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Congenital Myopathies
148 Congenital Myopathies
Jahannaz Dastgir, Hernan D. Gonorazky, Jonathan B. Strober, Nicolas Chrestian, and James J. Dowling
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Congenital myopathies are a clinically and genetically heterogeneous group of neuromuscular diseases. The most common clinical presentation is in the neonatal period as the floppy infant. However, congenital myopathies can present at essentially all life stages, making them an important diagnostic consideration in all individuals with muscle weakness. The prevalence of congenital myopathies is incompletely defined. The most accurate pediatric estimate (from a North American study) is approximately 1 : 26,000, though this is likely a significant underestimation given the increasing recognition of the condition and the delineation of an expanded range of clinical phenotypes considered under the congenital myopathy umbrella (North et al., 2014). Historically, congenital myopathies have been diagnosed and defined based on features observed on muscle biopsy. The first congenital myopathy described, central core disease (CCD), was by Shy and Magee in 1956. The most common histopathologic subtypes are nemaline myopathy (NM), centronuclear myopathy (CNM), core myopathy, and congenital fiber-type disproportion (CFTD). With significant improvements in the cost, availability, and diagnostic accuracy of genetic testing, a gene-based definition of congenital myopathies has recently taken shape. At present, the most accurate and parsimonious categorization for congenital myopathies incorporates clinical features, muscle biopsy findings, and genetic information. All congenital myopathies, with very rare exceptions, are assumed to have a genetic underpinning. To date, mutations in 20+ genes have been identified as causes of congenital myopathies (Table 148-1). These genes explain disease in approximately two thirds of all cases; in other words, about one third of the genetic burden of disease remains to be solved (Colombo et al., 2015). Inheritance can be autosomal dominant, autosomal recessive, and X-linked. Although a positive family history is often elicited, many cases are sporadic, and dominant mutations in particular often present (because of the severity of symptoms) as de novo. At present, no therapies have been defined for congenital myopathies that have been tested in controlled clinical trials (Wang et al., 2012). Therefore management has largely been symptomatic, with a strong focus on respiratory management, surgical correction of orthopedic complications, and application of physical and occupational therapy services to maximize motor function. For a select few congenital myopathies, cardiac management is also necessary. A handful of drugs, all of which seem to provide modest clinical benefit at best, have hinted at efficacy based on case-controlled studies. In addition, several candidate therapeutics have been developed in preclinical studies and are now on the cusp of assessment in the clinical arena. Efforts to evaluate these drug targets will hopefully usher in a new era of therapy for a group of previously untreatable and devastating diseases.
DIAGNOSTICS In general, congenital myopathies are considered in the setting of low muscle tone, depressed or absent reflexes, and extremity
muscle weakness, often of a long-standing nature, that exhibits limited active progression. Facial weakness is often a key additional clue (Fig. 148-1). Ultimately, the diagnosis of congenital myopathy, regardless of clinical presentation, is established through a compatible muscle biopsy result and/ or through positive genetic testing. The diagnostic strategy for assessing patients with neonatal hypotonia in whom congenital myopathy is suspected follows logically from the differential diagnoses (spinal muscular atrophy (SMA) DM1, congenital myasthenic syndromes, congenital muscular dystrophies, and Prader-Willi syndrome). Studies should include serum CPK levels (typically normal to maximum two to three times elevated in congenital myopathies), chromosomal microarray, genetic testing for SMA and congenital DM1, and (where available) electromyography and nerve conduction studies (EMG/NCS) (with repetitive stimulation) to evaluate for congenital myasthenic syndrome. Muscle magnetic resonance imaging (MRI) can also provide useful data in many cases. As mentioned, the diagnosis of congenital myopathy is only truly established through a consistent muscle biopsy and/or via positive genetic testing (see below under muscle biopsy and genetics sections). Similar strategies for diagnosis should be considered in the older child, keeping in mind that there will be a shift in consideration of potential alternative diagnoses based on age. A diagnostic algorithm that highlights some discriminative clinical and biopsy features is presented in Figure 148-2.
DIAGNOSTIC TESTING FOR CONGENITAL MYOPATHIES Muscle Biopsy The muscle biopsy has long been the definitive diagnostic study for congenital myopathies. In fact, congenital myopathies are defined and named by the characteristic observations seen by muscle pathology analysis. Each subtype of congenital myopathy is defined as follows (Dowling et al., 2015): Centronuclear myopathy (Jungbluth et al., 2008): The basic definition of CNM is the presence of centrally located nuclei in >25% of the muscle fibers. This number can be quite variable, and truly there is no specific threshold for establishing CNM. Central nuclei are best seen with hematoxylin/eosin (H/E) staining (Fig. 148-3, A), though can also be appreciated with Gomori trichrome. The diagnosis of CNM is thus usually established not only by the presence of central nuclei but also by other histopathologic features. These features include myofiber hypotrophy, type I fiber predominance, and central accumulation of staining product with oxidative stains. Nemaline myopathy: NMs are defined on biopsy by the presence of nemaline rods or nemaline bodies. Rods are composed primarily of proliferations of Z-band lattices. By light microscopy, rods are best visualized on Gomori trichrome staining, where they appear as eosinophilic aggregates (Fig. 148-3, B). The signature rod-like appearance from which the disorder derives its name is best appreciated by electron microscopy. In most cases, light microscopy is sufficient for
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TABLE 148-1 Classification of Congenital Myopathies by Genes Gene
Subtype
ACTA1
• Nemaline myopathy (NM) • Cap disease (NM variant) • Zebra body myopathy (NM variant) • Congenital fiber-type disproportion
TPM3
Inheritance Pattern
Protein
Features
AD, AR AD AD AD
Actin, alpha1, skeletal muscle
Onset; variable within families with variable severity. Could present severe arthrogryposis or fetal akinesia. Severe respiratory involvement out of proportion to muscle weakness rarely cardiomyopathy. One patient described with hypertonia.
• Nemaline myopathy (NM variant) • Cap disease (NM variant) • Congenital fiber-type disproportion
AD, AR AD AD
Tropomyosin 3
Onset at birth to early adolescence. Distal leg involvement with later involvement of proximal muscle. Slow progression. Respiratory involvement out of proportion to muscle weakness. Could present mild ptosis and mild facial involvement.
TPM2
• Nemaline myopathy(NM) • Cap disease (NM variant)
AD AD
Tropomyosin 2 (beta)
Onset at birth to early childhood. Distal leg weakness, severe arthrogryposis, fetal akinesia. Cardiac involvement (bifascicular ventricular block with right bundle block and left anterior hemiblock).
TNNT1
• Nemaline myopathy (NM)
AR
Troponin T type 1 (skeletal, slow)
Older order Amish and rare Dutch and Hispanic patients. Onset at birth, 1 month of age usually starts with tremor on the jaw and lower limbs (resolves by 3 months of age). Proximal weakness with mild proximal contractures, rigid chest wall severe respiratory involvement, death usually at the age of 2 years.
NEB
• Nemaline myopathy (NM)
AR
Nebulin
Variable onset, classic form, birth onset with dysmorphic features (high-arched palate, micrognathia, lower facial weakness with marked bulbar involvement chest deformities, nasal voice, and distal leg weakness respiratory involvement out of proportion to muscle weakness).
LMOD3
• Nemaline myopathy (NM)
AR
Leiomodin 3
Onset; prenatal. Polyhydramnios, multiple joint contractures, proximal distal and lower facial weakness with marked bulbar involvement, and ophthalmoplegia. Usually neonatal death.
KBTBD13
• Nemaline myopathy (NM)
AD
Kelch repeat and BTB (POZ) domain containing protein 13
Onset; childhood. Proximal and axial involvement, slow movements, high-arched palate, and thorax deformities.
CFL2
• Nemaline myopathy (NM)
AR
Cofilin 2 (muscle)
Onset at birth to early childhood. Proximal and axial weakness, prominent neck extensors involvement. Severe scoliosis.
KLHL40
• Nemaline myopathy (NM)
AR
Kelch-like family member 40
Onset; prenatal. Polyhydramnios, severe arthrogryposis and fetal akinesia, dysmorphic faces, severe respiratory and limb involvement, ophthalmoplegia usually death at the age of 5 months.
KLHL41
• Nemaline myopathy (NM)
AR
Kelch-like family member 41
Onset; prenatal. Fetal akinesia hip and knee dislocation with severe respiratory involvement early death. Missense mutations could present with mild forms with a survival into late childhood or early adulthood.
RYR1
• Central core myopathy • Multiminicore myopathy • Core rod myopathy • Nemaline myopathy • Congenital fiber-type disproportion • Centronuclear myopathy • Congenital neuromuscular disease with uniform type 1 fiber
AD, AR AR AD, AR AR AR AR AD
Ryanodine receptor I
Variable onset and severity. Proximal weakness, ptosis, ophthalmoplegia, hyperlaxity, congenital hip dislocation, scoliosis, moderate respiratory involvement, exercise induce myalgia, MHS. Could present rigid spine syndrome, and severe arthrogryposis.
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TABLE 148-1 Classification of Congenital Myopathies by Genes (Continued) Gene
Subtype
Inheritance Pattern
STAC3
• Native American myopathy
SEPN1
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Protein
Features
AR
SH3 and cysteine rich domain containing protein 3
Lumbee Indians in North Carolina. Congenital onset, dysmorphic features (telecanthus, cleft palate, downslating palpebral fissures, low ear set, ptosis), short stature, arthrogryposis proximal weakness, MHS.
• Multiminicore myopathy • Congenital fiber-type disproportion
AR AR
Selenoprotein N1
Onset birth to childhood. Predominant axial muscle involvement, poor head control, rigid spine, scoliosis at the age of 10 years, nocturnal hypoventilation central apnea during paradoxical sleep.
