Congenital Myopathies Clinical Presentation

The following are congenital myopathies with known genetic mutations:

Central core disease

Central core disease is due to a mutation in the ryanodine receptor (RYR1).

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. Patients usually live into adulthood.
• A history of decreased fetal movement or breech presentation is typical.
• Skeletal abnormalities are common, including congenital hip dislocation, kyphoscoliosis, and foot deformities.
• Typical MRI findings in the thigh include involvement of the adductor magnus, sartorius, and quadriceps group, except for the rectus femoris, which is spared along with the adductor longus and gracilis. In the calf, involvement of the soleus, lateral gastrocnemius, and peroneal group is observed, with sparing of the tibialis anterior.^[2]

Other presentations of ryanodine receptor mutations

Autosomal recessive (and autosomal dominant) inheritance have been described with several different presentations. Adolescent presentation may occur as a slowly progressive limb girdle syndrome.

Multiminicore disease (see below)

Presentation is in infancy with generalized weakenss and atrophy, external ophthalmoplegia, and bulbar and respiratory weakness.

Congenital myopathy with cores and rods

Presentation is at birth with delayed motor milestones, decreased childhood motor abilities, and facial weakness.^{[3, 4]} Weakness is slow or nonprogressive, with continued ability to walk into late adulthood. A severe presentation with prenatal akinesis, polyhydramnios, hypotonia at birth, respiratory failure, and death within 2 months has also been described.^[5]

Central nuclear myopathy

Seventeen of 24 patients with a histologic diagnosis of centronuclear myopathy but with no genetic diagnosis had a mutation in the RYR1 gene.^[6] Reduced fetal movements and hypotonia at birth were common. Weakness was nonprogressive, and all children attained unsupported sitting and about half walked independently. Bulbar, facial, and extraocular muscle weakness was common. Malignant hyperthermia was not noted.

Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1)

This is a rare disorder characterized by more than 99% type 1 muscle fibers without specific structural abnormality. Four of 10 patients with CNMDU1 were found to have a mutation in RYR. Clinical features included poor fetal movement, infantile hypotonia, poor suck, respiratory distress, proximal weakness, delayed motor milestones facial weakness, and skeletal deformity.^[7]

Malignant hyperthermia

See Complications. About 70% of patients with malignant hyperthermia have a mutation in the RYR1 gene.^[8] Malignant hyperthermia susceptibility 1 (MHS1) locus is the RYR1 gene. King-Denborough syndrome is included at this locus. Presentation is in childhood or adolescence usually with malignant hyperthermia. Non-progressive mild proximal weakness may be present. Mild dysmorphic facies and skeletal abnormalities such as short stature, pectus carinatum/excavatum, and scoliosis or kyphosis are often present.

Minimally or asymptomatic hyperCKemia

Presentation is usually as an adult with myalgia or fatigue. Malignant hyperthermia may occur. A severe variant has onset in utero with fetal akinesia and arthrogryposis. In the neonatal period, severe hypotonia and respiratory distress are noted.^[9]

Nemaline (rod) myopathy

Nemaline (rod) myopathy can be caused by mutations in at least 7 different genes. General features of all nemaline myopathies include minimally progressive or nonprogressive proximal limb, bulbar, and facial weakness starting in the neonatal or childhood periods; 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-onset or adult-onset cases. CNS disease is rare, but seizures have been reported in severe cases in the neonatal period.

Nemaline myopathy 1 (NEM1)

NEM1 is due to a mutation in the gene for α-tropomyosin 3 (TPM3). This is likely a rare cause (< 3%) of nemaline myopathy.^[10] 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)

NEM2 is due to a mutation in the gene for nebulin (NEB) and is likley the most common cause of nemaline myopathy. Inheritance in all cases has been autosomal recessive. Phenotypes are quite variable,^[11] with all but the adult-onset form being described in a large series encompassing 55 families.^[12]

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)

NEM3 is due to autosomal dominant, autosomal recessive, or sporadic de novo mutations in alpha-actin (ACTA1). It is likley the second most common cause of nemaline myopathy (20-30%), and overrepresents the severe phenotype.

