AUTHOR INFORMATION

Section 1 of 11

Authored by Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; 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

Edited by Robert Baumann, MD, Program Director, Professor, Departments of Neurology and Pediatrics, University of Kentucky; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Kenneth J Mack, MD, PhD, Visiting Associate Professor, Department of Neurology, University of Wisconsin at Madison; Associate Professor and Consultant, Department of Neurology, Division of Child and Adolescent Neurology, Mayo Medical School; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Glenn Lopate, MD
Editor's Email:	Robert Baumann, MD

eMedicine Journal, January 5 2007, VOLUME 8, Number 1

INTRODUCTION

Section 2 of 11

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

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.

With the advent of improved techniques such as electron microscopy, enzyme histochemistry, immunocytochemistry, and molecular genetics, the etiologies of several congenital myopathies are now well defined. This article focuses on the diseases defined as genetic. 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:

• Internationally: 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%)
    
    

  • Minimulticore 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

Section 3 of 11

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

• Central core disease


• • The most common presentation is at birth or in early childhood with weakness and hypotonia.

  • A history of decreased fetal movement or breech presentation is typical.

  • Progression is slow, but motor milestones are delayed.

  • Occasionally, facial weakness and cramps are present.

  • Skeletal abnormalities are common, including congenital hip dislocation, kyphoscoliosis, and foot deformities.

  • The disease can also present in adolescence as a slowly progressive limb-girdle syndrome.

  • A severe variant that has an onset in infancy has been noted in a few families with autosomal recessive inheritance.

  • 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 (Several different phenotypes have been described.)


• • 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 often need a wheelchair or ventilatory support by age 10 years.

  • The typical 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.

  • Myopathy (general features)
    • Proximal limb, facial, and neck flexor weakness

    • Dysarthria, dysphagia, drooling, nasal voice, and tongue wasting due to lingual and pharyngeal weakness

    • Hypotonia

    • Respiratory insufficiency is common in all forms of the disease and may be the presenting feature.

  • Skeletal deformities (general features)
    • Arthrogryposis in the severe congenital form (may be prominent)

    • Hypermobility of the joints in infancy

    • Late development of contractures

    • Kyphoscoliosis, pectus excavatum, and rigid spine (other noted deformities)
  
  
  
  • Cardiac disease (general features): Cardiomyopathy is rare but may occur early in the congenital forms and as a presenting or late complication in childhood or adult disease.

  • CNS disease (general features): Rarely, patients have seizures in the neonatal period.
  
  
  
• 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.
    • 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 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 weakness may be present. Skewed X-inactivation may result in a carrier who presents severely with infant-onset weakness, feeding difficulty, and skeletal deformities.

  • The autosomal recessive form can present in infancy, childhood, or early adulthood.
    • Features include hypotonia, proximal weakness, respiratory distress, facial and bulbar weakness, ptosis, and ophthalmoplegia.

    • Skeletal features include pectus excavatum, talipes equinovarus, and high-arched palate.

    • The course progresses slowly and eventually causes the loss of ambulation.

  • The autosomal dominant form can present from late childhood into adulthood.
    • Weakness is limb girdle in distribution.

    • Facial weakness, ptosis, and ophthalmoplegia are uncommon.

    • Progression is slow with a mild course.
  
  
  
• Multiminicore disease


• • Onset occurs in infancy or early childhood and is characterized by hypotonia and proximal weakness.

  • Antenatal polyhydramnios and decreased fetal movements are often noted.

  • Facial and bulbar weakness are common.

  • Progressive respiratory insufficiency often occurs out of proportion to muscle weakness.

  • Limb weakness progresses slowly or is nonprogressive.

  • Skeletal deformities include joint contractures, torticollis, chest deformities, rigid spine, and scoliosis.

  • Rare cardiac manifestations include septal defects, heart block, or cardiomyopathy.

  • Malignant hyperthermia has not been clearly associated.
  
  
  
• Hyaline body (myosin storage) myopathy


• • Onset usually is in infancy with generalized proximal weakness and hypotonia. The course of the disease progresses slowly or is nonprogressive.

  • Cases of childhood onset with diffuse proximal weakness have been rarely reported.

