Report of a novel ATP7A mutation causing distal motor neuropathy

Francesca Gualandi, Elisabetta Sette, Fernanda Fortunato, Stefania Bigoni, Domenico De Grandis, Chiara Scotton, Rita Selvatici, Marcella Neri, Alex Incensi, Rocco Liguori, Markus Storbeck, Mert Karakaya, Valentina Simioni, Stefano Squarzoni, Vincent Timmerman, Brunhilde Wirth, Vincenzo Donadio, Valeria Tugnoli, Alessandra Ferlini

Research output: Contribution to journalArticlepeer-review


We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients' blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

Original languageEnglish
Pages (from-to)776-785
Number of pages10
JournalNeuromuscular Disorders
Early online dateAug 23 2019
Publication statusPublished - Oct 2019


  • ATP7A mutation
  • Autonomic neuropathy
  • Peripheral neuropathy


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