Central Core Disease Of Muscle

A number sign (#) is used with this entry because of evidence that central core disease (CCD) and its variants can be caused by heterozygous, homozygous, or compound heterozygous mutation in the ryanodine receptor-1 gene (RYR1; 180901) on chromosome 19q13.

Biallelic mutation in the RYR1 gene can also cause minicore myopathy with external ophthalmoplegia (255320), which tends to be more clinically severe but shows overlapping features with central core disease.

Description

Typical central core disease is a relatively mild congenital myopathy, usually characterized by motor developmental delay and signs of mild proximal weakness most pronounced in the hip girdle musculature. Orthopedic complications, particularly congenital dislocation of the hips and scoliosis, are common, and CCD patients are at risk of having malignant hyperthermia (MHS1; 145600). Onset of CCD is usually in childhood, although adult onset has also been reported, illustrating phenotypic variability (Jungbluth et al., 2009). Some patients can present in utero or at birth with severe congenital myopathy (Bharucha-Goebel et al., 2013).

Clinical Features

Central core disease is one of the conditions that produces the 'floppy infant' (see 205000). Central core disease was the first described (Shy and Magee, 1956) example of a stationary muscle disorder, although the name was not given the entity until later. Five persons in 5 different sibships in 3 generations of the original family were affected. In the family studied by Engel et al. (1961), only the proband had clinical manifestations but his father had the same biochemical abnormality of muscle, namely, one involving the liberation of phosphate from glucose-6-phosphate.

Bethlem et al. (1966) described a nonprogressive myopathy in 3 females of 3 successive generations. The father of the earliest patient may have been affected. Histologic findings of central core disease were found. Muscle cramps followed exercise and no hypotonia was present in infancy--features different from previously reported cases of central core disease. Creatine excretion in the urine was greatly increased. Creatine kinase and oxidative phosphorylation in the muscles were normal. Dubowitz and Roy (1970) described 4 cases in 3 generations. The disorder consisted of slowly progressive weakness after the age of 5 years, resembling limb girdle muscular dystrophy. Only type 1 muscle fibers showed central cores. Isaacs et al. (1975) studied a South African kindred with affected members spanning 5 successive generations. Eng et al. (1978) observed autosomal dominant transmission through 5 generations with two skips in a kindred ascertained through a child with malignant hyperthermia (MHS; 145600). Frank et al. (1978) noted that 4 families with central core disease and malignant hyperthermia had been described and added another familial instance of the combination. Creatine kinase blood levels were increased. In vitro muscle contraction studies with caffeine and halothane identified those susceptible to malignant hyperthermia. See Frank et al. (1980) for the full report.

Gamstorp (1982) stated that this disorder is rare in Scandinavia. She described the case of a girl who at age 2 was found to be clumsy and to have weak hip muscles. Her facial expression was normal. The father 'had never been able to carry a heavy burden upstairs' and he was unable to sit up on a chair without the help of his hands. Muscle biopsy showed central core disease in the father as well as in the daughter, whose disorder had remained stationary to age 8 years. Byrne et al. (1982) described a kindred in which at least 37 members in 5 generations had suffered from CCD.

Fischer et al. (2006) performed muscle CT imaging in 11 CCD patients with RYR1 mutations. All patients showed a distinct homogeneous pattern of muscle involvement, with prominent involvement of the gluteus maximus, medial and anterior compartments of the thigh muscles, and soleus and lateral gastrocnemius muscles of the lower leg. These patterns of muscle involvement differed from those observed in affected members of 2 additional families unlinked to the RYR1 locus. The results suggested genetic heterogeneity in autosomal dominant core myopathies.