  • Cases of adult onset with scapuloperoneal pattern of weakness have also been rarely reported.
  
  
  
• Sarcotubular myopathy: Childhood or early adult onset of nonprogressive or slowly progressive limb girdle weakness occurs. Facial weakness as well as exercise-induced fatigue and myalgias may also occur. Inheritance is likely autosomal recessive. EM reveals numerous small, membrane-bound vacuoles that appeared to originate from the sarcotubular system and with reactivity to T-tubule and SR-associated proteins, most often affecting type 2 muscle fibers.



• 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
    • Congenital fiber type disproportion (CFTD): This term was initially coined to describe a group of infants with hypotonia and diffuse weakness that may improve with age. The primary pathologic abnormality is type 1 muscle fibers that are at least 12% smaller than type 2 muscle fibers. Other clinical features can include short stature; low body weight; multiple joint contractures; scoliosis; long, thin face; and high-arched palate. Less common features may include progressive weakness, bulbar weakness, respiratory insufficiency, ophthalmoplegia, cardiac disease, and mental retardation. Other common pathologic features can include type 1 fiber predominance and type 2B fiber absence.

      Many secondary causes of type 1 fiber hypotrophy exist, which should be excluded before the diagnosis of CFTD is made: other congenital myopathies (nemaline rod myopathy, myotubular myopathy, CCD), muscular dystrophies (eg, myotonic dystrophy), inflammatory myopathies (eg, polymyositis), CNS disease (eg, perinatal asphyxia), inherited neuropathy or anterior horn cell disease (eg, leukodystrophies, spinal muscular atrophy), skeletal disorders (eg, arthrogryposis), and metabolic myopathy (eg, Pompe disease). Autosomal recessive and autosomal dominant inheritance patterns have been described. No specific mutations have been described except for a few cases with mutations in a-actin with a severe phenotype but without the presence of rods (see Nemaline (rod) myopathy).

    • 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 I 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 Image 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
    • Reducing body myopathy: Onset occurs during infancy or early childhood with hypotonia and proximal weakness. Rapid progression ensues with death due to respiratory failure within a few years. Childhood or adult onset of the disease is characterized by proximal weakness and a nonprogressive course or a slowly progressive course with later death due to respiratory failure. Inheritance is sporadic or autosomal recessive. 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.

    • 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.

    • Cap myopathy: It has been described in 4 sporadic cases, 2 with congenital onset of progressive weakness and eventual death due to respiratory failure. Two other cases had a childhood onset of slowly progressive weakness. 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 EM, the caps were filled with abnormally arranged myofibrils, which lacked thick filaments.

    • 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 and congenital myopathy with cores (central cores and minicores).
  
  
  
  • RYR1 is the calcium channel on the sarcoplasmic reticulum (SR) that releases calcium into the sarcoplasmic space during excitation-contraction coupling, thereby allowing calcium to interact with muscle contractile proteins.
  
  
  
  • The clinical and pathologic abnormality (central cores) have been postulated to result from the following:
    • An increased tendency of calcium release from the SR in the center of the fiber due to a leaky ryanodine receptor (The excess sarcoplasmic calcium could activate proteases which, in turn, cause focal myofiber injury.)

    • An uncoupling of muscle excitation from calcium release within the center of the fiber resulting in inefficient contraction and subsequent weakness
  
  
  
  • Central cores are single, well-circumscribed, central, circular areas that extend the length of most type 1 muscle fibers (see Image 1).
    • They 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.

    • 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


• • Five different mutations have been described, all in components of the muscle thin filament. No clear associations exist among specific mutation, mode of inheritance, and clinical severity.
    • a-actin (ACTA1) (accounts for 15-25% of nemaline rod myopathies): This mutation is autosomal dominant or sporadic (rare autosomal recessive) missense mutations. Presentation varies from severe congenital to childhood-onset forms and is often variable within families. Actin aggregates are common in muscle biopsy samples.

    • Nebulin (NEB): This mutation is an autosomal recessive nonsense mutation resulting in protein truncation. This form presents as the typical congenital form (rare severe congenital form).