CCDC78
• Centronuclear myopathy
AD
Coiled coil domain containing protein 78
Congenital onset, distal involvement with slow progression, excessive fatigue mild to moderate cognitive impairment.
BIN 1
• Centronuclear myopathy
AR, AD
Amphiphysin
Variable onset. Severe forms present at birth or childhood. Proximal and lower facial weakness with marked bulbar involvement, ophthalmoparesis and ptosis, could present cardiomyopathy (dilated)
DNM2
• Centronuclear myopathy
AD
Dynamin 2
Variable onset. Distal muscle weakness, exercise induce myalgias, ophthalmoparesis, ptosis, lower facial weakness and marked bulbar involvement, slow progression hypertrophy of paravertebral muscles absent or reduce tendon reflexes, distal limb, contractures, scoliosis cardiomyopathy.
MTM1
• Myotubular myopathy
XR
Myotubularin 1
Onset; prenatal. Polyhydramnios, macrosomia, proximal and distal weakness with severe respiratory involvement at birth, lower facial weakness with marked bulbar involvement, usually early death, other features, bleeding diathesis, liver and gastrointestinal complications.
SPEG
• Centronuclear myopathy with dilated cardiomyopathy
AR
SPEG complex locus
Onset at birth, proximal weakness with lower face and bulbar involvement, ophthalmoplegia, hip contractures cardiomyopathy.
PTPLA (= HCDA1)
• Congenital myopathy related to PTPLA
AR
Protein tyrosine phosphatase-like (3-hydroxyacyl CoA dehydratase)
Onset birth. Lower facial and proximal weakness. Absent or reduce deep tendon reflexes. Severe presentation at onset with progressive improvement.
TTN
• Centronuclear myopathy • Congenital myopathy with fatal cardiomyopathy
AR AR
Titin
Onset, birth or infancy. Proximal and distal weakness with facial involvement. Could present asymmetric ptosis. Some with scapula-peroneal syndrome. Pseudohypertrophy of thighs and calves. Ambulation could be achieved in most of the cases. Scoliosis and absent reflexes. Cardiomyopathy (dilated)
MYH7
• Myosin storage myopathy • Myosin storage myopathy with cardiomyopathy • Congenital fiber-type disproportion
AD AR AD
Myosin, heavy chain 7, cardiac muscle
Onset at infancy or early childhood, distal weakness predominant, and week toe extensor (hanging big toe), scapular winging, mild facial involvement, cardiomyopathy (dilated or hypertrophic)
MYH2
• Myosin IIa myopathy
AD, AR
Myosin, heavy chain 2, skeletal muscle
Onset at birth, contractures, ophthalmoplegia, ptosis, mild to moderate proximal weakness
MEGF10
• Early onset myopathy, areflexia respiratory distress and dysphagia • Minicores
AR AR
Multiple EGF-like domains 10
Prenatal onset with reduced fetal movements. Proximal and distal weakness, distal contractures, scoliosis, areflexia, bulbar involvement, respiratory distress.
AD, autosomal dominant; AR, autosomal recessive; XR, X linked. (Adapted from Kaplan JC, et al. The 2015 version of the gene table of monogenic neuromuscular disorder. Neuromuscul Disord 2014;24:1123–53.)
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A
B
C
Figure 148-1. The “myopathic” facies. One of the characteristic clinical observations in many children with congenital myopathies is the so-called “myopathic” facial appearance. This can include both upper and lower facial weakness, as illustrated in these photomicrographs. Left panel: The patient depicted demonstrates ptosis, ocular misalignment caused by ophthalmoparesis, an inverted C-shape to her upper lip, and prominent lower facial weakness resulting in an open mouth appearance. The ultimate diagnosis in this case was nemaline myopathy caused by recessive mutation in the LMOD3 gene. Patients with nemaline myopathy often have particularly striking lower facial weakness. Middle panel: This individual has ptosis, ophthalmoparesis, and moderate lower facial weakness. He has DNM2-related centronuclear myopathy. Note also the muscle atrophy present in his chest and shoulders. Right panel: Photograph of a young boy with myotubular myopathy caused by MTM1 mutation. He has the characteristic long face with bilateral ptosis and ophthalmoparesis.
NEB
ACTA1
Muscle disease suspected (weakness, hypotonia, delayed motor miIestones)
Other NM
MTM1
Congenital myopathy suspected
CK normal or mildly elevated
RYR1
SEPN1
TTN
MYH7
Contractures Myopathic face
DNM2
Neck or Axial weakness
DNM2
Hip dysplasia/ scoliosis
Yes
Severe hypotonia NEB
Muscle MRI (Fig. 4)
MYH7
SPEG
Cardiomyopathy
Genetic testing (gene panel)
TTN
DNM2
LMOD3
EOM restricted
And\or
SEPN1
EO respiratory dysfunction
Physical Exam
Other diagnosis CMD Or repeat CK
RYR1
DNM2
Ptosis
No
Other CNM
And\or
ACTA1
Other NM
MTM1
Other CNM
Muscle biopsy Rods Cores Central nuclei
Confirmed Genetic diagnosis
Rods and cores Caps CFTD
Figure 148-2. Clinical approach to congenital myopathy, practical algorithm. ACTA1, ACTA1 nemaline myopathy; CFTD, congenital fiber-type disproportion; CK, creatine kinase; CMD, congenital muscular dystrophy; CNM, centronuclear myopathy; EO, early onset; EOM, extraocular movements; MM, mitochondrial myopathy; MYH7, MYH7 myopathy; NEB, nebulin mutation; NM, nemaline myopathy; Other NM, LMOD3, TPM2, TPM3, KBTBD13, TNNT1, KLHL40, KLHL41, and large spectrum of clinical presentation from mild to severe; RYR1, ryanodine receptor myopathy; SEPN1, SEPN1 myopathy; TTN, Titin myopathy.
establishing the diagnosis; however, there are instances where the rods are either poorly appreciated or else not seen at the light level and only revealed through electron microscopic analysis. In addition, there are histopathologic variants that are included within the nemaline umbrella. These include cap myopathy (where there is an accumulation of myofibrillar material sitting as a cap at the periphery of the myofiber) and zebra body myopathy (Dowling et al., 2015). Core myopathy (Jungbluth, 2007a,b): Core myopathies are typically subdivided into CCD and multiminicore myopathy. Cores are best appreciated on light microscopy with oxidative stains such as SDH and NADH (Fig. 148-3, C). They are defined as areas devoid of reactivity for these enzymes and reflect areas in the myofibers that lack mitochondria. Central cores are longitudinal and often traverse the entire length of the myofiber. Minicores are typically transverse in location and usually small. Core myopathies are often also seen in the context of type I fiber predominance and type I fiber hypotrophy, both features best seen with ATPase staining. Electron microscopy is often required for evaluation of core myopathies. This is because there are other conditions that can result in absence or change of SDH/NADH staining. Most prominent among them is the targetoid staining pattern seen with neurogenic lesions. On EM, cores appear as areas of myofibril disorganization that lack mitochondria. At times there will be a ring of mitochondria around the area of disorganization (referred to as a structured core). Congenital fiber-type disproportion: CFTD is defined by two biopsy features. The first is relative hypotrophy of type I fibers compared with type II fibers. The second is numerical predominance of type I fibers over type II fibers. The general criterion for calling CFTD is a 25% reduction in type I fiber size. Such a reduction is relatively nonspecific and can be seen in a range of disease, many of which are not primary myopathies. “True” CFTD, or CFTD caused by mutations in congenital myopathy genes, is usually characterized by much more significant reduction in type I fiber size (to <50% that of type IIs) and clear type I predominance (often >75% of fibers). CFTD can be seen by H/E staining, but is best diagnosed and evaluated using stains for fiber type (Fig. 148-3, D). These include enzymatic reactions (ATPase at acid pH [4.3 to 4.6] to stain type I fibers and at basic pH [9.4 to 10.2] to mark type II fibers) or immunostaining with myosin antibodies (slow myosin for type I and fast myosin for type II).
Genetics All pediatric-onset (and most adult-onset) congenital myopathies are considered to have a genetic underpinning. It is important to establish a genetic diagnosis, even when a child has a consistent muscle biopsy, because knowledge of the specific genetic subtype greatly contributes to understanding of specific clinical features, anticipatory care requirements, and prognostication (Wang et al., 2012; North et al., 2014). Mutations in congenital myopathies span the range of inheritance patterns (X-linked, autosomal recessive, autosomal dominant) and often are caused by sporadic/de novo variants. To date, mutations in 20 genes have been identified as causal in patients with congenital myopathy (see Table 148-1). The interplay between clinical presentation, biopsy diagnosis, and genetic subtype is complex. In particular, there are several genetic causes for each histopathologic grouping (e.g., mutations in 10 genes are associated with NM), and each genetic cause can result in a variety of clinical presentations and histopathologic diagnoses (e.g., RYR1 mutations have been described in every histopathologic subtype) (North et al., 2014). Of note, it is critically important that genetic counseling be offered to all patients with congenital myopathies and to their families,
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ideally starting at the time that genetic testing is first considered (Wang et al., 2012).
Muscle Imaging (MRI or Ultrasonography) Muscle imaging is an emerging modality for the diagnosis and care of patients with a range of neuromuscular disorders. For congenital myopathies it is used primarily as an adjunct diagnostic tool, though in the future may aid in assessment of disease status and progression. Muscle ultrasonography is the fastest and least expensive technique and offers the potential of application in the outpatient clinic and/or inpatient setting, though requires an experienced user for interpretation. Muscle MRI is widely available and does not require any particular advanced training to obtain or analyze; the downside is expense and the fact that some children (particularly those under age 5 years) may require sedation. The diagnostic value of muscle imaging lies in the fact that different genetic subtypes of myopathy present with different imaging patterns of muscle involvement. The pathognomonic patterns are best characterized with lower extremity imaging, though the value of whole-body MRI for diagnosis (particularly in the young child) is increasingly being recognized. Representative examples of muscle MRI and a diagnostic flow chart describing its application are presented in Figure 148-4.
