Congenital myopathies

INTRODUCTION — Congenital myopathies are a heterogenous group of hereditary primary muscle disorders that are present from birth, although their onset may be delayed until later in infancy or early childhood. The most common of these rare disorders are nemaline myopathy, central core disease, centronuclear (myotubular) myopathies, and congenital fiber type disproportion (table 1).

OVERVIEW — Congenital myopathies share some common features, though severity is highly variable. Affected individuals usually present at birth or in infancy with hypotonia, weakness, hypoactive deep tendon reflexes, delayed motor milestones, and normal intelligence [1,2]. Prominent facial weakness and ptosis are often present; associated findings may include dysmorphic features such as dolichocephaly, a long, narrow face, and a high-arched palate. The weakness is usually generalized or more prominent in proximal and limb-girdle muscles. However, the weakness in some congenital myopathies predominantly affects distal muscles or axial and respiratory muscles. Muscle weakness tends to be stable or slowly progressive over time. In the most severe cases, the presentation is that of the floppy infant with a frog-leg posture and respiratory and bulbar weakness.

The specific congenital myopathies are characterized by their histologic and histochemical features. These conditions are caused by genetic abnormalities of muscle development [3]. They are distinct from the metabolic myopathies, in which deficiencies of energy production in muscle result from defects in lipid and/or mitochondrial metabolism, glycogen storage disease, or defects in other metabolic pathways. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism" and "Overview of inherited disorders of glucose and glycogen metabolism".)

No specific treatment is currently available for congenital myopathies, although several specific therapies including gene therapy are either in preclinical development and/or in early trials. Management consists of physical therapy, nutritional support, assisted ventilation if indicated, and genetic counseling.

NEMALINE MYOPATHY — Nemaline myopathy derives its name from the characteristic rod bodies in muscle that appear threadlike in longitudinal section.

Clinical features — The clinical expression of nemaline myopathy is variable [4]. The presentation in affected newborns can be severe or relatively mild. In the former, profound generalized weakness and hypotonia involving the face, bulbar, and respiratory muscles is seen; the eye muscles are typically spared [5]. The milder form, with relatively less facial weakness and diaphragm impairment, also can present in children or adults. Intermediate forms also are identified. In a series of 143 cases, presentation was typical congenital, severe congenital, intermediate congenital, childhood onset, and adult onset in 46, 16, 20, 13, and 4 percent, respectively [6].

The pattern of weakness is variable. In a 2002 systematic review of individual patient data that covered 101 pediatric patients from 23 countries, neonatal hypotonia was the most common sign at presentation [4]. Axial and proximal weakness was reported in 31 percent, facial weakness in 29 percent, and distal weakness in 23 percent; weakness was unspecified in 22 percent. Early respiratory difficulty was noted in 36 percent, and neuromuscular respiratory weakness or failure developed in 56 percent.

Scoliosis, contractures, dysphagia, acid reflux, and bone fractures are common comorbidities [4,7]. Some affected children have minor anomalies including a long thin face, high arched palate, and pectus excavatum [8]. Other atypical features are arthrogryposis, and central nervous system involvement (eg, learning disability, seizures) [6,7]. Cardiac disease may occur, with a progressive cardiomyopathy leading to heart failure [9].

The clinical course depends upon the severity of the disease. In the severe neonatal form, death due to respiratory failure often occurs during the first year of life. However, prolonged survival with improvement has been reported [10]. The milder form is considered to be nonprogressive or slowly progressive [7,11].

The creatine kinase level usually is normal or only slightly elevated. Electromyography may show myopathic changes such as action potentials of small amplitude and short duration [12]. However, these findings occur more commonly in older patients than in newborns.

Diagnosis — The diagnosis of nemaline myopathy is typically achieved by genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing. A muscle biopsy may still be valuable, particularly if variants of uncertain significance are identified [13].

Pathologic features — The characteristic rod bodies are best seen with modified Gomori trichrome staining [14]. With this technique, they appear red against a blue-green myofibrillar background. The number of rods within muscle is variable and does not correlate with severity. Examples of nemaline rod muscle pathology are shown on the Washington University Neuromuscular Disease Center web site (http://neuromuscular.wustl.edu/pathol/rod.htm).

