Minicore Myopathy With External Ophthalmoplegia

A number sign (#) is used with this entry because of evidence that minicore myopathy with external ophthalmoplegia is caused by homozygous or compound heterozygous mutation in the RYR1 gene (180901) on chromosome 19q13.

Description

Multiminicore disease (MMD) is an inherited neuromuscular disorder defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity running along a limited extent of the longitudinal axis of the muscle fiber, so-called 'minicores.' These regions show sarcomere disorganization and mitochondria depletion. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. MMD is a pathologic diagnosis and shows clinical and genetic heterogeneity. Affected individuals have clinical features of a congenital myopathy, including neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable (Ferreiro and Fardeau, 2002).

Patients with recessive mutations in the RYR1 gene typically show severe congenital muscular dystrophy with ophthalmoplegia, although there is phenotypic variability. Some patients may present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations show variable features, including central cores (Jungbluth et al., 2007), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010).

Clinical Features

Engel et al. (1971) first reported multiminicore myopathy in 2 affected sibs. The disorder was a congenital myopathy associated with multifocal degeneration of muscle fibers on pathologic examination.

Swash and Schwartz (1981) reported 2 brothers and a sister with a congenital myopathy characterized clinically by proximal weakness and external ophthalmoplegia and histologically by multicores and areas of focal loss of cross-striations in skeletal muscles. Two other sisters and both parents were clinically normal. Both brothers showed highly arched palate. One brother, more severely affected than the other, developed respiratory failure in association with Mycoplasma pneumonia at age 14 years, and required mechanical ventilation for 3 days.

Bethlem et al. (1978) noted external ophthalmoplegia in 2 sibs (their family C) in whom muscle biopsies showed both multicores and focal loss of cross-striations. Central cores (see 117000) were longer than the lesions observed by Swash and Schwartz (1981), although there was overlap in the transverse dimension. Furthermore, in central core disease, each fiber usually contains only 1 core lesion and the abnormality is limited to type I fibers. Swash and Schwartz (1981) pointed out that previously reported patients in whom ophthalmoplegia was associated with core-like lesions have all had focal loss of cross-striations as a prominent feature, with or without multicores (Engel et al., 1971; Van Wijngaarden et al., 1977; Bethlem et al., 1978), as in their patients. The authors regarded this disorder as a genetically distinct subtype of multicore disease.

Tein et al. (1999) reported multicore myopathy with ophthalmoplegia in a wheelchair-bound 13.5-year-old Israeli girl with deficiency of short-chain acyl-CoA dehydrogenase (SCAD; 201470). Electron microscopy of a triceps muscle biopsy performed when she was 3 years old demonstrated decreased mitochondria in the region of multicores and minicores, with myofibrillar disorganization and loss and streaming of Z-bands.

Among 19 cases of minicore myopathy, Jungbluth et al. (2000) reported 2 with complete external ophthalmoplegia and a severe phenotype, including hypotonia and facial, axial, and proximal weakness.

Among 38 patients with histologically proven minicore myopathy, Ferreiro et al. (2000) reported 3 who had an antenatal-onset form with congenital generalized arthrogryposis, which the authors suggested was a distinct subtype of MMD. Other features included dolichocephaly, prominent nasal root, oblique palpebral fissures, high-arched palate, low-set ears, and short neck with mild pterygium colli. Two brothers also had a bell-shaped thorax, clinodactyly, bilateral cryptorchidism, and a single palmar crease. All 3 patients had moderate predominantly axial muscle weakness, early severe kyphosis or kyphoscoliosis, and reduced respiratory vital capacity.

During an international workshop on multiminicore disease, Ferreiro and Fardeau (2002) reported 4 patients with external ophthalmoplegia of variable severity in addition to a generalized muscle involvement similar to the classic form of the disease. In this group, facial weakness, especially in the lower face, was severe.

Jungbluth et al. (2005) reported 11 individuals from 5 families with multiminicore disease and external ophthalmoplegia. One of the families had previously been reported by Swash and Schwartz (1981). All patients showed a fairly homogeneous clinical phenotype with onset of marked generalized hypotonia and weakness in the neonatal period or early infancy associated with feeding and respiratory difficulties. Two patients from 1 family exhibited prenatal symptoms with reduced fetal movements, polyhydramnios, and hydrops. Most showed delayed motor development and difficulty running in childhood; some patients also reported limited walking distances. Patients showed muscle wasting of the neck and shoulder girdle muscles; weakness was most pronounced in the axial and proximal versus distal muscle groups. External ophthalmoplegia predominantly affected upward and lateral gaze. Weakness was exacerbated by cold in 6 patients. Other features included ligamentous laxity, moderate scoliosis, and moderately impaired respiratory function. Serum creatine kinase was normal. Skeletal muscle biopsies showed nonspecific myopathic changes with variability in fiber size and increased central nucleation. Both type 1 and 2 fibers showed multiple and single core lesions that extended the full fiber diameter but often did not run for the entire longitudinal axis. There was focal loss of cross striations and disorganization of the normal myofibrillar pattern. Leg muscle MRI of 5 patients showed relative sparing of the gracilis and gastrocnemii compared to the sartorius and soleus, respectively.

