eMedicine Specialties > Neurology > Pediatric Neurology

Congenital Myopathies

Author: Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
Contributor Information and Disclosures

Updated: May 26, 2009

Introduction

Background

The first report of a congenital myopathy was in 1956, when a patient with central core disease (CCD) was described. Since that time, other myopathies have been defined as congenital myopathies, which have the following characteristics:

  • Onset in early life with hypotonia, hyporeflexia, generalized weakness that is more often proximal than distal, and poor muscle bulk
  • Often with dysmorphic features that may be secondary to the weakness
  • Relatively nonprogressive
  • Hereditary
  • Unique morphological features on histochemical or ultrastructural examination of the muscle biopsy sample that originate within the myofiber

Hypotonia is the clinical hallmark of congenital myopathies. It presents in the neonatal period as head lag; lack of flexion of the hips, knees, and elbows; external rotation of the hips; diffuse weakness in facial, limb, and axial muscles; and reduced muscle mass.

The above features apparently do not apply to all cases of congenital myopathy. Some cases have been reported as adult onset or as a progressive course. Some of the morphological alterations are not disease specific but are seen in various congenital myopathies or in other myopathic or nonmyopathic conditions.

A recent review article1 divided the congenital myopathies based on genetic and morphological features into 4 main groups.

  • Myopathies with protein accumulation
    • Nemaline myopathy
    • Myosin storage myopathy
    • Cap disease
    • Reducing body myopathy
  • Myopathies with cores
    • Central core disease
    • Core-rod myopathy
    • Multiminicore disease
  • Myopathies with central nuclei
    • Myotubular myopathy
    • Centronuclear myopathy
  • Myopathies with fiber size variation
    • Congenital fiber type disproportion

With the advent of improved techniques such as electron microscopy, enzyme histochemistry, immunocytochemistry, and molecular genetics, the etiologies of many congenital myopathies are now well defined. This article focuses on the diseases with know mutations. The numerous rare congenital myopathies distinguished primarily based on a unique morphological feature on muscle biopsy are briefly discussed below (see Rare congenital myopathies).

Pathophysiology

In the common, well-described congenital myopathies, mutations have been identified in genes that encode for muscle proteins. The loss or dysfunction of these proteins presumably leads to the specific morphological feature on muscle biopsy samples and to the clinical muscle disease. The specific pathogenesis for each congenital myopathy is discussed below.

The same principle presumably leads to the morphological features determined by muscle biopsy in congenital myopathies whose genetic defects are not yet known.

Frequency

International

The true incidence of congenital myopathies is unknown. In a series of 250 infants with neonatal hypotonia described by Fardeau and Tome, muscle biopsy performed before age 2 months revealed that only 14% had a congenital myopathy. CNS disease is the most common cause of congenital hypotonia.

The same authors documented 180 cases of congenital myopathy over 20 years. The types were as follows:

  • Nemaline rod myopathy (20%)
  • Central core disease (16%)
  • Centronuclear myopathy (14%)
  • Multiminicore myopathy (10%)
  • Congenital fiber-type disproportion or type 1 fiber predominance (21%)
  • Six other miscellaneous congenital myopathies (19%)

Mortality/Morbidity

Associated morbidity and mortality rates have considerable variability.

  • Some patients die within the neonatal period, while others can have a normal life span.
  • Cardiopulmonary compromise is the most common cause of death.
  • Other complications include skeletal deformities and malignant hyperthermia.

Sex

  • Both sexes are affected equally in most congenital myopathies since inheritance is usually autosomal recessive or autosomal dominant.
  • In X-linked forms, boys are affected almost exclusively, although occasional female carriers with clinical manifestations have been described.

Age

Congenital myopathies usually present in the neonatal period but can also present later in life (even into adulthood).

Clinical

History

The following are congenital myopathies with known genetic mutations: History and Physical are discussed in this section.

