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An Overview of Congenital Myopathies Review Article Copyright © American Academy of Neurology Review Article 04/25/2018 on mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== by https://journals.lww.com/continuum from Downloaded Downloaded from Address correspondence to https://journals.lww.com/continuum Dr Jean K. Mah, Alberta Children’s Hospital, Division of An Overview of Pediatric Neurology, 2888 Shaganappi Trail NW, Calgary, AB T3B 6A8, Canada, Congenital Myopathies jean.mah@ albertahealthservices.ca. by Jean K. Mah, MD, MSc, FRCPC; Jeffrey T. Joseph, MD, PhD mAXWo3ZnzwrcFjDdvMDuzVysskaX4mZb8eYMgWVSPGPJOZ9l+mqFwgfuplwVY+jMyQlPQmIFeWtrhxj7jpeO+505hdQh14PDzV4LwkY42MCrzQCKIlw0d1O4YvrWMUvvHuYO4RRbviuuWR5DqyTbTk/icsrdbT0HfRYk7+ZAGvALtKGnuDXDohHaxFFu/7KNo26hIfzU/+BCy16w7w1bDw== Relationship Disclosure: Dr Mah has received personal compensation as a consultant for aTyr Pharma and PTC ABSTRACT Therapeutics and has received Purpose of Review: This article uses a case-based approach to highlight the clinical research/grant support as study and site investigator for Alberta features as well as recent advances in molecular genetics, muscle imaging, and patho- Children’s Hospital, Bristol-Myers physiology of the congenital myopathies. Squibb, Children’s Hospital of Recent Findings: Congenital myopathies refer to a heterogeneous group of genetic Eastern Ontario, Cooperative International Neuromuscular neuromuscular disorders characterized by early-onset muscle weakness, hypotonia, and Research Group, Eli Lilly and developmental delay. Congenital myopathies are further classified into core myopathies, Company, FSHD Global centronuclear myopathies, nemaline myopathies, and congenital fiber-type dispropor- Research Foundation, FSH Society, the Hospital for Sick tion based on the key pathologic features found in muscle biopsies. Genotype and Children, Muscular Dystrophy phenotype correlations are hampered by the diverse clinical variability of the genes Canada, Novartis AG, Pfizer responsible for congenital myopathies, ranging from a severe neonatal course with early Inc, PTC Therapeutics, and Sanofi Genzyme. Dr Joseph death to mildly affected adults with late-onset disease. An increasing number of genes has received research/grant have been identified, which, in turn, are associated with overlapping morphologic support from the Endowed changes in the myofibers. Precise genetic diagnosis has important implications for Chair of the University of Calgary to create the brain disease management, including family counseling; avoidance of anesthetic-related tissue bank and receives muscle injury for at-risk individuals; monitoring for potential cardiac, respiratory, or publishing royalties from orthopedic complications; as well as for participation in clinical trials or potential UpToDate, Inc and Wolters Kluwer. Dr Joseph also gave genetic therapies. expert testimony for Alberta Summary: Collaboration with neuromuscular experts, geneticists, neuroradiologists, neu- Justice, for which he did not ropathologists, and other specialists is needed to ensure accurate and timely diagnosis receive compensation. Unlabeled Use of based on clinical and pathologic features. An integrated multidisciplinary model of care Products/Investigational based on expert-guided standards will improve quality of care and optimize outcomes for Use Disclosure: patients and families with congenital myopathies. Drs Mah and Joseph report no disclosures. * 2016 American Academy Continuum (Minneap Minn) 2016;22(6):1932–1953. of Neurology. 2,3 INTRODUCTION tein aggregation. The three major Congenital myopathies refer to a geneti- groups of congenital myopathies include: cally and clinically heterogeneous group (1) core myopathies, which have foci devoid of oxidative enzymes in myo- of inherited skeletal muscle diseases fibers4; (2) centronuclear or myo- associated with early infantile or child- tubular myopathies, which are defined hood onset of motor weakness, hypoto- by the presence of internally located nia, and developmental delay, which have 5 1 myonuclei ;and(3)nemalinemyopa- a static or slowly progressive course. thies, which are marked by the presence Variants of congenital myopathies with of electron-dense nemaline bodies or onset or progression of muscle weakness rods within myofibers.6 Variants of in adulthood have also been described. nemaline myopathy include cap myopa- Pathologically, congenital myopathies thy, zebra body myopathy, and core-rod on have characteristic but not pathogno- 04/25/2018 myopathy. Other pathologic features of monic morphologic features such as the congenital myopathies include hyaline presence of focal myofibrillar disorgani- body or myosin storage