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.^[13] More than 50% of patients had the severe congenital form of nemaline myopathy, although rare adult-onset cases have been described.

In a large series reporting previously published reports and unpublished data from the authors (Laing NG, et al.)^[71] 177 differnet mutations were described, 157 being missense, 133 being private, 74 arising de novo (most of these de novo dominant). Mutations occurred in 29% of the amino acid residues throughout α-actin. Only 21 autosomal dominant mutations were described, most having a mild phenotype. 17 autosomal recessive mutations were described, most causing a premature stop codon, complete absence of α-actin, and with a severe phenotype (rarely with a mild phenotype).

Mutations in ACTA1 can also cause nemaline myopathy with intranuclear rods.^[14] 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. Other disesase described due to ACTA1 mutations include (1) actin filament aggregate myopathy^[72] usually causing severe disease, (2) myopathy with core-like areas^[73] , and (3) congenital fiber type disproportion (see below)

Nemaline myopathy 4 (NEM4)

NEM4 is due to an autosomal dominant mutation in the gene for β-tropomyosin (TPM2). 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.

One consanguenous family with autosomal recessive inheritance has been described with a TPM2 mutationand Escobar syndrome^[76] (thick skin folds keeping joints in a fixed position). Presentation was at birth with hypotonia, pterygia and arthrogryposis.

A mutation in TPM2 has also been described in cap myopathy.^[15] 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.

Distal arthrogryposis has also been described as due to a mutation in TPM2.^[75] Presentation is at birth with flexion contractures of hands and feet.

Nemaline myopathy 5 (NEM5)

NEM5 is due to an autosomal recessive mutation in the gene for troponin T1 (TNNT1) and has been described only in the Old Order Amish.^[16] 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 6 (NEM6)

NEM6 is due to a mutation in Kelch repeat and BTB/POZ domains-containing protein 13 (KBTBD13).^[77] Presentation is in childhood with inability to run or jump. Slow movements are noted in most patients. Proximal and neck weakness is prominent. Progression is slow.

Nemaline myopathy 7 (NEM7)

NEM7 is due to an autosomal recessive mutation in the gene for cofilin-2 (CFL2) and has been described in only one family.^[17] 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.

Autosomal dominant mutations in dynamin 2 (DNM2)^{[19, 20]}

• Mutations in DNM2 account for about 50% of cases. Most patients have a mild phenotype with onset in adolescence or adulthood with axial/neck flexor as well as distal more than proximal limb weakness and slow progression. Other features can include facial weakness, ptosis, ophthalmoplegia and contractures especially of the ankles.
• 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 and there is often slow improvement to young adulthood. Intermediate cases have also been described.^[67]
• Sporadic cases have have also been described which usually have the more severe phenotype.^[66]

X-linked mutations in myotubularin (MTM1)^[53]

• 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.

Autosomal recessive mutations in amphiphysin 2 (bridging integrator 1; BIN1)^[18]

• Onset is usually at birth, but presentation can be in childhood. Reduced fetal movements and oligohydramnios may be present.
• Features include hypotonia, proximal weakness, facial weakness, ptosis, and ophthalmoplegia. Other features can include contractures, dilated cardiomyopathy and mental retardation. The course is slowly progressive, with more than 50% of patients surviving childhood.

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 (Congenital Muscular Dystrophy).

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 described^[21] 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.
• 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 dominant or recessive mutations in the gene for the ryanodine receptor (see above for central core disease). Ophthalmoplegia has been reported in patients with a mutation in the selenoprotein N gene.

A third mild phenotype presents with pelvic girdle weakness and is also often due to a mutation in the ryanodine receptor which can be dominant or recessive(see above for central core disease). Onset may be in infancy or childhood and other features include minimal or mild respiratory involvement, but without respiratory failure as well as joint laxity, hip dislocation, and arthrogryposis. Patients may also present in adulthood with myalgias and hyperCKemia.^[9] These patients and at risk family members should be screened for malignant hyperthermia.