Monnier et al. (2008) reported 9 unrelated nonconsanguineous families in which affected individuals had a severe recessive form of myopathy resulting from biallelic mutations in the RYR1 gene. The clinical presentation was variable: 4 probands showed very severe neonatal hypotonia associated with major respiratory problems, whereas 5 other probands had a comparably intermediate or moderate phenotype. All documented patients had involvement of extraocular muscles, and other variable features included facial diplegia, amyotrophy, scoliosis, kyphosis, and joint contractures. Skeletal biopsies showed core lesions whose size and aspect ranged from small to large diffuse cores that extended various distances in the longitudinal axis. One of the affected males with neonatal onset showed mild intermittent 3-methylglutaconic aciduria, a nonspecific finding. All patients were found to have at least 1 null RYR1 allele in compound heterozygosity with another pathogenic mutation (see, e.g., 180901.0022 and 180901.0032), reflecting a critical functional decrease below 50% for the RYR1 protein. All heterozygous carriers were clinically unaffected.

Pathologic Variability

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. Physical examination showed myopathic facies with extraocular weakness and generalized muscle wasting and weakness. 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. 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 (117000). Molecular analysis 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.

Monnier et al. (2009) reported a newborn male with global hypotonia, total immobility of all 4 limbs, a frog position, and feeding difficulties. He had generalized muscle weakness affecting axial and facial muscles, resulting in amimia and difficulty in opening his eyes. There was mild distal arthrogryposis but no craniofacial abnormalities. He had progressive respiratory failure and died at age 2 months. Skeletal muscle biopsy showed fiber size variability, with internal nuclei in about 10% of fibers, and strong type I fiber predominance, corresponding to congenital fiber-type disproportion. Although no definite cores were present, focal, ill-defined lack of oxidative activity was observed, which could be interpreted as atypical cores. Electron microscopy showed focal loss of myofibrils and small foci of sarcomeric disorganization with Z-band streaming. The diagnosis was atypical multiminicore myopathy. Molecular analysis identified compound heterozygosity for 2 mutations in the RYR1 gene, 1 of which was a large genomic deletion. Each unaffected parent was heterozygous for 1 of the mutations.

Wilmshurst et al. (2010) reported 17 patients with a clinicopathologic diagnosis of centronuclear myopathy associated with RYR1 mutations. Twelve were from South Africa and 5 from European countries. All except 1 had onset from birth of neonatal hypotonia and weakness, and most had feeding difficulties. Decreased fetal movements were often reported. Clinical features included delayed motor development, achievement of sitting or walking only, extraocular muscle involvement, proximal muscle weakness, and frequent respiratory infections. Eight achieved sitting only, 8 achieved walking only, and 1 achieved neither. Bulbar involvement was also common, and 3 required gastrostomy. Three patients had scoliosis. All patients had a similar appearance, with myopathic facies, inverted V-shaped mouth, and ptosis. Skeletal muscle biopsies showed about 10% fibers with central nuclei and type 1 fiber predominance. There was also type 2 hypertrophy with fiber-type disproportion. None had core-like structures on early biopsies, but 2 of 3 patients with follow-up developed mild central or minicores. In addition, most biopsies showed central accumulation of oxidative abnormalities. Electron microscopic studies showed Z-line streaming, and 5 had apparent core-like structures. Wilmshurst et al. (2010) noted the phenotypic overlap with the patients reported by Jungbluth et al. (2007) and Monnier et al. (2008).

Clarke et al. (2010) identified compound heterozygous RYR1 mutations in affected members of 4 of 7 families with a congenital myopathy characterized by congenital fiber-type disproportion on muscle biopsy. All patients presented at birth or in early childhood with severe muscle weakness and variable but generalized features of myopathy, including myopathic facies, ophthalmoplegia, high-arched palate, and respiratory insufficiency. Muscle biopsies showed hypotrophy of type 1 fibers compared to type 2 fibers. Additional pathologic features included internalized nuclei and myofibrillary disarray. Muscle imaging showed greater involvement of the gluteus maximus, vastus lateralis, adductor magnus, and soleus muscles, with relative sparing of the rectus femoris, semitendinosis, gracilis, tibialis anterior, and gastrocnemius muscles. All patients carried 1 null RYR1 mutation and 1 missense mutation. Clarke et al. (2010) concluded that RYR1 mutations are a relatively common cause of CFTD.

