Clinical Approach to the Diagnosis of Congenital Myopathies
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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What's new in congenital myopathies?
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Cited by (33)
The translational value of animal models in orphan medicines designations for rare paediatric neurological diseases
2020, Regulatory Toxicology and PharmacologyCitation Excerpt :Suggestive clinical features common to all congenital myopathies are generalized muscle weakness ranging from mild to profound, hypotonia, hyporeflexia, poor muscle-mass, and dysmorphic features secondary to the myopathy and ophtalmoparesis. Some characteristics vary between genetic subtypes and severity varies between and within subtypes (North, 2011). There are many available rodent and non-rodent models of CNM in which disease-relevant endpoints can be measured (Table 2), namely abnormal organelle positioning, muscle atrophy and reduction in muscle strength.
A novel de novo ACTA1 variant in a patient with nemaline myopathy and mitochondrial Complex I deficiency
2020, Neuromuscular DisordersMyopathology of Congenital Myopathies: Bridging the Old and the New
2019, Seminars in Pediatric NeurologyCitation Excerpt :Specific tests including repetitive nerve stimulation and single fiber electromyography can be important in excluding congenital myasthenic syndromes (CMS), although, secondary abnormalities of the neuromuscular junction are now recognized in some CMs.17 In neonates and infants, there can be a significant clinical overlap with other neuromuscular disorders, and the differential diagnosis is wide, including the congenital muscular dystrophies (CMD), CMS, metabolic/mitochondrial myopathies, spinal muscular atrophy, and Prader-Willi syndrome, all of whom can have a “floppy infant” presentation.6 Cumulative evidence from studies in cell lines, patient tissues, and mutant animal models suggest shared pathomechanisms in CMs with areas of distinction within single gene disorders.
Signs and Symptoms in Congenital Myopathies
2019, Seminars in Pediatric NeurologyCitation Excerpt :Patients usually develop early axial weakness with progressive scoliosis around the age of 7 to 8years. Although quite restricted in axial movement, these patients are able to walk independently when they develop respiratory insufficiency.25,41 The differential diagnosis includes CMD (COL6-related myopathy and LMNA-related myopathies), dystrophies (CAPN3 and EMD), Pompe disease, and other myopathies with mutations in MYH7 and FHL1.42-45
Neonatal hypotonia and neuromuscular conditions
2019, Handbook of Clinical NeurologyCitation Excerpt :CK is generally normal or only mildly elevated. The diagnosis is based on muscle biopsy, showing the typical centronuclear features, or directly on genetic testing (North, 2011). Although centronuclear myopathy has been associated with mutations in five genes, the X-linked form of the disease is commonly associated with mutations in the myotubularin gene (MTM1) (Maggi et al., 2013).
Muscle and neuromuscular junction diseases
2015, Medicine (Spain)