  • Central core disease due to a mutation in the ryanodine receptor
    • Typical presentation
      • Central core disease has autosomal dominant inheritance.
      • Onset is at birth or in early childhood with nonprogressive limb weakness, mild facial weakness, and hypotonia.
      • A history of decreased fetal movement or breech presentation is typical.
      • Skeletal abnormalities are common, including congenital hip dislocation, kyphoscoliosis, and foot deformities.
    • Other presentations
      • Autosomal recessive (and autosomal dominant) inheritance have been described with several different presentations.
      • Presentation in infancy includes generalized weakness and atrophy, external ophthalmoplegia, and bulbar and respiratory weakness. This syndrome has features that overlap with multiminicore disease.
      • Adolescent presentation occurs as a slowly progressive limb-girdle syndrome.
      • A severe variant has onset in utero with fetal akinesia and arthrogryposis. In the neonatal period, severe hypotonia and respiratory distress are noted. 
    • Asymptomatic individuals may also present with a high creatine kinase (CK) level or malignant hyperthermia (see Complications).
    • About 25% of patients with CCD are susceptible to malignant hyperthermia.
  • Nemaline (rod) myopathy can be caused by mutations in at least 6 different genes. General features to all nemaline myopathies include minimally progressive or nonprogressive proximal limb, bulbar, and facial weakness; hypotonia; and respiratory insufficiency, which is the most common cause of death. Skeletal deformities range from arthrogryposis in the severe congenital form to limb contractures, kyphoscoliosis, pectus excavatum, and rigid spine. Cardiomyopathy is rare but can be present early with congenital presentation, or it can be a late complication in childhood- or adult-onset cases. CNS disease is rare, but seizures have been reported in severe cases in the neonatal period.    
    • Nemaline myopathy 1 (NEM1) is due to a mutation in the gene for α-tropomyosin 3. This is likely a rare cause (<3%) of nemaline myopathy.2
      • Autosomal dominant inheritance is usually due to a missense mutation and causes a moderate phenotype with onset between birth and 15 years. Weakness is diffuse and symmetric with slow progression often with need for a wheelchair in adulthood. Respiratory failure is common. Other features include kyphoscoliosis and a thin body habitus. 
      • Autosomal recessive inheritance is usually due to a nonsense mutation causing a stop codon. Onset is at birth with moderate-to-severe hypotonia and diffuse weakness. In the most severe cases, death can occur before 2 years. Less severe cases have delayed major motor milestones, and these patients may walk, but often need a wheelchair before 10 years.
    • Nemaline myopathy 2 (NEM2) is due to a mutation in the gene for nebulin and is a common cause of nemaline myopathy. Inheritance in all cases has been autosomal recessive. Phenotypes are quite variable,3 with all but the adult-onset form being described in a large series encompassing 55 families.4     
      • The severe congenital form presents at birth with severe hypotonia and weakness. Lack of movement, poor suck and swallow, and respiratory failure are frequent findings. Death in utero due to fetal akinesia has been described. Arthrogryposis and severe respiratory failure are associated with early death that usually occurs within the first 2 years of life.
      • The intermediate congenital form presents with weakness in early childhood and is characterized by delayed motor milestones and contractures. Children with this form usually need a wheelchair or ventilatory support by age 10 years.
      • The typical (most common) congenital form presents within the first year of life with hypotonia, generalized limb weakness, facial weakness, feeding difficulty, and mild respiratory weakness. Features such as elongated face, tent-shaped mouth, high-arched palate, and retrognathia are common. Progression is static or very slow, and, after an initial rocky course, stabilization leads to an independent life.
      • The childhood-onset form presents with distal leg weakness in the late first or early second decade. Proximal muscles are involved later, and wheelchair dependency occurs in midlife.
      • The adult-onset form presents with symmetric proximal weakness in persons aged 20-50 years. Other features may include neck extensor weakness, respiratory insufficiency, or rapid progression.
      • Other forms include patients who do not fit any of the above presentations and can have cardiomyopathy, ophthalmoplegia, or an unusual distribution of weakness.  
    • Nemaline myopathy 3 (NEM3) is due to autosomal dominant, autosomal recessive, or sporadic de novo mutations in alpha-actin (ACTA1). It is a relatively common cause of nemaline myopathy. 
      • Presentation can be with any of the above forms. Autosomal dominant cases are usually mild, and recessive cases are usually severe. In a large series of 109 patients with nemaline myopathy 26% had a mutation in ACTA1.5 More than 50% of patients had the severe congential form of nemaline myopathy, although rare adult-onset cases have been described. 
      • Mutations in ACTA1 can also cause actin myopathy with excess thin filaments. Presentation is of the severe or intermediate congenital forms.
      • Mutations in ACTA1 can also cause nemaline myopathy with intranuclear rods.6 Cases are most often sporadic but can be autosomal dominant. Presentation is likely similar to the typical nemaline myopathy, with 43% of cases having a severe congenital form, although adult-onset cases have been described.          
    • Nemaline myopathy 4 (NEM4) is due to an autosomal dominant mutation in the gene for β-tropomyosin (Tropomyosin 2). It is a rare cause of nemaline myopathy.
      • Presentation is from infancy to childhood with hypotonia and moderate-to-severe proximal weakness with minimal or no progression. Major motor milestones are delayed but independent ambulation is usually achieved, although a wheelchair may be needed in later life. 
      • Other problems can include feeding difficulties as an infant, facial weakness, long narrow face, high arched palate, kyphoscoliosis, and respiratory failure.     
      • A mutation in β-tropomyosin has also been described in cap myopathy.7 This disease has only been described in 5 sporadic cases and in one family with dominant inheritance. Presentation is either congenital or childhood onset of hypotonia with facial and slowly progressive proximal weakness. Respiratory failure may result in death in teenaged years. Other features include a long narrow face and scoliosis. About 50% of muscle fibers showed a crescent-shaped peripheral cap that was granular in appearance on the modified GT stain and reacted strongly to NADH, phosphorylase, and periodic acid-Schiff, but not to myosin ATPase. On electron microscopy (EM), the caps were filled with abnormally arranged myofibrils, which lacked thick filaments.
    • Nemaline myopathy 5 (NEM5) is due to an autosomal recessive mutation in the gene for troponin T1 and has been described only in the Old Order Amish.8
      • Onset is in the first few months of life with hypotonia, proximal weakness, and jaw and limb tremors that resolve over a few months. Death occurs before age 2 years due to respiratory failure.   
      • Other features include shoulder and hip contractures and pectus carinatum.
    • Nemaline myopathy 7 (NEM7) is due to an autosomal recessive mutation in the gene for cofilin-2 and has been described in only one family.9  
      • Presentation is at birth with hypotonia and generalized weakness. 
      • Major motor milestones are delayed, but independent ambulation is achieved.      
  • Centronuclear/myotubular myopathy: Three different presentations (ie, severe X-linked form, autosomal recessive form, autosomal dominant form) have been described.
