The term “congenital myopathy” was originally used to describe a group of myopathic disorders presenting preferentially, but not exclusively, at birth and being morphologically distinct from congenital muscular dystrophies (Table 28-1).^1–3 However, disorders that were once considered forms of muscular dystrophy are now known to be allelic to some types of congenital myopathy. For example, congenital muscular dystrophy with rigid spine syndrome, multi/minicore, and some cases of myofibrillar myopathy are caused by selenoprotein N1 mutations; sarcotubular myopathy and limb-girdle muscular dystrophy 2H (LGMD2H) are due to mutations in TRIM32; reducing body myopathy is now considered a type of LGMD. In addition, some disorders caused by mutations in sarcomeric proteins are classified as forms of LGMD (e.g., titinopathies, myotilinopathies, ZASPopathies), while others (e.g., actinomyosin, tropomyosin, α-actin, and troponin) are forms of congenital myopathy (nemaline myopathy). Thus, the nosology of what distinguishes a “congenital myopathy” from a “muscular dystrophy” on clinical and histopathologic grounds is not at all clear.

Usually, the congenital myopathies present in infancy as generalized hypotonia and weakness. Motor milestones are typically delayed. Affected infants are usually hypotonic and display delayed motor development. Some disorders with mutations in similar genes present later in childhood or even in adulthood. The congenital myopathies were initially considered as nonprogressive, although it is now clear that progressive weakness can occur.

Congenital myopathies can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked pattern. Within families, there can be considerable variation with respect to disease presentation and degree of muscle involvement. The serum creatine kinase (CK) levels are either normal or usually mildly elevated. The classification of congenital myopathies has been based almost exclusively on clinical presentation and light/electron microscopic structural alterations of the muscle biopsy specimen (Table 28-1).

CLINICAL FEATURES

Central core myopathy usually manifests at birth or early childhood as generalized weakness and hypotonia.^1–7 The degree of muscle weakness can vary even within families.³ Muscle weakness is stable or only slowly progressive. Motor milestones, such as the ability to sit and walk, are delayed. Some individuals who are affected never achieve independent ambulation, while others have only mild weakness. The proximal muscles, legs more than arms, are preferentially affected, leading to a wide-based hyperlordotic gait. Individuals who are affected may also demonstrate a Gowers sign when arising from the floor. There may be mild facial and neck flexor weakness. However, patients do not exhibit ptosis or extraocular muscle weakness—clinical features that can help distinguish central core myopathy clinically from centronuclear and nemaline myopathies. Muscle atrophy or hypertrophy are usually not seen in central core disease. Contractures are uncommon. Muscle stretch reflexes are normal or reduced. There are no apparent central nervous system abnormalities. Affected individuals may exhibit mild-to-moderate skeletal deformities including pes planus, pes cavus, kyphoscoliosis, and congenital hip dislocation. Mild ventilatory muscle weakness with reduced forced vital capacity and nocturnal hypoxemia is seen in some patients.³

LABORATORY FEATURES

The serum CK levels are normal or slightly elevated. Motor and sensory nerve conduction studies (NCS) are usually normal. Electromyography (EMG) may reveal fibrillation potentials and positive sharp waves and myopathic appearing motor unit action potentials (MUAPs) that recruit early in weak muscles.⁸ Long-duration, polyphasic MUAPs and units with satellite potentials may also be appreciated. Skeletal muscle MRI reveals early involvement of the vasti, sartorius, and adductor magnus in the thigh with relative sparing of the rectus femoris, adductor longus, and hamstrings.¹

HISTOPATHOLOGY

The characteristic histologic features are the structural alterations within the center of muscle fibers, so-called cores.^1–9 These cores appear only in type 1 muscle fibers and are particularly noticeable on nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) stains, where the cores are devoid of stain (Fig. 28-1). The cores can occasionally be eccentric and multiple within a given muscle fiber. The distinction between central core and multi/minicore is that in central core myopathy the “cores” extend along the entire length of the muscle fibers on longitudinal section. However, in some cases, the distinction between central cores and multi/minicores is not clear, as there can be typical multi/minicores in patients with central core myopathy. Furthermore, repeat biopsies in patients initially diagnosed with minicores may subsequently reveal central cores.¹⁰ In addition, muscle biopsies reveal variation in fiber size, increased internalized nuclei, and often a predominance of type 1 fibers that may be atrophic. Increased endomysial fibrosis and fat may be present,⁹ but the other features help distinguish the disorder from muscular dystrophies.