myopathy, neck- zation, nuclear centralization, and pro- lace fibers, radial sarcoplasmic strands, 1932 www.ContinuumJournal.com December 2016 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS and congenital fiber-type disproportion. States, as reported by Amburgey and h 14 Congenital myopathies The latter is defined by the presence colleagues. In another study, the carrier are characterized by of type 1 fiber hypotrophy with mean frequency of RYR1 mutation was esti- early-onset muscle diameter being uniformly smaller than matedtobe1in2000individualsinthe weakness, hypotonia, and 15 type 2 fibers by more than 35% to 40%, Japanese population. developmental delay, in the absence of other structural ab- Clinically, the diagnosis of congenital which have a static or normalities and accompanied by clinical myopathies remains challenging be- slowly progressive course. features consistent with congenital my- cause of the variable phenotypes. Sig- h The three major types of opathies.7 Each of the pathologic fea- nificant heterogeneity exists even within congenital myopathies tures can be attributed to a number of family members affected by the same are core myopathies, genetic mutations; furthermore, the genetic mutation. In one large case centronuclear or biopsy findings can be nonspecific or series of congenital myopathies, approx- myotubular myopathies, 1 evolve over time. imately one-third of patients remained and nemaline myopathies. To date, more than 20 genes have genetically unresolved.12 The lack of h The pathologic features been associated with the congenital molecular confirmation was in part in congenital myopathies myopathies (refer to Table 9-1 as well related to the nonspecific clinical fea- can be attributed to a tures (especially during the neonatal as to the useful websites section at the number of genetic period), the genetic heterogeneity of end of this article), and additional genes mutations; furthermore, are being updated based on advances congenital myopathies, as well as the the muscle biopsy findings 8 in molecular diagnostics. Emerging evi- large size of some involved genes, can be nonspecific or 14 dence suggests shared pathophysiolo- especially TTN and NEB. Recently, a change over time. A gic pathways among the congenital targeted exome sequencing strategy in repeat muscle biopsy with myopathies, including defects in muscle combination with muscle histology muscle imaging guidance is membrane remodeling, impaired has been proposed to identify disease- sometimes necessary. causing mutations in myopathies of excitation-contraction coupling, mito- h More than 20 genes have chondrial dysfunction, abnormal myofi- unknown causes. The sequencing in- been associated with brillar force generation, and imbalance cludes coverage of each exon of known congenital myopathies. 2 genes implicated in congenital myopa- related to protein synthesis or degradation. h thies to enable more precise genetic Atargetedexome EPIDEMIOLOGY diagnosis.9 sequencing strategy in Congenital myopathies are rare disor- combination with the ders; the overall prevalence is estimated DIAGNOSTIC APPROACH clinical features and muscle histology can at 1 in 25,000 individuals.9 Previous point The history and neurologic examination help identify prevalence of congenital myopathies are important first steps in the diagnostic disease-causing mutations approach. Careful review of the preg- ranged from 1.37 per 100,000 of all age in unspecified cases. groups in northern England10 to 5 per nancy, birth, growth and development, 100,000 of the pediatric population in family history, and direct examination of western Sweden.11 The true prevalence the parents is essential to exclude other is likely to be higher because of inherited neuromuscular disorders. In underrecognition of mildly affected in- addition to muscle weakness and hypo- dividualsaswellasasubstantialpropor- tonia, clues to the diagnosis of congeni- tion of cases with nonspecific histologic tal myopathies include the early onset of findings. Core myopathies including symptoms, static or slow rate of disease central core and multiminicore myopa- progression, the presence of myopathic thy are the most common histopatho- facies, ophthalmoplegia, or bulbar in- logic subtypes of congenital myopathies.12 volvement, as well as associated signs Mutations of the ryanodine receptor 1 such as muscle atrophy, hyporeflexia, (RYR1) gene are most often implicated spinal deformity, clubfoot, or other as the cause of congenital myopathies,13 orthopedic complications. Systemic in- with a point prevalence of 1 in 90,000 volvement may manifest as cardiomy- of the pediatric population in the United opathy, malignant hyperthermia, or Continuum (Minneap
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