CLINICAL REPORT
Childhood Onset of Left Ventricular Dysfunction in aFemale Manifesting Carrier of Muscular DystrophyHugo R. Martinez,1 Ricardo Pignatelli,1 John W. Belmont,2 William J. Craigen,2 and John L. Jefferies1,3*1Section of Pediatric Cardiology, Texas Children’s Hospital, Houston, Texas2Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas3The Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas
Received 18 March 2010; Accepted 4 October 2010
Duchenne muscular dystrophy and Becker muscular dystrophy
are X-linked disorders that result from a mutation in the dys-
trophin gene that reduces the production or effectiveness of the
protein dystrophin. These disorders are clinically characterized
by progressivemuscle degeneration.Manifesting female carriers
are generally not identified as such until after puberty, when
symptoms such as muscle weakness may arise. This clinical
report describes a female manifesting carrier who started to
show deterioration of left ventricular systolic function, but no
marked skeletal muscle weakness, at the age of 10 years. The
patient’s cardiac function improved significantly after dual drug
therapy with an ACE inhibitor (enalapril) and a beta-blocker
(carvedilol). Our case adds to the existing evidence that left
ventricularmyocardial dysfunctionmay occur during childhood
in female carriers of dystrophinopathies.
� 2011 Wiley Periodicals, Inc.
Key words: dystrophin; duchenne muscular dystrophy; left ven-
tricular dysfunction; manifesting carriers
INTRODUCTION
Duchennemuscular dystrophy (DMD) is a lethal X-linked disorder
that affects approximately 1newbornboy in 3,500–6,000 live births;Becker muscular dystrophy (BMD) is the milder form and has
an incidence of 1 in 30,000 male births [Miller et al., 2006]. These
conditions generally affect males and are transmitted by female
carriers who have a 50% risk of producing an affected son or a
carrier daughter. Both diseases result from amutation in theDMD
gene located at Xp21.2 that encodes the sarcolemmal protein
dystrophin, which is abundant in skeletal and cardiac muscle
cells but is also found in smooth muscle and brain tissue [Cox
and Kunkel, 1997].
A small proportion of affected carriers have mutations that
arise from a germline mosaicism or structural abnormalities in the
X chromosome. Approximately one-third of such mutations
occur de novo, with the remaining two-thirds being inherited from
carrier mothers [Bakker et al., 1989].
The phenotype of DMD/BMD female carriers is characterized
by mild skeletal muscle weakness and cardiac disease, which are
well-recognized complications in patients affected by and carriers
of X-linked dystrophinopathies (XLD) [Politano et al., 1996;
Hoogerwaard et al., 1999a; Grain et al., 2001]. The cardiac involve-
ment leads to a predictable decline in ventricular function with age.
This decline may manifest as left ventricular dysfunction in the
phenotypic form of dilated cardiomyopathy, arrhythmia, and/or
heart failure themost advanced stage of XLD, leading to pathologic
left ventricular remodeling with myocardial fibrosis and fatty
replacement tissue [Towbin et al., 1993; Nolan et al., 2003; Jefferies
et al., 2005]. Cardiac involvement in this population varies widely,
as several studies have reported; however, the prevalence of cardiac
abnormalities appears to increase with age, resulting in recognized
complications in adult carriers [Lukasik, 1975; Nolan et al., 2003].
The wide variability of symptoms among manifesting carriers
can be explained by the skewed X-chromosome inactivation. This,
combined with preferential inactivation of the X chromosome
that bears the normal dystrophin allele in most cells, was suggested
as a possible mechanism of the disease’s manifestation among
carriers [Dubowitz, 1982; Sumita et al., 1998].
Measuring creatine kinase (CK) levels may be a reliable initial
test to evaluate carriers because the serum activity of CK is raised to
a mild to moderate extent in the majority of the female carriers
of the abnormal gene [Dubowitz, 1982].Molecular genetic analysis
may be used if family history, physical examination, and CK
levels are not confirmatory. Southern blotting and multiplex
*Correspondence to:
John L. Jefferies, Texas Children’s Hospital, 6621 Fannin, MC 19345-C,
Houston, Texas 77030. E-mail: [email protected]
Published online 3 November 2011 in Wiley Online Library
(wileyonlinelibrary.com)
DOI 10.1002/ajmg.a.33784
How to Cite this Article:Martinez HR, Pignatelli R, Belmont JW,
Craigen WJ, Jefferies JL. 2011. Childhood
onset of left ventricular dysfunction in a
female manifesting carrier of muscular
dystrophy.