    • Troponin T1 (TNNT1): This mutation is an autosomal recessive nonsense mutation resulting in complete loss of troponin T1. It is reported in only Old Order Amish. This is a severe congenital form.

    • a-tropomyosin 3 (TPM3, NEM1) (2-3% of nemaline rod myopathies): This mutation is an autosomal dominant missense or autosomal recessive nonsense mutation. This form presents with severe, intermediate, and typical congenital, as well as childhood-onset forms.

    • b-tropomyosin (TPM2) (rare): This mutation is an autosomal dominant missense mutation. This form presents with typical congenital onset.

    • A sixth locus at 15q21-q24 has been described in a Dutch kindred with autosomal dominant inheritance, slow movements, proximal weakness, and rods revealed by examination of the muscle biopsy sample. The gene for a-tropomyosin 1 is within the critical region.
  
  
  
  • Rods, the pathologic hallmark, are only visible on modified Gomori trichrome (GT) stain (see Image 2) as dark red/purple structures.
    • Usually sarcolemmal but may be intranuclear in severe cases of rod myopathy

    • Derived from the Z-line: Rods are in continuity with the Z-line. They contain many Z-line proteins, including a actinin (the primary component of Z-lines), as well as the thin filament protein actin.

    • Rods may also be associated with target fibers due to acute denervation.
  
  
  
  • Other common features include type 1 fiber predominance or atrophy.
  
  
  
• Mutations in the various thin filament proteins associated with nemaline rod myopathy are likely (but not proven) to impair the proper formation of thin filaments and Z-lines. Improper function of these structures likely leads to subsequent muscle weakness.



• Centronuclear/myotubular myopathy


• • 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 interacts with proteins with the SET domain that are important in epigenetic mechanisms of gene regulation. While it has similarities to tyrosine phosphatases, its main enzymatic action is thought to be through dephosphorylation of the second messenger phosphatidylinositol 3 phosphate.

    • Myotubularin may serve as a link between genetic regulatory proteins and signaling pathways involved in vesicular trafficking of substrate necessary for myoblast fusion.

    • The failure of muscle growth and differentiation is hypothesized to lead to a failure of myogenic maturation and a persistence of immature muscles and myotubes.
  
  
  
  • The genetic basis for autosomally inherited myotubular myopathy is not known. One boy with an increased number of central nuclei has been described and was shown to have a dominant mutation in the gene for myogenic factor 6.
  
  
  
  • The pathologic hallmark of all myotubular myopathies (X linked and autosomal) is the predominance of type 1 fibers with large, centrally placed nuclei (see Image 3)
    • 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 a 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 sporadic or inherited in an autosomal recessive fashion.

  • 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). Congenital severe axial weakness, respiratory failure, scoliosis, and rigid spine are typical. Mutations in SEPN1 also cause congenital muscular dystrophy with rigid spine (see Congenital Muscular Dystrophy), and it has been proposed that the disorders be called SEPN-related myopathy. The role of selenoprotein N in causing multiminicore disease is unknown, but high expression has been found in fetal muscle, which suggests a role in muscle fiber differentiation.

  • Mutations in the ryanodine receptor 1 have been noted in some cases (see Central core disease) with autosomal recessive (or, rarely, autosomal dominant) inheritance.

  • 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.
  
  
  
• Hyaline body (myosin storage) myopathy
  • Mutations in the slow/b-cardiac myosin heavy chain gene (MYH7) have been reported in sporadic or autosomal dominantly inherited cases. Mutations in MYH7 have also been reported in Gowers-Laing distal myopathy and in some cases of familial 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. Type 1 muscle fiber predominance is common. 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.



• Sarcotubular myopathy
  • Inheritance is likely autosomal recessive.

  • A recent report revealed that all 4 cases have a mutation in the gene that encodes for Tripartite-motif containing gene 32 (TRIM32). Furthermore, the mutation is the same (D487N) that is present in all cases of limb girdle muscular dystrophy 2H (Manitoba Hutterite dystrophy).

  • TRIM 32 is a ubiquitin ligase. A mutation in this protein may result in accumulation of proteins that do not become ubiquitinated and, therefore, are not tagged for degradation by the proteosomal system.