Jungbluth et al. (2007) reported a 16-year-old girl with a history of neonatal hypotonia, muscle weakness, and feeding difficulties in the newborn period. She had delayed motor development and lost the ability to stand unsupported at age 14 years. Other features included talipes equinovarus, scoliosis, respiratory insufficiency, and epilepsy. Physical examination showed myopathic facies with extraocular weakness and generalized muscle wasting and weakness. Muscle MRI of the lower limbs showed diffuse involvement of the quadriceps and soleus with relative sparing of the rectus femoris, gracilis, and gastrocnemii. Skeletal muscle biopsy at age 1 year showed hypotrophy of type 1 fibers with centralized nuclei and no necrosis. Core-like structures were not apparent at that time, suggesting a clinical diagnosis of centronuclear myopathy (160150). However, biopsy at age 8 years showed fiber type variation, central nuclei in some fibers, and central loss of oxidative enzyme staining resembling central cores. Molecular analysis excluded a mutation in the DNM2 gene (602378) and identified a heterozygous mutation in the RYR1 gene. Jungbluth et al. (2007) noted that skeletal muscle biopsy findings such as central cores and central nuclei are nonspecific and can occur in genetically distinct disorders, and that the histologic features of disorders associated with mutations in the RYR1 gene may include mixed pathologic features that may also evolve over time.

Jungbluth et al. (2009) reported a 77-year-old man who presented with a 5 to 10-year history of increasing difficulty maintaining an erect posture and complaint of a 'wobbly' spine. He had a stooped posture and had to use 2 sticks to stand upright. He had no weakness in the arms or legs but reported that his legs were sometimes tired. Examination did not show weakness or wasting of distal or proximal limb muscles, and muscle tone and tendon reflexes were normal. Serum creatine kinase was mildly increased. EMG showed a myopathic pattern in the lumbar and lower thoracic paraspinal muscles but normal pattern in limb muscles. Skeletal muscle biopsy from the quadriceps showed fiber size variation, increased internal nucleation, marked type 1 fiber predominance, and defined central and eccentric cores on oxidative stains. Genetic analysis revealed a heterozygous mutation in the RYR1 gene. Jungbluth et al. (2009) noted that the phenotypes associated with RYR1 mutations are highly variable and suggested that genetically determined congenital muscular dystrophies with late onset may be underreported.

Pathologic Features

Central core disease is characterized pathologically by the presence of central core lesions extending the length of type I muscle fibers. The cores are regions of sarcomeric disorganization, absent mitochondria, and lack of oxidative activity (Quane et al., 1993). Ultrastructural studies show changes in the sarcoplasmic reticulum and t-tubules.

Nemaline myopathy (161800, 256030), a clinically similar myopathy characterized by the presence of rods in muscle fibers, and central core disease have been described in the same family and indeed in the same patient (Afifi et al., 1965, Monnier et al., 2000, Scacheri et al., 2000). It is possible that the 'central core' morphologic change is nonspecific, i.e., may occur with other types of myopathy in addition to the specific entity to which the name can be applied.

Minicore disease (multicore disease) is a distinct autosomal recessive myopathy characterized by multiple core lesions of type I and type II myofibril degeneration, loss of mitochondria, and lack of oxidative activity. Several forms are recognized (see 602771).

Fananapazir et al. (1993) demonstrated that many patients with hypertrophic cardiomyopathy (CMH1; 192600) due to mutation in the beta-myosin heavy chain gene (MYH7; 160760) have histologic changes on soleus muscle biopsy consistent with central core disease. A few of the patients had 'significant muscle weakness' and 2 adults and 3 children from a family with the leu908-to-val mutation of the MYH7 gene were observed to have CCD changes in the soleus muscle with no cardiac hypertrophy as defined by echocardiogram. The histologic hallmark of CCD was the absence of mitochondria in the center of many type I fibers as revealed by light microscopic examination of NADH-stained fresh-frozen skeletal muscle sections. McKenna (1993), who stated that he had never seen clinical evidence of skeletal myopathy in CMH1, doubted the significance of the findings.

Sewry et al. (2002) presented the pathologic features of affected members of 3 families with RYR1 mutations in the C-terminal transmembrane domain. In 1 family, an affected 4-month-old girl had no cores on biopsy and uniform type 1 fibers, whereas her older brother showed classic cores, suggesting that pathologic changes can occur over time. In a second family, the mother had large classic cores on biopsy, whereas her 2 children showed minicores. Sewry et al. (2002) noted the very variable pathologic findings, even within families, and noted that absence of defining features does not exclude the diagnosis of RYR1-associated myopathies.

