New guidance issued for CMD management


Clinicians caring for children with congenital muscular dystrophy (CMD) now have new evidence-based recommendations to guide their evaluation, diagnosis, and management of the disease in pediatric patients.

Clinicians caring for children with congenital muscular dystrophy (CMD) now have new evidence-based recommendations to guide their evaluation, diagnosis, and management of the disease in pediatric patients.

Successful healthcare is a team effort, and the diagnosis and management of CMD is no exception.

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In the new set of guidelinesauthored by the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine, researchers recommend collaborative efforts between pediatricians and neuromuscular specialists.

“An actively involved and engaged pediatrician is critical for the care of children with congenital muscular dystrophy, as these children often have multiorgan system complications,” says lead author Peter B. Kang, MD, chief of pediatric neurology and associate professor of pediatrics at the University of Florida College of Medicine. “The pediatrician should work with physicians who have relevant expertise such as pediatric neuromuscular specialists to pinpoint subtype-specific diagnoses for these children whenever possible, as that information will help with prognosis and identification of potential complications. The pediatrician should be an active member of the patient's team, referring to and coordinating care plans with relevant pediatric subspecialists.”

The goal of the study was to identify the best diagnostic and therapeutic strategies for managing CMD by combing through currently available literature. That analysis was then used to establish evidence-based guidelines that encourage physicians to evaluate symptoms, family history, physical exams, and results from lab tests to diagnose specific subtypes of muscular dystrophy.

Congenital muscular dystrophies are a family of rare muscular dystrophies having symptoms that are present at birth. Unlike congenital myopathies, which can be confirmed through pathologic features, and genetic etiologies, some subtypes of CMD can be diagnosed through genetic testing, but not all the causative genes of CMD have been identified.

The prevalence of CMDs among European populations is around 1 in 100,000 persons, according to the study, and any MDs whose symptoms present during infancy or in the first 2 years of life are usually considered to be CMDs. Three major categories of CMDs are recognized: collagenopathies (collagen VI-related myopathies); merosinopathies (merosin-deficient CMDs; laminin α2 [LAMA2]-related CMDs; and MDC1A); and dystroglycanopathies (α-dystroglycan–related MDs).

Although identifying these categories, as well as genetic, pathophysiologic, and pathologic features of CMDs, has helped improve CMD management, the researchers say “optimal diagnostic and therapeutic approaches remain unclear.” A new set of algorithms has been published, however, that they say may help the diagnosis process in suspected CMD cases.

NEXT: Determining subtype


In cases of suspected CMD, the guidelines encourage physicians to determine how well the geographic location and ethnicity, clinical features, brain imaging findings, muscle imaging findings, and muscle biopsy findings help determine a subtype-specific diagnosis.

In terms of geography and ethnicity, the study notes that CMD clusters have been found in the Japanese and Korean (Fukuyama CMD), Ashkenazi Jewish (Walker-Warburg syndrome), and Turkish (A200P haplotype in the POMT1 gene) populations, but other founder mutations could exist. Thus physicians should note the geographic and ethnic background of suspected CMD cases.

Cardinal symptoms of CMD generally present as progressive skeletal weakness and hypotonia, and serum creatine kinase (CK) levels are typically-but not always-elevated. Manifestations of the collagenopathy subtype may include distal joint hyperlaxity, congenital hypotonia, and joint contractures.

The merosinopathy subtype can present with congenital weakness, elevated CK levels, and brain magnetic resonance imaging (MRI) evidence of white matter signal abnormalities. Dystroglycanopathy subtypes are often characterized by muscle weakness, eye abnormalities, and cortical brain abnormalities. These subtypes also may be revealed on a brain MRI through evidence of polymicrogyria, white matter legions, pontine hypoplasia, and subcortical cerebellar cysts.

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Children who present with specific clinical features can therefore help predict the subtype-specific diagnosis and the causative genes, according to the study.

Skeletal muscle imaging may also hold clues as to the subtype of the CMD diagnosis, with collagenopathies and SEPN1-related myopathy often presenting with rigidity of the spine.

Muscle biopsy findings are closely related to those found in other MDs, according to the study, including necrosis, regenerating fibers, fiber size variability, and increased perimysial and endomysial connective tissue. Researchers concluded, however, that there is insufficient evidence to determine the efficacy of muscle biopsies in determining collagenopathies.

Many CMDs are autosomal recessive, but the study notes that in some cases they may also be autosomal dominant patterns, by direct inheritance, spontaneous mutations, or mosaicism. Although the genetic origins of many types of CMD have been discovered, the study notes that there are still a number of cases without a genetic diagnosis, indicating that novel disease genes have yet to be identified. For CMD genes that have been identified, clinical genetic testing is available, and mutation detection rates for CMDs are 20% to 46%.

Wide ranges of complications are found in CMD patients, and researchers note that 58% of patients suffer from some type of cognitive impairment. Children with Fukuyama CMD experienced seizures in 1 study, and another associated dystroglycanopathy had epilepsy associated with unusual electroencephalogram findings. In addition to cognitive symptoms, the researchers say 12% of CMD patients also suffer from some type of respiratory complications, 6% had cardiac complications, and an unspecified percentage of cases reported feeding difficulties.

The general recommendations developed by the research team emphasize the use of multidisciplinary teams in caring for patients with CMD.

“Patients with CMD may develop various combinations of cardiovascular, gastrointestinal/nutritional, neurologic, ophthalmologic, orthopedic, and pulmonary manifestations,” the study notes. “Neuromuscular specialists, particularly child neurologists and physiatrists with subspecialty training, are key members of such teams, as are physicians from other specialties (eg, cardiology, gastroenterology, neurology, ophthalmology, orthopedic surgery, pulmonology) and allied health professionals with relevant expertise (eg, dieticians, genetic counselors, nurses, nurse practitioners, occupational therapists, physical therapists, and speech−language pathologists).”