SPECIFIC SUBTYPES OF CONGENITAL MYOPATHY Centronuclear Myopathies Centronuclear myopathies, even though clinically heterogeneous (particularly in terms of symptom onset and severity), often feature prominent eye muscle weakness (ptosis and ophthalmoparesis) in addition to lower facial and extremity weakness (Jungbluth et al., 2008). In infancy and childhood, these features can appear like those seen in congenital myasthenic syndromes. The extremity weakness may have significant distal involvement, including distal predominance in some individuals. There are six established genetic causes of CNM. Mutations in myotubularin (MTM1) are associated with the distinctive, severe, neonatal-onset X-linked condition myotubular myopathy (XLMTM or MTM) (Das et al., 1993). Mutations in dynamin-2 (DNM2) are the most common cause of dominant CNM; patients typically present either in the first year or two of life (with de novo mutations) or in late childhood. Recessive causes of CNM include mutations in RYR1, BIN1, TTN, and SPEG. RYR1 mutations are the most common and can present in infancy in a manner resembling MTM. BIN1 mutations typically cause childhood-onset CNM, though one particular homozygous splice mutation results in a rare, rapidly progressive form. There is also a late-onset CNM in some families with dominant BIN1 mutations. SPEG mutations cause a rare, severe form of CNM that also includes cardiomyopathy. There are currently no therapies that have been proven to be efficacious for CNM. There is mounting evidence, however, including several case reports and compelling preclinical data, that acetylcholinesterase inhibitors such as pyridostigmine provide modest but definitive improvement in clinical symptomatology. Patients with mutations in RYR1, DNM2, and MTM1 have all been reported in these case series. In terms of experimental therapies, there is considerable excitement concerning both gene therapy and enzyme replacement therapy for MTM. These strategies have shown robust disease correction in the MTM mouse model, and gene therapy
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additionally has been effective in a spontaneous dog model of the disease.
Nemaline Myopathies NMs are characterized in general by the presence of significant bulbar dysfunction (because of lower face and neck flexor weakness) in the setting of additional and variable extremity weakness (North et al., 2014). The disease is noted to have significant clinical variability and has thus been classically subdivided into groups based on age of onset and clinical severity: (1) severe congenital NM (16% of NM cases), (2) intermediate congenital NM (20%), (3) typical congenital NM (46%), (4) childhood-/juvenile-onset NM (13%), and (5) adult-onset NM (4%) (North and Ryan, 1993). There is considerable overlap between the groups, though the distinctions can be helpful (e.g., individuals with severe congenital NM have a high risk of death in infancy, whereas those with typical congenital NM tend to show stabilization and even improvement). There are 10 known genetic causes of NM. Mutations in ACTA1 are the most common dominant/de novo cause (25% of all NM), whereas those in nebulin (NEB) are the most common autosomal-recessive cause (~50% of all NM). Mutations in ACTA1 are associated with a tremendous variability in age of presentation and clinical expression, not only between different mutations in the gene but also among family members with the same mutation. They are the most common cause of severe congenital NM (severe weakness, reduced or absent fetal/neonatal movements, respiratory failure, and often death in infancy). Mutations in NEB are most frequently encountered with typical congenital NM (neonatal hypotonia, weakness, feeding difficulties, ability to eventually ambulate, static/slowly progressive course). The specific breakdown in terms of relative prevalence of the other genetic subtypes is otherwise not well established. Some are associated primarily with specific clinical groupings. LMOD3 and KLHL40 mutations are seen almost exclusively with severe congenital NM. Dominant mutations in TPM2 and TPM3 are associated with symptoms ranging from typical congenital to mild childhood (with TPM2 mutations usually milder), whereas rare recessive mutations in TPM3 are associated with severe disease. TPM2 mutations can additionally been seen in the absence of overt weakness with distal arthrogryposis syndromes. Dominant mutations in KBTBD13 are seen with childhood-onset NM and characteristic slowness of movements. Recessive mutations in TNNT1 (Amish NM) and CFL2 (severe or typical congenital) are extremely rarely encountered. Of note, ophthalmoparesis is infrequently observed in NM (with the exception of LMOD3 mutations), and may serve as a means of distinguishing NM from other congenital myopathies. At present, there are no specific therapies that have proven efficacious for NM. L-tyrosine has been examined in a mouse model of Acta1 and shown to increase muscle strength; a limited patient case series examining L-tyrosine found that it improves some bulbar symptoms and specifically sialorrhea. Its impact on disease course is likely limited, and true efficacy awaits more systematic clinical study. There are no other therapies currently in the clinical pipeline, though a few are at the stage of preclinical assessment.
Core Myopathies Core myopathies can be subdivided into CCD and multiminicore disease (MmD). CCD is caused by RYR1 mutations (usually dominant/de novo) in approximately 90% of cases (Jungbluth, 2007a). The other well-described cause
is dominant MYH7 mutation. Minicore disease, along with the more general categorization of myopathy with cores, has several genetic causes (Jungbluth, 2007b). Most classically, it is caused by mutations in either SEPN1 (MmD without ophthalmoparesis) or RYR1 (MmD with ophthalmoparesis). Other genetic causes include ACTA1, TTN, MEGF10, and CCDC78; biopsies in these settings typically include additional histopathologic abnormalities (such as rods or protein aggregates). In addition, there can be both cores and rods in the same biopsy (termed “core-rod” myopathy), with known causes, including TPM2, NEB, RYR1, ACTA1, and KBTBD13.
RYR1-Related Myopathies Myopathies caused by mutations in the skeletal muscle ryanodine receptor (RYR1) are the commonest group of nondystrophic muscle conditions. These are also termed “RYR1-related myopathies,” and encompass a broad clinical spectrum that spans the entire gamut of histopathologic subtypes. RYR1related myopathies are subdivided primarily either by mode of inheritance (recessive vs. dominant/de novo) or by histopathology (CCD, MmD, CNM, etc.), though there are distinctive clinical conditions that do not classically fall into a specific grouping (e.g., axial myopathy, malignant hyperthermia, exertional rhabdomyolysis, isolated ophthalmoparesis). CCD associated with RYR1 mutation is almost entirely caused by dominant mutations (Jungbluth, 2007a). The typical pediatric presentation for CCD is one of neonatal hypotonia, muscle hypotrophy, and extremity muscle weakness, often accompanied by significant skeletal abnormalities such as chest wall deformities, scoliosis, joint contractures, and hip dysplasia. Respiratory failure is present in some instances, though rarely requires tracheostomy and often improves. The course of disease is typically quite stable, and, although delayed, individuals often acquire all motor developmental milestones. Of note, there may be some mild facial muscle involvement, including ptosis and lower facial weakness, but ophthalmoparesis is rarely encountered. There is also a milder CCD presentation that includes minimal weakness that may only be recognized in adulthood; there are also several cases of dominant mutations causing late-onset axial myopathy. Rarely, heterozygous de novo mutations can present with extreme weakness in the perinatal period that results in death in infancy. The mutations in RYR1 that cause CCD are enriched in the C-terminal aspect of the gene. Some are additionally associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic condition of hypermetabolism and muscle breakdown in response to exposure to volatile anesthetics. The other histopathologic subtypes (MmD, CNM, core-rod myopathy, and CFTD) are most commonly seen with recessive RYR1 mutations. The most frequently encountered recessive subtype is minicore disease, which typically presents with diffuse weakness in combination with ophthalmoparesis. Onset is usually in the neonatal period or in early childhood, and can be severe enough to result in respiratory failure with chronic ventilator support and wheelchair dependence. As with CCD, skeletal abnormalities (particularly joint contractures and scoliosis) are quite frequently encountered. These are often accompanied by severe facial weakness that can include ophthalmoparesis. Axial muscle involvement can also be quite pronounced. At present, there are no specific treatments for RYR1-related myopathies. Salbutamol has been shown in a small casecontrol series to improve strength and motor function. This result has not been followed up with additional clinical trials, and the medication is not widely used in RYR1 patients. An intriguing candidate drug class is the RyCals; RyCals interact with RyR1 and augment its ability to release calcium. RyCals
have yet to be tested for efficacy in patients, and have not been examined in any preclinical models of RYR1 myopathy. One drug that has shown promising results in animal models and in patient cells is the antioxidant N-acetylcysteine (NAC). NAC is currently being evaluated in a placebo-controlled clinical trial in ambulant RYR1 myopathy patients. Of note, dantrolene is the standard therapy for treating MH. It has yet to be tested in other dynamic RYR1-related phenotypes such as rhabdomyolysis. Because it reduces RyR1 calcium release, it is unlikely to be effective in the majority of instances of RYR1 mutations that cause static muscle weakness.