  • EM reveals numerous small, membrane-bound vacuoles that appear to originate from the sarcotubular system and with reactivity to T-tubule and SR-associated proteins, most often affecting type 2 muscle fibers.

DIFFERENTIALS

Section 4 of 11

Cerebral Palsy
Congenital Muscular Dystrophy
Limb-Girdle Muscular Dystrophy
Metabolic Myopathies
Myasthenia Gravis
Spinal Muscular Atrophy

Other Problems to be Considered:

Congenital myotonic dystrophy
Congenital myasthenic syndromes
Mitochondrial cytopathies
Myotonic diseases
Fascioscapulohumeral dystrophy
Congenital hypomyelinating neuropathies

WORKUP

Section 5 of 11

Lab Studies:

• Creatine kinase level


• • CK level is either in the reference range or mildly elevated in all of the congenital myopathies.
  
  
  
  • It can be elevated moderately in CCD and may also be elevated in asymptomatic carriers of the ryanodine receptor mutation in CCD.
  
  
  
  • If the CK level is very high, other disorders such as Duchenne-Becker or limb-girdle muscular dystrophy should be considered.
  
  
  

Other Tests:

• Electromyography and nerve conduction studies


• • Electromyography (EMG) and nerve conduction studies (NCSs) should be performed in all patients in whom a congenital myopathy is suspected.
  
  
  
  • In the differential diagnosis, rule out other diseases such as spinal muscular atrophy, congenital myasthenia, and hereditary neuropathy.
  
  
  
  • In congenital myopathy, NCS findings are normal and EMG findings are either normal or show the typical small-amplitude, narrow-duration motor unit potentials (MUPs) that are seen in myopathies. Fibrillations and positive sharp waves are rare.
  
  
  
• Electrocardiogram (ECG): Cardiac disease may be prominent in nemaline myopathy or at times in other congenital myopathies. Obtain ECG when considering these diagnoses.

Procedures:

• Muscle biopsy


• • Obtain a muscle biopsy in all patients in whom a congenital myopathy is suspected. Pathological examination should be performed at a center whose staff has expertise in muscle pathology.
  
  
  
  • Other causes of weakness need to be ruled out. In addition, the morphologic characteristics necessary to make the diagnosis need to be established.
  
  
  
  • Ultrastructural examination of muscle is often necessary, since several of the pathologic features are based on the EM appearance of muscle.
  
  
  

TREATMENT

Section 6 of 11

Medical Care:

• No specific treatment is available for any of the congenital myopathies, but aggressive supportive care is essential to preserve muscle activity, to allow for maximal functional ability, and to prolong life expectancy.

• The primary concerns affecting prognosis are preventing and correcting skeletal abnormalities (eg, scoliosis, foot deformities, and contractures) to maintain ambulation and to prevent or delay the development of respiratory insufficiency.

• Respiratory failure due to diaphragmatic weakness can occur at any age and may be independent of the degree of limb weakness.


• • A restrictive pattern on pulmonary function tests (PFTs) may be apparent before the onset of symptoms.

  • Early symptoms of nocturnal hypoxia can include poor sleep, nightmares, morning headache, daytime sleepiness, and weight loss.

  • All patients should have baseline PFTs that are repeated in at least yearly intervals.

  • Treatment options include chest physiotherapy, manually assisted cough, early treatment of respiratory infections, noninvasive ventilation, and tracheostomy combined with permanent ventilation.
  
  
  
• Skeletal abnormalities are frequent complications of patients with a congenital myopathy.


• • Treatment to prevent contractures includes aggressive use of passive stretching, exercise, bracing, and surgical release procedures; these allow the patient to remain independent for as long as possible.

  • The development of scoliosis or kyphosis may impede standing, sitting, walking, and respiratory function. Bracing or surgical correction with spinal fusion are treatment options.
  
  
  
• The special concern of malignant hyperthermia in patients with CCD is discussed in Complications.



• As for other hereditary myopathies, a team approach, including a neurologist, pulmonologist, cardiologist, orthopedic surgeon, physiatrist, physical/occupational therapist, orthotist, and counselors, ensures the best possible therapy.