    • The most common is the severe X-linked form due to a mutation in myotubularin.
      • Affected males often present in utero with decreased fetal movements and polyhydramnios.
      • At birth, severe weakness and hypotonia, feeding difficulty, and respiratory distress are present.
      • Bilateral ptosis, facial weakness, and ophthalmoplegia are common.
      • Skeletal features include pectus carinatum, micrognathia, knee and hip contractures, elongated birth length, narrow face, slender/long digits, and macrocephaly.
      • Systemic features may include cryptorchidism, pyloric stenosis, gallstones, hepatic dysfunction, spherocytosis, renal calcinosis, and bleeding diathesis.
      • The prognosis is poor, with at least one third of those affected dying in the first year of life. Seventy-five percent of survivors older than 1 year need ventilatory support; however, these survivors have nonprogressive weakness and can live into adulthood.
      • Most carriers are asymptomatic, but mild facial and limb weakness may be present. Progression may result in gait difficulty and kyphoscoliosis. Skewed X-inactivation may result in a carrier who presents severely with infant-onset weakness, feeding difficulty, and skeletal deformities.
      • Mutations in amphiphysin 2 (bridging integrator 1; BIN1) cause centronuclear myopathy with autosomal recessive inheritance.10  
      • Onset is usually at birth, but one patient presented at 8 years of age. Reduced fetal movements and oligohydramnios may be present.
      • Features include hypotonia, proximal weakness, facial weakness, ptosis, and ophthalmoplegia.
      • Other features can include contractures and dilated cardiomyopathy. 
      • The course is slowly progressive, with more than 50% of patients surviving childhood.  
    • Mutations in dynamin 2 (DNM2) cause centronuclear myopathy with autosomal dominant inheritance.11,12   
      • Most patients have a mild phenotype with onset in adolescence or adulthood with axial as well as distal more than proximal limb weakness and slow progression. Other features can include facial weakness, ptosis, and contractures.  
      • However, a more severe phenotype has also been described with hypotonia at birth and poor suck. Facial weakness, high-arched palate, ptosis, ophthalmoplegia, joint hyperlaxity, and contractures are common. Weakness is distal more than proximal, resulting in delayed major motor milestones, but ambulation is usually obtained.    
  • Multiminicore disease
    • The classic and most common phenotype presents with spinal rigidity, axial weakness, scoliosis, and early respiratory impairment. It is most often due to a mutation in the gene for selenoprotein N.
      • Mutations in selenoprotein N cause 4 overlapping phenotypes: multiminicore disease, congenital muscular dystrophy with rigid spine, congenital fiber-type disproportion (CFTD), and desmin-related myopathy with Mallory body–like inclusions. Eleven patients from eight families with a mutation in selenoprotein N were described13 and have the classic phenotype.
      • Onset occurs in infancy or early childhood and is characterized by proximal and axial weakness and hypotonia that is either nonprogressive or only minimally progressive. Body mass index is often very low. 
      • Antenatal polyhydramnios and decreased fetal movements may be noted.
      • Facial and bulbar weakness are common.
      • Progressive respiratory insufficiency often occurs out of proportion to muscle weakness and need for ventilatory support may occur in ambulant individuals. 
      • Skeletal deformities can include joint contractures, torticollis, chest deformities, rigid spine, and scoliosis.
      • Malignant hyperthermia has not been clearly associated.
      • Intelligence is normal. 
    • A second phenotype that is similar to the classic phenotype with the added finding of ophthalmoplegia is most often due to a mutation in the gene for the ryanodine receptor.
    • A third mild phenotype with pelvic girdle weakness is also due to a mutation in the ryanodine receptor. Other features include minimal or mild respiratory involvement, but without respiratory failure as well as joint laxity, hip dislocation, and arthrogryposis.
    • Lastly, a fourth phenotype presents antenatally with arthrogryposis. Other findings include head, face, trunk, and limb dysmorphic features; proximal muscle weakness; and respiratory insufficiency. Scoliosis or kyphoscoliosis is severe.     
  • Congenital fiber-type disproportion (CFTD): This term was initially coined to describe a group of infants with small type 1 muscle fibers and the clinical syndrome of hypotonia and diffuse weakness that may improve with age. Other clinical features can include facial, bulbar, and respiratory weakness; short stature; low body weight; multiple joint contractures; scoliosis; long, thin face; and high-arched palate. Ophthalmoplegia, cardiac disease, and mental retardation are rare. Mutations in 3 genes can cause CFTD. 
    • Mutations in TPM3 may account for up to 25% of cases.14
      • Onset is usually before 1 year of age but may be in young adulthood.
      • Hypotonia and delayed major motor milestones are early features, but independent ambulation is always achieved. Weakness of axial, proximal limb, facial, and ankle dorsiflexor muscles is common, as is ptosis, scapular winging, and a thin body habitus. Nearly all patients have respiratory insufficiency with nocturnal noninvasive ventilation needed in 50% of patients between ages 3 and 55 years.    
    • Mutations in the gene for selenoprotein N account for fewer than 10% of cases.15
      • Presentation is before 1 year of age with hypotonia and poor head control.
      • Neck and axial muscle weakness is common, leading to scoliosis that may require spinal fusion surgery. A wheelchair may be needed in adulthood. Osteoporosis and fractures are common. Respiratory insufficiency usually results in the need for nocturnal ventilation in the 20s.   
    • Mutations in the gene for ACAT1 account for fewer than 10% of cases.16
      • Presentation is at birth with severe weakness most prominent in proximal, truncal, facial, and respiratory muscles. 
      • Severe feeding difficulties are present, and invasive ventilation is often needed. Most patients die due to progressive respiratory failure before 4 years of age.     
    • Note that there are many other causes of type 1 fiber hypotrophy including other congenital myopathies (nemaline rod myopathy, centronuclear/myotubular myopathy, multiminicore myopathy), muscular dystrophies (eg, Emery-Dreifuss muscular dystrophy, LGMD2A, congenital muscular dystrophy with spine rigidity due to mutations in selenoprotein N), polymyositis, perinatal asphyxia, leukodystrophies, spinal muscular atrophy, arthrogryposis, and Pompe disease.
  • Myosin storage myopathy (hyaline body myopathy)
    • Onset usually is in infancy or childhood but with variable penetrance; some patients present in adult life or may even be asymptomatic in their 40s.17  
    • Weakness can be proximal, proximal and distal, or scapuloperoneal in distribution. Progression is minimal or very slow (rare cases may have more rapid progression).  
    • Occasional cardiac arrhythmias may be present. 
    • The disease is allelic with Laing early adult-onset distal myopathy type 3, and patients with myosin storage myopathy may have overlapping features of finger, toe, and ankle extensor weakness.   
  • Sarcotubular myopathy
    • Inheritance is autosomal recessive. Onset is in childhood in most but in mid-adult life in some, with mild-to-moderate proximal weakness and mild facial weakness. Other features include muscle atrophy, contractures, exercise-induced myalgias, and scapular winging. This disease is allelic with LGMD 2H, which has a variable clinical phenotype, making it likely that these two diseases are the same disorder.18   
  • Reducing body myopathy has been described with two phenotypes, but both are due to mutations in Four and a half LIM domain 1 (FHL1).
