Chapter 93 Congenital Myopathies
The congenital myopathies are a group of disorders characterized by their histopathologic findings on muscle biopsy. A prevalence of 3.5–5/10,000 children has been reported for all congenital myopathies [Chung et al., 2003; Sharma et al., 2009]. The discovery of this heterogeneous group of disorders grew out of the technical ability to investigate abnormal muscle by histochemistry, introduced in the 1950s and 1960s [Jungbluth et al., 2003]. Since then, electron microscopy, proteomics, and genomics have expanded the understanding of these conditions, as well as complicated physicians’ ability to create a simple classification schema.
The majority of these conditions manifest at or shortly after birth with hypotonia, static or nonprogressive muscle weakness, normal to decreased deep tendon reflexes, and delays in reaching milestones [Riggs et al., 2003; Taratuto, 2002]. They can also become apparent in late childhood or adulthood. Patients may have a mildly progressive course or may even be asymptomatic when presenting later in life [Riggs et al., 2003]. The serum creatine kinase level is typically normal or mildly elevated, and electromyography often reveals a myopathic pattern: namely, short, small-action potentials with rapid recruitment. A muscle biopsy is usually necessary to classify the condition and improve the clinician’s ability to prognosticate for the patient and family. The findings commonly seen in the biopsy include type I fiber predominance or hypotrophy, or both, with the absence of fiber necrosis and other evidence of chronic degeneration, such as endomysial fibrosis and fatty infiltration, findings typically seen in muscular dystrophies. Protein aggregation, often of defective proteins, then allows for final classification. Overall, there are no cures for these conditions, but supportive care is important for quality of life and longevity.
Central Core Disease
Central core disease was the first congenital myopathy described by Magee and Shy [1956]. It was named for the round delineated areas, typically within type I muscle fibers, that are devoid of oxidative enzyme activity [Jungbluth et al., 2003; Quinlivan et al., 2003; Taratuto, 2002].
Clinical Features
In addition to the hypotonia, muscle weakness (which typically affects the pelvic girdle), and developmental delay, children often present with skeletal deformities, such as scoliosis, congenital hip dislocation, and pes cavus [Jungbluth et al., 2003; Quinlivan et al., 2003; Taratuto, 2002]. Facial weakness can also be present, is usually mild, and may be seen only in the inability to bury the eyelashes completely [De Cauwer et al., 2002; Jungbluth et al., 2003]. It mainly manifests in infancy or early childhood, although it can appear later in life or even never. The weakness tends to be static or slowly progressive. Many patients are able to walk eventually, and some families may report muscle cramping [Jungbluth et al., 2003]. Central core disease is allelic with malignant hyperthermia [Quinlivan et al., 2003]. The serum creatine kinase level tends to be normal to mildly elevated.
Pathology
Muscle biopsy specimens from patients with central core disease demonstrate type I fiber predominance, with cores seen in the center of many type 1 fibers that extend throughout a large part of the fiber’s length [Jungbluth et al., 2003; Taratuto, 2002]. The cores are seen most easily when stained with the nicotinamide adenine dinucleotide-tetrazolium reductase technique [Riggs et al., 2003].
The 1995 diagnostic criteria created by the European Neuromuscular Centre include the presence of cores, which are central, although they may be eccentric or multiple, and well demarcated, visible with oxidative stains, and affecting only type 1 fibers [De Cauwer et al., 2002]. Histologic diagnosis also requires distinctive electron microscopy and a type 1 fiber predominance. Corelike lesions can also be seen with denervation and are called targetoid lesions or targets if they are trilayered [Goebel, 2003]. Various proteins have been found to accumulate within cores (Box 93-1), and this finding often helps differentiate central core disease from mini-core disease, which is discussed later.
Genetics
Central core disease is most commonly an autosomal-dominant condition with variable penetrance; however, sporadic cases have been reported [Jungbluth et al., 2003; Riggs et al., 2003; Taratuto, 2002]. It has been mapped to chromosome region 19q12–p13.1 [Fananapazir et al., 1993; Haan et al., 1990; Monnier et al., 2000; Tilgen et al., 2001], which is also associated with malignant hyperthermia. This locus is linked to a ryanodine receptor (RYR1), which is a ligand-gated release channel for calcium [McCarthy et al., 2000], mediating calcium release after sarcolemma depolarization [Taratuto, 2002]. Mutations in this gene can give rise to malignant hyperthermia, central core disease, or both, and account for almost 80 percent of cases of central core disease [Taratuto, 2002]. There are three regions on the RYR1 gene where mutations have been found. The majority of lesions are found in regions 1 and 2, which reside in the myoplasmic foot domain [Tilgen et al., 2001]. Mutations have been reported more recently in region 3, which is located in the highly conserved transmembrane C-terminal region. A mutation in this region has been found in a French family with a severe form of the disease, characterized by malignant hyperthermia and cores and rods in muscle fibers on biopsy [Monnier et al., 2000]. Central core disease has also been reported with hypertrophic cardiomyopathy, but not malignant hyperthermia, and found to result from a mutation in β-myosin heavy gene [Fananapazir et al., 1993].
