Dear Editors,
We read with interest the article published by Silva et al.[1] on functional performance and muscular strength in symptomatic female carriers of
the Duchenne muscular dystrophy (DMD) gene. If a female individual carries the dystrophin
gene mutation on one of the two chromosomes, the second X-chromosome ‘protects’ her
due to the production of a regular dystrophin protein. However, some of these female
carriers can present symptoms varying from mild muscle weakness to a more severe course,
being classified as symptomatic carriers. Age at symptom onset in female carriers
ranges from 15 to 31 years (mean of 30.6 years), and age at diagnosis for asymptomatic
carriers ranges from 4 to 38 years (mean of 24.5 years)[2]. They usually present with asymmetric bilateral leg weakness and can develop myalgia,
cramps, fatigue, dilated cardiomyopathy, and enlarged calf muscles (pseudohypertrophy)
with elevated serum creatine kinase (CK) levels.
We had two cases of female symptomatic carriers of the dystrophin gene, mothers of
two boys, both showing duplication of exons disturbing the open reading frame of the
DMD gene. Both of them had significant limitation of their functionality, causing
limitation in the physical support for their sons. We propose that they should be
classified and treated as patients with the disease.
The first case was a 38-year-old woman with weakness in upper and lower limbs, leading
to frequent falls and pain during efforts, which began by age 18. Neurological exam
revealed proximal muscle atrophy in the right lower limb (flexors, extensors, and
adductors of the hip graded 3/5) and interosseous muscles of both hands. Serum CK
levels were elevated at 1,500 U/L (normal values range from 26 to 192 U/L), and electromyography
(EMG) studies showed myopathic changes. Cardiac investigation, including echocardiogram
and 24-h Holter analysis, were regular. She had a son with DMD, which prompted us
to ask for molecular analysis of the dystrophin gene that revealed a pathogenic duplication
of exons 8 and 9 modifying the open reading frame of the DMD gene by means of the
Multiplex Ligation-dependent Probe Amplification (MLPA) method.
The second case is a 32-year-old woman whose son was diagnosed with DMD. She became
symptomatic 10 years before, presenting with gait difficulties and frequent falls.
She developed myopathic gait, lumbar scoliosis, and needed unilateral support. Neurological
exam revealed muscle strength 3/5 proximally in the lower and upper limbs, involving
flexors, extensors and abductors of the shoulder and flexors, extensors, and adductors
of hip muscles. CK levels were 2,366, but they ranged from 10 to 20 times the normal
value (ranging from 26 to 192 U/L) throughout the years. Cardiac investigation was
regular. MLPA molecular analysis of the dystrophin gene revealed duplication of exons
60 and 62 modifying the open reading frame of the DMD gene.
Development of symptoms in DMD mutation carriers has been attributed to skewed X-chromosome
inactivation (XCI), in which the X chromosome expression with the DMD mutated allele
is favored[3]. Juan-Mateu et al[3]. showed that the extent of XCI skewing is related to phenotype severity, with symptomatic
carriers exhibiting 49.2% more skewed XCI profiles than asymptomatic carriers. However,
this mechanism is still controversial. The first study that deeply explored the DMD
transcriptional behavior found no relationship between the total DMD transcript level
and the relative proportion of the wild-type transcript, with the symptomatic phenotype[4].
Zhong et al.[5], in their clinical and genetic study of 78 female dystrophinopathy carriers, including
four symptomatic and 74 asymptomatic carriers, found that all symptomatic carriers
had a duplication mutation. Among asymptomatic carriers, almost 42% had deletion mutations,
while around 45% had point mutations in exons and only 13.5% cases carried duplication
mutation. MLPA for the dystrophin gene exons, along with next-generation sequencing
and Sanger sequencing, were effective for diagnosing symptomatic carriers and determining
the status of probable carriers. The authors also showed that CK levels have high
diagnostic sensitivity and specificity among female carriers. In our two patients,
we found duplication mutations by means of the MLPA method. Silva et al.[1] found only one duplication, with deletions being the most common mutation in seven
patients.
We have presented herein two illustrative cases of female symptomatic ‘carriers’ with
significant motor impairments. Our major limitation was the lack of additional tests
(in particular, muscle magnetic resonance imaging and biopsy) to ascertain that no
additional cause was responsible for myopathic symptoms or to provide pathogenicity
evidence in the investigation of atypical DMD presentations. Even though muscle biopsy
was not performed, clinical and laboratory tests excluded other potential causes for
myopathy, such as immune-mediated or toxic ones. By definition, the word ‘carriers’
is applied to someone with unexpressed genetic trait without disease symptoms. We
therefore propose that female symptomatic patients should no longer be classified
as carriers and should be appropriately evaluated and treated. Since we still have
no guidelines or expert recommendations, the treatment of our two patients was not
pursued. However, we stress the need to further discuss treatment in these patients,
mainly through steroids.