Clinical Variability

Ferreiro et al. (2002) reported 3 affected members of a consanguineous Algerian family with central core disease transiently presenting as minicore myopathy. The 3 children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. Muscle biopsies from the 3 patients in adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. Genetic analysis identified a homozygous mutation in the RYR1 gene (180901.0021). The family represented the first variant of central core disease with genetically proven recessive inheritance and transient presentation as minicore myopathy.

Tojo et al. (2000) reported a family in which the father had CCD and the son had congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). CNMDU1 is characterized pathologically by the exclusive presence of type 1 muscle fiber (greater than 99%) without any specific structural abnormality such as cores, nemaline bodies, or centrally placed nuclei. Limited sequencing of the RYR1 gene did not reveal mutations. Tojo et al. (2000) concluded that the 2 disorders were related and suggested that cores on biopsy may develop with age.

Clinically, CNMDU1 shares common features with congenital myopathy, including early onset, mild proximal muscle weakness, hypo- or areflexia, normal creatine kinase levels, and myopathic electromyography findings. Sato et al. (2008) identified heterozygous mutations in the RYR1 gene (see, e.g., 180901.0019; 180901.0033-180901.0034) in 4 of 10 Japanese patients with a diagnosis of CNMDU1. The father of 1 patient had the same mutation as his son but was diagnosed with CCD. Sato et al. (2008) noted that distinguishing CCD from CNMDU1 based on clinical features alone is difficult, and that uniform type 1 fibers on biopsy can be found in both disorders. Younger patients may show CNMDU1, whereas older patients in the same family may show CCD, which would suggest that the 2 disorders are part of a phenotypic spectrum. However, no patients have had intermediate pathologic findings of uniform type 1 fibers with cores in a few fibers, suggesting that the 2 disorders may be distinct.

Klein et al. (2012) reported 40 patients from 35 families with myopathy associated with a heterozygous RYR1 mutation. Severity and age at onset were highly variable: onset ranged from reduced fetal movements and polyhydramnios prenatally to adult-onset muscle weakness. Although most patients could walk, only 14 could run. In the same report, Klein et al. (2012) described 46 patients from 36 families with biallelic RYR1 mutations, consistent with autosomal recessive inheritance. All patients with recessive mutations presented within the first 10 years of life, most at birth or prenatally. All had proximal weakness, some had distal weakness, and most had axial and facial weakness. More variable features included feeding difficulties and extraocular muscle involvement. Overall, the clinical features of patients with recessive mutations were more severe than those with dominant mutations. Skeletal muscle biopsies in both groups tended to show type 1 fiber predominance or uniformity and core-like lesions; a few showed minicores. Klein et al. (2012) concluded that biallelic RYR1 mutations are at least as frequent as heterozygous mutations, and that there is marked variability in the clinical and pathologic features of RYR1-associated myopathies.

Bharucha-Goebel et al. (2013) reported 11 patients, including 2 sibs, with severe congenital RYR1-associated myopathy. Four patients had a dominant RYR1 mutation and 7 had recessive mutations. Nine patients had symptoms noted in utero, including decreased fetal movements, polyhydramnios, and intrauterine growth restriction. Variable features present at birth included hypotonia, feeding difficulties, arthrogryposis, hip dislocation, and respiratory insufficiency. Other variable features included kyphoscoliosis, cleft palate, rigid spine, and ophthalmoparesis. All patients had delayed motor milestones, but none showed evidence of intellectual impairment. Skeletal muscle biopsy in those with dominant mutations tended to show classic cores, whereas biopsies in recessive cases were highly variable, showing fibrosis, small fibers, nonspecific myopathic changes, and a predominance of type 1 fibers, with or without ill-defined cores. Imaging tended to show sparing of the rectus femoris muscle. There were no genotype/phenotype correlations, and functional studies of the variants were not performed.