Am J Med Genet Part A 155:3025–3029.
� 2011 Wiley Periodicals, Inc. 3025
ligation-dependent probe amplification (MLPA) can detect 65%
of the deletions and duplications found in such cases, and real-time
PCR can detect another 7–10%. Point mutation scanning and
sequencing analysis for detecting small deletions, single-base
changes, and splicing mutations also have clinical utility and may
detect the remaining 30–35% of mutations in theDMD gene [Piko
et al., 2009].
Historically, standard two-dimensional echocardiography has
been used to detect global systolic dysfunction and to obtain the
data needed to calculate the left ventricular ejection fraction
(LVEF). This technique provides only limited information regard-
ing regional abnormalities of systolic function and offers no reliable
data regarding diastolic function. In contrast, tissue Doppler
imaging (TDI) has considerable value in detecting regional systolic
dysfunction in patients with XLD [Corrado et al., 2002;Ogata et al.,
2007; Mertens et al., 2008]. In addition, TDI offers information
about diastolic dysfunction, which often contributes significantly
to symptoms associated with decompensated heart failure.
This clinical report describes the case of one of the youngest
manifesting female carriers ever reported, who had depressed
cardiac function, but no marked muscle weakness, when she was
10 years old and whose left ventricular systolic function improved
significantly after institution of dual drug therapy consisting of
an ACE inhibitor (enalapril) and a beta-blocker (carvedilol).
CLINICAL REPORT
A 4-year-old Caucasian girl was incidentally found to have elevated
liver function enzymes and CK values after she was taken to a
pediatrician for some swollen lymph nodes. Laboratory analysis
revealed that her CK level was 7,085U/L (reference range:
60–365U/L). Her serum aldolase level was also elevated (45U/L;
reference range: <8U/L). Although her liver function test results
subsequently improved, her serum CK level remained elevated
(in the 2,000–3,000U/L range). These findings suggested underly-
ingmuscle disease, and after an evaluation in theNeurology service,
she underwent muscle biopsy and DNA mutation analysis.
Immunostaining of the muscle biopsy for dystrophin showed
a clearminor population of dystrophin-negative fibers. In addition,
dysferlin staining, done on an experimental basis, producednormal
results. Subsequent investigations included DNA analysis, which
revealed deletion of exons 8 and 9 that resulted in a frameshift
mutation and a premature stop codon. The serum CK levels and
the DNA of the patient’s mother and sister were analyzed; the
results were normal, suggesting that the patient had a de novo
mutation. Additionally, X inactivation studies were performed that
showed random chromosomal inactivation on the patient’s lym-
phocytes. Moreover, a chromosomal analysis revealed a normal
female karyotype. A chest radiograph suggested mild enlargement
of the heart silhouette, and an electrocardiogram (ECG) revealed
possible left ventricular hypertrophy, which prompted a referral
to the Cardiovascular Genetics Clinic.
At first presentation, the patient was 4 years and 1 month old.
A review of hermedical history revealed that she was born full-term
to a 22-year-old woman who had received good prenatal care.
Both the mother and infant were discharged on the day after the
delivery. During the index presentation, the patient’s mother
recalled that the patient had shown modest symptoms of weakness
during her first few years of life. Specifically, the mother noted that
the patient was somewhat clumsy while walking and especially
while running. The mother also reported a delay in the patient’s
language development, saying that the patient had not become
able to combine two words until she was 3.5 years old. The family
history was unremarkable for muscle disease or using assistive
devices for ambulation. There was no family history of cardiomy-
opathy, heart failure, or sudden cardiac death.
On physical examination, the patient appeared well developed
and active. Her vital signs were within the normal range. Her fronto
-occipital circumference, height, and weight were between the
50th and 75th percentiles. The lung fields were clear, and her heart
auscultation revealed a regular rate and rhythm. Her abdominal
examination was unremarkable. An ECG revealed a normal sinus
rhythm of 111 beats per minute and possible left ventricular
hypertrophy. Echocardiography revealed normal cardiac size,
anatomy, ventricular thickness, and function; the patient’s calcu-
lated LVEF was 64%.
