P-09

MX-linked centronuclear myopathy: from clinical diagnosis to genetic counseling

Maria João Sá^I,II; Ana Rita Soares^I; Gabriela Soares^I; Ana Maria Fortuna^I; Ricardo Taipa^IV; Manuel Melo Pires^IV; Jorge Oliveira^V; Rosário Santos^V; Manuela Santos^III; Cristina Garrido^III

^IUnidade de Genética Médica, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, E.P.E., Porto, Portugal
^II  Unidade Multidisciplinar de Investigação Biomédica, ICBAS-UP
^IIIConsulta de Doenças Neuromusculares. Consulta de Neuropediatria, Centro Hospitalar do Porto E.P.E., Porto, Portugal ]]> ^IVUnidade de Neuropatologia, Centro Hospitalar do Porto E.P.E., Porto, Portugal
^IVUnidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal

m.joao.sa@chporto.min-saude.pt

Background: X-Linked Centronuclear Myopathy is a rare congenital myopathy characterized by hypotonia, muscle weakness and respiratory distress at birth, although the presentation may be delayed. It is the most severe and the most common of the three inheritance forms, which also include the autosomal dominant and the autosomal recessive centronuclear myopathies. While muscle biopsy is crucial to differentiate centronuclear myopathies from other congenital myopathies and muscular dystrophies, genetic testing is essential to establish a definitive diagnosis and to perform a precise genetic counseling.

Clinical report: We report a proband, first son of healthy non-consanguineous parents, who presented with severe  congenital  hypotonia,  global  muscle  weakness and bilateral hand contractures. He was born prematurely, shortly after polyhydramnios diagnosis, at 30 gestational weeks. Ventilatory support was required since his birth. At examination, dolichocephaly was evident and he had ptosis and ophtalmoparesis, facial diparesia, as well as a weak cry. Muscle biopsy revealed fibers with variable diameter, including round atrophic fibers, with centrally located nuclei, as well as central areas of increased oxidative activity surrounded by a bright halo, which was compatible with a centronuclear myopathy. The previously reported pathogenic missense variant c.566A>G  (p.Asn189Ser)  was  detected in the MTM1 gene, in hemizygosity in the proband and heterozygosity in the mother, confirming the diagnosis of X-Linked Centronuclear Myopathy.

Discussion: The genetic testing of the X-linked form is warranted as a first-tier investigation in male infants with a severe phenotype and a characteristic muscle biopsy, since the autosomal forms of centronuclear myopathies present with a relatively mild phenotype in both males and females. The identification of a pathogenic MTM1 mutation will enable preimplantation genetic diagnosis or prenatal diagnosis, as additional reproductive options for this couple.