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 4 genes can cause CFTD.

Mutations in TPM3 may account for up to 25% of cases.^[22] 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.^[23] Selenoprotein N mutations also cause congenital muscular dystrophy with spinal rigidity (Congenital Muscular Dystrophy). 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.^[24] 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.

Mutations in the gene for RYR1 may be a common cause of CFTD, possibly up to 10% of cases.^[25] In 4 of 7 families with small type 1 fibers as the main histologic feature, clinical features consistent with CFTD and no mutation in ACAT1 or TPM3, a compound heterozygous mutation was found in RYR1.

• All patients presented at birth with severe weakness and hypotonia except for one who presented at 2 years with difficulty running. The most severe cases developed progressive respiratory failure and died between 1 month and 3 years. Milder cases walked into their teens, although one patient at age 29 could only walk a few steps.
• Progressive proximal weakness, facial weakness and in three of five patients ophthalmoplegia was present.

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

Myosin storage myopathy (hyaline body myopathy) is due to a mutation in the myosin heavy chain 7 gene (MYH7) and is autosomal dominant or sporadic.

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.^[26]

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 same mutation may present with variable phenotypes as exemplified by one mutation (Leu1793Pro) shown to present with neonatal hypotonia, adult onset proximal weakness and isolated neonatal cardiomyopathy.^[27]

One family was described with histologic findings of CFTD in younger patients while in an older patient biopsy there was aggregates of slow myosin heavy chains.^[28]

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.

Mutations in MYH7 also cause hypertrophic cardiomyopathy (CMH-1), dilated cardiomyopathy (CMD-1S), and familial left ventricular non compaction.

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 (Limb-Girdle Muscular Dystrophy) making it likely that these two diseases are the same disorder.^[29]

Reducing Body myopathy

Reducing body myopathy has been shown to be due to a mutation in Four and a half LIM domain 1 (FHL1) on the X-chromosome. Several syndromes harbor the same mutation. Overlapping features include progressive weakness, rigid spine, scapular winging and contractures. Cardiomyopathy and respiratory involvement are seen in most subtypes. However, there are also differences in age of onset, distribution and severity of weakness and rate of progression.^[30]

• The most severe of the FHL1 myopathies is reducing body myopathy, named because of staining characteristics of intracytoplasmic aggregates. Age of onset varies from infancy to childhood and a few adult cases. In severe cases early onset motor delay leads to progressive weakness with spine rigidity early loss of ambulation and death in infancy or childhood due to respiratory failure. Adult-onset cases present in the third or fourth decade with asymmetric proximal and scapuloperoneal weakness which is slowly progressive. Cardiomyopathy is uncommon.^[31]
• X-linked dominant scapuloperoneal myopathy presents in the third or fourth decade with footdrop, proximal weakness, scapular winging and cardiomyopathy. Rigid spine and contractures are late features. Men are affected earlier and more severely usually becoming wheelchair bound.^[32]
• X-linked myopathy with postural muscle atrophy presents in the third decade with scapulo-axial-peroneal weakness, atrophy of postural muscles and bent/rigid spine. Hypertrophy of proximal upper limb muscles gives patients a pseudoathletic appearance.^[33]
• Emery-Dreifuss Muscular Dystrophy presentation is more fully described elsewhere. Typical features include cardiomyopathy and arrhythmia, progressive scapuloperoneal weakness and contractures of the elbow, ankle and spine.^[34]
• Rigid spine syndrome has been described in only one patient, a thirteen year old presenting with rigid spine, contractures, proximal weakness, scapular winging and respiratory involvement. Cardiomyopathy was present.^[35]

Spheroid body myopathy

Spheroid body myopathy due to a mutation in the myotilin gene has been found in one large kindred.^[36] This myopathy can be considered a myofibrillar myopathy/ desminopathy since aggregates include desmin. Mutations in myotilin also cause LGMD type 1A (Limb-Girdle Muscular Dystrophy.