On electron microscopy, the rods appear to originate from the Z-discs (the band normally found at both ends of the sarcomere) [15]. They sometimes are seen within the nucleus in the severe neonatal form [16]. The rods are composed of alpha actinin and actin [17,18]. Another consistent finding on muscle biopsy is the predominance of the smaller type 1 fibers.

Genetics — Nemaline myopathy results from abnormalities of the thin filaments of skeletal muscle and is genetically heterogeneous [19]. Specific defects involve pathogenic variants in the following genes [4]:

●NEB

●ACTA1

●TPM2

●TPM3

●TNNT1

●TNNT3

●CFL2

●LMOD3

●KBTBD13

●KLHL40

●KLHL41

●MYPN

Pathogenic variants in NEB and ACTA1 are the most common causes of nemaline myopathy [4]. Several of these genes (NEB, ACTA1, TPM3, TNNT1, TPM2, CFL2, and LMOD3) encode for proteins that are components of or interact with muscle thin filaments. KBTBD13, KLHL40, and KLHL41 play a role in ubiquitination and protein degradation [19].

The most common milder form of nemaline myopathy is caused by pathogenic variants in the NEB gene [20]. The inheritance pattern is autosomal recessive. A severe form of nemaline myopathy has been associated with pathogenic variants in the ACTA1 gene. In one series, pathogenic variants in ACTA1 were identified in approximately 15 percent of patients with nemaline myopathy [21]. In another series, ACTA1 pathogenic variants accounted for more than one-half of severe cases and one-quarter of all nemaline myopathy cases [22]. Inheritance of this form often is sporadic but may be autosomal dominant or recessive [23].

Pathogenic variants in TNNT1, TPM2, and TPM3 are rare, accounting for 5 percent or less of all nemaline myopathy cases. TNNT1 causes an autosomal recessive form, and TPM2 a dominant form. TPM3 related nemaline myopathy has been associated with both autosomal dominant and recessive inheritance patterns [24]. A rare autosomal-dominant form of nemaline myopathy caused by missense mutations in the KBTBD13 gene is characterized by normal neonatal development followed by childhood onset of slowly progressive weakness and slowness of movements [25-27].

CENTRAL CORE DISEASE — Central core disease (also called central core disease of muscle) was the first specific congenital myopathy to be recognized.

Clinical features — Central core disease typically presents in the neonatal period, although it may sometimes not be recognized until later infancy. The principal clinical findings are hypotonia and muscle weakness, which usually are more prominent in the proximal extremities. Muscle involvement is variable and ranges from undetectable to severe [28]. In one series of eleven cases, motor function ranged from clinically normal to no independent ambulation [29]. Patients often have mild facial weakness, but do not have ptosis, extraocular muscle weakness, dysphagia, or respiratory difficulty [11]. Tendon reflexes usually are present, although they are reduced proportionally to the severity of the disease.

Musculoskeletal abnormalities commonly occur. They include congenital hip dislocation, kyphoscoliosis, joint contractures, and foot deformities [28]. Affected patients are at risk for developing malignant hyperthermia [30]. (See "Severe nonexertional hyperthermia (classic heat stroke) in adults".)

The clinical course typically is nonprogressive. However, later progression of weakness can occur [31]. In a series of 11 patients 4 to 20 years of age, two patients could not walk unassisted and two had difficulty climbing stairs [32]. Motor milestones usually are delayed.

The creatine kinase level usually is normal. Electromyography may show minor myopathic changes.

Diagnosis — The diagnosis is typically achieved by genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing [13]. A muscle biopsy may still be valuable, particularly if variants of uncertain significance are identified.

Pathologic features — The diagnostic finding is the presence of cores of degenerated myofibrils in 20 to 100 percent of muscle fibers, which are predominantly type 1 [11]. The cores are central or slightly eccentric in location and may be single or multiple in a specific fiber. Histochemical stains for oxidative enzymes show lack of staining in the core region resulting from the absence of mitochondria. Atrophy of type 1 fibers is common [33]. Examples of central core muscle pathology are shown on the Washington University Neuromuscular Disease Center web site (http://neuromuscular.wustl.edu/pathol/centcore.htm).