SEPN1-Related Myopathies Recessive mutations in SEPN1 were first described in a rare muscular dystrophy subtype called rigid spine muscular dystrophy. However, SEPN1 mutations are most typically found associated with multiminicore disease; they are also seen with other histopathologic patterns, including CFTD and Mallory Body myopathy. Regardless of histopathologic phenotype, patients with SEPN1 mutations present a relatively uniform clinical picture. This picture includes early onset hypotonia and axial muscle weakness with relative sparing of the extremity muscles. It also includes spinal rigidity; severe, progressive scoliosis; and potentially lethal, progressive respiratory failure. These severe axial symptoms are not matched by corresponding limb weakness, with the resulting appearance often one of an ambulant patient with ventilator dependence. Patients do not have ophthalmoparesis, a distinguishing feature from RYR1 mutations. SEPN1 encodes selenoprotein N1 (SelN1), a selenocysteinecontaining protein located in the endoplasmic reticulum. The functions of SelN1 in relation to muscle structure and function have been relatively elusive, though it seems clear that one of its major roles is to regulate oxidative stress. Based on this, the consequences of SEPN1 mutations (which in general result in loss of SelN1 expression and/or function) are predicted to be increased basal oxidative stress, susceptibility to the consequences of oxidative species, and ultimately impaired redox related RyR1 function. As with RYR1 myopathies, the antioxidant NAC protects SEPN1-patient-derived myotubes from oxidant-related death, and is now being considered for clinical trial in SEPN1-related myopathy patients.
Congenital Fiber-Type Disproportion CFTD is a diagnosis applied in the context of clinical symptoms of myopathy and fiber-type disproportion on biopsy (significantly smaller type I fibers, usually type I predominance) (Clarke, 2011). The biopsy observation of CFTD often precedes or is accompanied by other pathologic features (rods, cores, etc.); in such cases, the individual is typically described as having the diagnoses corresponding to the other biopsy features (e.g., NM when rods are present). Some individuals, however, do have “pure” CFTD (usually considered when type I fibers are >40% smaller). When this occurs, the recognized genetic causes are mutations in TPM3, TPM2, RYR1, SEPN1, and ACTA1. The clinical presentations in these cases are primarily dictated by the underlying genetic cause; for example, patients with CFTD caused by TPM3 mutations resemble those with similar mutations and NM on biopsy.
GENERAL MANAGEMENT OF CONGENITAL MYOPATHIES General management guidelines for congenital myopathies are based on practical experience, expert opinion, and inferences from other similar neuromuscular conditions. These
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guidelines are summarized here, and also found in extensive detail in the recently published standards of care for congenital myopathies (Wang et al., 2012).
Respiratory Respiratory dysfunction is the likeliest cause of morbidity and mortality in children with congenital myopathies. This relates to the fact that the diaphragm and intercostal muscles are often weakened in these conditions, leading to poor rib excursion, impaired mucus expectoration and airway clearance, and sleep apnea. The recognition of early respiratory compromise (often identified via sleep study or pulmonary function testing in both the seated and supine positions) leads to early intervention via noninvasive ventilation, typically first at night and then during daytime in more severe or progressive cases. Identifying a weak cough in patients is also an important predictor of how a child may respond to an upper respiratory infection. A weak cough can predispose to mucus plugging and bronchiectasis and hence cause risk for fatal pneumonias. This can be prevented with the use of a cough assist device (either while sick or best also when healthy) as a form of pulmonary physical therapy. A thairvest, which employs chest vibration to loosen mucus, may also be used, though it is imperative that this treatment is followed by cough assist regimen. This is so that the mucus that is loosened as a result of this procedure can actually be expectorated and not actually make things worse by being left to plug the airways.
Nutrition, Gastrointestinal, and Oromotor Management Nutritional management guidelines for congenital myopathies are essentially nonexistent despite the fact that poor nutrition and growth are inherent to many of these conditions. Weakness in oromotor function is a contributing factor, particularly in nemaline and centronuclear myopathies. Efforts should be made to monitor patient weight and height (either erect or via ulnar length) in conjunction with calorie intake. If calorie intake is limited, or the risk of aspiration pneumonia is high, the placement of a gastrostomy tube should be discussed with families early in the disease course. Improved nutritional status has been related to improved growth and decreased respiratory problems. Yearly assessments of calcium and vitamin D levels should also be made in order to address bone health, as osteopenia is a concern in any individual with long-standing muscle weakness. Gastrointestinal dysmotility is also a frequent problem in children with congenital myopathies. Dysmotility may present as gastroesophageal reflux, which can be managed with medication (e.g., proton pump inhibitors, H2 blockers, and antacids), nonpharmacologically (e.g., thickening of formula and adjusting feeding positions), and/or surgically (e.g., with Nissen fundoplication). Dysmotility can also present with delayed gastric emptying and constipation, symptoms that can be treated with diet modification, stool softeners/ laxatives, and the use of prokinetic drugs (erythromycin or metaclopromide). Excessive oral secretions are often a significant problem in congenital myopathies. This is related to bulbar and facial weakness and particularly seen in nemaline and CNM. Speech and occupational therapy can be used to address this, primarily through facial muscle–strengthening exercises. If this is not successful, anticholinergic drugs may be administered systemically (e.g., robinul and scopolamine), though they are not without systemic side effects (e.g., constipation). A small study has also found evidence that L-tyrosine supplementation may
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be helpful with sialorrhea in NM. Botulinum toxin injections and surgical management are considered in very rare circumstances when secretions are particularly debilitating, though such strategies are controversial.
Cardiac The majority of congenital myopathy subtypes are not associated with primary cardiac involvement. Baseline and periodic follow-up cardiac evaluations, however, should be provided to all patients with congenital myopathy until the specific genetic cause has been identified. This is because certain gene mutations, such as those in TTN, MYH7, SPEG, and (more rarely) ACTA1, can cause cardiomyopathy. In addition, continued cardiac screening is indicated in settings (SEPN1related myopathy, for example) where secondary right-sided heart failure is of concern because of chronic respiratory compromise.
Orthopedic Scoliosis is a pervasive problem in these conditions and should be monitored from the initial presentation of symptoms. This can initially be done via clinical examination (with the patient assessed in forward flexion at the hip), but once any curvature is noted, routine x-rays should be obtained. Once scoliosis has been diagnosed, patients should be referred to orthopedics for the management of the progressive curvature with either a conservative (e.g., bracing/casting) or invasive/surgical approach. The management of scoliosis is essential for maintaining respiratory function. Joint contractures are a concern for the majority of congenital myopathy patients, and may in fact be the presenting sign of patients in some individuals. Ankle contractures are typically managed with physical therapy, passive stretching, and ankle-foot orthoses, which are used in the ambulant patient to slow contracture progressive and to improve gait, and in the nonambulant patient to aid in comfort and wheelchair positioning. Surgery to release contractures is rarely indicated, as it often does not appreciably improve range of motion and can potential worsen muscle weakness. Exceptions include contractures that significantly hinder ambulation (in the setting of relatively preserved strength) and those that cause considerable discomfort (in the nonambulant patient).
Physical Therapy/Exercise Physical therapy is mainstay of management in children with congenital myopathy. It helps with strengthening and improves range of motion. It should be utilized regularly and in a manner that matches the child’s pattern of weakness. Assist devices can complement therapy services, and include gait trainers and stationary bikes. The impact of exercise on muscle strength and motor function in congenital myopathies has yet to be formally addressed, though there is anecdotal evidence that exercise in children with myopathies is safe and potentially of benefit. Further work is necessary to establish this as a formal recommendation.
SUMMARY Congenital myopathies represent a clinically and genetically heterogeneous group of childhood muscle disorders. With
improvements in clinical recognition and genetic testing, it is now clear that these disorders represent a significant portion of childhood genetic neuromuscular disease. The availability of gene panels and whole-exome sequencing has improved diagnostics, has enabled the discovery of new myopathy genes, and has greatly broadened the genotype-phenotype spectrum of these disorders. It has also presented challenges related to disease classification and genetic variants of unknown clinical significance; in addition, the genetic cause in many individuals still remains elusive. Currently there are few, if any, therapies available for these often devastating disorders; however, work using preclinical model systems has identified several promising candidates for translation into the clinical arena. One of the key challenges in the future will be effectively translating these drugs, and factors related to disease natural history and clinical trial readiness are becoming of paramount importance as the field moves forward toward hopefully identifying meaningful therapies. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Clarke, N.F., 2011. Congenital fiber-type disproportion. Semin. Pediatr. Neurol. 18, 264–271. Colombo, I., et al., 2015. Congenital myopathies: natural history of a large pediatric cohort. Neurology 84, 28–35. Das, S., Dowling, J., Pierson, C.R., 1993. X-Linked centronuclear myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington–Seattle, Seattle, WA, pp. 1993–2016. Dowling, J.J., et al., 2015. Congenital and other structural myopathies. In: Darras, B.T., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Elsevier, New York, pp. 502–537. Jungbluth, H., 2007a. Central core disease. Orphanet J. Rare Dis. 2, 25. Jungbluth, H., 2007b. Multi-minicore disease. Orphanet J. Rare Dis. 2, 31. Jungbluth, H., Wallgren-Pettersson, C., Laporte, J., 2008. Centronuclear (myotubular) myopathy. Orphanet J. Rare Dis. 3, 26. North, K.N., Ryan, M.M., 1993. Nemaline myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington– Seattle, Seattle, WA, pp. 1993–2016. North, K.N., et al., 2014. Approach to the diagnosis of congenital myopathies. Neuromuscul. Disord. 24, 97–116. Wang, C.H., et al., 2012. Consensus statement on standard of care for congenital myopathies. J. Child Neurol. 27, 363–382.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 148-3. The common congenital myopathy subtypes by histopathology. Fig. 148-4. Muscle MRI in congenital myopathies. Fig. 148-5. MTM- and DNM2-related centronuclear myopathy. Fig. 148-6. ACTA1- and NEB-related nemaline myopathies. Fig. 148-7. RYR1-related myopathy.