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 need for 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 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, as shown below. 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.
  • 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.

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. Ordered 2-dimensional arrays are formed at the junctional terminal cisternae, in which each of the 4 subunits in every other RYR1 tetramer is physically coupled to a dihydropteridine receptor, and each RYR1 tetramer is physically coupled to 4 other tetramers.

Over 300 mostly missense (96%) mutations have been described. Mutations have been found throughout the entire length of RYR1, although 3 relative hot spots have been described.

One hypotheses proposed to explain malignant hyperthermia suggests that it results from abnormal repetitive Ca²⁺ cycling, characterized by spontaneous Ca²⁺ release and reuptake triggered by volatile anesthetics, stress, or elevated temperature.^[37]

• The basis for this hypothesis is that RyR1 mutations cause a lowered threshold for store overload-induced Ca²⁺ release (SOICR). SOICR is the process by which there is a rapid release of Ca²⁺ store when the size of the Ca²⁺ store reaches a certain threshold triggered by luminal Ca²⁺ concentration. (This sensor mechanism is in addition to a cytosolic Ca²⁺ sensor).
• Halothane further lowers the mutation-lowered SOICR threshold causing RYR1 to be triggered to open when the free luminal Ca²⁺ level overshoots its lowered SOICR threshold. Elevated cytosolic Ca²⁺ then triggers muscle contraction and hypermetabolism.

Other proposed mechanisms for malignant hyperthermia include inter-domain unzipping of RYR subunits, changes in RYR redox status, increased rate of Ca²⁺ entry into the sarcoplasmic reticulum lumen following adrenergic stimulus, changes in RyR phosphorylation status and elevated enzymatic Ryr function.

A hypothesis to explain phenotypic variability, variable penetrance and core formation is based on nonuniformity of the Ca²⁺ release unit.^[37] The Ca²⁺ release unit refers to the two-dimensional array of RyR1 molecules described above.

Because CCD is typically associated with heterozygous missense mutations, both wild type and mutant subunits are expressed. Random combination of subunits into RyR1 tetramers would produce 16 possible arrangements with 6 variants (homotetrameric wild type channels [1], homotetrameric mutant channels [1] and heterotetrameric channels in arrangements 3:1 [4]; 1:3 [4], 2:2 (side by side-[4]); 2:2 (diagonal-[2]).

The random association of different subunits within each tetramer followed by the random association of the 16 different types of tetramers within each Ca²⁺ release unit would set the stage for nonuniformity of Ca²⁺ release. This could also lead to nonuniformity of contraction among sarcomeric domains and subsequently to nonuniformity within myofibrils, myofibers, and muscle fasciculi ultimately, resulting in variable degrees of weakness that characterize RyR1-related myopathies.

Cores could be formed due to discordant contraction between adjacent myofibers. This would cause physical stress that could lead to tearing and shearing between myofibrils as well as displacement of mitochondria and the sarcotubular system. Eventually, small foci of damage would coalesce and manifest as cores.

Patients with autosomal recessive inheritance may have a more severe phenotype often with ophthalmoplegia. Mutations are spread throughout the RyR1 protein.^[38] 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).

Pathology

Central cores are single, well-circumscribed, central, circular areas that extend the length of most type 1 muscle fibers. See the image below.

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 histochemical features, aside from the central cores, include type 1 muscle fiber predominance, variable muscle fiber size, and increased internal nuclei.

Nemaline (rod) myopathy

Seven different mutations have been described, all but one (KBTBD13) 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.

