Clinical Approach to the Diagnosis of Congenital Myopathies

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In this issue of Seminars in Pediatric Neurology, each chapter will focus on the features and management of individual congenital myopathies. This introductory chapter will provide an overview of the clinical features that alert the clinician to the likely diagnosis of a congenital myopathy, and specific features on history and examination that are characteristic of a specific genetic subtype. Most congenital myopathies share a common pattern of clinical features, which makes it difficult to predict the genetic cause in a patient by clinical assessment alone. Although no single feature is specific for the congenital myopathies, the presence of this common pattern highlights patients in whom a muscle biopsy is likely to provide important diagnostic information. The diagnosis of a specific congenital myopathy should only be made when the defining morphologic feature is the predominant pathologic change, other possible causes have been excluded, and the clinical course is nonprogressive or only slowly progressive.

Section snippets

Clinical Features of Congenital Myopathies

Clinically, the congenital myopathies have the following common features: generalized weakness, hypotonia, hyporeflexia, poor muscle bulk, and dysmorphic features secondary to the myopathy (eg, pectus carinatum, scoliosis, foot deformities, a high-arched palate, and elongated facies). Most congenital myopathies present at birth or in early infancy; however, it is now recognized that there can be a wide variation in clinical severity within each subtype, ranging from neonates with profound

Investigations

Creatine kinase levels are within normal limits or only mildly elevated (although it must be noted that creatine kinase levels can be nonspecifically elevated in the first week of life). Electromyography results are either normal or myopathic (although neuropathic changes can be observed with severe neonatal weakness or in distal muscles later in the disease course). Nerve conduction study results are normal.

Muscle imaging, particularly muscle magnetic resonance imaging (MRI), can be

Common Differential Diagnoses

There is marked clinical overlap between congenital myopathies and other neuromuscular disorders, including the muscular dystrophies, congenital myotonic dystrophy, metabolic myopathies such as Pompe disease, congenital myasthenic syndromes, spinal muscular atrophy, congenital hypomyelination neuropathy, and Prader–Willi syndrome, all of which can present in the newborn period with marked hypotonia. As noted earlier in the text, congenital myopathies are often a diagnosis of exclusion, and

Clinical Clues to the Diagnosis of Specific Subtypes of Congenital Myopathy

As outlined previously (Goebel, Introduction: Table 1), the congenital myopathies are genetically heterogeneous. For example, there are currently 7 known genetic loci for NM. In addition, mutations in the same gene can cause different muscle pathologies. Mutations in the ryanodine receptor 1 gene (RYR1) are classically associated with dominant central core disease, relatively mild late-onset weakness, and increased risk of malignant hyperthermia; however, recent studies have shown that

Conclusion

Accurate genetic diagnosis is essential in guiding management, for prediction of prognosis and recurrence risk, for prevention through prenatal and preimplantation diagnosis, for presymptomatic diagnosis, and, increasingly, for eligibility to participate in clinical trials of new therapeutic agents. Historically, the congenital myopathies have been categorized based on muscle biopsy findings, but the exponential growth in our understanding of the genetic basis for these disorders has revealed

Acknowledgments

During the past 2 years, the US-based Foundation for Building Strength has been instrumental in establishing an International Standard of Care Committee for Congenital Myopathies, coordinated by Dr Ching H. Wang, MD, PhD. Detailed guidelines to the diagnosis of congenital myopathies have been produced by this Committee and have been submitted for publication. The author would like to acknowledge the discussions and contributions of the following people who have contributed to these guidelines

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