Jahannaz Dastgir, Hernan D. Gonorazky, Jonathan B. Strober, Nicolas Chrestian, and James J. Dowling
An expanded version of this chapter is available on www.expertconsult.com. See inside cover for registration details. Congenital myopathies are a clinically and genetically heterogeneous group of neuromuscular diseases. The most common clinical presentation is in the neonatal period as the floppy infant. However, congenital myopathies can present at essentially all life stages, making them an important diagnostic consideration in all individuals with muscle weakness. The prevalence of congenital myopathies is incompletely defined. The most accurate pediatric estimate (from a North American study) is approximately 1 : 26,000, though this is likely a significant underestimation given the increasing recognition of the condition and the delineation of an expanded range of clinical phenotypes considered under the congenital myopathy umbrella (North et al., 2014). Historically, congenital myopathies have been diagnosed and defined based on features observed on muscle biopsy. The first congenital myopathy described, central core disease (CCD), was by Shy and Magee in 1956. The most common histopathologic subtypes are nemaline myopathy (NM), centronuclear myopathy (CNM), core myopathy, and congenital fiber-type disproportion (CFTD). With significant improvements in the cost, availability, and diagnostic accuracy of genetic testing, a gene-based definition of congenital myopathies has recently taken shape. At present, the most accurate and parsimonious categorization for congenital myopathies incorporates clinical features, muscle biopsy findings, and genetic information. All congenital myopathies, with very rare exceptions, are assumed to have a genetic underpinning. To date, mutations in 20+ genes have been identified as causes of congenital myopathies (Table 148-1). These genes explain disease in approximately two thirds of all cases; in other words, about one third of the genetic burden of disease remains to be solved (Colombo et al., 2015). Inheritance can be autosomal dominant, autosomal recessive, and X-linked. Although a positive family history is often elicited, many cases are sporadic, and dominant mutations in particular often present (because of the severity of symptoms) as de novo. At present, no therapies have been defined for congenital myopathies that have been tested in controlled clinical trials (Wang et al., 2012). Therefore management has largely been symptomatic, with a strong focus on respiratory management, surgical correction of orthopedic complications, and application of physical and occupational therapy services to maximize motor function. For a select few congenital myopathies, cardiac management is also necessary. A handful of drugs, all of which seem to provide modest clinical benefit at best, have hinted at efficacy based on case-controlled studies. In addition, several candidate therapeutics have been developed in preclinical studies and are now on the cusp of assessment in the clinical arena. Efforts to evaluate these drug targets will hopefully usher in a new era of therapy for a group of previously untreatable and devastating diseases.
DIAGNOSTICS In general, congenital myopathies are considered in the setting of low muscle tone, depressed or absent reflexes, and extremity
muscle weakness, often of a long-standing nature, that exhibits limited active progression. Facial weakness is often a key additional clue (Fig. 148-1). Ultimately, the diagnosis of congenital myopathy, regardless of clinical presentation, is established through a compatible muscle biopsy result and/ or through positive genetic testing. The diagnostic strategy for assessing patients with neonatal hypotonia in whom congenital myopathy is suspected follows logically from the differential diagnoses (spinal muscular atrophy (SMA) DM1, congenital myasthenic syndromes, congenital muscular dystrophies, and Prader-Willi syndrome). Studies should include serum CPK levels (typically normal to maximum two to three times elevated in congenital myopathies), chromosomal microarray, genetic testing for SMA and congenital DM1, and (where available) electromyography and nerve conduction studies (EMG/NCS) (with repetitive stimulation) to evaluate for congenital myasthenic syndrome. Muscle magnetic resonance imaging (MRI) can also provide useful data in many cases. As mentioned, the diagnosis of congenital myopathy is only truly established through a consistent muscle biopsy and/or via positive genetic testing (see below under muscle biopsy and genetics sections). Similar strategies for diagnosis should be considered in the older child, keeping in mind that there will be a shift in consideration of potential alternative diagnoses based on age. A diagnostic algorithm that highlights some discriminative clinical and biopsy features is presented in Figure 148-2.
DIAGNOSTIC TESTING FOR CONGENITAL MYOPATHIES Muscle Biopsy The muscle biopsy has long been the definitive diagnostic study for congenital myopathies. In fact, congenital myopathies are defined and named by the characteristic observations seen by muscle pathology analysis. Each subtype of congenital myopathy is defined as follows (Dowling et al., 2015): Centronuclear myopathy (Jungbluth et al., 2008): The basic definition of CNM is the presence of centrally located nuclei in >25% of the muscle fibers. This number can be quite variable, and truly there is no specific threshold for establishing CNM. Central nuclei are best seen with hematoxylin/eosin (H/E) staining (Fig. 148-3, A), though can also be appreciated with Gomori trichrome. The diagnosis of CNM is thus usually established not only by the presence of central nuclei but also by other histopathologic features. These features include myofiber hypotrophy, type I fiber predominance, and central accumulation of staining product with oxidative stains. Nemaline myopathy: NMs are defined on biopsy by the presence of nemaline rods or nemaline bodies. Rods are composed primarily of proliferations of Z-band lattices. By light microscopy, rods are best visualized on Gomori trichrome staining, where they appear as eosinophilic aggregates (Fig. 148-3, B). The signature rod-like appearance from which the disorder derives its name is best appreciated by electron microscopy. In most cases, light microscopy is sufficient for
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TABLE 148-1 Classification of Congenital Myopathies by Genes Gene
Subtype
ACTA1
• Nemaline myopathy (NM) • Cap disease (NM variant) • Zebra body myopathy (NM variant) • Congenital fiber-type disproportion
TPM3
Inheritance Pattern
Protein
Features
AD, AR AD AD AD
Actin, alpha1, skeletal muscle
Onset; variable within families with variable severity. Could present severe arthrogryposis or fetal akinesia. Severe respiratory involvement out of proportion to muscle weakness rarely cardiomyopathy. One patient described with hypertonia.
• Nemaline myopathy (NM variant) • Cap disease (NM variant) • Congenital fiber-type disproportion
AD, AR AD AD
Tropomyosin 3
Onset at birth to early adolescence. Distal leg involvement with later involvement of proximal muscle. Slow progression. Respiratory involvement out of proportion to muscle weakness. Could present mild ptosis and mild facial involvement.
TPM2
• Nemaline myopathy(NM) • Cap disease (NM variant)
AD AD
Tropomyosin 2 (beta)
Onset at birth to early childhood. Distal leg weakness, severe arthrogryposis, fetal akinesia. Cardiac involvement (bifascicular ventricular block with right bundle block and left anterior hemiblock).
TNNT1
• Nemaline myopathy (NM)
AR
Troponin T type 1 (skeletal, slow)
Older order Amish and rare Dutch and Hispanic patients. Onset at birth, 1 month of age usually starts with tremor on the jaw and lower limbs (resolves by 3 months of age). Proximal weakness with mild proximal contractures, rigid chest wall severe respiratory involvement, death usually at the age of 2 years.
NEB
• Nemaline myopathy (NM)
AR
Nebulin
Variable onset, classic form, birth onset with dysmorphic features (high-arched palate, micrognathia, lower facial weakness with marked bulbar involvement chest deformities, nasal voice, and distal leg weakness respiratory involvement out of proportion to muscle weakness).
LMOD3
• Nemaline myopathy (NM)
AR
Leiomodin 3
Onset; prenatal. Polyhydramnios, multiple joint contractures, proximal distal and lower facial weakness with marked bulbar involvement, and ophthalmoplegia. Usually neonatal death.
KBTBD13
• Nemaline myopathy (NM)
AD
Kelch repeat and BTB (POZ) domain containing protein 13
Onset; childhood. Proximal and axial involvement, slow movements, high-arched palate, and thorax deformities.
CFL2
• Nemaline myopathy (NM)
AR
Cofilin 2 (muscle)
Onset at birth to early childhood. Proximal and axial weakness, prominent neck extensors involvement. Severe scoliosis.
KLHL40
• Nemaline myopathy (NM)
AR
Kelch-like family member 40
Onset; prenatal. Polyhydramnios, severe arthrogryposis and fetal akinesia, dysmorphic faces, severe respiratory and limb involvement, ophthalmoplegia usually death at the age of 5 months.
KLHL41
• Nemaline myopathy (NM)
AR
Kelch-like family member 41
Onset; prenatal. Fetal akinesia hip and knee dislocation with severe respiratory involvement early death. Missense mutations could present with mild forms with a survival into late childhood or early adulthood.
RYR1
• Central core myopathy • Multiminicore myopathy • Core rod myopathy • Nemaline myopathy • Congenital fiber-type disproportion • Centronuclear myopathy • Congenital neuromuscular disease with uniform type 1 fiber
AD, AR AR AD, AR AR AR AR AD
Ryanodine receptor I
Variable onset and severity. Proximal weakness, ptosis, ophthalmoplegia, hyperlaxity, congenital hip dislocation, scoliosis, moderate respiratory involvement, exercise induce myalgia, MHS. Could present rigid spine syndrome, and severe arthrogryposis.
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TABLE 148-1 Classification of Congenital Myopathies by Genes (Continued) Gene
Subtype
Inheritance Pattern
STAC3
• Native American myopathy
SEPN1
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Protein
Features
AR
SH3 and cysteine rich domain containing protein 3
Lumbee Indians in North Carolina. Congenital onset, dysmorphic features (telecanthus, cleft palate, downslating palpebral fissures, low ear set, ptosis), short stature, arthrogryposis proximal weakness, MHS.
• Multiminicore myopathy • Congenital fiber-type disproportion
AR AR
Selenoprotein N1
Onset birth to childhood. Predominant axial muscle involvement, poor head control, rigid spine, scoliosis at the age of 10 years, nocturnal hypoventilation central apnea during paradoxical sleep.
CCDC78
• Centronuclear myopathy
AD
Coiled coil domain containing protein 78
Congenital onset, distal involvement with slow progression, excessive fatigue mild to moderate cognitive impairment.