NEM1 is due to mutations in the gene for α-tropomyosin (TPM3)

Autosomal dominant or recessive mutations in the gene for α-tropomyosin 3 (TPM3) cause NEM1. TPM3 mutations more commonly cause congenital fiber size disproportion. Tropomyosins are a family of actin-binding coiled coil proteins that help to regulate calcium-dependent muscle contraction. Multiple isoforms exist, with three stiated muscle isoforms; α-tropomyosin_fast (TPM1), β-tropomyosin (TPM2), and α-tropomyosin_slow (TPM3). In muscle the heterodimers α-tropomyosin_slow -β-tropomyosin (slow twitch) and α-tropomyosin_fast -β-tropomyosin (fast twitch) are most common.

In human and animal studies of a dominant mutation of TPM3 a number of functinoal defects were noted. There was reduced affinity for F-actin, reduced formation of preferred α/β heterodimers in favor of α/α heterodimers, destabilization of the coiled coil, impaired binding to tropomodulin and reduced sensitivity of isometric force production to activating calcium.^[39] ,^[79] ,^[80]

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.

NEM2 is due to mutations in the gene for nebulin (NEB)

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 present in skeletal and cardiac muscle. It is required for the proper assembly of thin filaments and for the maintenance of thin filament length and contractile function. It is also likely responsible for proper periodicity of the troponin/tropomyosin complex. Multiple isoforms exist, differing in the C-terminal structure, which binds α-actinin in the Z-disk and nebulin likely plays a role in Z-disk assembly.

Small deletions and duplications causing frameshifts and point mutations causing stop signals or altered splicing are more common than missense mutations.^[12] 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 affect 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.

NEM3 is due to mutations in the gene for α-actin (ACTA1)

Mutations in 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. The actin monomer, 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. F-actin binds to other thin filament proteins including nebulin, tropomyosins and troponins and most importatnly binds myosin during muscle contraction.

Most mutations are missense and spread throughout the gene. Autosomal dominant mutations 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. ACTA1 mutations may have one or more effects; increase or decrease 1) polymerization into F-actin, 2) the sliding speed of actin filaments, 3) calcium regulation or 4) the strength of binding to α-actinin.^[71]

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. Therefore, nemaline rods may result from either changes in normal stoichiometry of sarcomeric proteins or due to the presence of mutant α-actinin.

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.

NEM4 is due to mutations in the gene for β-tropomyosin (TPM2)

Autosomal dominant mutations in TPM2 are a rare cause of nemaline rod myopathy. Abnormal tropomyosin-actin interactions resulting in reduction in force generation, increased activation of myosin ATPase and destabiliztion of the coiled coil structure have been reported.

Mutations have also been associated wtih distal arthrogryposis and pterygia suggesting that β-tropomyosin may have a unique role during fetal development, particulary in distal muscles.

NEM5 is due to mutations in the gene for troponin T1 (TNNT1)

Three troponin subunits act as a complex to bind calcium and either block or unblock the myosin-binding site on actin. Troponin T binds to tropomyosin, troponin I inhibits actin-myosin interaction and troponin C binds calcium. Mutations in different isoforms of all of the three subunits cause distal arthrogryposis and cardiomyopathy.

Autosomal recessive mutations in the gene for troponin T1 (TNNT1) cause NEM5 in the Older Order Amish.^[16] The mutation causes a premature stop codon. the truncated protein 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. There is therfore a complete loss of troponin T1. Early compensation at birth may be due to fetal transcription of TNNT2 and TNNT3.^[81]

NEM6 is due to a mutation in KBTBD13

Autosomal dominant mutations in KBTBD13 cause NEM6. KBTBD13 protein localizes to the cytoplasm of skeletal and cardiac muscle. Over 60 proteins of the BTB/Ketch family have been identified. Functions include cytoskeletal modulation, regulation of gene transcription, ubiquitination, cell migration and myofibril assembly.^[77]

Pathological changes in muscle biopsies include numerous rods near Z-disks, type 1 fiber predominance and hypertrophy, and unstructured cores devoid of oxidative enzyme activity.^[77]

NEM7 is due to a mutation in cofilin-2 (CFL2)

Autosomal recessive mutation in the gene for cofilin-2 (CFL2) cause NEM7 in one family.^[17] 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.