Surgical Care: Orthopedic surgery may be needed to help correct or prevent contractures, foot deformities, and scoliosis. A gastrostomy tube may be needed for newborns who have persistent feeding difficulties, although many neonates improve and can tolerate bottle-feeding after a few months of gavage feeding.

Consultations:

• Orthopedic surgeon



• Pulmonologist



• Cardiologist



• Gastroenterologist/dietician



• Geneticist/genetic counselor



• Physiatrist

• Physical/occupational therapist

• Orthotist

• Muscular Dystrophy Association

Diet: While no dietary restrictions are indicated in the myopathies, the diet should be tailored to the caloric needs of the patient. This may include restricting calories, especially in children with minimal mobility.

Activity: As mentioned above, one of the main goals of treatment is maintaining ambulation and functional ability with the aggressive use of physical therapy and bracing. Children should attend school either in regular classes or in classes designed to meet their specific physical needs. Regular exercise helps with cardiovascular fitness and general well-being.

FOLLOW-UP

Section 7 of 11

Further Inpatient Care:

• Neonates with severe weakness and hypotonia may need prolonged hospitalization for respiratory insufficiency and feeding difficulties. If the disease is nonprogressive, support can often be successfully withdrawn as symptoms improve.



• Older children may need admission for surgical care or cardiopulmonary complications.

Further Outpatient Care:

• Assess the following at least yearly:


• • Muscle function
  
  
  
  • Contractures
  
  
  
  • Ability to perform activities of daily living
  
  
  
  • Cardiopulmonary function
  
  
  

Complications:

• Patients with CCD (less frequently with multicore disease) are inclined to develop malignant hyperthermia. However, since the precise diagnosis may not be known, precautions should be taken in all patients with a presumed diagnosis of congenital myopathy. General anesthesia usually triggers a full-blown episode, but excessive heat, neuroleptic drugs, alcohol, or infections may trigger milder episodes.


• • If surgery is required, these patients (and their relatives) should avoid inhaled anesthetics (except nitrous oxide) and succinylcholine.
  
  
  
  • Signs and symptoms of malignant hyperthermia include the following:
    • Elevated pCO₂

    • Muscle rigidity

    • Tachycardia

    • Hemodynamic instability

    • Hyperventilation

    • Cyanosis

    • Lactic acidosis

    • Fever

    • Hyperkalemia

    • Hypercalcemia

    • Myoglobinuria
  
  
  
  • Death may result from pulmonary edema, coagulopathy, ventricular fibrillation, cerebral edema, or renal failure.
  
  
  
  • Appropriate treatment includes the following:
    • Stopping inhalational anesthetics or succinylcholine

    • Hyperventilating the patient with 100% oxygen

    • Administering dantrolene up to 10 mg/kg

    • Providing bicarbonate for metabolic acidosis

    • Cooling the patient

    • Monitoring for arrhythmias and hyperkalemia

    • Maintaining urine output over 2 mL/kg/h

    • Avoiding calcium antagonists and beta-blockers

    • Monitoring in an ICU for 24-48 hours
  
  
  
• Cardiac involvement can occur in patients with congenital myopathies, especially nemaline myopathy, CCD, and multiminicore disease.



• Pulmonary insufficiency can occur in any form of congenital myopathy that presents with severe neonatal hypotonia. It is more common or more severe in nemaline myopathy, X-linked and autosomal myotubular/centronuclear myopathy, multiminicore disease, and reducing body myopathy. This is especially important to assess before surgery since postoperative respiratory failure can occur.



• Skeletal deformities, including contractures and scoliosis, are common in patients with most of the congenital myopathies.



• Obstetric complications are uncommon in mothers with congenital myopathy during childbirth. However, neonatal complications can include polyhydramnios; decreased fetal movements; or complications related to fetal distress, abnormal presentation, failure to progress, or prematurity.

Prognosis:

• The prognosis depends on the form of congenital myopathy.


• • Severe disease often results in death in the neonatal period.
  
  
  
  • Less severe disease can result in lifelong disability.
  
  
  
  • Milder forms of congenital myopathy may result in only minor disability with a relatively normal life expectancy.
  