    • Adult-onset cases present with scapuloperoneal weakness as well as axial weakness and atrophy, resulting in spinal rigidity or bent spine syndrome. Early in life, many patients were athletic with muscle hypertrophy. Ankle contractures were common, and several patients died from cardiomyopathy.19  
    • Childhood-onset cases included boys presenting before age 10 years with weakness. In one patient, ambulation was lost as a teenager, and another patient became ventilator dependent and developed a cardiomyopathy in the second decade. Two girls presented with severe weakness before age 4 years, with rapid progression leading to respiratory failure and death before age 10 years.20  
  • Spheroid body myopathy due to a mutation in the myotilin gene has been found in one large kindred.21 Mutations in myotilin also cause LGMD type 1A and a myofibrillar myopathy. 
    • Presentation varied from childhood to the eighth decade, most often with proximal weakness that slowly progressed as well as dysarthric speech. 
    • Swallowing difficulties, loss of ambulation, and respiratory support occurred in a few individuals.  
  • Rare congenital myopathies: In the most recent edition of the textbook Myology (2004), the remaining congenital myopathies are divided into "probable," meaning several familial cases have been reported, and "possible or doubtful," meaning fewer than 10 cases have been reported.
    • Probable congenital myopathies
      • Fingerprint body myopathy: Patients present with hypotonia from infancy, proximal muscle weakness, and a delay in attaining motor milestones. Weakness progresses slowly or is nonprogressive. Additional features can include pectus excavatum and mental retardation. Inheritance is likely autosomal recessive or sporadic. Small inclusions can be seen on H&E section in a subsarcolemmal distribution. On electron microscopy (EM), the fingerprint inclusions consist of non–membrane-bound perinuclear collections of convoluted lamellae, most often in type 1 muscle fibers.
      • Cylindrical spirals myopathy: Onset occurs in late childhood to adulthood. Phenotypes are variable, and manifestations can include weakness (at times facioscapular), abnormal gait, scoliosis, myotonia, cramps, and scoliosis. Inheritance is autosomal dominant or sporadic. Light microscopy shows subsarcolemmal or intermyofibrillar clusters that stain blue on H&E, red-purple on modified GT stain, and negatively for myosin ATPase and SDH, most often in type 2 fibers. EM reveals the cylindrical spirals to appear as concentrically wrapped lamellae merging into tubular structures that resemble tubular aggregates.
      • Myopathy with tubular aggregates: These myopathies fall into the following 4 groups: (1) Childhood or adulthood onset of exercise-induced cramps, pain, and stiffness is the most common phenotype. Males are most commonly affected. Inheritance is sporadic, autosomal dominant, or autosomal recessive. (2) The onset occurs during childhood or adulthood and is a slowly progressive proximal weakness that may be accompanied by myalgias, cramps, or stiffness. Inheritance is sporadic, autosomal dominant, or autosomal recessive. (3) The onset occurs during infancy or childhood and includes myasthenic features of limb weakness and fatigability. Inheritance is autosomal recessive. (4) The onset occurs during late childhood and includes gyrate atrophy of the choroids and retina, resulting in progressive blindness. Inheritance is autosomal recessive and due to a deficiency in ornithine aminotransferase.
      • Tubular aggregate pathology includes the following: Tubular aggregates are collections of 50- to 80-nm tubules that originate in the SR. They are best visualized on NADH, where they stain a dark blue (see Media file 4). They stain negatively with myosin ATPase and SDH. Aggregates are usually present in type 2 muscle fibers but also can be seen in type 1 fibers. They contain calsequestrin, heat shock proteins, SR ATPase, and SR calcium-pump proteins. Tubular aggregates also commonly occur in hypokalemic periodic paralysis and myotonia congenita, as well as less commonly in malignant hyperthermia, inflammatory myopathies, and alcoholic myopathy. Certain drugs, toxins, or hypoxia can also induce them. The tubular aggregates have been hypothesized to be an adaptive response to genetic or functional abnormalities affecting intracellular calcium flux, excitation-contraction coupling, or muscle fiber excitation.
    • Possible congenital myopathies
      • Myopathy with hexagonally cross-linked tubular arrays: Onset occurs during childhood or adulthood and includes slowly progressive, proximal weakness; fatigue; and exertional myalgia. Inheritance is unknown. EM reveals subsarcolemmal non–membrane-bound inclusions that, on cross-section, are arranged in a 6-spoked hexagonal pattern. The inclusions stain dark purple with modified GT stain and are found in only type 2 muscle fibers.
      • Trilaminar myopathy: Only 1 case has been reported with presentation at birth and was characterized by minimal movement, rigidity, and contractures. The course was nonprogressive. Light microscopy revealed a trilaminar appearance with 3 concentric zones when reacted with the modified GT or NADH stains. The inner and outer zones were densely stained, and the intermediate zone was unstained. On EM, the innermost zone had densely packed mitochondria, glycogen, electron-dense material, and filaments. The middle zone contained Z-disk streaming and well-organized myofibrils. The outermost zone contained cytoplasm with rare mitochondria, filaments, vesicles, and lipids.
      • Zebra body myopathy: Only 2 congenital-onset cases have been reported and were characterized by hypotonia and weakness that progressed slowly or was nonprogressive. On EM, zebra bodies are characterized by Z-band material connected by fine filaments in a pseudosarcomeric pattern, resulting in a striped appearance. Zebra bodies are normally present in myotendinous junctions, intrafusal fibers, extrafusal fibers, extraocular muscle, and cardiac muscle. Their function is unknown.
      • Congenital myopathy with mosaic fibers and interlacing sarcomeres: Only 1 case with childhood onset, which was characterized by proximal weakness, scoliosis, and talipes equinovarus, has been reported. Progression was minimal, but cardiomyopathy and respiratory insufficiency developed in adulthood. Light microscopy revealed a mosaic pattern of light and dark staining on myosin ATPase. EM revealed bands of myofibrils at right angles to other myofibrils, resulting in an interlacing appearance.
      • Congenital myopathy with apoptotic changes: Only 1 case has been reported and was characterized by congenital-onset hypotonia, proximal weakness, and severe mental retardation. Light microscopy and EM revealed chromatin condensation and nuclear fragmentation. Some fibers were positive for Bax, caspase-3, or TUNNEL.
      • Broad A-band disease: Two sporadic cases have been described with congenital-onset hypotonia and mild nonprogressive proximal muscle weakness. EM revealed disorganization of the thick filaments, leading to a loss of distinct A-band/I-band demarcation and the appearance of smearing or broadening of the A-band.
      • Lamellar body myopathy: Only 1 case has been described and was characterized by congenital onset, weakness with progression to respiratory failure, and death at age 5 years. Light microscopy revealed increased connective tissue surrounding muscle fibers that stained positively for laminin and fibronectin. EM revealed that these areas contained concentric lamellar bodies between the 2 layers of basement membrane.
      • Myopathy with muscle spindle excess: Only 1 case has been described and was characterized by congenital onset, hypotonia, proximal weakness, and arthrogryposis. Cardiomyopathy and respiratory failure led to death at about age 1 year. Light microscopy revealed an excess of muscle fiber clusters within fibrous capsules consistent with muscle spindles.

