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AAN and AANEM Issue Evidence-Based Review of Research on Congenital Muscular Dystrophy

ARTICLE IN BRIEF

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CONGENITAL MUSCULAR DYSTROPHY in a three-year-old, showing flexed and abducted hips that are externally rotated with moderate knee-flexion contractures.

In a new evidence-based review of research on congenital muscular dystrophy, the AAN Guideline Development Subcommittee and the American Association of Neuromuscular & Electrodiagnostic Medicine's Practice Issues Review Panel recommend that an interdisciplinary team work together to diagnose and manage care of children with congenital muscular dystrophy. Team members should include neuromuscular specialists, particularly child neurologists and physiatrists with subspecialty training, together with dieticians, genetic counselors, nurses, nurse practitioners, occupational therapists, physical therapists, and speech-language pathologists.

The American Academy of Neurology has released a comprehensive new guideline recommending a multidisciplinary team approach in evaluating, diagnosing, and managing congenital muscular dystrophy (CMD).

The American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) Practice Issues Review Panel and the AAN Guideline Development Subcommittee jointly developed the evidence-based guideline. The recommendations, published in the March 31 edition of Neurology, reflect the best evidence in the medical literature as defined by the AAN classification of evidence system, which rates studies as Class I, II, III, or IV based on methodology and trial type, among other factors.

Leslie Morrison, MD, a professor of neurology and pediatrics at the University of New Mexico Health Science Center in Albuquerque, discussed the findings and the supporting evidence in a telephone interview with Neurology Today.

COULD YOU SUMMARIZE THE RECOMMENDATIONS?

Due to the range of symptoms associated with CMDs, we found that it takes experienced multidisciplinary teams to coordinate care for these patients. Even so, there is a paucity of good evidence available to rate the efficacy of various treatment interventions.

There are a number of CMD subtypes, some of which appear to occur in certain specific geographic locations and/or involve children from different ethnic backgrounds. Although children anywhere can be born with the disease, certain mutations have been linked to clusters in Japanese, Korean, and Ashkenazi Jewish populations, as well as in Turkish infants. We believe that other founder mutations are likely to exist. This is especially true in Japan, where one particular form of CMD is prevalent and severe.

There are also specific patterns of muscle weakness and problems with mobility once children become toddlers. Blood testing is helpful in detecting increased levels of creatine kinase (CK) in some but not all children with CMD.

WHAT CLINICAL FEATURES ARE USED FOR DIAGNOSIS?

In general, we found that progressive skeletal muscle weakness and hypotonia are the cardinal primary early manifestations.

One Class II study and one Class III study demonstrated that distal joint hyperlaxity, congenital hypotonia, and joint contractures may be characteristic of collagenopathy, a rare inherited disorder of connective tissue in the spine and skeleton.

Also, serum CK levels are typically but not always elevated.

There is also evidence that confirms congenital weakness in infants with CMDs, as well as elevated serum CK levels and abnormal white matter signaling on magnetic resonance imaging (MRI), which may help predict severe weakness of the trunk and limbs and hypotonia at birth. One Class II study showed that congenital weakness, elevated serum CK levels, and white matter signal abnormalities on brain MRI predict the merosinopathy subtype.

Classic patterns of muscle weakness, structural eye abnormalities, and cortical brain abnormalities can predict mutations in known genes for patients with dystroglycanopathies — muscular dystrophies that are associated with aberrant glycosylation of alpha-dystroglycan. This is supported by several Class III studies.

HOW IS A CLINICAL DIAGNOSIS MADE?

Some children exhibit symptoms at birth while others may not have them until later. Infants with CMD tend to be very sick. With the youngest, there may be eye components and abnormal brain activity, including seizures, for which MRI is very useful, as well as cardiac symptoms. But because many children are asymptomatic until they are older, cardiac symptoms can be difficult to assess because these kids do not usually complain about chest pain or rhythm problems.

WHAT COMPLICATIONS CAN OCCUR?

A broad range of complications involving multiple organ systems have been reported in the literature, but these often have delayed onset. They can include cardiac and respiratory symptoms, swallowing difficulties, and muscle problems, as well as effects on the central nervous system, scoliosis, and a breakdown of skin tissue. This is one reason why such children should be referred to multidisciplinary specialty clinics.

One Class II article found that 58 percent of patients with CMD had cognitive impairment, while a Class III paper reported a high incidence of seizures in Japanese children with Fukuyama CMD. One Class II study reported respiratory complications in 12 percent of patients, which is why supplementary oxygen may be required.

ARE THERE EFFECTIVE TREATMENTS FOR COMPLICATIONS OF CMD?