At a cardiology follow-up evaluation performed 10 months
later, when the patient was 4 years and 11 months old, her 12-lead
ECG was normal, and echocardiography revealed an LVEF of 61%
and a shortening fraction (SF) of 35%. In addition, the patient had
a complete neuropsychologic evaluation that revealed an overall
learning disability (Table I). Her general intellectual abilities fell
below the average range for the Wechsler Intelligence Scale for
Children-Fourth Edition (WISC-IV), and she displayed particular
weakness on tasks that assess verbal intellectual ability. Likewise,
her language comprehension and language expression skills were
well below the norm for her age. She also displayed weaknesses in
fine motor dexterity.
When the patient was 10 years and 5months of age, she was again
seen in theCardiovascularGeneticsClinic. She had remainedwithout
cardiac symptoms, according to her mother. The patient’s ECG and
Holter monitor readings were normal. Echocardiography showed
an SF of approximately 29% and an LVEF of 54%. The left
ventricular diastolic septal thickness (LVDST) was 0.56 cm (Z-
score, �2.32), the left ventricular end-diastolic dimension was at
the upper limits of normal for the patient’s body surface area,
and systolic function was at the low end of the normal range.
However,TDIvelocitieswerebelow the lowendof thenormal range
(Table II). Overall, there was some degree of deterioration in
the patient’s cardiac function as indicated by her LVEF and SF.
Moreover, her septumwas somewhat thin. Treatment with an ACE
TABLE I. Patient’s Scores on the Wechsler Intelligence Scale for
Children-Fourth Edition (WISC-IV)
Index Standardized scorea PercentileVerbal comprehension 75 5Perceptual reasoning 88 21Working memory 86 18Processing speed 88 21
aMean¼ 100, SD¼ 15.
3026 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
inhibitorwas suggested, so thepatient began taking 2.5mgenalapril
orally twice daily.
At a follow-up evaluation 8 months later (when the patient was
11 years and 1 month old), 12-lead ECG was normal. The patient
had an SF of 27% (Z-score,�2.42), her LVEF had decreased to 45%
(from 54% at the previous visit), and her TDI velocities were below
the normal range (Table II). Global left ventricular function was
slightly worse than it had been at the most recent previous study.
The enalapril dosage was up-titrated to 5mg orally twice daily.
At her fifth visit, 7 months later, the patient (aged 11 years and
8 months) remained physically active, but her overall symptom-
atology includedmild fatigue and some proximalmuscle weakness.
A positive Gower sign was noted. The Holter monitor showed
normal sinus rhythm. During this evaluation, the left ventricular
systolic septal thickness (LVSST)was belownormal limits (Z-score,
�2.04), and the left ventricular systolic wall thickness (LVSWT)
had a Z-score of�2.59. The calculated LVEF had declined to 43%,
and the SF had dropped to 26% (Z-score,�2.73). The patient’s TDI
velocities remained below the normal range (Table II). The lack
of improvement of her left ventricular function prompted the
initiation of dual drug therapy: the patient began taking carvedilol
3.125mg twice daily and continued taking enalapril.
A follow-up echocardiogram performed 6 months later, when
the patientwas 12 years and 2months old, showed an improvement
in cardiac function. The patient’s LVEFhad risen from43% to55%,
her SF had increased from 26% (Z-score, �2.73) to 32% (Z-score,
�0.54), and her TDI showed some degree of improvement, as
well. Additionally, LVSST and LVSWT were within normal limits
(Z-scores, �1.06 and �1.03, respectively).
Eight months later, the patient (aged 12 years and 10 months)
reported no cardiac symptoms but still had mild muscle weakness.
An echocardiogram revealed an LVEF of 59% and an SF of 31%.
DISCUSSION
We describe a young manifesting carrier of DMD with cardiac
involvement characterized by left ventricular dysfunction by the
age of 10 years. Her diagnosis was based on clinical manifestations
ofmild weakness and delays, high serumCK levels (2,000–7,085U/L), the results of her muscle biopsy, and the DNA analysis that
revealed evidence of a heterozygous deletion of exons 8 and 9; to
our knowledge, this is the first reported case of such a deletion in
the dystrophin gene. It is noteworthy that the fluorescence in situ
hybridization (FISH) that the patient underwent in the Neurology
Clinic did not show any mutation in the DMD gene. However, the
probe used for the FISH analysis is relatively large and could miss
a smaller deletion. Inour case, theDMDmutationwas later detected
during the DNA analysis.