Causes

  • Central core disease
    • CCD is usually transmitted in an autosomal dominant fashion with variable expression and incomplete penetrance (rare autosomal recessive and sporadic cases) and is almost always due to a mutation in the ryanodine receptor 1 (RYR1). CCD has been reported in a few families with familial hypertrophic cardiomyopathy due to a mutation in the cardiac myosin b-heavy chain.
    • Mutations (most often missense) in RYR1 can cause CCD, as described above, malignant hyperthermia susceptibility, or both. Mutations in RYR1 can also cause core-rod myopathy, multiminicore myopathy, and rare cases of centronuclear myopathy.
    • RYR1 is the calcium channel on the sarcoplasmic reticulum (SR) that releases calcium into the muscle cytoplasm during excitation-contraction coupling, thereby allowing calcium to interact with muscle contractile proteins. It exists as a tetrameric structure and associates with several other proteins including the dihydropteridine receptor, calmodulin and calsequestrin. 
    • More than 170 mostly missense (96%) mutations have been described. Most patients (~80%) with typical autosomal dominant central core disease have a mutation in the hydrophobic carboxy-terminal pore forming region of RyR1. Two hypotheses have been proposed to explain the weakness (and cores) in these patients;
      • A leaky ryanodine receptor results in an increased tendency of calcium release from the SR resulting in reduced sarcoplasmic stores of calcium. The excess cytoplasmic calcium could activate proteases, which, in turn, cause focal myofiber injury in the center of the muscle fiber.
      • Functional uncoupling of muscle excitation from sarcoplasmic calcium release results in inefficient excitation-contraction coupling and subsequent weakness.
    • Patients with autosomal recessive inheritance may have a more severe phenotype often with ophthalmoplegia. Mutations are spread throughout the RyR1 protein.22  In several of these patients, a heterozygous missense mutation was expressed on a background of a second nontranscribed allele (epigenetic silencing). In these patients, a dramatic reduction in RyR1 protein levels occurred (patients with typical CCD have normal protein levels).
    • Malignant hyperthermia as the primary disease manifestation is usually due to mutations in the N-terminal and central regions of the ryanodine receptor.    
    • Central cores are single, well-circumscribed, central, circular areas that extend the length of most type 1 muscle fibers (see Media file 1).
      • Central cores are devoid of SR and mitochondria and have reduced or absent oxidative enzymes, such as nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH), and cytochrome oxidase (COX), and are therefore best visualized as negative staining areas when muscle tissue is reacted for these enzymes. Reduced staining is also usually seen when muscle sections are reacted for phosphorylase, glycogen, and myosin ATPase.
      • Electron microscopy often shows disruption of the contractile apparatus within the cores.
      • Structured cores maintain the sarcomeric structure, which is lost in unstructured cores because of muscle fiber degeneration.
      • Cores often immunostain for a variety of molecules, including desmin, RYR1, and g-filamin.
  • Other common features, aside from the central cores, include type 1 muscle fiber predominance, variable muscle fiber size, and increased internal nuclei.
  • Nemaline (rod) myopathy: Six different mutations have been described, all in components of the muscle thin filament. Mutations likely impair the proper formation, maintenance, or function of thin filaments, which results in accumulation of sarcomeric components and formation of nemaline bodies (rods) and the associated muscle weakness. No clear associations exist among specific mutations, mode of inheritance, and clinical severity, although mutations in ACTA1 likely account for about 50% of severe congenital disease.  
    • Autosomal dominant or recessive mutations in the gene for α-tropomyosin 3 (TPM3) cause NEM1. Tropomyosins are a family actin-binding coiled coil proteins that help to regulate calcium-dependent muscle contraction. Three isoforms (2 alpha and 1 beta) exist in skeletal muscle, with 1 alpha and 1 beta joining to form a functional dimer. 
      • In human and animal studies of a dominant mutation of TPM3, an imbalance of other tropomyosin isoforms was noted, likely due to a dominant negative effect that was hypothesized to be responsible for disease pathogenesis.23
      • In autosomal recessive cases in which no functional α-tropomyosin is present, altered ratios of the remaining sarcomeric proteins may be sufficient to cause the formation of rods.  
    • Autosomal recessive mutations in the gene for nebulin (NEB) cause NEM2, likely the most common cause of nemaline myopathy. Nebulin is a large protein that extends the whole length of the thin filament. It has a highly repetitive structure (repeats have an α-helical structure) and can bind up to 200 actin molecules. It is also likely responsible for proper periodicity of the troponin/tropomyosin complex. It is required for the proper assembly of thin filaments and for the maintenance of thin filament length and contractile function. Multiple isoforms exist, differing in the C-terminal structure, which binds α-actinin in the Z disk.     
      • Small deletions and duplications causing frameshifts and point mutations causing stop signals or altered splicing are more common than missense mutations.4  No mutational hotspots exist. It is expected that nonsense and frameshift mutations cause mRNA instability or truncated nebulin molecules while missense mutations likely disrupt the binding of actin to nebulin or effect the secondary structure of nebulin. 
      • A clear genotype-phenotype correlation does not exist, but, in milder disease, it is likely that several normal isoforms are expressed.
    • Mutations in the gene for α-actin (ACTA1) cause NEM3 and account for 15-25% of nemaline rod myopathies. α-actin is present in skeletal muscle but not cardiac muscle. It makes up 10-20% of muscle protein. G-actin (has binding site for myosin) polymerizes to form F-actin. Two strands of F-actin combine in a double helix as part of the thin filament. 
      • Most mutations are missense and spread throughout the gene. Autosomal dominant mutations that exert a dominant negative effect and autosomal recessive mutations that result in no functional actin both cause cytoplasmic rods, suggesting that multiple mechanisms are responsible for disease manifestations. In autosomal dominant disease, there are likely abnormalities in folding, polymerization, or aggregation of mutant actin, whereas, in autosomal recessive disease, altered ratios of sarcomeric proteins during development or turnover of the thin filament are sufficient to form rods.
      • The degree of sarcomeric disruption, as seen on electron microscopy, correlates with disease severity such that, in general, the most severely affected patients have the most myofibrillar disorganization. 
      • Actin aggregates are common and has lead to these biopsy specimens being described as actin myopathy with excess of thin filaments. 
    • Autosomal dominant mutations in the gene for β-tropomyosin (TPM2) cause NEM4. TPM2 is another tropomyosin and likely causes disease in a similar fashion to the dominant negative mechanism thought to be responsible for NEM1.
    • Autosomal recessive mutations in the gene for troponin T1 (TNNT1) cause NEM5 in the Older Order Amish.8 Three troponins act as a complex to bind calcium and either block or unblock the myosin-binding site on actin. Troponin T acts primarily to bind to tropomyosin. The mutation in the Amish population truncates the protein and removes the principal site of binding to troponin C and troponin I. It is hypothesized that the mutation results in mutant message undergoing nonsense-mediated decay or an unstable protein that is degraded or mislocalized.        
    • Autosomal recessive mutation in the gene for cofilin-2 (CFL2) cause NEM7 in one family. Cofilins are actin-modulating proteins that act to depolymerize F-actin and inhibit the polymerization of G-actin. Cofilin-2 is a muscle-specific isoform that exerts its effect on actin, in part, through interactions with tropomyosin.   
    • Rods, the pathologic hallmark of nemaline rod myopathy, are only visible on modified Gomori trichrome (GT) stain (see Media file 2) as dark red/purple structures.
      • Usually, the rods are sarcolemmal but may be intranuclear.
      • Derived from the Z-line, rods are often in continuity with the Z-line. They are composed of primarily α-actinin (the primary component of Z-lines) as well as other Z-line and thin filament proteins, including actin, telethonin, and myotilin.
      • Rods may be seen in many other diseases including inflammatory myopathies, muscular dystrophies, mitochondrial myopathies, HIV myopathy, chronic renal failure, spinal muscular atrophy, Charcot-Marie-Tooth disease, and monoclonal gammopathy.
      • Other common pathologic features include type-1 fiber predominance or atrophy.
  • Centronuclear/myotubular myopathy can be due to several different mutations, but all affected proteins have a role in membrane trafficking.24
    • X-linked myotubular myopathy is due to a mutation in the myotubularin (MTM1) gene. Point mutations (missense, nonsense, and splice site), as well as small or large insertions and deletions, have been found throughout the gene. A clear genotype-phenotype correlation does not exist, but most nonsense and splice site, as well as some missense mutations in conserved residues, result in a severe phenotype, and many missense mutations or deletions have a mild phenotype. Myotubularin is ubiquitously expressed in the nucleus of most cells.
      • Myotubularin is a lipid phosphatase whose main action is to dephosphorylate phosphoinositide-3-phosphate. Phosphoinositides are specialized lipids that target localization of proteins to various subcellular organelles and are important in membrane trafficking. 
      • Myotubularin interacts with proteins with the SET domain that are important in epigenetic mechanisms of gene regulation.  Myotubularin may serve as a link between genetic regulatory proteins and signaling pathways involved in vesicular trafficking of substrate necessary for myoblast fusion.
      • In myotubularin knockout mice, muscle development occurs normally, but a myopathy develops suggesting that the absence of myotubularin affects muscle maintenance, not muscle formation.  
    • Autosomal dominant centronuclear myopathy is due to a mutation in dynamin 2 (DNM2). Dynamins are large GTPases that are involved in organelle fission events. Dynamin 2 has been implicated in endocytosis, and a likely hypothesis is that endocytotic function is disrupted due to mutations in dynamin 2. Other actions of dynamin that may play a role in disease pathogenesis include actin assembly, cytokinesis, and regulation of centrosomal function. Dynamin 2 mutations can also cause a CMT 2 phenotype with axonal neuropathy and clinical features that overlap with autosomal dominant centronuclear myopathy.   
    • Autosomal recessive centronuclear myopathy is due to a mutation in amphiphysin 2 (bridging integrator 1; BIN1). Amphphysins are involved in endocytosis, signal transduction, transcriptional regulation, and vesicle fusion. Amphiphysin 2 mutations have been shown to impair T-tubule function, formation or maintenance, in some cases by inhibiting dynamin 2 binding to the T-tubu.10  
    • The pathologic hallmark of all myotubular myopathies (X-linked and autosomal) is the predominance of type-1 fibers with large, centrally placed nuclei (see Media file 3). However, it is not known how any of the above mutations cause the pathologic abnormality.
       