On electron microscopy (EM), the cores may be “structured” or “unstructured” (Fig. 28-2). In structured cores, there is streaming of the Z-band, but the sarcomeres are preserved. In unstructured cores, there is severe myofibrillar disruption and loss of the normal sarcomere organization. In both structured and unstructured cores, mitochondria and glycogen granules are reduced or absent. The cores appear to contain desmin, dystrophin, actin, α-actinin, gelsolin, nebulin, myotilin, β-amyloid precursor protein, NCAM, and various cyclin-dependent kinases based on immunocytochemistry; the cores are also variably congophilic.¹¹

MOLECULAR GENETICS AND PATHOGENESIS

Central core myopathy is an autosomal-dominant disorder caused by mutations in the ryanodine receptor gene (RYR1) on chromosome 19q13.1 in the majority of cases.^{1–3,12–15} Rarely, autosomal-recessive inheritance may occur with RYR1 mutations.¹⁶ Of note, mutations in the RYR1 are responsible for one form of familial malignant hyperthermia; thus, patients with central core myopathy are at risk of malignant hyperthermia (Table 28-1).¹⁷ Why these “cores” form in the center of the muscle fibers is unknown. The ryanodine receptor is a tetramer of RYR1 proteins, which bridges the gap between the sarcoplasmic reticulum and the T-tubules in skeletal muscle and forms a calcium-release channel. Thus, the ryanodine receptor likely plays an important role in excitation–contraction coupling. Most of the mutations associated with the classic phenotype are seen in the C-terminal domain that corresponds to the transmembrane domain of the protein.^1,2 In experimental studies of mutant myotubes, voltage-gated calcium release was reduced by approximately 90%, while caffeine-induced Ca²⁺ release was only marginally reduced in mutant myotubes, indicating the disruption of voltage-sensor activation of calcium release.^18,19

Mutations in muscle slow/β cardiac myosin heavy chain 7 gene (MYH7) have been associated with eccentric cores and multi/minicores.^1,2,20 Mutations in the genes that encode actin 1 (ACTA1), titin (TTN), coiled–coiled domain-containing gene, CCDC78, have also been associated with core-like changes on muscle biopsy, while mutations in NEB that encodes nebulin and KBTBD13 encoding Kelch repeat and BTB may cause cores and nemaline rods.^1–3,21,22

TREATMENT

There is no specific medical treatment available for central core myopathy. Patients may benefit from physical therapy and orthotic devices. Patients with central core disease and their families should be informed of their risk of developing malignant hyperthermia with general anesthesia. Appropriate precautions and avoidance of certain anesthetic agents (e.g., halothane) and neuromuscular blocking agents (succinylcholine) need to be taken during surgical procedures.

CLINICAL FEATURES

Although it is generally agreed that multi/minicore disease (MmD) constitutes a distinct entity, the morphologic lesions defining it are nonspecific, and the clinical expression of the disease is highly variable.^{1–3,23–28} MmD usually presents in infancy or early childhood, but adult-onset cases have been reported as well. Affected infants are usually hypotonic and weak. Motor milestones are delayed, but ambulation is usually achieved. Most patients have generalized muscle weakness and atrophy predominantly affecting axial and proximal extremity muscles. Distal muscles are usually normal or only slightly involved. However, there may be a subgroup of MmD that manifests with predominantly distal hand weakness.^25,26 Facial muscle weakness, ptosis, and occasionally ophthalmoparesis can also be seen. It is unclear if these patients represent a distinct subgroup of MmD.

Muscle contractures and multiple skeletal deformities such as kyphoscoliosis, high-arched palate, and club feet are common findings. Weakness is usually stable or only slowly progressive.²⁶ Neck extensors and trunk muscles may be contracted, leading to rigidity of the spine. Cardiomyopathy and ventilatory muscle involvement can also develop.^27,28 Ventilatory involvement can be disproportionate to the degree of scoliosis.^2,26 Patients may require intermittent or continuous positive-pressure ventilation.