Physical therapy can help, and nutrition is very important. One Class III study of spinal fusion found that correction and prevention of progression of scoliosis and pelvic obliquity over two years resulted in improved or stable balance and sitting posture. Aside from supplementary oxygen, if needed, the impact of specific treatments on respiratory status and other complications requires further research.

IS GENETIC TESTING USEFUL IN CONFIRMING A DIAGNOSIS?

The genetic origins of many cases of CMD have been discovered, and genetic testing is available for virtually all known genes, so targeted genetic testing can be valuable. However, many affected individuals remain without a genetic diagnosis, which indicates that other genes and genetic mutations have yet to be identified. While founder mutations — the original genetic variant — are established in a handful of geographic and ethnic groups, these mutations are no longer confined to any specific region, so it is important that physicians with children manifesting the characteristic signs of CMDs ask parents about their origins.

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DR. LESLIE MORRISON: “Perhaps the most important need is to identify unknown congenital muscular dystrophy genes. There are also significant gaps in knowledge about the clinical courses of, complications associated with, and optimal treatment regimens for various CMD subtypes. Establishing standardized outcome measures would promote more rigorous research that could help identify complications and optimize treatment.”

One significant aim of our guideline is to encourage more genetic testing to better identify such children as early as possible. Accurate diagnosis is critical, and genetic information helps.

WHAT ABOUT BRAIN IMAGING?

Some studies have reported that abnormal findings on brain imaging can predict subtype-specific diagnosis in some cases, especially in merosinopathy (white matter abnormalities) and some dystroglycanopathies (polymicrogyria, white matter lesions, pontine hypoplasia, and subcortical cerebellar cysts). This is supported by two Class II studies and one Class III study.

IS MUSCLE IMAGING USEFUL?

Several studies have provided evidence that skeletal muscle imaging using MRI, ultrasound, and computed tomography (CT) often demonstrates signal abnormalities indicating subtype-specific diagnoses. This has been most extensively documented in CMD subtypes associated with rigidity of the spine, such as collagenopathies and SEPN1-related myopathy.

Three Class II and three Class III articles demonstrate that immunohistochemistry can identify the presence of a merosinopathy (LAMA2) or dystroglycanopathy, but there is insufficient evidence to determine the capability of muscle biopsies to identify collagenopathies.

WHAT ABOUT MUSCLE BIOPSIES AND MUSCLE IMAGING?

CMDs share characteristic muscle biopsy findings with other muscular dystrophies, including necrosis, regenerating fibers, fiber size variability, and increased perimysial and endomysial connective tissue. MRI appears to be the best option for muscle evaluation, especially characteristic patterns of muscle deficits in younger children.

Several articles demonstrated that immunohistochemistry can identify merosinopathy or dystroglycanopathy. However, the evidence is insufficient to determine whether or not muscle biopsies can identify collagenopathies.

WHAT ABOUT CARDIAC COMPLICATIONS?

One Class III study found an overall rate of 6 percent, while three Class III studies reported that 8 percent to 30 percent of patients with merosin-positive congenital muscular dystrophy had depressed cardiac function. We recommend that all children with CMD have a baseline cardiac evaluation in order to assess possible future cardiologic complications.

WHAT PRACTICE RECOMMENDATIONS DID THE PANEL MAKE?

First, children with CMD may develop various combinations of cardiovascular, gastrointestinal/nutritional, neurologic, ophthalmologic, orthopedic, and pulmonary problems, so again, multidisciplinary teams are recommended.

Key members of such teams include neuromuscular specialists, particularly child neurologists and physiatrists with subspecialty training, together with other health professionals such as dieticians, genetic counselors, nurses, nurse practitioners, occupational therapists, physical therapists, and speech-language pathologists. It is important that physicians caring for children with CMD consult a pediatric neuromuscular specialist for diagnosis and management. Pediatric neuromuscular specialists should coordinate the multidisciplinary care when such resources are available to interested families.

Interpretation of muscle biopsy findings, especially in children, is heavily dependent on technique and the experience of the pathologist or neuromuscular specialist who interprets them. Proper interpretation requires knowledge of the clinical context as well advanced testing capabilities.

WHAT SHOULD BE THE FOCUS OF FUTURE RESEARCH?

Perhaps the most important need is to identify unknown congenital muscular dystrophy genes. There are also significant gaps in knowledge about the clinical courses of, complications associated with, and optimal treatment regimens for various CMD subtypes. Establishing standardized outcome measures would promote more rigorous research that could help identify complications and optimize treatment.

Genotype–phenotype studies are needed, especially longitudinal studies, as is research on the frequency and risk factors for various complications in CMDs and the merits of various therapeutic interventions.

LINK UP FOR MORE INFORMATION:

•. Kang PB, Morrison L, Iannaccone ST, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine http://www.neurology.org/content/84/13/1369.abstract. Neurology 2015;84: 1369–1378.