      • Most fibers are small and round and resemble fetal myotubes, which normally have central nuclei. The central part of the fiber contains an abundance of mitochondrial enzymes but lacks myosin ATPase activity.
      • Type-1 muscle fiber hypotrophy is usually present.
      • Immunohistochemical studies have shown persistence of fetal vimentin and desmin and of neonatal myosin, giving further credence to the maturational arrest of muscle fibers.
      • Muscle fibers with central nuclei can also be seen in denervation, muscle fiber regeneration, and any chronic myopathy.
  • Multiminicore disease
    • Most cases are inherited in an autosomal recessive fashion, but sporadic cases have also been reported.
    • Mutations in the selenoprotein N gene (SEPN1) have been found in several families with a typical severe presentation and autosomal recessive inheritance (~30% of mulitminicore disease). Mutations in SEPN1 also cause congenital muscular dystrophy with rigid spine (see Congenital Muscular Dystrophy), and it has been proposed that these disorders be called SEPN-related myopathies. The role of selenoprotein N in causing multiminicore disease is unknown, but its expression is developmentally regulated in muscle. More than 20 mutations have been described, with more than half resulting in a truncated protein that is likely degraded. Selenoprotein N may play a role in redox reactions of membrane proteins, including the ryanodine receptor, and lack of this protein may result in oxidative stress leading to abnormal receptor function.25  
    • Mutations in the ryanodine receptor 1 (RyR1) have been noted in some cases of multiminicore disease with autosomal recessive (rarely autosomal dominant) inheritance. Mutations in RyR1 more commonly cause central core disease with or without malignant hyperthermia. The reason why mutations in the same protein result in different phenotypes is not known. Potential defects may be related to instability of the RyR1 macromolecular complex or to a reduction in the number of RyR1 receptors on the sarcoplasmic reticulum.25      
    • The pathologic hallmark of the disease is the presence of multiple areas of sarcomeric disorganization associated with diminished mitochondrial oxidative activity.
      • The disease is best identified with muscle reacted for oxidative enzymes NADH, SDH, and COX. Reduced staining for myosin ATPase, glycogen, and phosphorylase may also be noted.
      • Multiminicores differ from central cores in the following ways: occur in type 1 and type 2 fibers; poorly defined limits; vary in orientation to muscle fiber axis; multiple lesions within one muscle fiber; and smaller in size, never extending the length of the muscle fiber.
      • Other features may include increased endomysial connective tissue, increased internal nuclei, and type-1 muscle fiber predominance.
      • Multiminicores may be present as a nonspecific feature in many other diseases, including mitochondrial diseases, CNS disorders, and denervation.
  • Congenital fiber-type disproportion has as the main pathologic hallmark small type-1 muscle fibers. The original definition requires that type-1 fibers are 12% smaller in diameter than type-2 fibers, although often the difference is closer to 50%. Other common features are type-1 fiber predominance and reduced or absent type-2B fibers.
    • The most common cause is due to autosomal dominant or sporadic (likely de novo autosomal dominant) mutations in the gene for α-tropomyosin 3 (TPM3). Mutations in TPM3 are a rare cause of nemaline myopathy, but they are a common cause of CFTD.14  The reason why certain mutations cause rod formation while others cause CFTD is not known. Biopsy samples showed a predominance of type-1 fibers (83%) that were 72% smaller than type-2 fibers. Some mutations can cause CFTD in some family members and rod formation in others. 
    • Autosomal recessive mutations in the gene for selenoprotein N are a rare cause of CFTD. Mutations in the gene for selenoprotein N also cause multiminicore disease and congenital muscular dystrophy with rigid spine. The reason why different mutations cause different muscle pathologies, but clinical syndromes overlap with most patients having a rigid spine and respiratory insufficiency is not known.13
    • Autosomal dominant mutations in ACTA1 are a rare cause of CFTD. Mutations in the gene for α-actin are a common cause of nemaline myopathy. It has been shown that CFTD mutant α-actin is unable to properly interact with tropomyosin, leaving tropomyosin in the "switched off" position, thereby not allowing actin to interact with myosin. Furthermore, the sarcomeric disruption common in α-actin mutations that cause severe nemaline myopathy is not seen in patients with severe weakness due to CFTD. These data have lead to the hypothesis that the α-actin mutations that cause CFTD result in disturbed sarcomeric function rather than structure.26         
  • Myosin storage myopathy (hyaline body myopathy)
    • Mutations in the slow/β-cardiac myosin heavy-chain gene (MYH7) have been reported in sporadic or autosomal dominantly inherited cases. Mutations in MYH7 also cause Laing early adult-onset distal myopathy type 3 and cases of familial hypertrophic cardiomyopathy.
    • Hyaline bodies are subsarcolemmal areas, mostly in type-1 muscle fibers, that are devoid of sarcomeres and react with myosin ATPase but not oxidative enzymes or glycogen. They are pink on hematoxylin and eosin (H&E) staining, and pale green with modified GT staining. They are composed of granular and filamentous material in continuity with adjacent thick myosin filaments. The hyaline bodies immunostain intensely with antibodies against the slow myosin heavy chain and have been proposed to result from myofibrillolysis of the mutated slow myosin heavy chain within type-1 muscle fibers.
    • Type-1 muscle fiber predominance is common.
    • Interestingly, some patients with a mutation in MYH7 do not have hyaline bodies on muscle biopsy sample.
  • Sarcotubular myopathy is due to a mutation in Tripartite-motif containing gene 32 (TRIM32). 
    • Inheritance is autosomal recessive, and all cases have the same mutation (D487N) that causes limb-girdle muscular dystrophy 2H (Manitoba Hutterite dystrophy).
    • TRIM 32 is an E3 ubiquitin ligase that is expressed in muscle. It interacts with myosin and can ubiquinate actin. E3 ubiquitin ligase activity is not abolished due to this mutation. Nevertheless, altered ability to ubiquinate may result in accumulation of proteins that are not tagged for degradation by the proteosomal system.27  
    • EM reveals numerous small, membrane-bound vacuoles that appear to originate from the sarcotubular system and have reactivity to T-tubule and SR-associated proteins, most often affecting type-2 muscle fibers.
  • Reducing body myopathy is an X-linked dominant disease due to a mutation in Four and a half LIM domain 1 (FHL1).
    • LIM domains are zinc-finger protein interaction motifs, and FHL proteins are thought to be involved in cytoskeletal scaffolding and regulation of transcription factors. FHL1 localizes to the sarcomere and is thought to be involved in muscle growth and differentiation as well as assembly of the sarcomere.   
    • An X-linked dominant negative mutation can explain the severe phenotype in girls. Skewed X-inactivation may be a modifier to explain mild symptoms in carriers. 
    • EM reveals numerous subsarcolemmal, non–membrane-bound inclusions composed of granulofilamentous and tubular structures, which stain pink with H&E and purple with the modified GT stain. The name "reducing body" was coined when the inclusions were found to have reducing activity when salts are applied to the muscle fiber. 
    • Immunohistochemical analysis has shown features similar to that of aggresomes including perinuclear location and the presence of desmin, ubiquitin, and luminal endoplasmic reticulum chaperone GRP78. Wild-type and mutated FHL1 is also present in the inclusions and the aggregation of these (and other as yet unidentified) proteins may play a role in the pathogenesis of the disease.  
  • Spheroid body myopathy is due to an autosomal dominant mutation in the gene for myotilin (titin immunoglobulin domain protein; TTID), which also causes LGMD type 1A and a myofibrillar myopathy. 
    • Spheroid bodies are more common in type-1 muscle fibers and devoid of enzymatic activity. Electron microscopy showed fine filaments and streaming of Z disks. Immunohistochemical studies showed the presence of desmin and ubiquitin, similar to what is found in many myofibrillar myopathies. 
    • Myotilin binds actin and is thought to be involved in stabilization of actin bundles and anchorage of thin filaments at the Z disk.

