Manifesting carrier of a dystrophinopathy with a duplication noted in exon 5-11 of the dystrophin gene. Her X-inactivation studies showed marked skewing, with 95% inactivation of the wild-type allele.
The present case is an uncommon example of a manifesting Duchenne carrier presenting with myalgias and proximal muscle weakness. Although cases of pediatric females presenting with symptoms are particularly rare, there are several reported cases of manifesting female Duchenne Muscular Dystrophy (DMD) and Becker's Muscular Dystrophy (BMD) carriers presenting between 20 and 40 years of age. Typically the latter cases present with mild proximal weakness and dilated cardiomyopathy (4). According to Hoogerwaard et al, muscular weakness can be demonstrated in 19% of female DMD carriers and 14% of female BMD carriers (3). Myalgia and muscle cramps, however, are only present in 4-7% of this patient group. Furthermore, the mean age of onset of symptoms in these carriers is 33 years and signs do not tend to occur before age 16 (3).
There have been two previous case reports describing the presentations of young female dystrophinopathy carriers. The first patient presented with an episode similar to our own, namely exertional muscle pain (2). Interestingly, this patient did not have muscle weakness related to the pain or enlarged calf muscles. She was found to have a mutation related to the presentation of BMD with no evidence of skewed X-inactivation. The second patient presented with a single episode of rhabdomyolysis. She was found to have an out-of-frame mutation and classified as a DMD genotype. Her X-inactivation studies showed marked skewing with 85% inactivation of the wild-type allele, offering some explanation for her early onset of symptoms (8). Both girls were found to have elevated CK levels and their diagnoses confirmed by muscle biopsy and dystrophin immunohistochemistry (IHC).
In female carriers of DMD or BMD, one normal X-chromosome provides some balance for the X-chromosome harboring the defective dystrophin gene. In multinuclear skeletal muscle cells, there is further balance afforded. Furthermore, while random X-inactivation should lead to approximately 50% expression, there is evidence that dystrophin levels as low as 30% are sufficient to prevent symptoms in female carriers.
In addition to skewed X-inactivation, there are several additional rare circumstances in which a female carrier may manifest with earlier and more severe dystrophy. Monosomy X (Turner's syndrome- 45X) with a dystrophin gene mutation on the lone X chromosome or uniparental disomy (specifically maternal isosomy) of the X-chromosome would each lead to an unbalanced mutation (7). An X-autosome translocation interrupting the dystrophin gene may also result in dystrophinopathy (1). An even more rare presentation is that of a phenotypic female, but genotypic male (46 XY) carrying both a dystrophin and androgen receptor mutations (5). Finally, the possibility exists, albeit unreported, for coincident inheritance of mutations on both the X chromosomes.
In our case, non-randomized X-inactivation or unfavourable lyonization was the mechanism for marked dystrophin underexpression. X-inactivation is considered non-randomized or 'skewed' if 80% or more lymphocytes in the blood have the same active X-chromosome ( 6). In a study by Yoshioka et al., all female manifesting carriers studied showed skewed X-inactivation while all unaffected carriers studied showed symmetrical X-inactivation (10). However, there are examples where symptomatic patients do not display significant X-inactivation (2). These experiences have demonstrated that the relationship between disease and X-inactivation is not a simple one.
The gold standard for diagnosis of a dystrophinopathy remains immunohistochemical staining for dystrophin in muscle and this is a reliable way to diagnose dystrophinopathies in female manifesting carriers. The characteristic finding in female carriers of DMD and BMD (both manifesting and asymptomatic) is a mosaic distribution of dystrophin-positive and dystrophin-negative fibers in both cardiac and skeletal muscles. Although immunohistochemistry may be optimal for diagnosis, it has not been shown to correlate accurately with the severity of disease. Sewry et al. found no correlation between the degree of weakness and the number of dystrophin deficient fibers in manifesting carriers(9). Hoogerwaard et al. were also unable to find a reliable association between dystrophin expression and clinical variables in DMD and BMD carriers(4). These studies also point to other variables influential in the development of symptoms in manifesting dystrophinopathy carriers.
While predicting progression of disease in such patients remains a challenge, in part because of the rarity of such cases, an early and accurate diagnosis is essential to genetic counselling and to increase the experience of the medical literature.
Contributed by Natashia Seemann, Robert Hammond, Dr. Chitra Prasad , Craig Campbell