Female Carriers of Duchenne Muscular Dystrophy

Abstract

males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers.1, 2, 4) Therefore, here we reviewed recent studies to meet the need for a better understanding about the characterization of female carriers of DMD. What is dystrophinopathies?Duchenne's description of DMD was published in 1861. He referred to the disease as "hypertrophic paraplegia of infancy due to a cerebral cause". IntroductionDuchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular dystrophy. The milder form of this disease is called Becker muscular dystrophy(BMD).1) The disorder is also called dystrophinopathy because it caused by mutations in the DMD gene, which encodes dystrophin, on Xp21.2) Most heterozygous female carriers of DMD are subclinical. Therefore, identification of dystrophinopathy carriers may be only con sidered on clinical grounds such as clear X-linked family history of muscular dystrophy. However, myopathic muscle biopsy and advanced molecular diagnostic analysis can be used to identify the carrier state of DMD without a positive family history of dystrophinopathy , which is present in 10% of women with hyperCKemia.3) In addition, two-thirds of mothers of affected www.e-kjgm.org Dystrophinopathy, caused by mutations in the DMD gene, presents with variable clinical phenotypes ranging from the severe Duchenne muscular dystrophy (DMD) to the milder Becker muscular dystrophy(BMD) forms. DMD is a recessive X-linked form of muscular dystrophy. Two-thirds of mothers of affected males are thought to be DMD carriers. Approximately 2.5-7.8% of female DMD carriers have muscle weakness and are categorized as manifesting DMD carriers. The symptoms of female carriers of DMD range from mild muscle weakness to severe gait problems. The most commonly presented symptom is mild proximal muscle weakness, which is often asymmetric and progressive, but shows variable clinical spectrum with BMD of more severe DMD-like phenotype. Atypical presentations in manifesting carriers are myalgia or cramps without limb weakness, isolated cardiomyopathy and camptocormia. Multiplex PCR and MLPA analysis are common techniques to identify mutations in the DMD gene. Relationship between X-chromosome inactivation and clinical severity is not clear. Female carriers of DMD are not less common, and they have an important role of birth of a male DMD.

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

“…Manifesting carriers of DMD present with incongruent degrees of muscle weakness, pain, fatigue, and reduced endurance [ 9 , 66 , 67 ]. Although other mdx rodent models display stronger phenotypes similar to the human DMD disease, the mdx strain was selected because it is a genetic homolog to DMD and is the most studied and characterized strain since its discovery [ 68 , 69 ].…”

Clinical and Genetic Characterization of Female Dystrophinopathy

“…Several mechanisms have been proposed to explain symptom manifestation in women with DMD/BMD. 5 6 7 8 9 The most frequently reported mechanisms are skewed X-chromosome inactivation (XCI), in which expression of the X chromosome with the DMD mutated allele is favored, 11 and balanced X-autosome translocation. 12 The relationship between XCI and clinical severity is not clear, and the prognostic value of XCI is controversial.…”

“… 5 Since most heterozygous female carriers of DMD have subclinical symptoms, screening of dystrophinopathy carriers may only be performed on clinical grounds such as a clear X-linked family history of muscular dystrophy. 6 However, myopathic muscle biopsy and advanced molecular diagnostic analysis can be used to identify DMD carriers who do not have a positive family history of dystrophinopathy; 10% of women with abnormally elevated serum creatine kinase (CK) are DMD carriers. 3 The clinical characteristics of genetically confirmed female dystrophinopathy carriers were explored in this study.…”

Cardiac involvement in female carriers of duchenne or becker muscular dystrophy

“…Most female carriers of a dystrophin gene mutation do not exhibit muscle weakness, although some can develop muscle symptoms (“manifesting carriers”) . Other than in isolated early case reports, Politano et al were the first in 1996 to raise concerns that female Xp21 mutation carriers without skeletal symptoms were at risk to develop cardiac dystrophinopathy .…”