LABORATORY FEATURES

Serum CK is usually normal or only slightly elevated. Pulmonary function tests often reveal reduced forced vital capacities. Polysomnographic studies may disclose nocturnal oxygen desaturation and short apneic periods. NCS are normal. EMG usually reveals normal insertional and spontaneous activity, although early recruitment of short-duration, small-amplitude MUAPs may be appreciated.⁸

HISTOPATHOLOGY

Muscle biopsies reveal multiple small regions within muscle fibers of variable size (minicores) formed by disorganization of the myofibrils (Fig. 28-3).^25,26 These minicores are similar to central cores but are much smaller and do not extend the entire length of the muscle fiber as do central cores. In addition, minicores can occur in either type 1 or type 2 muscle fibers. Type 1 fiber predominance and atrophy as well as fiber size variation are also noted. There can be increased endomysial connective tissue as well. EM demonstrates myofibrillar disruption similar to that seen in central cores (Fig. 28-4).

MOLECULAR GENETICS AND PATHOGENESIS

This is a genetically heterogeneous group of disorders. The absence of clear dominant transmission in any well-established case and the presence of several consanguineous families strongly suggest that MmD is usually an autosomal-recessive entity or the result of spontaneous mutations.^1–3,26 Interestingly though, some patients with MmD (usually cases associated with external ophthalmoplegia and ptosis) have demonstrable mutations in the RyR1 gene similar to central core myopathy.^1–3,10,29 Mutations in the selenoprotein N gene (SEPN1), which is located on chromosome 1p36, are the most common cause in individuals with classic MmD.³⁰ Of note, this is the same gene responsible for the congenital muscular dystrophy with rigid spine syndrome and some cases of myofibrillar myopathy.³⁰ The dystrophic changes and histologic features of myofibrillar myopathy apparent on some muscle biopsies and SEPN1 mutations identified in some cases of MmD highlight the difficult nosologic boundaries between various types of congenital myopathies and muscular dystrophies. In addition, mutations in coiflin-2 gene, CFL2, encoded on chromosome 14q13 have been reported in two siblings that had nemaline rods and minicores on muscle biopsy. Mutations in myosin heavy chain 7 gene (MYH7)^31,32, titin (TTN)³³, and multiple EGF-like-domains 10 (MEGF10)³⁴ can be associated with minicores as well.

TREATMENT

No specific medical treatment is available. Patients may be at risk of malignant hyperthermia and should be counseled accordingly (see Central Core Myopathy).^35,36 Early-onset scoliosis is common and may require extensive arthrodesis. Patients may require intermittent or continuous positive-pressure ventilation.

CLINICAL FEATURES

Central core and nemaline rod myopathies are generally considered two genetically and histologically distinct disorders.^{1–3,37–44} However, there are scattered reports in the literature of the simultaneous occurrence of both cores and rods in the same muscle biopsy. Onset of symptoms is variable (congenital or early adult life) as is severity. The weakness can be proximal, distal, or generalized. Some cases have ptosis and/or skeletal deformities (e.g., contractures, scoliosis).

LABORATORY FEATURES

The serum CK level can be normal or slightly elevated. NCS are usually normal. Early recruitment of small-amplitude, short-duration MUAPs are appreciated in weak muscles on EMG.

HISTOPATHOLOGY

Muscle biopsies, as implied by the name, can show both cores and rods along with type 1 fiber predominance (Figure 28-5).

MOLECULAR GENETICS AND PATHOGENESIS

Mutations in the ryanodine receptor gene (RYR1) account for most cases, however mutations in the genes that encode actin 1 (ACTA1), nebulin (NEB), and Kelch repeat and BTB (KBTBD13) have also been associated with muscle biopsies demonstrating both cores and nemaline rods.^1,2,37–44

TREATMENT

No specific medical treatment is available. Those cases with RYR1 mutations should be counseled in regard to possible risk of malignant hyperthermia.

