The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins

doi:10.1016/0022-510X(87)90240-1

Journal of the Neurological Sciences

Volume 79, Issue 3, July 1987, Pages 337-344

https://doi.org/10.1016/0022-510X(87)90240-1 Get rights and content

Abstract

We have ascertained retrospectively a female patient, one of identical twins, who was diagnosed at age 23 years as having Duchenne muscular dystrophy (DMD). A muscle biopsy at that time showed a pattern in which large areas of destroyed muscle fibers replaced with adipose tissue were interspersed with normal-appearing muscle fascicles. The visualization of Barr bodies in the muscle biopsy, plus the patient's normal menstrual history served to rule out Turner's syndrome.

The clinical expression of DMD in only one of monozygotic twins is strongly suggestive of uneven lyonization, with an excess of paternally derived X-chromosomes being inactivated in the patient. This view is supported by the appearance of the muscle biopsy. Twinning may conceivably predispose to uneven lyonization by reducing the size of the muscle cell anlage at the time of X-chromosome inactivation. Alternatively, lyonization may occur before the splitting of the embryonic mass, and by chance, the two embryonic centers could end up with a significantly different proportion of active maternal and paternal X-chromosomes.

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Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers
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Muscle pathology, dystrophin expression and X-inactivation patterns were studied in the muscle of five asymptomatic females heterozygous for deletions in the dystrophin gene (non-manifesting carriers) and five symptomatic carriers (manifesting carriers). Muscle from the non-manifesting carriers showed an increase in the population of centrally nucleated fibres (9.0 ± 2.8%; controls, 1.4 ± 0.3%), frequent fibers with abnormally interrupted dystrophin staining (38 ± 5%), and, in sections from three individuals, small numbers of dystrophinnegative fibers (1–4%). The amount of dystrophin measured by immunoblotting was reduced to 64 ± 5% (P<0.001 n=5) of normal. The pattern of X-inactivation in muscle DNA was nonbiased (50 : 50–60 : 40) in all cases. In the manifesting carriers both highly biased (90 : 10) and non-biased patterns of X-inactivation were found, but no consistent relationship was apparent between the patterns of X-inactivation and the proportions of dystrophin-negative fibers. We conclude from studies of the non-manifesting carriers that the proportion of residual dystrophin is similar to the relative activation in muscle of the X-chromosome carrying the wild-type allele. Extreme bias of X-inactivation can be associated with early clinical symptoms and severe pathology. However, as non-manifesting and some manifesting adult carriers had identical patterns of X-inactivation, abnormalities in the distribution of dystrophin, as well as overall levels of expression, may be important for the development of myopathic pathology.

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^☆: Supported by the Medical Research Council of Canada, The Muscular Dystrophy Association of Canada and the Killam Fund of the Montreal Neurological Institute.

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The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins☆

Abstract

Am. J. Med.

Duchenne muscular dystrophy in one of monozygotic twin girls

J. Med. Genet.

Dystrophie musculaire de Duchenne chez une petite fille porteuse d'une translocation (†X;3) (p21;q13) de novo

Ann. Genet.

Duchenne muscular dystrophy: plasma membrane loss initiates muscle cell necrosis unless it is repaired

Brain

Monozygotic twins discordant for the clinical manifestations of Duchenne muscular dystrophy

Neurology

Molecular genetics of the human X-chromosome

J. Med. Genet.

Duchenne muscular dystrophy - genetic aspects, carrier detection and antenatal diagnosis

Brit. Med. Bull.

Familial occurrence of heterozygous manifestations in X-linked muscular dystrophies

Rev. Brasil Genet.