Genetics — Most cases of central core disease are caused by pathogenic variants in the gene encoding the ryanodine receptor (RYR1) that is localized on chromosome 19q13.1 [30,34-36]. The gene product forms the key channel that mediates calcium release in skeletal muscle during excitation-contraction coupling. In at least one mutation in this gene, muscle weakness in central core disease has been attributed to an uncoupling of excitation from calcium release [37]. Pathogenic variants in the RYR1 gene also account for more than 50 percent of cases of malignant hyperthermia. (See "Susceptibility to malignant hyperthermia: Evaluation and management".)

Pathogenic variants in RYR1 have also been implicated as a cause of several other types of congenital myopathies, including multiminicore disease, centronuclear myopathy, and congenital fiber type disproportion. (See 'Multiminicore disease' below and 'Centronuclear (myotubular) myopathies' below and 'Congenital fiber type disproportion' below.)

MULTIMINICORE DISEASE — Multiminicore disease (MmD; also known as minicore myopathy and multicore myopathy) is an autosomal recessive congenital myopathy [38]. The disease is named for the characteristic short core lesions called minicores that are present in most muscle fibers.

Clinical features — The clinical expression of MmD is variable [39]. Four subgroups are recognized [40]:

●Classic form

●Moderate form with hand involvement

●Antenatal form with arthrogryposis multiplex congenita

●Ophthalmoplegic form

The classic form of MmD is the most common, accounting for approximately 75 percent of cases [40]. Onset is typically at birth or early in childhood. Manifestations include neonatal hypotonia, delayed motor development, and predominantly axial/proximal muscle weakness. Some infants present with feeding difficulties and failure to thrive [38].

Scoliosis (mean age of onset 8.5 years) and respiratory impairment occur in approximately two-thirds of patients with classic MmD [39]. Respiratory involvement is often associated with secondary cardiac impairment, particularly right ventricular failure and cardiomyopathy [41].

Varying degrees of spinal rigidity are associated with the classic form. The spectrum includes rigid spine syndrome, also known as rigid spine muscular dystrophy, which some consider to be a form of classic MmD [42]. This disorder is caused by contractures of spinal extensor muscles and manifests with limited flexion of the spine, severe scoliosis in the first decade of life, marked respiratory involvement, a relatively mild and slowly progressive myopathy, and elbow and ankle contractures [43].

The moderate form of MmD is characterized by hand weakness with joint hypermobility [40]. The distal legs are relatively spared, and there is minimal scoliosis and respiratory involvement.

The antenatal form of MmD is characterized by polyhydramnios and poor fetal movement leading to generalized joint contractures at birth (arthrogryposis multiplex congenita) [40].

The ophthalmoplegic form of MmD (multiminicore disease with external ophthalmoplegia) is characterized by onset in the neonatal period or early infancy of hypotonia, weakness of the extraocular, axial, and proximal muscles, generalized hyperlaxity of ligaments, and failure to thrive [40]. Extraocular muscle weakness is most pronounced with upward and lateral gaze. Respiratory function is moderately impaired.

Diagnosis — The diagnosis of MmD is suspected in the setting of predominantly axial and proximal muscle weakness that is static or slowly progressive. The diagnosis is typically achieved by genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing [13]. If clinical suspicion for MmD is high, mutation analysis of the SEPN1 gene should be performed first since it is more common. The RYR1 gene can be analyzed if no SEPN1 pathogenic variants are found. Muscle biopsy, though often not necessary, typically shows multiple minicores (see 'Pathologic features' below). However, a muscle biopsy may still be valuable, particularly if variants of uncertain significance in the disease genes are identified [13].

Pathologic features — On muscle biopsy, type 1 fibers predominate and appear atrophic [33]. Light microscopy reveals minicores, which are multiple foci of sarcomeric disorganization and/or loss of oxidative activity [40]. On electron microscopy, mitochondria and oxidative enzymes are decreased. There may be a histopathologic continuum between RYR1-associated central core disease and the moderate form of MmD [38].

Examples of multiminicore (multicore) muscle pathology can be found on the Washington University Neuromuscular Disease Center web site (http://neuromuscular.wustl.edu/pathol/multicore.htm).

Minicores are a nonspecific finding on muscle biopsy [39]. Thus, the detection of minicores is not sufficient to make a diagnosis of MmD in the absence of clinical features that suggest a congenital myopathy.

