 9 Neurology Department, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
  10. 10 Neurogenetics Research Group, Instituto de Investigaciones Sanitarias (IDIS), and Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain
  11. 11 Department of Clinical Neurophysiology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
  12. 12 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Spain
  13. 13 Department of Medicine, Universitat de València, Valencia, Spain
  1. Correspondence to Dr Vincenzo Lupo, Centro de Investigación Príncipe Felipe (CIPF), Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Valencia 46012, Spain; vlupo{at} and Dr Teresa Sevilla, Hospital Universitari i Politècnic la Fe, Department of Neurology, Valencia 46026, Spain; sevilla_ter{at}


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.

  • clinical genetics
  • peripheral nerve disease
  • neuromuscular disease
  • diagnostics
  • genetic screening/counselling

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  • VL and MF contributed equally.

  • CE and TS contributed equally.

  • Contributors VL and TS conceived the study. VL, TS and MF participated in the study design and in the draft of the manuscript. VL, AS-M, MDM-R and CE performed, collected and implemented the genetic studies. MF, ALP-N, TG-S, MJS, JP, MM, JG-G, MJS, MJC, JJV and JFV-C performed, collected and implemented the clinical studies. All authors approved the final version of the manuscript.

  • Funding This project was funded by the Instituto de Salud Carlos III (ISCIII), FEDER (Grants no. PI12/00946 and PI16/00403 to TS, PI15/00187 to CE). MF holds a grant funded by the IIS La Fe (Grant no. 2015/0085). AS-M holds a grant funded by the Fundació Per Amor a l’Art (FPAA). JFV-C holds a ‘ Rio Hortega’ contract funded by the ISCIII.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval Hospital Universitari i Politècnic La Fe, Valencia, Spain; Hospital Universitario Marqués de Valdecilla, Santander, Spain.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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