  
  

Patient Education:

• Genetic counseling is often helpful to assist patients with family-planning decisions. However, definitive prenatal diagnosis is only possible if a disease-causing mutation has been identified, and then usually only on a research basis since no laboratories performing this analysis are clinically available. Even with these difficulties, genetic counseling is important, especially for families of patients with CCD, to avoid unexpected cases of malignant hyperthermia in asymptomatic relatives.

MISCELLANEOUS

Section 8 of 11

Medical/Legal Pitfalls:

• CK level in the reference range and normal EMG findings do not rule out the presence of a congenital myopathy; a biopsy is almost always indicated.



• Because the diagnosis of congenital myopathy is often difficult, a clinician experienced in the diagnosis and treatment of neuromuscular diseases should interpret the findings of laboratory tests (ie, CK level), electrodiagnostic studies, and muscle biopsies.

Special Concerns:

• Additional information - Neuromuscular Disease Center at Washington University, St. Louis, Mo.

TEST QUESTIONS

Section 9 of 11

CME Question 1: A 1-year-old girl is referred for weakness. Findings from the examination show weakness of the arms and legs that is more proximal than distal and bilateral hip dislocation; the remaining findings of the examination are normal. Her creatine kinase (CK) level is moderately elevated. The family history includes an autosomal-dominant distribution of proximal weakness beginning in childhood or adolescence; an uncle died of unknown causes during minor surgery. What is the most likely diagnosis?

A: Centronuclear myopathy
B: Cerebral palsy
C: Congenital myotonic dystrophy
D: Central core disease
E: Nemaline rod myopathy

The correct answer is D: The correct answer is central core disease. This condition presents with congenital hip dislocation and a moderately elevated CK level, which are rare in other congenital myopathies. Malignant hyperthermia, an associated condition, may have been the cause of the uncle’s death.

CME Question 2: A 16-year-old adolescent boy presents with proximal muscle weakness. Which of these diseases is not in the differential diagnosis?

A: Centronuclear myopathy
B: Nemaline rod myopathy
C: Multiminicore disease
D: Limb-girdle muscular dystrophy
E: None of the above

The correct answer is C: Multiminicore disease has been described only in neonates or infants.

Pearl Question 1 (T/F): People with nemaline rod myopathy can have prominent cardiac complications.

The correct answer is True: Nemaline rod myopathy, central core disease, and multiminicore disease may have prominent cardiac complications.

Pearl Question 2 (T/F): People with central core disease often have prominent respiratory complications.

The correct answer is False: Nemaline rod myopathy, myotubular/centronuclear myopathy, multiminicore disease, and reducing body myopathy are often associated with prominent respiratory complications.

Pearl Question 3 (T/F): Patients with central core disease and their asymptomatic family members share an increased risk of malignant hyperthermia.

The correct answer is True: Malignant hyperthermia occurs significantly more frequently in these individuals than in the general population.

Pearl Question 4 (T/F): Congenital myotonic dystrophy is the most common type of congenital myopathy.

The correct answer is False: Nemaline rod myopathy is the most common congenital myopathy in most large series. Central core disease and centronuclear myopathy are also relatively common.

PICTURES

Section 10 of 11

Caption: Picture 1. Central core disease, nicotinamide adenine dinucleotide (NADH) stain. In the central core, mitochondria and oxidative enzymes are absent. Cores are also present on cytochrome oxidase and succinate dehydrogenase (SDH) stains.
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Caption: Picture 2. Nemaline rod myopathy, Gomori trichrome (GT) stain. Dark blue structures are seen only with this stain. They contain Z disk material, including alpha-actinin and tropomyosin.
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Caption: Picture 3. Centronuclear myopathy, hematoxylin and eosin stain. Note the numerous, centrally placed nuclei. Normal nuclei are at the periphery of the muscle fiber.
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Caption: Picture 4. Tubular aggregates, nicotinamide adenine dinucleotide (NADH) stain. Cytoplasmic collections of membranous tubules (derived from the sarcoplasmic reticulum) can be present in various myopathies, including myopathy with tubular aggregates, hypokalemic periodic paralysis, malignant hyperthermia, myotonia congenita, and ceratin toxic myopathies.
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BIBLIOGRAPHY

Section 11 of 11

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