Genetics — Autosomal recessive pathogenic variants in two genes – SEPN1 and RYR1 – account for approximately one-half of all reported MmD cases. Additional genetic heterogeneity is suspected.

●SEPN1 pathogenic variants account for approximately 30 percent of cases of MmD and approximately 50 percent of the classic form of MmD [42]. Mutations in SEPN1 are also implicated in congenital muscular dystrophy with rigid spine syndrome [44,45], which some consider a form of classic MmD [42]. The term SEPN1-related myopathy is increasingly used to describe a number of overlapping myopathies related to SEPN1 pathogenic variants with histopathologic features of multiminicore disease, congenital fiber type disproportion (see 'Congenital fiber type disproportion' below), or myopathy with Mallory-body-like inclusions [46].

●Autosomal recessive RYR1 pathogenic variants are associated with the moderate and ophthalmoplegic forms of MmD [47-49]. Mutations in the RYR1 gene are also associated with central core disease and malignant hyperthermia, centronuclear myopathy, and congenital fiber type disproportion. (See 'Central core disease' above and "Susceptibility to malignant hyperthermia: Evaluation and management" and 'Centronuclear (myotubular) myopathies' below and 'Congenital fiber type disproportion' below.)

CENTRONUCLEAR (MYOTUBULAR) MYOPATHIES — The centronuclear myopathies, which include X-linked myotubular myopathy, are a clinically and genetically heterogeneous group of disorders characterized by muscle fibers with large central nuclei that resemble myotubes, the early fetal muscle fibers.

Clinical features — Centronuclear myopathies have two main clinical presentations [11].

●The severe, more common form of the disease is X-linked myotubular myopathy, which occurs in males. Male infants have marked hypotonia and skeletal muscle weakness. Respiratory muscle impairment leads to respiratory failure [50]. Facial weakness, ptosis, and extraocular muscle weakness are common, and impaired bulbar function contributes to feeding difficulty. Rarely, abnormal genital development (ambiguous genitalia or severe hypospadias) occurs [51]. Heterozygous female carriers of the associated pathogenic variants may present with limb girdle and facial weakness [52].

Prenatal history in X-linked myotubular myopathy includes polyhydramnios (caused by impaired swallowing) and decreased fetal movement in 50 to 60 percent of cases [11]. Many infants fail to establish effective breathing at birth.

Approximately one-third of severely affected patients die from respiratory complications during infancy and outcome is poor in many survivors. In one series of 55 males with the disorder, 64 percent survived longer than one year, although 80 percent were completely or partially ventilator-dependent [53]. The disease appeared to be non-progressive, and cognitive function was normal in the absence of significant hypoxic-ischemic injury.

●The less common form occurs with autosomal dominant or recessive inheritance and consists of relatively mild weakness and hypotonia that may be unrecognized in the neonatal period [11]. This form occurs in both males and females. Five additional clinical subgroups have been characterized [54]. Two of these are autosomal dominant:

•A classic form characterized by late onset and slow progression

•A form similar to the classic but with diffuse muscle hypertrophy

Three subgroups have been described for autosomal recessive and sporadic presentations [54]:

•Early onset with ophthalmoparesis

•Early onset without ophthalmoparesis

•Late onset without ophthalmoparesis

Diagnosis — The diagnosis of centronuclear myopathies is typically achieved by genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing [13]. Single gene testing including deletion/duplication testing as well as genetic testing for familial pathogenic variants is available. A muscle biopsy may still be of value, particularly if variants of uncertain significance in the disease genes are identified.

Creatine kinase usually is in the normal range, although occasionally it is elevated. Myopathic changes may be seen on the electromyography.

Pathologic features — The distinctive feature of the centronuclear myopathies is the appearance in muscle fibers of one or more centrally placed nuclei with a surrounding clear area due to the absence of myofibrils. Some characteristics of fetal muscle that are present include neural cell adhesion molecules, persistence of the fetal cytoskeletal proteins vimentin and desmin, and intracytoplasmic distribution of dystrophin, implicating a disorder of muscle development in the pathogenesis of this disease [55-57]. Type 1 fibers predominate, and type 1 fiber atrophy is common [33,54]. A radial distribution of sarcoplasmic strands has been noted on oxidative stains [54].