Inheritance

Reports of families with central core disease of muscle by Shy and Magee (1956), Bethlem et al. (1966), Isaacs et al. (1975), Eng et al. (1978), and others support autosomal dominant inheritance. However, cases consistent with autosomal recessive inheritance have also been reported (Manzur et al., 1998, Ferreiro et al., 2002, Jungbluth et al., 2002).

Zhou et al. (2006) presented evidence that the RYR1 gene, mutations in which are the usual cause of central core disease of muscle, undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this can unveil recessive mutations in patients with core myopathies. Their data also suggested that imprinting is a likely mechanism for this phenomenon and that similar mechanisms can play a role in human phenotypic heterogeneity and in irregularities of inheritance patterns.

Mapping

Haan et al. (1990) mapped the CCO gene to 19q12-q13.2 by family linkage studies. Kausch et al. (1991) also mapped the CCD gene to proximal 19q13.1 by linkage to markers.

The work of Mulley et al. (1993) supported the possibility that the CCO gene is an allele at the RYR1 (180901) locus, which maps to the same region of chromosome 19. In a large kindred in which the gene for CCO was segregating, 2-point linkage analysis gave a maximum lod score, between CCO and the RYR1 locus, of 11.8, with no recombination. Recombination was observed between CCO and the markers flanking RYR1.

Molecular Genetics

Zhang et al. (1993) and Quane et al. (1993) identified mutations in the ryanodine receptor-1 gene in patients with central core disease (see e.g. 180901.0003 and 180901.0005).

Lynch et al. (1999) studied a large Mexican kindred in which all affected members suffered from a clinically severe and highly penetrant form of CCD. Sequencing of the entire RYR1 cDNA in an affected member identified a single mutation in the C-terminal transmembrane/luminal domain of the protein (180901.0012). The introduction of this mutation into a recombinant RyR1 protein expressed in HEK293 cells resulted in loss of channel activation by caffeine and halothane and a significant reduction in ryanodine binding. These and additional findings, which pointed to a high basal activity of the mutant Ca(2+) channel, could explain the muscle weakness and muscle atrophy observed in CCD patients in this family.

Jungbluth et al. (2002) reported 3 patients from 2 consanguineous families with symptoms of congenital myopathy, cores on muscle biopsy, and linkage to the RYR1 locus. Molecular genetic studies in 1 family identified a homozygous mutation in the RYR1 gene (180901.0022), suggesting autosomal recessive inheritance.

Scacheri et al. (2000) identified a heterozygous mutation in the RYR1 gene (180901.0030) in affected members of a large family with CCD. Skeletal muscle biopsies from 2 affected individuals showed the presence of central cores in over 85% of myofibers and nemaline rods in 5 to 25% of myofibers. Scacheri et al. (2000) suggested that nemaline bodies may be a secondary feature in CCD.

Transient Multiminicore Myopathy

In a consanguineous Algerian family with central core disease transiently presenting as minicore myopathy, Ferreiro et al. (2002) found linkage to 19q13, subsequently, in 3 additional families showing a similar phenotype, with a maximum lod score of 5.19 for D19S570. The locus was excluded in 16 other minicore myopathy families with predominantly axial weakness, scoliosis, and respiratory insufficiency ('classic' phenotype (602771)). Genetic analysis identified a homozygous mutation in the RYR1 gene (180901.0021). The group of families studied by Ferreiro et al. (2002) represented the first variant of central core disease with genetically proven recessive inheritance and transient presentation as minicore myopathy.

Animal Model

The involvement of RYR1 mutations in a congenital myopathy is supported by the findings of Takeshima et al. (1994). Mice homozygous for a targeted mutation in the skeletal muscle ryanodine receptor gene died perinatally with gross abnormalities of skeletal muscle. The contractile response to electrical stimulation under physiologic conditions was totally abolished in the mutant muscle, although ryanodine receptors other than the skeletal-muscle type seemed to exist because the response to caffeine was retained. Takeshima et al. (1994) interpreted the results as indicating that the skeletal muscle ryanodine receptor is essential for both muscular maturation and excitation-contraction (E-C) coupling, and that the function of the skeletal muscle receptor during EC coupling cannot be substituted by other subtypes of the receptor.