BIN 1
• Centronuclear myopathy
AR, AD
Amphiphysin
Variable onset. Severe forms present at birth or childhood. Proximal and lower facial weakness with marked bulbar involvement, ophthalmoparesis and ptosis, could present cardiomyopathy (dilated)
DNM2
• Centronuclear myopathy
AD
Dynamin 2
Variable onset. Distal muscle weakness, exercise induce myalgias, ophthalmoparesis, ptosis, lower facial weakness and marked bulbar involvement, slow progression hypertrophy of paravertebral muscles absent or reduce tendon reflexes, distal limb, contractures, scoliosis cardiomyopathy.
MTM1
• Myotubular myopathy
XR
Myotubularin 1
Onset; prenatal. Polyhydramnios, macrosomia, proximal and distal weakness with severe respiratory involvement at birth, lower facial weakness with marked bulbar involvement, usually early death, other features, bleeding diathesis, liver and gastrointestinal complications.
SPEG
• Centronuclear myopathy with dilated cardiomyopathy
AR
SPEG complex locus
Onset at birth, proximal weakness with lower face and bulbar involvement, ophthalmoplegia, hip contractures cardiomyopathy.
PTPLA (= HCDA1)
• Congenital myopathy related to PTPLA
AR
Protein tyrosine phosphatase-like (3-hydroxyacyl CoA dehydratase)
Onset birth. Lower facial and proximal weakness. Absent or reduce deep tendon reflexes. Severe presentation at onset with progressive improvement.
TTN
• Centronuclear myopathy • Congenital myopathy with fatal cardiomyopathy
AR AR
Titin
Onset, birth or infancy. Proximal and distal weakness with facial involvement. Could present asymmetric ptosis. Some with scapula-peroneal syndrome. Pseudohypertrophy of thighs and calves. Ambulation could be achieved in most of the cases. Scoliosis and absent reflexes. Cardiomyopathy (dilated)
MYH7
• Myosin storage myopathy • Myosin storage myopathy with cardiomyopathy • Congenital fiber-type disproportion
AD AR AD
Myosin, heavy chain 7, cardiac muscle
Onset at infancy or early childhood, distal weakness predominant, and week toe extensor (hanging big toe), scapular winging, mild facial involvement, cardiomyopathy (dilated or hypertrophic)
MYH2
• Myosin IIa myopathy
AD, AR
Myosin, heavy chain 2, skeletal muscle
Onset at birth, contractures, ophthalmoplegia, ptosis, mild to moderate proximal weakness
MEGF10
• Early onset myopathy, areflexia respiratory distress and dysphagia • Minicores
AR AR
Multiple EGF-like domains 10
Prenatal onset with reduced fetal movements. Proximal and distal weakness, distal contractures, scoliosis, areflexia, bulbar involvement, respiratory distress.
AD, autosomal dominant; AR, autosomal recessive; XR, X linked. (Adapted from Kaplan JC, et al. The 2015 version of the gene table of monogenic neuromuscular disorder. Neuromuscul Disord 2014;24:1123–53.)
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A
B
C
Figure 148-1. The “myopathic” facies. One of the characteristic clinical observations in many children with congenital myopathies is the so-called “myopathic” facial appearance. This can include both upper and lower facial weakness, as illustrated in these photomicrographs. Left panel: The patient depicted demonstrates ptosis, ocular misalignment caused by ophthalmoparesis, an inverted C-shape to her upper lip, and prominent lower facial weakness resulting in an open mouth appearance. The ultimate diagnosis in this case was nemaline myopathy caused by recessive mutation in the LMOD3 gene. Patients with nemaline myopathy often have particularly striking lower facial weakness. Middle panel: This individual has ptosis, ophthalmoparesis, and moderate lower facial weakness. He has DNM2-related centronuclear myopathy. Note also the muscle atrophy present in his chest and shoulders. Right panel: Photograph of a young boy with myotubular myopathy caused by MTM1 mutation. He has the characteristic long face with bilateral ptosis and ophthalmoparesis.
NEB
ACTA1
Muscle disease suspected (weakness, hypotonia, delayed motor miIestones)
Other NM
MTM1
Congenital myopathy suspected
CK normal or mildly elevated
RYR1
SEPN1
TTN
MYH7
Contractures Myopathic face
DNM2
Neck or Axial weakness
DNM2
Hip dysplasia/ scoliosis
Yes
Severe hypotonia NEB
Muscle MRI (Fig. 4)
MYH7
SPEG
Cardiomyopathy
Genetic testing (gene panel)
TTN
DNM2
LMOD3
EOM restricted
And\or
SEPN1
EO respiratory dysfunction
Physical Exam
Other diagnosis CMD Or repeat CK
RYR1
DNM2
Ptosis
No
Other CNM
And\or
ACTA1
Other NM
MTM1
Other CNM
Muscle biopsy Rods Cores Central nuclei
Confirmed Genetic diagnosis
Rods and cores Caps CFTD
Figure 148-2. Clinical approach to congenital myopathy, practical algorithm. ACTA1, ACTA1 nemaline myopathy; CFTD, congenital fiber-type disproportion; CK, creatine kinase; CMD, congenital muscular dystrophy; CNM, centronuclear myopathy; EO, early onset; EOM, extraocular movements; MM, mitochondrial myopathy; MYH7, MYH7 myopathy; NEB, nebulin mutation; NM, nemaline myopathy; Other NM, LMOD3, TPM2, TPM3, KBTBD13, TNNT1, KLHL40, KLHL41, and large spectrum of clinical presentation from mild to severe; RYR1, ryanodine receptor myopathy; SEPN1, SEPN1 myopathy; TTN, Titin myopathy.
establishing the diagnosis; however, there are instances where the rods are either poorly appreciated or else not seen at the light level and only revealed through electron microscopic analysis. In addition, there are histopathologic variants that are included within the nemaline umbrella. These include cap myopathy (where there is an accumulation of myofibrillar material sitting as a cap at the periphery of the myofiber) and zebra body myopathy (Dowling et al., 2015). Core myopathy (Jungbluth, 2007a,b): Core myopathies are typically subdivided into CCD and multiminicore myopathy. Cores are best appreciated on light microscopy with oxidative stains such as SDH and NADH (Fig. 148-3, C). They are defined as areas devoid of reactivity for these enzymes and reflect areas in the myofibers that lack mitochondria. Central cores are longitudinal and often traverse the entire length of the myofiber. Minicores are typically transverse in location and usually small. Core myopathies are often also seen in the context of type I fiber predominance and type I fiber hypotrophy, both features best seen with ATPase staining. Electron microscopy is often required for evaluation of core myopathies. This is because there are other conditions that can result in absence or change of SDH/NADH staining. Most prominent among them is the targetoid staining pattern seen with neurogenic lesions. On EM, cores appear as areas of myofibril disorganization that lack mitochondria. At times there will be a ring of mitochondria around the area of disorganization (referred to as a structured core). Congenital fiber-type disproportion: CFTD is defined by two biopsy features. The first is relative hypotrophy of type I fibers compared with type II fibers. The second is numerical predominance of type I fibers over type II fibers. The general criterion for calling CFTD is a 25% reduction in type I fiber size. Such a reduction is relatively nonspecific and can be seen in a range of disease, many of which are not primary myopathies. “True” CFTD, or CFTD caused by mutations in congenital myopathy genes, is usually characterized by much more significant reduction in type I fiber size (to <50% that of type IIs) and clear type I predominance (often >75% of fibers). CFTD can be seen by H/E staining, but is best diagnosed and evaluated using stains for fiber type (Fig. 148-3, D). These include enzymatic reactions (ATPase at acid pH [4.3 to 4.6] to stain type I fibers and at basic pH [9.4 to 10.2] to mark type II fibers) or immunostaining with myosin antibodies (slow myosin for type I and fast myosin for type II).
Genetics All pediatric-onset (and most adult-onset) congenital myopathies are considered to have a genetic underpinning. It is important to establish a genetic diagnosis, even when a child has a consistent muscle biopsy, because knowledge of the specific genetic subtype greatly contributes to understanding of specific clinical features, anticipatory care requirements, and prognostication (Wang et al., 2012; North et al., 2014). Mutations in congenital myopathies span the range of inheritance patterns (X-linked, autosomal recessive, autosomal dominant) and often are caused by sporadic/de novo variants. To date, mutations in 20 genes have been identified as causal in patients with congenital myopathy (see Table 148-1). The interplay between clinical presentation, biopsy diagnosis, and genetic subtype is complex. In particular, there are several genetic causes for each histopathologic grouping (e.g., mutations in 10 genes are associated with NM), and each genetic cause can result in a variety of clinical presentations and histopathologic diagnoses (e.g., RYR1 mutations have been described in every histopathologic subtype) (North et al., 2014). Of note, it is critically important that genetic counseling be offered to all patients with congenital myopathies and to their families,
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ideally starting at the time that genetic testing is first considered (Wang et al., 2012).
Muscle Imaging (MRI or Ultrasonography) Muscle imaging is an emerging modality for the diagnosis and care of patients with a range of neuromuscular disorders. For congenital myopathies it is used primarily as an adjunct diagnostic tool, though in the future may aid in assessment of disease status and progression. Muscle ultrasonography is the fastest and least expensive technique and offers the potential of application in the outpatient clinic and/or inpatient setting, though requires an experienced user for interpretation. Muscle MRI is widely available and does not require any particular advanced training to obtain or analyze; the downside is expense and the fact that some children (particularly those under age 5 years) may require sedation. The diagnostic value of muscle imaging lies in the fact that different genetic subtypes of myopathy present with different imaging patterns of muscle involvement. The pathognomonic patterns are best characterized with lower extremity imaging, though the value of whole-body MRI for diagnosis (particularly in the young child) is increasingly being recognized. Representative examples of muscle MRI and a diagnostic flow chart describing its application are presented in Figure 148-4.