As previously discussed, the clinical phenotype associated with RYR1 mutations is large and aside from central core and multi/minicore myopathies that usually occur early in life, also cause malignant hyperthermia. In addition, RYR1 mutations have been identified as a cause of exertional myalgias and rhabdomyolysis in the absence of baseline weakness.⁴⁵ King–Denborough syndrome is a rare disorder characterized by a susceptibility to malignant hyperthermia, delayed motor development, short stature, cryptorchidism, skeletal abnormalities, and variable dysmorphic features that in some cases, but not all, have been associated with RYR1 mutations.^46,47

Furthermore, late-onset axial myopathy manifesting as bent spine syndrome (camptocormia) or neck extensor myopathy have been found to have RYR1 mutations.^48–50 CKs are normal or slightly elevated. EMG may be normal in extremities and demonstrate fibrillation potentials and positive sharp waves only in axial/paraspinal muscles. In our experience, muscle biopsies of extremity muscles that are strong may be unrevealing while biopsy of upper trapezius or paraspinal muscles may demonstrate cores, multiminicores, or moth-eaten fibers.

CLINICAL FEATURES

Nemaline myopathy is clinically and genetically heterogeneous. It can be inherited in an autosomal-dominant or autosomal-recessive fashion. There are three major clinical presentations of nemaline myopathy: (1) a severe infantile form, (2) a static or slowly progressive form, and (3) an adult-onset form.^51–64

The severe infantile form is characterized by severe generalized weakness and hypotonia at birth. Muscle stretch and Moro reflexes are usually absent. Affected infants have a weak cry and suck. Because of ventilatory muscle involvement, they often need to be mechanically ventilated. Most children with this severe infantile-onset form of nemaline myopathy die in the first year of life due to ventilatory complications. Arthrogryposis, neonatal ventilatory failure, and failure to achieve early motor milestones are associated with early mortality.⁵⁷ Most are inherited in an autosomal-recessive pattern, but autosomal-dominant inheritance also occurs.^1–3

More commonly, nemaline myopathy manifests as mild, nonprogressive, or slowly progressive weakness beginning in infancy or early childhood. Both proximal and distal extremity muscles are affected and associated with generalized reduction in muscle bulk. Some patients have a facioscapuloperoneal distribution of weakness. Motor milestones are often delayed, and the children may exhibit a wide-based, waddling, hyperlordotic gait. Slight facial and masticatory muscle weakness may be appreciated, but ptosis and extraocular weakness are not typical. Many have a characteristic dysmorphic narrow facies with high-arched palate and micrognathia. In addition, multiple skeletal deformities such as pectus excavatum, kyphoscoliosis, temporal mandibular ankylosis, pes cavus, or club feet are common. Deep tendon reflexes are reduced or absent.

The adult-onset type of nemaline rod myopathy is associated with mild proximal and occasionally distally predominant muscle weakness presenting in adulthood. Some patients have minimal skeletal muscle weakness but manifest with a cardiomyopathy. The adult-onset form is not associated with dysmorphic facial features or skeletal deformities typical of the early-onset forms.

LABORATORY FEATURES

The serum CK level is normal or slightly elevated. NCS are usually normal. Early recruitment of small-amplitude, short-duration MUAPs are appreciated in weak muscles on EMG. In the severe infantile forms, EMG may demonstrate increased insertional and spontaneous activity in the form of fibrillation potentials and positive sharp waves. Such abnormal spontaneous activity is usually not appreciated in the more benign forms of the myopathy.

HISTOPATHOLOGY

Muscle biopsies often reveal type 1 fiber predominance and hypotrophy in the congenital forms but not in the adult-onset form of the disease. On routine histochemistry, the nemaline rods are best appreciated on modified Gomori trichrome stain, on which the rods appear as small, red or bluish purple staining bodies in the subsarcolemma and occasionally perinuclear regions (Fig. 28-6). On EM, the typical “rod bodies” measure 3–6 μm in length and 1–3 μm in diameter, giving the appearance of threads (nemaline: Greek for “thread like”). The nemaline rods have a density similar to the Z-disc (Fig. 28-7). Intranuclear rods may be observed, and early reports suggested that these represent a marker for this severe form of the disease (Fig. 28-8).^62–64 However, intranuclear rods are not demonstrated in all severe infantile cases and can also be found in milder adult-onset cases of nemaline myopathy.⁵⁶ Immunohistochemistry reveals that the rods and Z-disc are strongly immunoreactive for α-actinin.⁶⁵ Rods are not specific for congenital nemaline myopathy and have been reported following tenotomy, in HIV-associated myopathy, myofibrillar myopathy, inclusion body myositis, and hypothyroidism.