Patholgy

Rods, the pathologic hallmark of nemaline rod myopathy, are only visible on modified Gomori trichrome (GT) stain as dark red/purple structures, as shown below.

Usually, the rods are sarcolemmal but may be intranuclear.

Derived from the Z-disk, 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 presumably form secondary to contractile protein (especially thin filament) dysfunction.

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

Centronuclear/myotubular myopathy can be due to several different mutations, but all affected proteins have a role membrane trafficking or in the maintenance of skeletal muscle fiber orignization, especially in the postitioning of nuclei.^[40]

MTM1 mutations

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.

DNM2 mutations

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.

BIN1 mutations

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. BIN1 protein binds to DNM2 protein and mutations in BIN1 may disrupt this binding or binding to T-tubules.^[18]

Pathology

The pathologic hallmark of all myotubular myopathies (X-linked and autosomal) is the predominance of type-1 fibers with large, centrally placed nuclei, as shown below. However, it is not known how any of the above mutations cause the pathologic abnormality. In DNM2 -related centronuclear myopathy the additional finding of radiating sarcoplasmic strands from the central nuclei is often present, often best seen on NADH staining.^[68]

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 and glycogen, but lacks myosin ATPase activity.

Type-1 muscle fiber hypotrophy is usually present. A variable degree of endomysial fibrosis and fatty replacement is present, often depending on time course and severity with more severe abnormalities increasing with age.

Internal nuclei (not necessarily centrally placed) are more common in patients with RYR1 mutations.^[68]

Necklace fibers - fibers with internalized nuclei in a basophilic ring just below the sarcolemma have been described in patients with MTM1 and DNM2 mutations.^{[69, 70]}

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.^[41]

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.^[41]

Pathology

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

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.^[22] 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 is not clear, but clinical syndromes overlap with most patients having a rigid spine and respiratory insufficiency.^[21]

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.^[42]

Autosomal recessive mutations in RYR1 may be the second most common cause of CFTD. All patients had one null mutation and one missense mutation. Biopsies showed type 1 fibers 51-84% smaller than type 2 fibers. Why RYR1 mutations cause CFTD in some patients and central core disease in others is unknown. Although none of the patients with CFTD had a family history of malignant hyperthermia, standard precautions are prudent.^[25]

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, dilated cardiomyopathy and left ventricular noncompaction.

Pathology

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

This 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.^[43]

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

This is an X-linked dominant disease due to a mutation in Four and a half LIM domain 1 (FHL1).^[30]

The LIM domain is a cysteine-rich double zinc-finger structure that bind zinc ions for protein stabilization. FHL proteins scaffold cytoskeletal and cell signaling complexes and help regulate gene transcription. FHL proteins are thought to be involved in myoblast migration and elongation as well as sarcomere formation through binding of myosin-binding protein C. In adult myofibers, FHL1 through the calcineurin signaling pathway helps to regulate myoblast fusion, skeletal muscle hypertrophy, and oxidative fiber-type shifting.

Cardiomyopathy is common in patients with FHL1 mutations and FHL1 plays multiple roles in the heart including modulation of conduction through interaction with the potassium channel KCNA5, regulation of cardiac hypertrophy through binding components of the MAPK signaling pathway and detection of mechanical stretch through interaction with the elastic N2B region of titin.

Why different mutations in FHL1 cause different syndromes is unknown, but mutations causing the more severe reducing body myopathy are often in exons 4/5 whereas mutations in the less severe Emery-Dreifuss muscular dystrophy are in exons 5-8.

In most patients FHL1 levels are reduced suggesting that loss of normal protein function via reduced FHL1 protein expression of impairment of protein-partner binding may also be important in disease pathogenesis.

Pathology

EM reveals numerous subsarcolemmal, non–membrane-bound aggregates 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 through a toxic gain of function.

Spheroid body myopathy

This 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.