Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype

University of Rome Tor Vergata, Roma, Latium, Italy
Human Genetics (Impact Factor: 4.82). 03/2003; 112(2):135-42. DOI: 10.1007/s00439-002-0869-1
Source: PubMed


X-linked myotubular myopathy is characterised by neonatal hypotonia, muscle weakness and respiratory distress in affected males, leading often to early death, although prolonged survival is observed in milder forms, or as a result of prolongation of ventilation support. It is caused by mutations in the MTM1 gene, which encodes a phosphatase called myotubularin, which has been highly conserved during evolution, down to yeasts ( S. cerevisiae and S. pombe). To date, 251 mutations have been identified in unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene. We have found additional mutations in 77 patients, including 35 novel ones. We identified a missense mutation N180K in a 67-year-old grandfather (the oldest known patient with an MTM1 mutation), previously suspected to have autosomal centronuclear myopathy, and in his two grandsons also mildly affected. Mild and moderate phenotypes associated with novel missense mutations and with a translation initiation defect mutation are discussed, as well as severe phenotypes associated with particular novel mutations. With the present report, 192 different mutations in the MTM1 gene have been described in 328 families. The spectrum of mutations is now enlarged from the very severe classic neonatal phenotype to very mild phenotype allowing survival to the age of 67 years.

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    • "Considering that this was found in patients who had survived into adolescence, indicates a higher prevalence of the disease than the 2% that was reported by Maggi et al. [16] in children below age 1.5 years, and by Amburgey et al. [17] in a pediatric population. The observation of patients with MTM1 mutations having survived infancy is not new; several studies [9] [10] [11] [12] have reported patients with milder phenotypes who survived into adulthood, but in this study we report detailed information on phenotypes and courses of disease from birth to adulthood, besides the prevalence data. Two of our XLMTM patients were not genetically diagnosed until age 14 and 25 years despite the fact that muscle biopsy had shown central nuclei at an early age. "
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    ABSTRACT: Centronuclear myopathy (CNM) is one of four main subtypes of congenital myopathy. X-linked myotubular myopathy (XLMTM) is considered one of the most severe forms, but survivors past infancy have been described. However, detailed information on XLMTM phenotypes in patients who survive infancy is scarce. The aim of the study was to report the genetic findings in patients with a predominant centronuclear finding on muscle biopsy and describe the prevalence, phenotypes and the course of the disease in patients with XLMTM in a Danish cohort of patients with congenital myopathies older than five years. Ninety-four out of 119 invited patients older than five years were included in the study and assessed by muscle tests, functional tests, muscle biopsy, plasma creatine kinase levels and genetic testing. Genes related to CNM were sequenced in patients who had centronuclear findings on muscle histology. In patients with MTM1 mutations, medical records from local hospitals were reviewed to obtain information on birth history and course of disease. Sixteen of 94 patients had CNM on muscle biopsy; three male patients, aged 14-25 years, carried a pathogenic MTM1 mutation, six patients carried a pathogenic DNM2 mutation and two pathogenic RYR1 mutations. The mutations have all been described before to cause CNM. The MTM phenotypes ranged from severe (classical) to mild; one patient had always been non-ambulant, one had lost ambulation, and one was still ambulant at 25 years. Our findings show that CNM caused by DNM2 mutations is the most common form of CNM in Danish patients older than 5 years, but XLMTM is not negligible even past age 5 years, and the phenotype may be much milder than generally described - also in patients with the classically described infantile form of the disease.
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    • "Patients 8 and 9 are brothers (Table 1). Eight of the 15 XLMTM patients are described for the first time and for seven of the 15 patients the molecular defects have been reported previously (Table 2) (Laporte et al. 1997; Buj-Bello et al. 1999; Biancalana et al. 2003). Prenatal diagnosis was not made for any patient. "
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    ABSTRACT: The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM 1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM 1-mutations according to the "adjusted-age" at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM 1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.
    Brain and Behavior 07/2013; 3(4):476-86. DOI:10.1002/brb3.147 · 2.24 Impact Factor
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    • "Patients with XLMTM display severe generalized hypotonia at birth accompanied by respiratory insufficiency requiring ventilator support. While the life expectancy is usually strongly reduced, up to 40% of patients survive into childhood and even adulthood, most of them requiring some degree of respiratory support [3] [4] [5] [6]. XLMTM primarily affects males, and myopathic manifestations in female carriers have been found to be associated with skewed X-inactivation, with or without chromosomal rearrangements [7] [8] [9]. "
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    ABSTRACT: X-linked centronuclear myopathy (XLMTM), also called myotubular myopathy, is a severe congenital myopathy characterized by generalized hypotonia and weakness at birth and the typical histological finding of centralization of myo-nuclei. It is caused by mutations in the MTM1 gene encoding the 3-phosphoinositides phosphatase myotubularin. Mutations in dynamin 2 and amphiphysin 2 genes lead to autosomal forms of centronuclear myopathy (CNM). While XLMTM is the most frequent and severe form of CNM, no mutations are found in about 30% of patients by sequencing all MTM1 exons. Moreover, the impact of MTM1 sequence variants is sometimes difficult to assess. It is thus important to devise a complete molecular diagnostic strategy that includes analysis of the myotubularin transcript and protein expression. We therefore developed novel antibodies against human myotubularin and showed that they are able to detect the endogenous protein by direct Western blot from muscle samples and from cultured cells. In conjunction with RT-PCR analysis we validated the consequences of missense and splice mutations on transcript integrity and protein level. We also detected and characterized a novel deep intronic mutation consisting of a single nucleotide change that induces exonisation of a conserved intronic sequence. Patients with centronuclear myopathy and no molecular diagnosis should be investigated for MTM1 defects at the cDNA and protein level.
    Neuromuscular Disorders 04/2010; 20(6):375-81. DOI:10.1016/j.nmd.2010.03.015 · 2.64 Impact Factor
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