SPECIFIC SUBTYPES OF CONGENITAL MYOPATHY Centronuclear Myopathies Centronuclear myopathies, even though clinically heterogeneous (particularly in terms of symptom onset and severity), often feature prominent eye muscle weakness (ptosis and ophthalmoparesis) in addition to lower facial and extremity weakness (Jungbluth et al., 2008). In infancy and childhood, these features can appear like those seen in congenital myasthenic syndromes. The extremity weakness may have significant distal involvement, including distal predominance in some individuals. There are six established genetic causes of CNM. Mutations in myotubularin (MTM1) are associated with the distinctive, severe, neonatal-onset X-linked condition myotubular myopathy (XLMTM or MTM) (Das et al., 1993). Mutations in dynamin-2 (DNM2) are the most common cause of dominant CNM; patients typically present either in the first year or two of life (with de novo mutations) or in late childhood. Recessive causes of CNM include mutations in RYR1, BIN1, TTN, and SPEG. RYR1 mutations are the most common and can present in infancy in a manner resembling MTM. BIN1 mutations typically cause childhood-onset CNM, though one particular homozygous splice mutation results in a rare, rapidly progressive form. There is also a late-onset CNM in some families with dominant BIN1 mutations. SPEG mutations cause a rare, severe form of CNM that also includes cardiomyopathy. There are currently no therapies that have been proven to be efficacious for CNM. There is mounting evidence, however, including several case reports and compelling preclinical data, that acetylcholinesterase inhibitors such as pyridostigmine provide modest but definitive improvement in clinical symptomatology. Patients with mutations in RYR1, DNM2, and MTM1 have all been reported in these case series. In terms of experimental therapies, there is considerable excitement concerning both gene therapy and enzyme replacement therapy for MTM. These strategies have shown robust disease correction in the MTM mouse model, and gene therapy
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additionally has been effective in a spontaneous dog model of the disease.
Nemaline Myopathies NMs are characterized in general by the presence of significant bulbar dysfunction (because of lower face and neck flexor weakness) in the setting of additional and variable extremity weakness (North et al., 2014). The disease is noted to have significant clinical variability and has thus been classically subdivided into groups based on age of onset and clinical severity: (1) severe congenital NM (16% of NM cases), (2) intermediate congenital NM (20%), (3) typical congenital NM (46%), (4) childhood-/juvenile-onset NM (13%), and (5) adult-onset NM (4%) (North and Ryan, 1993). There is considerable overlap between the groups, though the distinctions can be helpful (e.g., individuals with severe congenital NM have a high risk of death in infancy, whereas those with typical congenital NM tend to show stabilization and even improvement). There are 10 known genetic causes of NM. Mutations in ACTA1 are the most common dominant/de novo cause (25% of all NM), whereas those in nebulin (NEB) are the most common autosomal-recessive cause (~50% of all NM). Mutations in ACTA1 are associated with a tremendous variability in age of presentation and clinical expression, not only between different mutations in the gene but also among family members with the same mutation. They are the most common cause of severe congenital NM (severe weakness, reduced or absent fetal/neonatal movements, respiratory failure, and often death in infancy). Mutations in NEB are most frequently encountered with typical congenital NM (neonatal hypotonia, weakness, feeding difficulties, ability to eventually ambulate, static/slowly progressive course). The specific breakdown in terms of relative prevalence of the other genetic subtypes is otherwise not well established. Some are associated primarily with specific clinical groupings. LMOD3 and KLHL40 mutations are seen almost exclusively with severe congenital NM. Dominant mutations in TPM2 and TPM3 are associated with symptoms ranging from typical congenital to mild childhood (with TPM2 mutations usually milder), whereas rare recessive mutations in TPM3 are associated with severe disease. TPM2 mutations can additionally been seen in the absence of overt weakness with distal arthrogryposis syndromes. Dominant mutations in KBTBD13 are seen with childhood-onset NM and characteristic slowness of movements. Recessive mutations in TNNT1 (Amish NM) and CFL2 (severe or typical congenital) are extremely rarely encountered. Of note, ophthalmoparesis is infrequently observed in NM (with the exception of LMOD3 mutations), and may serve as a means of distinguishing NM from other congenital myopathies. At present, there are no specific therapies that have proven efficacious for NM. L-tyrosine has been examined in a mouse model of Acta1 and shown to increase muscle strength; a limited patient case series examining L-tyrosine found that it improves some bulbar symptoms and specifically sialorrhea. Its impact on disease course is likely limited, and true efficacy awaits more systematic clinical study. There are no other therapies currently in the clinical pipeline, though a few are at the stage of preclinical assessment.
Core Myopathies Core myopathies can be subdivided into CCD and multiminicore disease (MmD). CCD is caused by RYR1 mutations (usually dominant/de novo) in approximately 90% of cases (Jungbluth, 2007a). The other well-described cause
is dominant MYH7 mutation. Minicore disease, along with the more general categorization of myopathy with cores, has several genetic causes (Jungbluth, 2007b). Most classically, it is caused by mutations in either SEPN1 (MmD without ophthalmoparesis) or RYR1 (MmD with ophthalmoparesis). Other genetic causes include ACTA1, TTN, MEGF10, and CCDC78; biopsies in these settings typically include additional histopathologic abnormalities (such as rods or protein aggregates). In addition, there can be both cores and rods in the same biopsy (termed “core-rod” myopathy), with known causes, including TPM2, NEB, RYR1, ACTA1, and KBTBD13.
RYR1-Related Myopathies Myopathies caused by mutations in the skeletal muscle ryanodine receptor (RYR1) are the commonest group of nondystrophic muscle conditions. These are also termed “RYR1-related myopathies,” and encompass a broad clinical spectrum that spans the entire gamut of histopathologic subtypes. RYR1related myopathies are subdivided primarily either by mode of inheritance (recessive vs. dominant/de novo) or by histopathology (CCD, MmD, CNM, etc.), though there are distinctive clinical conditions that do not classically fall into a specific grouping (e.g., axial myopathy, malignant hyperthermia, exertional rhabdomyolysis, isolated ophthalmoparesis). CCD associated with RYR1 mutation is almost entirely caused by dominant mutations (Jungbluth, 2007a). The typical pediatric presentation for CCD is one of neonatal hypotonia, muscle hypotrophy, and extremity muscle weakness, often accompanied by significant skeletal abnormalities such as chest wall deformities, scoliosis, joint contractures, and hip dysplasia. Respiratory failure is present in some instances, though rarely requires tracheostomy and often improves. The course of disease is typically quite stable, and, although delayed, individuals often acquire all motor developmental milestones. Of note, there may be some mild facial muscle involvement, including ptosis and lower facial weakness, but ophthalmoparesis is rarely encountered. There is also a milder CCD presentation that includes minimal weakness that may only be recognized in adulthood; there are also several cases of dominant mutations causing late-onset axial myopathy. Rarely, heterozygous de novo mutations can present with extreme weakness in the perinatal period that results in death in infancy. The mutations in RYR1 that cause CCD are enriched in the C-terminal aspect of the gene. Some are additionally associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic condition of hypermetabolism and muscle breakdown in response to exposure to volatile anesthetics. The other histopathologic subtypes (MmD, CNM, core-rod myopathy, and CFTD) are most commonly seen with recessive RYR1 mutations. The most frequently encountered recessive subtype is minicore disease, which typically presents with diffuse weakness in combination with ophthalmoparesis. Onset is usually in the neonatal period or in early childhood, and can be severe enough to result in respiratory failure with chronic ventilator support and wheelchair dependence. As with CCD, skeletal abnormalities (particularly joint contractures and scoliosis) are quite frequently encountered. These are often accompanied by severe facial weakness that can include ophthalmoparesis. Axial muscle involvement can also be quite pronounced. At present, there are no specific treatments for RYR1-related myopathies. Salbutamol has been shown in a small casecontrol series to improve strength and motor function. This result has not been followed up with additional clinical trials, and the medication is not widely used in RYR1 patients. An intriguing candidate drug class is the RyCals; RyCals interact with RyR1 and augment its ability to release calcium. RyCals
have yet to be tested for efficacy in patients, and have not been examined in any preclinical models of RYR1 myopathy. One drug that has shown promising results in animal models and in patient cells is the antioxidant N-acetylcysteine (NAC). NAC is currently being evaluated in a placebo-controlled clinical trial in ambulant RYR1 myopathy patients. Of note, dantrolene is the standard therapy for treating MH. It has yet to be tested in other dynamic RYR1-related phenotypes such as rhabdomyolysis. Because it reduces RyR1 calcium release, it is unlikely to be effective in the majority of instances of RYR1 mutations that cause static muscle weakness.
SEPN1-Related Myopathies Recessive mutations in SEPN1 were first described in a rare muscular dystrophy subtype called rigid spine muscular dystrophy. However, SEPN1 mutations are most typically found associated with multiminicore disease; they are also seen with other histopathologic patterns, including CFTD and Mallory Body myopathy. Regardless of histopathologic phenotype, patients with SEPN1 mutations present a relatively uniform clinical picture. This picture includes early onset hypotonia and axial muscle weakness with relative sparing of the extremity muscles. It also includes spinal rigidity; severe, progressive scoliosis; and potentially lethal, progressive respiratory failure. These severe axial symptoms are not matched by corresponding limb weakness, with the resulting appearance often one of an ambulant patient with ventilator dependence. Patients do not have ophthalmoparesis, a distinguishing feature from RYR1 mutations. SEPN1 encodes selenoprotein N1 (SelN1), a selenocysteinecontaining protein located in the endoplasmic reticulum. The functions of SelN1 in relation to muscle structure and function have been relatively elusive, though it seems clear that one of its major roles is to regulate oxidative stress. Based on this, the consequences of SEPN1 mutations (which in general result in loss of SelN1 expression and/or function) are predicted to be increased basal oxidative stress, susceptibility to the consequences of oxidative species, and ultimately impaired redox related RyR1 function. As with RYR1 myopathies, the antioxidant NAC protects SEPN1-patient-derived myotubes from oxidant-related death, and is now being considered for clinical trial in SEPN1-related myopathy patients.