The patient’s mother and sister did not show symptomatology
suggestive of heart failure, and both had normal CK levels and no
mutations detectable by DNA analysis. This strongly suggests
that the patient had a de novo mutation; however, a germline
mosaicism cannot be ruled out. The patient’s left ventricular
dysfunctionwas evidencedby the thinning of the LVwall, decreased
systolic function, and decreased TDI values that were revealed by
echocardiography (Table II).
Skeletal muscle weakness and ECG and echocardiogram abnor-
malities have been described previously among carriers of XLD,
but usually after the second and third decade of life [Lukasik, 1975;
Politano et al., 1996; Hoogerwaard et al., 1999a; Grain et al., 2001].
All female cells start having twoX chromosomes, which doubles the
dosage of X genes. To prevent this high dosage from disrupting
the normal function of the cell, each cell of the X chromosome
is randomly selected and inactivated early in the embryo growth.
Normally, the ratio of healthy to unhealthy active cells is 50:50.
This allows enough normal protein production to minimize any
symptoms of the disorder. However, in some female XLD carriers,
more than 90% of the inactivation is skewed towards the healthy
chromosome, resulting in functional loss and the possible onset
of symptoms of the illness. The clinical findings are dependent
on the proportion of cells in which the normal X chromosome has
been inactivated [Quan et al., 1997; Sumita et al., 1998]. The
prevalence of muscle weakness among carriers may be as high as
17% [Hoogerwaard et al., 1999b].
TABLE II. Echocardiographic and Electrocardiographic Data Collected During Each Patient Visit
Patientage
LVEF(%a)
SF%(Z-score)a
TDI velocityfindings
LVSWT,Z-score
LVSST,Z-score
LVEDD, cm(Z-score)
LVESD, cm(Z-score)
ECG/Holterfindingsb
4 years, 1 m 64 32 (�1.51) n/a �0.85 �0.24 3.70 (1.57) 2.50 (1.78) Normal/—4 years, 11m 61 35 (�0.20) n/a �0.20 �1.89 3.67 (0.95) 2.38 (0.86) Normal/—10 years, 5mc 54 29 (�1.81) Abnormal �1.46 �1.46f 4.86 (1.46) 3.44 (1.86) Normal/normal11 years, 1m 45 27 (�2.42) Abnormal �1.68 �1.73 4.64 (0.73) 3.40 (1.60) Normal/—11 years, 8md 43 26 (�2.73) Abnormal �2.59 �2.04 4.75 (0.93) 3.44 (1.6) Normal/normal12 years, 2me 55 32 (�0.54) Abnormal �1.03 �1.06 5.00 (1.39) 3.40 (1.38) Normal/—12 years, 10m 59 31 (�1.41) Abnormal �1.19 �0.09 4.57 (0.19) 3.16 (0.87) Normal/normal
ECG, electrocardiogram; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction; LVSST,left ventricular systolic septal thickness; LVSWT, left ventricular systolic wall thickness; SF, shortening fraction; TDI, tissue Doppler imaging.aComputed from left ventricular dimensions. The normal mean value for LVEF is 62� 12%, and the normal range for SF is 28–41%.b12-lead electrocardiogram and 24-hr Holter ECG monitor.cMedical therapy (ACE inhibitor) initiated at this visit.dDual medical therapy (ACE inhibitor and beta-blocker) initiated at this visit.eMarked improvement of LV size and function observed after start of dual therapy.fAlthough LVSST was normal, LVDST measured 0.56 cm (Z-score, �2.32), indicating some degree of deterioration in cardiac function.
MARTINEZ ET AL. 3027
This phenotypic variation has been shown in several studies,
such as the one performed in 2003 by Nolan et al. They assessed
23 carriers aged 6.2–15.9 years, all of whom had normal cardiac
examination findings. In contrast, Grain et al. [2001] studied 56
carriers aged 18–69 years and found that 10 of them had cardiac
abnormalities (including 4 cases of cardiomyopathy). Emery
[1969] and Lukasik [1975] reported 6.6% and 16.4% rates
of abnormal ECG findings, respectively, in their cohorts.