Examples of centronuclear (myotubular) muscle pathology are shown on the Washington University Neuromuscular Disease Center web site (http://neuromuscular.wustl.edu/pathol/centnucl.htm).

Genetics — There are three forms of inheritance for the centronuclear myopathies:

●Autosomal dominant

●Autosomal recessive

●X-linked myotubular myopathy

Although definitive data are lacking, X-linked recessive (myotubular) and autosomal dominant (centronuclear) are the most common modes of inheritance. In one series of 228 patients, X-linked recessive transmission was found in 84 males belonging to 14 families, and autosomal dominant transmission occurred in 65 patients in 14 families [58]. Autosomal recessive forms of centronuclear myopathies occur less commonly than autosomal dominant and X-linked recessive forms [59].

Centronuclear myopathies are genetically heterogeneous, with causative pathogenic variants described in the DNM2, MTM1, RYR1, BIN1, and TTN genes:

●Missense mutations in the dynamin 2 gene (DNM2) on chromosome 19p13.2 have been identified in some cases of autosomal dominant centronuclear myopathy [60]. In addition, DNM2 pathogenic variants (missense and deletion) were identified in sporadic cases of centronuclear myopathy with neonatal onset [61].

●Mutations responsible for X-linked myotubular myopathy are in the gene encoding the myotubularin protein (MTM1), a protein tyrosine phosphatase required for muscle cell differentiation [62,63]. The gene is located on chromosome Xq28 [64]. Cultured cells in most patients with pathogenic variants in the MTM1 gene have abnormal levels of myotubularin [65]. A large number of point mutations or deletions have been identified in the MTM1 gene [66]. In family studies, female carriers are identified in the majority of cases. However, in one series, 17 percent were de novo mutations [67]. When the family history is positive, prenatal diagnosis of X-linked recessive centronuclear myopathy can be performed [68].

●Mutations in the RYR1 gene appear to be a common cause of centronuclear myopathy, and most identified cases were compatible with recessive inheritance [69]. As noted earlier, pathogenic variants in RYR1 have been implicated as a cause of several other types of congenital myopathies, including central core disease, multiminicore disease, and congenital fiber type disproportion. (See 'Central core disease' above and 'Multiminicore disease' above and 'Congenital fiber type disproportion' below.)

●Homozygous pathogenic variants in the BIN1 gene (also known as amphiphysin 2) on chromosome 2q14 have been identified in three families with autosomal recessive inheritance [70], and heterozygous pathogenic variants in the BIN1 gene have been identified in several families with autosomal dominant inheritance [71].

●Truncating pathogenic variants in the titin (TTN) gene were found in five unrelated individuals with a clinicopathologic diagnosis of centronuclear myopathy and autosomal recessive inheritance [72].

CONGENITAL FIBER TYPE DISPROPORTION — Congenital fiber type disproportion is a poorly defined condition that is characterized by small type 1 fibers on muscle biopsy, but it does not have the structural changes seen in other congenital myopathies.

Clinical features — Infants with congenital fiber type disproportion present with generalized hypotonia and weakness of the limbs, neck, trunk, and facial muscles [11]. Although most infants are severely affected, the extent of hypotonia and weakness is variable. Ophthalmoplegia occurs uncommonly.

Patients may have deformational features including an elongated face, high arched palate, and multiple contractures. Musculoskeletal abnormalities, such as congenital hip dislocation, torticollis, and foot deformities typically occur, and scoliosis often develops later as a result of muscle weakness. Foot deformities, as well as polyhydramnios and decreased fetal movements, may be noted on prenatal assessment [73].

The clinical course is variable. Most patients, even those with respiratory failure in the neonatal period, improve with age [74,75]. In the largest kindred reported to date, the clinical course was notable for onset in early infancy with mild limb weakness, and slow progression into adulthood, characterized by moderate to severe mainly proximal weakness without loss of ambulation [76]. However, others have significant disability in childhood and may develop progressive respiratory failure [77]. Rare cases of cardiomyopathy have been reported [78].

Serum creatine kinase levels in congenital fiber type disproportion typically are normal. The electromyography usually shows mild myopathic changes.