    • More on Congenital Myopathies

    Overview: Congenital Myopathies
    Differential Diagnoses & Workup: Congenital Myopathies
    Treatment & Medication: Congenital Myopathies
    Follow-up: Congenital Myopathies
    Multimedia: Congenital Myopathies
    References
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    References

    1. North K. What's new in congenital myopathies?. Neuromuscul Disord. Jun 2008;18(6):433-42. [Medline].

    2. Wattanasirichaigoon D, Swoboda KJ, Takada F, et al. Mutations of the slow muscle alpha-tropomyosin gene, TPM3, are a rare cause of nemaline myopathy. Neurology. Aug 27 2002;59(4):613-7. [Medline].

    3. Wallgren-Pettersson C, Clarke A, Samson F, et al. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J Med Genet. Sep 1995;32(9):673-9. [Medline].

    4. Lehtokari VL, Pelin K, Sandbacka M, et al. Identification of 45 novel mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Hum Mutat. Sep 2006;27(9):946-56. [Medline].

    5. Agrawal PB, Strickland CD, Midgett C, et al. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol. Jul 2004;56(1):86-96. [Medline].

    6. Hutchinson DO, Charlton A, Laing NG, Ilkovski B, North KN. Autosomal dominant nemaline myopathy with intranuclear rods due to mutation of the skeletal muscle ACTA1 gene: clinical and pathological variability within a kindred. Neuromuscul Disord. Feb 2006;16(2):113-21. [Medline].

    7. Lehtokari VL, Ceuterick-de Groote C, de Jonghe P, et al. Cap disease caused by heterozygous deletion of the beta-tropomyosin gene TPM2. Neuromuscul Disord. Jun 2007;17(6):433-42. [Medline].

    8. Johnston JJ, Kelley RI, Crawford TO, et al. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet. Oct 2000;67(4):814-21. [Medline].

    9. Agrawal PB, Greenleaf RS, Tomczak KK, et al. Nemaline myopathy with minicores caused by mutation of the CFL2 gene encoding the skeletal muscle actin-binding protein, cofilin-2. Am J Hum Genet. Jan 2007;80(1):162-7. [Medline].

    10. Nicot AS, Toussaint A, Tosch V, et al. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. Nat Genet. Sep 2007;39(9):1134-9. [Medline].

    11. Bitoun M, Bevilacqua JA, Prudhon B, et al. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann Neurol. Dec 2007;62(6):666-70. [Medline].

    12. Bitoun M, Maugenre S, Jeannet PY, et al. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nat Genet. Nov 2005;37(11):1207-9. [Medline].

    13. Schara U, Kress W, Bonnemann CG, et al. The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy. Eur J Paediatr Neurol. May 2008;12(3):224-30. [Medline].

    14. Clarke NF, Kolski H, Dye DE, et al. Mutations in TPM3 are a common cause of congenital fiber type disproportion. Ann Neurol. Mar 2008;63(3):329-37. [Medline].

    15. Clarke NF, Kidson W, Quijano-Roy S, et al. SEPN1: associated with congenital fiber-type disproportion and insulin resistance. Ann Neurol. Mar 2006;59(3):546-52. [Medline].

    16. Laing NG, Clarke NF, Dye DE, et al. Actin mutations are one cause of congenital fibre type disproportion. Ann Neurol. Nov 2004;56(5):689-94. [Medline].

    17. Pegoraro E, Gavassini BF, Borsato C, et al. MYH7 gene mutation in myosin storage myopathy and scapulo-peroneal myopathy. Neuromuscul Disord. Apr 2007;17(4):321-9. [Medline].

    18. Schoser BG, Frosk P, Engel AG, Klutzny U, Lochmuller H, Wrogemann K. Commonality of TRIM32 mutation in causing sarcotubular myopathy and LGMD2H. Ann Neurol. Apr 2005;57(4):591-5. [Medline].

    19. Windpassinger C, Schoser B, Straub V, et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. Jan 2008;82(1):88-99. [Medline].

    20. Schessl J, Zou Y, McGrath MJ, et al. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy. J Clin Invest. Mar 2008;118(3):904-12. [Medline].