Hoogerwaard et al. [1999a] examined 129 carriers aged 18–60 years;47% had ECG changes, 36% had abnormal echocardiographic
findings, and 8% had dilated cardiomyopathy at a mean age of
36.9 years. Nolan et al. [1996] found myocardial involvement in
84.3% of their cohort and noted that its prevalence increased signifi-
cantly with age, from 54.5% in carriers aged 5–16 years to 90.2% in
carriers older than 16 years. These data suggest that female carrier age
may greatly affect the findings regarding cardiac involvement.
Although Nolan et al. described three DMD and two BMD
carriers aged 5–15 years with evident cardiac involvement, they
did not report the specific ages of these individuals, making our
patient one of the youngest manifesting carriers whose case has
ever been reported. Other published reports of young manifesting
carriers include a report describing a case ofTurner’s syndrome that
was due to a partial dystrophin deletion in the remaining
X chromosome, which caused the patient to be confined to a
wheelchair at age 9 [Chelly et al., 1986]. Another report describes
the case of a 6-year-old girl with marked muscular manifestations
resulting from maternal isodisomy of the X chromosome [Quan
et al., 1997]. In our patient, we ruled out the possibility of structural
chromosome abnormalities because none were visible on a high-
resolution karyotype and, even more importantly, because the
X inactivation studies of lymphocytes showed a random pattern.
Dystrophin provides structural support to the cardiomyocytes
and is also found in brain tissue and some other tissues, so affected
patients can present with muscle cramps, myoglobinuria, and
cognitive dysfunction [Hoffman et al., 1987; Nolan et al., 2003].
In our patient, intelligence testing produced abnormal findings.
The pathology of XLD starts at a subcellular stage in the
myocardium and skeletal muscles before the clinical picture forms
[Hoffman et al., 1987]. The cardiac involvement in XLD has been
attributed to the disruption of the amino-terminus of the dystro-
phinmolecule [Jefferies et al., 2005]. This process permits an excess
of calcium to penetrate the cell membrane, activating a complex of
cascading processes. With the disruption of dystrophin, muscle
fibers necrose and, ultimately, are replaced by adipose and fibrous
tissue. This process has been posited as the ‘‘final common
pathway’’ for all end-stage heart failure, regardless of its initial
cause [Towbin et al., 1993; Bowles et al., 2000]. The accuracy of this
model has been confirmed by studies that revealed disruption of
the dystrophin protein in patients with enteroviral myocarditis
[Badorff and Knowlton, 2004].
It is worth mentioning that our patient never underwent an
endomyocardial biopsy, so we could not rule out a secondary,
concomitant, or viral cause of our patient’s depressed cardiac
function. To our knowledge, there are no clear data that link exons
8 and 9 of the dystrophin gene to early development of dilated
cardiomyopathy in females. Jefferies et al. [2005] reported severe
forms of cardiac involvement in DMD patients with deletions
in exons 12 and 14–17 and some milder forms in affected males
with deletions in exons 51 and 52. Further investigation is needed
in female carriers.
In our case, the initial indicator of deteriorating myocardial
function was the abnormal echocardiographic findings in the
context of normal ECG results. As suggested by the findings of
[Meune et al., 2004], TDI enabled us to obtain more information
than just LVEF and SF, enabling us to assess myocardial function
more rigorously. The use of TDI in our case was confirmatory
for regional cardiac dysfunction.
CONCLUSION
Our case—that of a female DMD/BMD carrier who had evidence
of myocardial dysfunction in childhood—suggests that left ven-
tricular myocardial dysfunction may occur in female carriers at
a much earlier age than has been previously reported. In addition,
our patient had a favorable response tomedical therapy, suggesting
that early detection of myocardial involvement may have direct
benefits for such patients, especially after the use ofmedical therapy
for heart failure, which may delay the progression of heart failure
in XLD carriers. Early cardiac screening of known female carriers
may be warranted. We suggest that XLD be made part of the
differential diagnosis of girls with unexplained left ventricular
dysfunction and high serum levels of CK.
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