Diagnosis — The diagnosis is typically achieved by genetic testing using a next generation sequencing targeted gene panel, whole exome sequencing, or whole genome sequencing [13]. Single gene testing including deletion/duplication testing as well as genetic testing for familial pathogenic variants is available. A muscle biopsy may still be of value, particularly if variants of uncertain significance in the disease genes are identified [13].

Pathologic features — The characteristic features of congenital fiber type disproportion are the increased proportion of type 1 fibers and their small size [11,33]. In normal muscle, type 1 fibers comprise 30 to 55 percent of the total, and the diameters of type 1 and 2 fibers are approximately equal. In congenital fiber type disproportion, type 1 fibers comprise more than 55 percent of the total, and the mean diameter of type 1 fibers is at least 12 percent less than that of type 2 fibers.

Examples of congenital fiber type disproportion muscle pathology are shown on the Washington University Neuromuscular Disease Center web site (http://neuromuscular.wustl.edu/pathol/1small.htm).

Genetics — Congenital fiber type disproportion is genetically heterogeneous. The disorder has been associated with pathogenic variants in a number of genes, including:

●TPM3 [79]

●ACTA1 [80]

●SEPN1 [81]

●RYR1 [82]

●MAP3K20 (ZAK) [83]

As previously noted, pathogenic variants in RYR1 also cause other types of congenital myopathies, including central core disease, multiminicore disease, and centronuclear myopathy. (See 'Central core disease' above and 'Multiminicore disease' above and 'Centronuclear (myotubular) myopathies' above.)

Furthermore, the term SEPN1-related myopathy is increasingly used to describe a number of overlapping myopathies related to SEPN1 pathogenic variants with histopathologic features of multiminicore disease (see 'Multiminicore disease' above), congenital fiber type disproportion, or myopathy with Mallory-body like inclusions [46].

Most cases of congenital fiber type disproportion are sporadic, but familial cases occur as follows [82,84]:

●Mutations in ACTA1 are associated with autosomal dominant inheritance

●Mutations in RYR1 and SEPN1 are associated with autosomal recessive inheritance

●Mutations in TPM3 may be autosomal dominant or recessive

An X-linked inheritance pattern was identified in one family with a candidate gene locus at Xq13.1-q22.1 [85].

The pathogenesis of congenital fiber type disproportion is unknown. Because it sometimes is associated with cerebellar hypoplasia, one proposed mechanism is a disturbance of innervation of the developing muscle mediated through the bulbospinal pathways [5]. Alternatively, a primary disorder of muscle development may be involved. In cases related to ACTA1 pathogenic variants, it is possible that mutant actin disrupts sarcomere function, perhaps by interfering with normal actin-tropomyosin interactions [80,86].

OTHER MYOPATHIES — Other myopathies that are less well characterized may present in the newborn period [66,87,88]. These rare disorders include the following conditions:

●Early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD), discussed below

●Autophagic vacuolar myopathy [89]

●Cap disease [90]

●Congenital myopathy with arrest of myogenesis [91]

●Myosin storage (hyaline body) myopathy [92]

●Zebra body myopathy [93]

●SCN4A-related congenital myopathy [94,95]

Early onset myopathy, areflexia, respiratory distress, and dysphagia — Early onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is a rare autosomal recessive congenital myopathy characterized by respiratory distress due to diaphragmatic paralysis that presents at birth or in early infancy [96,97]. It has been described in a small number of individuals from five kindreds. The areflexia, muscle weakness, and hypotonia predominantly involve the upper limbs. All infants with EMARDD have dysphagia and become ventilator dependent or die from respiratory failure. Electromyography shows myopathic features, while nerve conduction velocities are normal. On muscle biopsy, abnormalities include small and incompletely fused muscle fibers with a reduced number of nuclei per fiber. The disorder is caused by pathogenic variants in the MEGF10 gene [96].

The phenotype of EMARDD, particularly the early onset of diaphragmatic paralysis, is similar to a condition called spinal muscular atrophy with respiratory distress type 1 (SMARD1). (See "Spinal muscular atrophy", section on 'Spinal muscular atrophy with respiratory distress type 1'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Muscular dystrophy".)