NEXT: Building a team to coordinate care


Specifically, the report suggests that physicians caring for pediatric CMD patients consult with a pediatric neuromuscular specialist for the diagnosis and management of the condition, and that the specialist continue to coordinate the care of the patient going forward.

Genetic counselors should be utilized to help make family-planning decisions and interpret test results, the study adds. In addition to genetic testing, physicians should rely on clinical features such as symptoms, ethnicity and geographic location, the level of CNS involvement, other organ involvement, and serum CK levels when diagnosing CMD subtype.

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“Interpretation of muscle biopsy findings, especially in children, is heavily dependent on technique and the experience of the pathologist or neuromuscular specialist who interprets the studies,” according to the study. “Proper interpretation of these studies requires knowledge of the clinical context as well as availability of advanced testing capabilities. The knowledge obtained from a muscle biopsy may help families and providers better understand the disease process affecting specific patients.”

In cases where subtype-specific diagnosis can’t be made after initial testing, the report recommends immunohistochemical staining for relevant proteins if the risk associated with general anesthesia is determined to be acceptable. Additionally, the biopsies should be performed and interpreted by specialists in that field-even if that means obtaining the biopsy and interpreting it at different locations.

Brain MRI findings that indicate white matter abnormalities are typically found in children aged older than 6 months with merosinopathies, and structural brain abnormalities are often present in cases of dystroglycanopathies. The report notes that muscle ultrasound and MRI studies can help identify specific CMD subtypes. Therefore, physicians should order brain MRI scans, and possibly muscle imaging studies of the lower extremities, to assist in the diagnosis of specific CMD subtypes

Although genetic testing is widely available and can help in identifying causative mutations in CMD subtypes, traditional Sanger sequencing can be cost-prohibitive for many patients. “Genetic diagnoses are beneficial to the patient, as they often enable physicians to provide more accurate prognoses and facilitate genetic counseling and family-planning discussions, and may enable patients to become more aware of future clinical trials for which they may be eligible,” the study notes.

To overcome this hurdle, the guidelines recommend that physicians order targeted genetic testing for specific CMD subtypes.

For patients who do not have a previously identified mutation or whose CMD phenotype has not been well-characterized, the researchers recommend whole-genome sequencing as it becomes more accessible and affordable. “The cost of next-generation sequencing (whole-exome and whole-genome sequencing) is dropping rapidly, to the point where these technologies are now readily available to many researchers who seek novel causative disease genes,” they write.

As for treatment recommendations, the guidelines stress that there is no cure for CMD symptoms, only management techniques. “There are currently no curative CMD subtype-specific interventions. Thus, all complication screening and interventions are intended to promote growth and potential development, mitigate cumulative morbidities, optimize function, and limit mortality while maximizing quality of life,” according to the report.

NEXT: Musculoskeletal complications


Study authors recommend that physicians advise families about clinical outcomes as well as the value of any interventions in terms of the longevity and quality of life they offer. Physicians should also explain to families how to monitor for ongoing complications of CMD.

In respiratory complications, the guidelines state that respiratory failure from neuromuscular-related weakness may not always be preceded by symptoms such as dyspnea. To manage these potential complications, the guidelines recommend that physicians warn families to watch for signs of respiratory insufficiency, and that physicians monitor pulmonary function tests in waking and sleeping states. Referral to pulmonary or aerodigestive care teams may be necessary because they can provide specific guidance on assessments, complications, and potential interventions.

Physicians must also be aware of dysphagia risks in CMD, which may manifest as failure to thrive and result in more visits to critical care units and greater risk of mortality.

The guidelines recommend that neuromuscular specialists work with primary care providers on nutrition and growth trajectories, as well as order evaluations from swallow therapists, gastroenterologists, and respiratory therapists. Gastronomy placement with or without fundoplication may need to be considered, according to the study.

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Other complications of CMD management include periprocedural complications such as longer recovery times, airway problems, and obstacles to effective pain control. Families should be made aware of the increased risks, particularly in cases of elective procedures, and physicians should lengthen their postoperative monitoring of CMD patients.

In treating the musculoskeletal complications that all CMD patients are at risk of developing, range-of-motion exercises and bracing are low risk, but their efficacy has not be proven. The guidelines recommend that physical and occupational therapists, orthopedic surgeons, and mobility specialists be enlisted to help maximize function while slowing the progression of musculoskeletal complications.

“Physicians may recommend range-of-motion exercises, orthotic devices, heel cord-lengthening procedures, or a combination of these interventions for children with CMD in certain circumstances,” according to the guidelines. “Physicians might avoid using neuromuscular blocking agents (eg, botulinum toxin) in patients with CMD unless the contractures are determined to cause significantly greater impairment than would any potential worsening of weakness in the targeted muscle groups.”

The researchers note that further research will discover novel CMD genes and reveal more information about the clinical courses of CMD as well as its complications and the effectiveness of future treatments. “Standardized outcome measures would promote more rigorous research that would help identify complications and optimize treatment in these patients,” they wrote.

Specifically, the researchers request additional research into gene discovery, genotype-phenotype studies, frequency and risk factors for CMD complications, and the efficacy of various CMD interventions.

The new guidelines have been endorsed by the American Academy of Pediatrics, the American Occupational Therapy Association, the Child Neurology Society, and the National Association of Neonatal Nurses.

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