    21. Foroud T, Pankratz N, Batchman AP, et al. A mutation in myotilin causes spheroid body myopathy. Neurology. Dec 27 2005;65(12):1936-40. [Medline].

    22. Zhou H, Jungbluth H, Sewry CA, et al. Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies. Brain. Aug 2007;130:2024-36. [Medline].

    23. Corbett MA, Akkari PA, Domazetovska A, et al. An alphaTropomyosin mutation alters dimer preference in nemaline myopathy. Ann Neurol. Jan 2005;57(1):42-9. [Medline].

    24. Dowling JJ, Gibbs EM, Feldman EL. Membrane traffic and muscle: lessons from human disease. Traffic. Jul 2008;9(7):1035-43. [Medline].

    25. Zorzato F, Jungbluth H, Zhou H, Muntoni F, Treves S. Functional effects of mutations identified in patients with multiminicore disease. IUBMB Life. Jan 2007;59(1):14-20. [Medline].

    26. Clarke NF, Ilkovski B, Cooper S, et al. The pathogenesis of ACTA1-related congenital fiber type disproportion. Ann Neurol. Jun 2007;61(6):552-61. [Medline].

    27. Kudryashova E, Kudryashov D, Kramerova I, Spencer MJ. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol. Nov 25 2005;354(2):413-24. [Medline].

    28. Brooke MH, Engel WK. The histographic analysis of human muscle biopsies with regard to fiber types. 4. Children's biopsies. Neurology. Jun 1969;19(6):591-605. [Medline].

    29. Donner K, Ollikainen M, Ridanpaa M, et al. Mutations in the beta-tropomyosin (TPM2) gene--a rare cause of nemaline myopathy. Neuromuscul Disord. Feb 2002;12(2):151-8. [Medline].

    30. Engel AG, Gomez MR, Groover RV. Multicore disease. A recently recognized congenital myopathy associated with multifocal degeneration of muscle fibers. Mayo Clin Proc. Oct 1971;46(10):666-81. [Medline].

    31. Engel WK. Mitochondrial aggregates in muscle disease. J Histochem Cytochem. Jan 1964;12:46-8. [Medline].

    32. Goebel HH. Congenital myopathies at their molecular dawning. Muscle Nerve. May 2003;27(5):527-48. [Medline].

    33. Goldfarb LG, Park KY, Cervenakova L, et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nat Genet. Aug 1998;19(4):402-3. [Medline].

    34. Griggs RC, Mendell JR, Miller RG. Congenital myopathies. In: Evaluation and Treatment of Myopathies. Philadelphia: FA Davis Co; 1995:211-46.

    35. Herman GE, Finegold M, Zhao W, de Gouyon B, Metzenberg A. Medical complications in long-term survivors with X-linked myotubular myopathy. J Pediatr. Feb 1999;134(2):206-14. [Medline].

    36. Laing NG, Wilton SD, Akkari PA, et al. A mutation in the alpha tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nat Genet. Jan 1995;9(1):75-9. [Medline].

    37. Laporte J, Guiraud-Chaumeil C, Vincent MC, et al. Mutations in the MTM1 gene implicated in X-linked myotubular myopathy. ENMC International Consortium on Myotubular Myopathy. European Neuro-Muscular Center. Hum Mol Genet. Sep 1997;6(9):1505-11. [Medline].

    38. Loke J, MacLennan DH. Malignant hyperthermia and central core disease: disorders of Ca2+ release channels. Am J Med. May 1998;104(5):470-86. [Medline].

    39. McEntagart M, Parsons G, Buj-Bello A, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord. Dec 2002;12(10):939-46. [Medline].

    40. North K. Congenital myopathies. In: Engel AG, Franzini-Armstrong C, eds. Myology. 3rd ed. New York, NY: McGraw Hill; 2004:1473-1533.

    41. Nowak KJ, Wattanasirichaigoon D, Goebel HH, et al. Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy. Nat Genet. Oct 1999;23(2):208-12. [Medline].

    42. Pelin K, Hilpela P, Donner K, et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc Natl Acad Sci U S A. Mar 2 1999;96(5):2305-10. [Medline].

    43. Quane KA, Healy JM, Keating KE, et al. Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia. Nat Genet. Sep 1993;5(1):51-5. [Medline].

    44. Ryan MM, Schnell C, Strickland CD, et al. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol. Sep 2001;50(3):312-20. [Medline].

    45. Shuaib A, Paasuke RT, Brownell KW. Central core disease. Clinical features in 13 patients. Medicine (Baltimore). Sep 1987;66(5):389-96. [Medline].

    46. Tajsharghi H, Thornell LE, Lindberg C, Lindvall B, Henriksson KG, Oldfors A. Myosin storage myopathy associated with a heterozygous missense mutation in MYH7. Ann Neurol. Oct 2003;54(4):494-500. [Medline].

    47. Vicart P, Caron A, Guicheney P, et al. A missense mutation in the alphaB-crystallin chaperone gene causes a desmin-related myopathy. Nat Genet. Sep 1998;20(1):92-5. [Medline].

    48. Wallgren-Pettersson C, Laing NG. Report of the 70th ENMC International Workshop: nemaline myopathy, 11-13 June 1999, Naarden, The Netherlands. Neuromuscul Disord. Jun 2000;10(4-5):299-306. [Medline].

    49. Zhang Y, Chen HS, Khanna VK, et al. A mutation in the human ryanodine receptor gene associated with central core disease. Nat Genet. Sep 1993;5(1):46-50. [Medline].

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    Further Reading

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    Keywords

    congenital myopathy, congenital myopathies, broad A-band disease, cap myopathy, central core disease, CCD, congenital fiber type disproportion, congential myopathy with apoptotic changes, congenital myopathy with mosaic fibers and interlacing sarcomeres, cylindrical spirals myopathy, fingerprint body myopathy, hyaline body (myosin storage) myopathy, lamellar body myopathy, multiminicore disease, myopathy with hexagonally cross-linked tubular arrays, myopathy with muscle spindle excess, myopathy with tubular aggregates, myotubular/centronuclear myopathy, nemaline (rod) myopathy, reducing body myopathy, sarcotubular myopathy, trilaminar fiber myopathy, zebra body myopathy, amyotonia congenita, benign congenital hypotonia, nemaline rod myopathy, myotubular myopathy, CNS disease

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    Contributor Information and Disclosures

    Author

    Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCare, Consulting Staff, Barnes Jewish Hospital
    Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
    Disclosure: Nothing to disclose.

    Medical Editor

    Robert Baumann, MD, Program Director, Professor, Departments of Neurology and Pediatrics, University of Kentucky
    Robert Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American College of Epidemiology, American Epilepsy Society, and Child Neurology Society
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    Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience
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    Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
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    Chief Editor

    Amy Kao, MD, Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children
    Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society
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