Keywords
pregnancy - desminopathy - restrictive cardiomyopathy -
DES gene
Rarely encountered in the obstetric population, presenting symptoms of desmin-related
myopathy include progressive myopathy, neuropathy, and cardiomyopathy between the
second and fourth decades.[1] Mutations (point substitutions, insertions, and deletions) in the DES gene results in altered myocyte intracellular structure, characterized by changes
in nuclear shape, disturbances in mitochondrial morphology, abnormal accumulation
of cytoskeletal proteins, and malalignment of myofibrils.[1]
[2]
[3] Affected individuals initially experience lower extremity weakness and paresthesias,
which may then extend insidiously into the trunk, neck, facial, and respiratory musculature.[1]
[2] Intestinal and cardiac manifestations including arrhythmias or cardiomyopathy have
been reported.[4] The prevalence of DES mutations in dilated cardiomyopathy is rare ranging between 1 and 2%.[5] Although most commonly inherited in an autosomal dominant manner or as a de novo/sporadic
mutation, autosomal recessive patterns have rarely been described with variable phenotypic
penetrance.[1]
Formal diagnostic measures are based on clinical criteria of progressive muscle weakness,
cardiomyopathy with/without associated arrhythmia, or restrictive cardiac dysfunction,
in conjunction with confirmatory molecular testing revealing characteristic DES gene mutation(s).[1]
[2] To date, pregnancy has only been reported in a single patient with long QT syndrome
and heart failure who was subsequently diagnosed postpartum with desmin-related cardiomyopathy
(DRCM).[6] This case report constitutes the first description of DRCM recognized before conception
and managed prospectively.
Case
A 28-year-old primigravida was referred to us for consultation at 8 5/7 weeks' gestation because of the DRCM diagnosed 2 years prior. Her medical history
was significant for third-degree heart block requiring pacemaker placement 4 years
previously; concurrent echocardiography demonstrated normal left ventricular ejection
fraction (EF) of 60%. Because of the symptomatic peripheral edema and intermittent
arrhythmias, therapy with furosemide and carvedilol was instituted. Interestingly,
the following year, her identical twin sister experienced a similar episode of third-degree
heart block and cardiomyopathy and genetic testing was pursued revealing an Arg406Trp
mutation in the DES gene, confirmatory for desmin myopathy. Repeat echocardiography in our patient 2
years after the initial episode showed left ventricular diastolic dysfunction with
preserved EF. Comprehensive genetic evaluation in our patient revealed an identical
mutation to her sister, and she was formally diagnosed with DRCM. Six months before
the conception, a hospital admission was required for decompensated diastolic cardiac
failure, which was successfully managed with the addition of an angiotensin-converting
enzyme (ACE) inhibitor. In addition to the ACE inhibitor, before the pregnancy, she
was managed on carvedilol and furosemide.
Following discovery of pregnancy, the ACE inhibitor was promptly discontinued, however,
she remained on carvedilol and furosemide therapy. Although she met New York Heart
Association class II functional criteria because of the persistent orthopnea with
CARPREG score 2,[7]
[8] echocardiography revealed a preserved left ventricular EF of 61% with a normal left
ventricular chamber size. Given the impending physiologic increased cardiac demands
of pregnancy, an uncertain prognosis was discussed. The patient elected to continue
the pregnancy and declined the option of prenatal diagnosis for DRCM. Repeat maternal
transthoracic echocardiogram at 19 weeks' gestation demonstrated stable cardiac function
with normal left ventricular chamber size and EF of 57%. Fetal echocardiogram was
unremarkable. At 35 weeks' gestation, she was admitted for dyspnea with increasing
peripheral edema and a repeat maternal echocardiogram showed preserved left ventricular
EF of 58% with a normal left ventricular chamber size. Intravenous diuretic therapy
was administered and she was maintained on carvedilol medication. She was readmitted
the following week for similar symptoms without requiring further treatment.
Fetal growth was monitored sonographically on a monthly basis during the pregnancy
and was consistently normal. At 39 1/7 weeks' gestation, she presented in active labor, and a regional anesthetic was placed.
Her intrapartum course was uneventful, and a low vacuum-assisted operative vaginal
delivery was performed because of the category II fetal heart rate pattern late in
the second stage of labor with delivery of a healthy female infant weighing 2,710
g. Postpartum hemorrhage because of the uterine atony was encountered, and due to
symptomatic hypotension and fall in hemoglobin from 11 to 7 g/dL, 2 units of blood
were transfused. The remainder of her postpartum course was unremarkable, and both
mother and infant were discharged home on the second day postdelivery. Neonatal echocardiogram
and electrocardiogram were normal. Neonatal molecular genetic evaluation returned
as positive for the mutation in the DES gene, Arg406Trp, the known disease causing mutation for myopathy and cardiomyopathy.
Postpartum maternal cardiac evaluation revealed stable status without symptoms suggestive
of cardiopulmonary exacerbation.
Discussion
At a cellular level, desmin functions as an intermediate filament cytoskeletal protein,
playing a crucial role in cytoskeleton maintenance. Desmin links Z bands and connects them to various intracellular structures including the sarcolemma,
cytoplasmic organelles, and nuclear and plasma membranes.[9] In affected individuals, the defective desmin transcript accumulates in a disorganized
fashion, leading to a disrupted and abnormal formation of filaments.[9] Myofibrillar myopathy or “desminopathy” is described as a familial or sporadic disorder
from a mutation within the DES gene, leading to an abnormal accumulation of desmin protein within cardiac and skeletal
muscles.[1]
[2] Several other abnormalities include abnormal electromyography, elevated serum creatinine
kinase levels, and muscle biopsy histopathology may also allude to the diagnosis.[2] Preconceptually, our patient had persistently elevated creatinine kinase of 699
and 1,113 units/L.
Desmin-related myopathy has been characterized by an abnormal accumulation of desmin
within cardiac and skeletal muscle.[2] Therefore, we would not expect it to significantly affect the uterine smooth muscle.
Antenatally, our patient had no issues surrounding cervical shortening, preterm contractions,
or preterm labor. Moreover, her intrapartum course was unremarkable—tocometer monitoring
and labor partogram was not suggestive of uterine dysfunction. Although there was
uterine atony following delivery, it responded to conventional therapy, was not difficult
to control, and did not recur.
According to one review, less than 100 patients with desmin myopathy have been identified
to date.[2] Unfortunately, no specific treatment currently exists for DRCM, and individuals
are managed on a symptomatic basis. Pathologic cardiac arrhythmias or advanced heart
block represents an indication for pacemaker/defibrillator implantation.[1]
[2] From a clinical perspective, DRCM mimics a restrictive cardiomyopathy process with
preserved systolic function. Symptomatic restrictive cardiomyopathy generally carries
a poor prognosis, with a 10-year survival rate of 37%.[10]
[11] Pregnancy is typically not advised in this population.[10]
[11]
[12]
There is a paucity of information on the optimal management of reproductive-aged women
with desminopathy, and little evidence exists in the literature to guide physicians
with respect to counseling these women on pregnancy-related outcomes. This report
describes the first case of pregnancy in a patient with symptomatic DRCM. Although
complicated by repeated inpatient admissions and postpartum hemorrhage, the pregnancy
continued until term without apparent permanent deterioration in cardiac function,
suggesting that this condition does not appear to represent an absolute contraindication
to pregnancy.