Multi-Mini-Core Disease
Multi-mini-core disease is histologically similar to central core disease; however, there are many significant differences. It was first described by Engel and associates in 1971 and is characterized by multiple small areas of sarcomeric disorganization lacking oxidative activity [Ferreiro and Fardeau, 2002].
Clinical Features
There are four phenotypic groups identified, all of which are characterized by approximately normal creatine kinase levels, myopathic findings on electromyography, and no cardiac involvement [Ferreiro and Fardeau, 2002]. Patients typically present at birth or within the first 18 months of life. The classic form, or first group, manifests with severe neonatal hypotonia; predominant axial muscle weakness, especially in neck flexors; delayed motor development; severe scoliosis; and significant respiratory involvement. Its characteristics are similar to those of congenital muscular dystrophy with early rigidity of the spine (RSMD1) [Jungbluth et al., 2003]. Limb joint hyperlaxity and myopia have been found in many of the patients [Ferreiro and Fardeau, 2002; Taratuto, 2002]. The second group, or ophthalmoplegia form, consists of the typical findings plus variable ophthalmoplegia and often severe facial weakness. The third group manifests with early onset and arthrogryposis, and the fourth group is characterized by slow progression and hand amyotrophy.
Pathology
There are several pathologic differences between central core and mini-core disease. In multi-mini-core disease, the lesions tend to have poorly defined boundaries and are short; thus, longitudinal muscle sections must be evaluated to help differentiate the two conditions. Mini-cores are found in both fiber types, as opposed to just type 1 fibers in central core disease [Ferreiro and Fardeau, 2002], and contain different proteins (see Box 93-1) [Goebel, 2003].
Genetics
These disorders are mostly autosomal-recessive, but many sporadic cases have been reported [Jungbluth et al., 2003]. Recessive mutations have been found in the RYR1 gene in patients with group 3 disease [Jungbluth et al., 2002] and in one family with distal weakness and amyotrophy [Ferreiro et al., 2002a]. Patients with the classic form have been found to have recessive mutations in the selenoprotein N gene [Ferreiro et al., 2002b] and in the RSMD1 gene [Moghadaszadeh et al., 2001]. Selenoprotein N is a glycoprotein found in the endoplasmic reticulum, expressed mostly in fetal tissues and in dividing cells [Petit et al., 2003].
Nemaline Myopathy
Nemaline myopathy was the second congenital myopathy to be reported. Its classification system has undergone a dramatic change as a result of advances in molecular genetics, and six different clinical forms can be identified [Goebel, 2003].
Clinical Features
The severe congenital form manifests with no spontaneous movements or respirations at birth, and may be associated with contractures and congenital fractures [Wallgren-Pettersson and Laing, 2000]. The fetal akinesia sequence has been reported to be associated with intrauterine onset [Lammens et al., 1997]. High-arched palate [Taratuto, 2002], cardiomyopathy, and ophthalmoplegia have also been associated with this form [Wallgren-Pettersson and Laing, 2000]. Children affected with the intermediate congenital type are able to breathe and move at birth, but during early childhood they become unable to breathe independently and typically cannot sit or walk [Wallgren-Pettersson and Laing, 2000]. Contractures tend to develop early. The typical form manifests in early childhood with proximal weakness, especially in neck flexors, in association with facial, bulbar, and respiratory weakness [Wallgren-Pettersson and Laing, 2000]. Distal involvement can occur later, but affected children are able to reach their milestones, albeit delayed, and have a slowly progressive or even nonprogressive course [Wallgren-Pettersson and Laing, 2000]. The mild childhood or juvenile form is similar to the classic form without facial weakness [Goebel, 2003]. There is also an adult-onset form and other, less common forms that may manifest with an unusual distribution of weakness [Wallgren-Pettersson and Laing, 2000].
Pathology
Nemaline myopathy is histopathologically characterized through the use of the Gomori trichrome technique by red-staining “rods” that are predominantly subsarcolemmal [Jungbluth et al., 2003], although they can be intermyofibrillar or intranuclear and are reactive to α-actin [Taratuto, 2002]. They are associated with the Z-disk and often are in continuity with the Z-lines [Jungbluth et al., 2003; Riggs et al., 2003]. They have a similar lattice structure and are composed of filaments. There is no correlation between the amount of rods seen and the severity of the condition [Jungbluth et al., 2003; Taratuto, 2002]. The rods can be seen solely in type I fibers or in both fiber types, and measure 2–7 mm in length [Riggs et al., 2003]. These findings are typically in conjunction with type 1 fiber predominance or type 1 fiber hypotrophy, or both.
Genetics
Currently, five filament encoding genes have been found to carry mutations. The rods have been found to be morphologically the same among all types [Goebel, 2003]. The most common mutations have been found in the α-actin and nebulin genes. Alpha-actin gene mutations, which account for 10–20 percent of cases [Taratuto, 2002], are frequently reported in the severe cases [Wallgren-Pettersson and Laing, 2001