Congenital Fiber-Type Disproportion CFTD is a diagnosis applied in the context of clinical symptoms of myopathy and fiber-type disproportion on biopsy (significantly smaller type I fibers, usually type I predominance) (Clarke, 2011). The biopsy observation of CFTD often precedes or is accompanied by other pathologic features (rods, cores, etc.); in such cases, the individual is typically described as having the diagnoses corresponding to the other biopsy features (e.g., NM when rods are present). Some individuals, however, do have “pure” CFTD (usually considered when type I fibers are >40% smaller). When this occurs, the recognized genetic causes are mutations in TPM3, TPM2, RYR1, SEPN1, and ACTA1. The clinical presentations in these cases are primarily dictated by the underlying genetic cause; for example, patients with CFTD caused by TPM3 mutations resemble those with similar mutations and NM on biopsy.
GENERAL MANAGEMENT OF CONGENITAL MYOPATHIES General management guidelines for congenital myopathies are based on practical experience, expert opinion, and inferences from other similar neuromuscular conditions. These
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guidelines are summarized here, and also found in extensive detail in the recently published standards of care for congenital myopathies (Wang et al., 2012).
Respiratory Respiratory dysfunction is the likeliest cause of morbidity and mortality in children with congenital myopathies. This relates to the fact that the diaphragm and intercostal muscles are often weakened in these conditions, leading to poor rib excursion, impaired mucus expectoration and airway clearance, and sleep apnea. The recognition of early respiratory compromise (often identified via sleep study or pulmonary function testing in both the seated and supine positions) leads to early intervention via noninvasive ventilation, typically first at night and then during daytime in more severe or progressive cases. Identifying a weak cough in patients is also an important predictor of how a child may respond to an upper respiratory infection. A weak cough can predispose to mucus plugging and bronchiectasis and hence cause risk for fatal pneumonias. This can be prevented with the use of a cough assist device (either while sick or best also when healthy) as a form of pulmonary physical therapy. A thairvest, which employs chest vibration to loosen mucus, may also be used, though it is imperative that this treatment is followed by cough assist regimen. This is so that the mucus that is loosened as a result of this procedure can actually be expectorated and not actually make things worse by being left to plug the airways.
Nutrition, Gastrointestinal, and Oromotor Management Nutritional management guidelines for congenital myopathies are essentially nonexistent despite the fact that poor nutrition and growth are inherent to many of these conditions. Weakness in oromotor function is a contributing factor, particularly in nemaline and centronuclear myopathies. Efforts should be made to monitor patient weight and height (either erect or via ulnar length) in conjunction with calorie intake. If calorie intake is limited, or the risk of aspiration pneumonia is high, the placement of a gastrostomy tube should be discussed with families early in the disease course. Improved nutritional status has been related to improved growth and decreased respiratory problems. Yearly assessments of calcium and vitamin D levels should also be made in order to address bone health, as osteopenia is a concern in any individual with long-standing muscle weakness. Gastrointestinal dysmotility is also a frequent problem in children with congenital myopathies. Dysmotility may present as gastroesophageal reflux, which can be managed with medication (e.g., proton pump inhibitors, H2 blockers, and antacids), nonpharmacologically (e.g., thickening of formula and adjusting feeding positions), and/or surgically (e.g., with Nissen fundoplication). Dysmotility can also present with delayed gastric emptying and constipation, symptoms that can be treated with diet modification, stool softeners/ laxatives, and the use of prokinetic drugs (erythromycin or metaclopromide). Excessive oral secretions are often a significant problem in congenital myopathies. This is related to bulbar and facial weakness and particularly seen in nemaline and CNM. Speech and occupational therapy can be used to address this, primarily through facial muscle–strengthening exercises. If this is not successful, anticholinergic drugs may be administered systemically (e.g., robinul and scopolamine), though they are not without systemic side effects (e.g., constipation). A small study has also found evidence that L-tyrosine supplementation may
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be helpful with sialorrhea in NM. Botulinum toxin injections and surgical management are considered in very rare circumstances when secretions are particularly debilitating, though such strategies are controversial.
Cardiac The majority of congenital myopathy subtypes are not associated with primary cardiac involvement. Baseline and periodic follow-up cardiac evaluations, however, should be provided to all patients with congenital myopathy until the specific genetic cause has been identified. This is because certain gene mutations, such as those in TTN, MYH7, SPEG, and (more rarely) ACTA1, can cause cardiomyopathy. In addition, continued cardiac screening is indicated in settings (SEPN1related myopathy, for example) where secondary right-sided heart failure is of concern because of chronic respiratory compromise.
Orthopedic Scoliosis is a pervasive problem in these conditions and should be monitored from the initial presentation of symptoms. This can initially be done via clinical examination (with the patient assessed in forward flexion at the hip), but once any curvature is noted, routine x-rays should be obtained. Once scoliosis has been diagnosed, patients should be referred to orthopedics for the management of the progressive curvature with either a conservative (e.g., bracing/casting) or invasive/surgical approach. The management of scoliosis is essential for maintaining respiratory function. Joint contractures are a concern for the majority of congenital myopathy patients, and may in fact be the presenting sign of patients in some individuals. Ankle contractures are typically managed with physical therapy, passive stretching, and ankle-foot orthoses, which are used in the ambulant patient to slow contracture progressive and to improve gait, and in the nonambulant patient to aid in comfort and wheelchair positioning. Surgery to release contractures is rarely indicated, as it often does not appreciably improve range of motion and can potential worsen muscle weakness. Exceptions include contractures that significantly hinder ambulation (in the setting of relatively preserved strength) and those that cause considerable discomfort (in the nonambulant patient).
Physical Therapy/Exercise Physical therapy is mainstay of management in children with congenital myopathy. It helps with strengthening and improves range of motion. It should be utilized regularly and in a manner that matches the child’s pattern of weakness. Assist devices can complement therapy services, and include gait trainers and stationary bikes. The impact of exercise on muscle strength and motor function in congenital myopathies has yet to be formally addressed, though there is anecdotal evidence that exercise in children with myopathies is safe and potentially of benefit. Further work is necessary to establish this as a formal recommendation.
SUMMARY Congenital myopathies represent a clinically and genetically heterogeneous group of childhood muscle disorders. With
improvements in clinical recognition and genetic testing, it is now clear that these disorders represent a significant portion of childhood genetic neuromuscular disease. The availability of gene panels and whole-exome sequencing has improved diagnostics, has enabled the discovery of new myopathy genes, and has greatly broadened the genotype-phenotype spectrum of these disorders. It has also presented challenges related to disease classification and genetic variants of unknown clinical significance; in addition, the genetic cause in many individuals still remains elusive. Currently there are few, if any, therapies available for these often devastating disorders; however, work using preclinical model systems has identified several promising candidates for translation into the clinical arena. One of the key challenges in the future will be effectively translating these drugs, and factors related to disease natural history and clinical trial readiness are becoming of paramount importance as the field moves forward toward hopefully identifying meaningful therapies. REFERENCES The complete list of references for this chapter is available in the e-book at www.expertconsult.com. See inside cover for registration details. SELECTED REFERENCES Clarke, N.F., 2011. Congenital fiber-type disproportion. Semin. Pediatr. Neurol. 18, 264–271. Colombo, I., et al., 2015. Congenital myopathies: natural history of a large pediatric cohort. Neurology 84, 28–35. Das, S., Dowling, J., Pierson, C.R., 1993. X-Linked centronuclear myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington–Seattle, Seattle, WA, pp. 1993–2016. Dowling, J.J., et al., 2015. Congenital and other structural myopathies. In: Darras, B.T., et al. (Eds.), Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. Elsevier, New York, pp. 502–537. Jungbluth, H., 2007a. Central core disease. Orphanet J. Rare Dis. 2, 25. Jungbluth, H., 2007b. Multi-minicore disease. Orphanet J. Rare Dis. 2, 31. Jungbluth, H., Wallgren-Pettersson, C., Laporte, J., 2008. Centronuclear (myotubular) myopathy. Orphanet J. Rare Dis. 3, 26. North, K.N., Ryan, M.M., 1993. Nemaline myopathy. In: Pagon, R.A., et al. (Eds.), GeneReviews® [Internet]. University of Washington– Seattle, Seattle, WA, pp. 1993–2016. North, K.N., et al., 2014. Approach to the diagnosis of congenital myopathies. Neuromuscul. Disord. 24, 97–116. Wang, C.H., et al., 2012. Consensus statement on standard of care for congenital myopathies. J. Child Neurol. 27, 363–382.
E-BOOK FIGURES AND TABLES The following figures and tables are available in the e-book at www.expertconsult.com. See inside cover for registration details. Fig. 148-3. The common congenital myopathy subtypes by histopathology. Fig. 148-4. Muscle MRI in congenital myopathies. Fig. 148-5. MTM- and DNM2-related centronuclear myopathy. Fig. 148-6. ACTA1- and NEB-related nemaline myopathies. Fig. 148-7. RYR1-related myopathy.