SUMMARY — Congenital myopathies are primary muscle disorders that are present from birth, although their expression may be delayed until later in infancy or childhood. These conditions are rare. The most common are nemaline myopathy, central core disease, centronuclear/myotubular myopathies, and congenital fiber type disproportion (table 1). The specific disorders are characterized on the basis of their histologic and histochemical features. These conditions are caused by genetic abnormalities of muscle development.

●Nemaline myopathy derives its name from the characteristic rod bodies in muscle that appear threadlike in longitudinal section. The clinical expression is variable. The presentation in affected newborns can be severe or relatively mild. In the former, profound generalized weakness and hypotonia involving the face, bulbar, and respiratory muscles is seen; the eye muscles are spared. The milder form, with relatively less facial weakness and diaphragm impairment, also can present in children or adults. Intermediate forms also are identified. (See 'Nemaline myopathy' above.)

●Central core disease typically presents in the neonatal period, although it may not be recognized until later infancy. The principal findings are hypotonia and muscle weakness, which usually are more prominent in the proximal extremities. Muscle involvement is variable and ranges from undetectable to severe. Patients often have mild facial weakness, but do not have ptosis, extraocular muscle weakness, dysphagia, or respiratory difficulty. Tendon reflexes usually are present, although they are reduced proportionally to the severity of the disease. Commonly associated musculoskeletal abnormalities include congenital hip dislocation, kyphoscoliosis, joint contractures, and foot deformities. Affected patients are at risk for developing malignant hyperthermia. The clinical course typically is nonprogressive. (See 'Central core disease' above.)

●Multiminicore disease (MmD; also known as multicore myopathy) is an autosomal recessive congenital myopathy that is named for the characteristic lesions called minicores that are present in most muscle fibers. The classic form of MmD is the most common. Onset is typically at birth or early in childhood. Manifestations include neonatal hypotonia, delayed motor development, and predominantly axial/proximal muscle weakness. Some infants present with feeding difficulty and failure to thrive. Scoliosis and respiratory impairment occur in approximately two-thirds of patients with classic MmD. Respiratory involvement is often associated with secondary cardiac impairment, particularly right ventricular failure and cardiomyopathy. Varying degrees of spinal rigidity are associated with the classic form. The spectrum includes rigid spine syndrome, which some consider to be a form of classic MmD. Additional types of MmD include a moderate form with hand involvement, an antenatal form with arthrogryposis multiplex congenita, and an ophthalmoplegic form. (See 'Multiminicore disease' above.)

●The centronuclear myopathies, which include X-linked myotubular myopathy, are a clinically and genetically heterogeneous group of disorders characterized by muscle fibers with large central nuclei that resemble myotubes, the early fetal muscle fibers. Centronuclear myopathies have two main clinical presentations. The severe, more common form of the disease is X-linked myotubular myopathy that occurs in males. Male infants have marked hypotonia and skeletal muscle weakness. Respiratory muscle impairment leads to respiratory failure. Facial weakness, ptosis, and extraocular muscle weakness are common, and impaired bulbar function contributes to feeding difficulty. Prenatal history includes polyhydramnios caused by impaired swallowing and decreased fetal movement in 50 to 60 percent of cases. Many infants fail to establish effective breathing at birth. The less common form occurs with autosomal dominant or recessive inheritance and consists of relatively mild weakness and hypotonia that may be unrecognized in the neonatal period. This form occurs in both males and females. Additional clinical subgroups have been characterized. (See 'Centronuclear (myotubular) myopathies' above.)

●Congenital fiber type disproportion is characterized by small type 1 fibers on muscle biopsy, but without the structural changes seen in other congenital myopathies. Infants present with generalized hypotonia and weakness of the limbs, neck, trunk, and facial muscles. Most infants are severely affected but the extent of hypotonia and weakness is variable. Deformational features can include an elongated face, high arched palate, and multiple contractures. Musculoskeletal abnormalities, such as congenital hip dislocation, torticollis, and foot deformities typically occur. Scoliosis often develops later as a result of muscle weakness. Foot deformities, as well as polyhydramnios and decreased fetal movements, may be noted on prenatal assessment. The clinical course is variable. Most patients, even those with respiratory failure in the neonatal period, improve with age. However, others have significant disability in childhood and may develop progressive respiratory failure. (See 'Congenital fiber type disproportion' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Geoffrey Miller, MD, who contributed to an earlier version of this topic review.