MOLECULAR GENETICS AND PATHOGENESIS

Nemaline rods arise secondary to a derangement of proteins necessary to maintain normal Z-disc structure. The myopathy is genetically heterogeneous, with mutations having been identified in the genes that encode nebulin (NEB), α-tropomyosin (TPM3), β-tropomyosin (TPN2), troponin T (TNNT1), α-actin (ACTA1), Cofilin-2/(CFL2), Kelch repeat and BTB 13 (KBTBD13), and Kelch-like family member 40 and 41 (KLHL40 and KLHL41) (Table 28-1).^{1–3,66–85}

Most of the autosomal-recessive cases (around 50%) are caused by mutations in the nebulin gene (NEB).^{1–3,66–68} The clinical phenotype associated with nebulin mutations can be mild or severe. Mutations in the α-actin gene (ACTA1) can cause autosomal-recessive and autosomal-dominant nemaline myopathy.^{1–3,53,69–72} ACTA1 mutations are the second most common cause of nemaline myopathy (15–30%) but are responsible for about 50% of the severe lethal congenital-onset cases. The severity of the disease ranges from lack of spontaneous movements at birth requiring immediate mechanical ventilation to mild disease compatible with life to adulthood. There are rare reported cases with adult onset as well.⁵³ Mutations in the ACTA1 gene are also responsible for previously reported cases of “congenital myopathy with excess of thin filaments.”¹

Mutations in the α-tropomyosin gene (TPM3) on chromosome 1q21–q23 can result in autosomal-dominant or autosomal-recessive nemaline myopathy.^73–75 The severity of cases with TPM3 mutations vary from severe infantile to late childhood-onset, slowly progressive forms. A useful clue for TPM3 mutations is when rods are only present in type 1 fibers as TMP3 is not expressed in type 2 fibers. Mutations in the β-tropomyosin gene (TPN2) cause autosomal-dominant rod myopathy that may manifest with neck and distal lower extremity weakness (foot drop) and cardiomyopathy.^1,76 A severe, rare, infantile form of autosomal-recessive nemaline myopathy found in Amish communities is caused by mutations in the muscle troponin T (TNNT1) gene.⁷⁷ Mutations in the gene that encodes for the actin-binding protein, coiflin-2 (CFL2), have been identified nemaline myopathy and minicores.^78–80

A recent study utilizing whole-exome sequencing found autosomal-recessive mutations in the Kelch-like family member 40 gene (KLHL40) in 28 apparently unrelated kindreds of various ethnicities with nemaline myopathy.⁸¹ This accounted for 28% of the tested individuals in the Japanese cohort making KLHL40 the most common cause of this severe form of nemaline myopathy in this population. Another study using whole-exome sequencing identified recessive small deletions and missense changes mutations in the Kelch-like family member 41 gene (KLHL41) in 5 unrelated individuals.⁸² These studies along with cases of core–rod myopathy associated with mutations in Kelch repeat and BTB domain containing 13 (KBTBD13)⁴⁴ mutations suggest an importance of BTB-Kelch family members in maintenance of Z-disc and sarcomeric integrity.

As mentioned in the core–rod myopathy section, there are several other genes (ACTA1, NEB, KBTBD13) associated with muscle biopsies showing both nemaline rods with cores. Further, both caps and nemaline rods were found in one patient caused by an autosomal-dominant mutation in the TPM3 gene (discussed later in the Cap Myopathy section).⁸³

TREATMENT

No specific medical treatment is available. Morbidity from respiratory tract infections and feeding difficulties frequently diminish with increasing age; therefore, aggressive early management is warranted in most cases of severe infantile nemaline myopathy. Individuals who are affected may benefit from physical therapy and bracing.