Kondo et al. (2012) reported a Japanese male infant with severe congenital myopathy associated with compound heterozygous mutations in the RYR1 gene. The fetal period was complicated by nuchal translucency, fetal akinesia, and polyhydramnios. After birth, he showed generalized hypotonia, cyanosis, and bradycardia, necessitating intubation. He was noted to have a narrow face with facial muscle weakness, high-arched palate, ophthalmoplegia, and frog-leg posturing. Other features included micropenis, hypoplastic scrotum, and cryptorchidism. Although he had severe growth retardation in infancy, he later caught up to normal parameters. However, he had no ocular or swallowing movement. At age 1 year 9 months he showed an expressive face and some active limb movement, but he was mechanically ventilated and could not sit or speak. He showed some social development. Muscle biopsy showed cytoplasmic nemaline bodies and very small type 1 fibers, which were the predominant fiber type (71%). Central cores or minicores were not observed. The RYR1 mutations were identified by massively parallel sequencing and confirmed by Sanger sequencing; each unaffected parent was heterozygous for 1 of the mutations. Kondo et al. (2012) commented that RYR1 mutations are usually not associated with the pathologic finding of nemaline rods, but that congenital myopathies can be heterogeneous in presentation.

Lethal Fetal Akinesia Phenotype

McKie et al. (2014) reported 3 unrelated consanguineous families with recurrent fetal akinesia resulting in termination of pregnancy or lethality in utero. The families were of Dutch, Pakistani, and Palestinian descent, respectively. Prenatal ultrasounds showed fetal akinesia, joint contractures, and increased nuchal translucency. Postmortem examination showed arthrogryposis, lung hypoplasia, cystic hygroma, and often clubfoot. Some affected fetuses had pterygia and/or dysmorphic facial features, such as hypertelorism, downslanting palpebral fissures, low-set ears, and cleft palate. Intrauterine growth was not restricted. Skeletal muscle biopsies of 2 affected sibs showed fiber loss, increased fiber size variability, increased endomysial spacing with fibrosis, and tendency toward hypotrophy of type 1 fibers. Ultrastructural examination showed muscle fiber hypotrophy with myofibrillar disarray and Z-disc loss.

Molecular Genetics

Monnier et al. (2003) found a homozygous splicing mutation in the RYR1 gene (180901.0025) in a patient in whom the diagnosis of multiminicore congenital myopathy with ophthalmoplegia had been made. The 12-year-old boy, whose parents were first cousins, had 'a particularly severe form of classic MMD associated with a mild limitation of external eye movements.'

In affected members from 3 families with multiminicore disease and external ophthalmoplegia, including the family reported by Swash and Schwartz (1981), Jungbluth et al. (2005) identified biallelic mutations in the RYR1 gene (180901.0026-180901.0029).

In 17 patients with a clinicopathologic diagnosis of centronuclear myopathy (CNM), Wilmshurst et al. (2010) identified mutations in the RYR1 gene (see, e.g., 180901.0035-180901.0037). Compound heterozygosity for a nonsense and missense mutation was found in all except 3 patients, in whom a second pathogenic allele could not be found. Twelve of the patients were from South Africa, and haplotype analysis suggested founder effects for some of the mutant alleles. The 17 patients were ascertained from a larger group of 24 patients with a diagnosis of CNM, indicating that RYR1 mutations can account for this subtype of myopathy.

In 3 (8.3%) of 36 families with fetal akinesia deformation/lethal pterygium syndrome, McKie et al. (2014) identified 3 different homozygous nonsense or intragenic deletion mutations in the RYR1 gene (180901.0039-180901.0041). McKie et al. (2014) suggested that RYR1 mutation analysis should be performed in cases with severe early lethal fetal akinesia even in the absence of specific histopathologic indicators of RYR1-related disease.

Pathogenesis

Zhou et al. (2013) found that levels of mutant RYR1 transcripts and protein were decreased in skeletal muscle from patients with recessive RYR1 mutations. Although mRNA levels of CACNA1S (114208), the alpha subunit of the dihydropyridine receptor (DHPR) were normal, there were decreased protein levels of DHPR in patient muscle, as well as disruption of DHPR-RYR1 colocalization in skeletal muscle. Human myoblasts transfected with RYR1 siRNA confirmed that knockdown of RYR1 downregulates not only the DHPR, but also the expression of other proteins involved in excitation-contraction (EC) coupling. These changes were also paralleled by the upregulation of all 3 inositol-1,4,5-triphosphate receptors (ITPR1, 147265; ITPR2, 600144; ITPR3, 147267). However, upregulation of the ITPR calcium channels did not compensate for the lack of RYR1-mediated calcium release. The results suggested that RYR1 deficiency can cause EC uncoupling and alter the expression pattern of several proteins involved in calcium homeostasis, which may influence the manifestation of these diseases.