Case reportA clinical and genetic study of a manifesting heterozygote with X-linked myotubular myopathy
Introduction
Currently, three forms of myotubular myopathy are recognised on the basis of inheritance, onset and severity. The X-linked form (XLMTM; McKusick *310400) is the best defined. It has prenatal or neonatal onset and is the most severe variant. Autosomal recessive and dominant forms of lesser severity have been described, although Wallgren-Pettersson et al. identified only two such families with verified male-to-male transmission and there are no reports of fully examined families with healthy parents of affected children of both sexes [1].
Consensus clinical diagnostic criteria for XLMTM include male sex, perinatal onset and severe generalised muscle hypotonia and weakness associated with respiratory failure [2]. Additional features may include polyhydramnios, dysphagia, thin ribs, contractures of the hips or knees, puffy eyelids and ophthalmoplegia [1]. The course is often fatal, but long-term survival is possible. A family history of miscarriages or neonatal deaths of male infants in the maternal line add to evidence suggesting X-linked inheritance.
Identification of female heterozygotes is often important for genetic counselling. Despite many family studies, there have only been two reports of manifesting heterozygotes [3], [4]. Both were mothers of typically affected boys and had asymptomatic facial weakness only. A review of the use of muscle biopsy to detect female carriers concluded that approximately 50% of carriers show definite histological abnormalities [1]. The XLMTM gene was identified in 1996 (MTM1), allowing the identification of mutations in most families, including carrier detection [5]. The protein encoded by the MTM1 gene contains the consensus sequence for the active site of the tyrosine phosphatases, a broad class of proteins involved in signal transduction.
Starr et al. previously described a family with typical XLMTM [6]. We have identified a female heterozygote from this family with disabling muscle manifestations of this disease. We describe the clinical and genetic features of this patient.
Section snippets
Case report
This female (‘Patient A’), aged 57 years, comes from a large previously described pedigree (patient III-2; [6]), with clear X-linked inheritance of myotubular myopathy. The family includes ten affected males with a typically severe phenotype resulting in death within the first year of life, often a few hours after birth. Apart from the described patient there were no other females with clinical manifestations. Genetic analysis of the family showed linkage to Xq28 without any recombinations [6].
Discussion
Our patient did not have any recorded neonatal manifestations, but had slowly progressive muscular weakness that became evident in childhood and slowly progressed throughout adulthood. The distribution of muscle weakness was similar to that observed in affected male infants with XLMTM, with facial, respiratory and proximal limb weakness, although in this patient the weakness was asymmetric. She had no clinical or MR evidence of CNS pathology.
The muscle biopsy identified central nuclei in a
Acknowledgements
We thank Dr. J.P. Frankel for referring the patient.
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2021, Neuromuscular DisordersWhole exome sequencing discloses a pathogenic MTM1 gene mutation and ends the diagnostic odyssey in an older woman with a progressive and seemingly sporadic myopathy: Case report and literature review of MTM1 manifesting female carriers
2018, Neuromuscular DisordersCitation Excerpt :Later, Tanner et al. reported the case of a 39-year-old woman with weakness beginning at age 5 years in which the manifesting carrier status was discovered following the neonatal death of two nephews whose muscle biopsies were consistent with XLMTM [7]. Including these cases, 25 cases of DNA-proven female manifesting carriers have been reported in the medical literature [3,6–18]. We recently evaluated a 58-year-old woman with a progressive and seemingly sporadic myopathy who, later through whole exome sequencing, was diagnosed as an XLMTM manifesting carrier.
Novel findings associated with MTM1 suggest a higher number of female symptomatic carriers
2016, Neuromuscular DisordersCitation Excerpt :Moreover, a skewed X-inactivation has been considered as the cause of the phenotype in female carriers. However, a re-evaluation of the previously published data seems not to support this hypothesis: in the 5 year old girl with hypotonia and general weakness, described by Schara et al. [34], a unilateral X-inactivation was detected in the muscles but not in the blood; eight females showed a random expression [32,33,35–38]; and in only 5 cases was a skewed expression confirmed in the blood [19,30,31,35,37]. In addition, in our case V, a skewed inactivation was not observed (ratio < 60:40).
Myopathy in a woman and her daughter associated with a novel splice site MTM1 mutation
2012, Neuromuscular DisordersDiagnosis of myotubular myopathy in the oldest known manifesting female carrier: A clinical and genetic study
2007, Neuromuscular DisordersCitation Excerpt :A skeletal asymmetry, emphasized by the same authors [8], was not obvious in our case. An asymmetry of the weakness was noticed in two previous reported cases [4,8], here, it was present only in the upper limbs. Females with severe phenotype (early childhood onset) of X-linked myotubular myopathy are very rare and associated with a skewed inactivation of the normal X-chromosome.