This disorder represents a congenital myopathy characterized by proximal and generalized muscle weakness, respiratory difficulties, joint contractures, and scoliosis. More variable features include cleft palate and feeding difficulties. There is variable severity: some patients become ventilator-dependent, never achieve ... This disorder represents a congenital myopathy characterized by proximal and generalized muscle weakness, respiratory difficulties, joint contractures, and scoliosis. More variable features include cleft palate and feeding difficulties. There is variable severity: some patients become ventilator-dependent, never achieve walking, and die in childhood, whereas others have a longer and more favorable course (summary by Logan et al., 2011 and Boyden et al., 2012).
Hartley et al. (2007) reported 2 unrelated but consanguineous families from Qatar and Sri Lanka, respectively, in which 2 sibs in each family had a severe congenital myopathy particularly affecting the diaphragm. The older daughter in the first ... Hartley et al. (2007) reported 2 unrelated but consanguineous families from Qatar and Sri Lanka, respectively, in which 2 sibs in each family had a severe congenital myopathy particularly affecting the diaphragm. The older daughter in the first family was born full term after a pregnancy complicated by decreased fetal movements and growth retardation. She had poor respiratory effort necessitating resuscitation at birth, and she became ventilator-dependent at age 18 months. Chest radiograph showed paralysis of the right hemidiaphragm. She also had poor feeding, necessitating a feeding tube. She could walk with assistance at age 18 months. Other features included narrow bifrontal diameter, facial weakness, long fingers with finger flexor tightness, thin muscles, and areflexia. Cognitive development was normal. She later developed scoliosis and died at age 9 years following a respiratory infection. Her 30-month-old sister showed respiratory distress at age 1 week as well as feeding difficulties resulting in failure to thrive. She became ventilator-dependent at age 7 months, and was able to sit up, but did not achieve any additional motor skills. Muscle weakness was more marked in the upper limbs and distally. She had cleft palate, hypotonia, thin musculature, pectus excavatum, facial weakness, narrow bifrontal diameter, and areflexia. EMG studies in both girls showed a myopathic pattern and muscle biopsies showed minimal fiber size variability without inclusions. In the second family, both sibs presented at birth with hypotonia and poor feeding, and developed respiratory failure at age 5 months necessitating ventilation. Both also were fed by gastrostomy. One child was able to walk at age 3 years. The other developed an encephalopathy with subsequent global developmental delay after respiratory arrest and brain hypoxia/ischemia. Both had contractures of the finger flexors and equinovarus positions of the feet, scoliosis, bulbar weakness, and well-controlled seizures. Genetic analysis excluded mutations in the IGHMBP2 gene (600502). Logan et al. (2011) reported 7 patients from 5 families with EMARDD. Two of the families had previously been reported by Hartley et al. (2007). All patients presented at birth or early in infancy with respiratory distress caused by diaphragmatic paralysis. All affected subjects became ventilator-dependent, and all had dysphagia, which necessitated gastrostomy feeding in some. All had severe muscular hypotonia and weakness, more prominent in the upper limbs and in the distal muscles, and areflexia. Other more variable features included high-arched palate or cleft palate, contractures of the fingers, and pes equinovarus. Electromyography showed myopathic changes, and nerve conduction velocities were normal. Skeletal muscle biopsies showed small and incompletely fused muscle fibers and sparsely nucleated syncytia. The findings were consistent with reduced myoblast and satellite cell proliferation. - Clinical Variability Boyden et al. (2012) reported a nonconsanguineous Caucasian family of mixed European ancestry in which 3 sisters had a congenital myopathy. All presented with generalized weakness by 12 months of age, initially in the neck and later mainly involving the proximal, axial, and facial muscles. All had contractures of the neck in infancy with later development of contractures of other joints and severe scoliosis; reflexes were mostly absent. There was also respiratory involvement, and all needed assisted ventilation at night. One had a cleft palate and another had a midline ridge of the palate; all had hypernasal speech. Two had dysphagia with pills, and 1 had acid reflux. All were alive in their mid-twenties. Serum creatine kinase was mildly increased. Muscle biopsy showed fatty replacement of myofibers, increased connective tissue, and isolated regenerating fibers, similar to muscular dystrophy. However, there were also moth-eaten fibers and minicores, suggestive of a congenital myopathy. There was a slight predominance of type I fibers, which showed more size variability than type II fibers. An unrelated girl of distant Portuguese ancestry had a diagnosis of multiminicore disease. She presented in infancy with weak neck and floppy head, high-arched palate, and failure to thrive as a result of poor feeding. She also had blue-tinged sclera and hyperflexible joints. She later showed mainly proximal weakness and developed scoliosis. Although she had recurrent pulmonary infections, breathing was normal. Muscle biopsy showed marked fiber size variation, internalized nuclei, and increased endomysial connective tissue, as well as prominent patches of decreased NADH activity within myofibers, consistent with moth-eaten fibers or minicores. Electron microscopy showed focal areas of Z-band disarray with absent mitochondria.
In 7 patients from 5 families with EMARDD, Logan et al. (2011) identified homozygous or compound heterozygous mutations in the MEGF10 gene (612453.0001-612453.0006). All but 1 of the mutations were truncating, resulting in loss of protein function. ... In 7 patients from 5 families with EMARDD, Logan et al. (2011) identified homozygous or compound heterozygous mutations in the MEGF10 gene (612453.0001-612453.0006). All but 1 of the mutations were truncating, resulting in loss of protein function. In 3 sisters with a milder variant of EMARDD, characterized by congenital myopathy, scoliosis, and respiratory impairment, Boyden et al. (2012) identified compound heterozygosity for 2 missense mutations in the MEGF10 gene (C326R, 612453.0007 and C774R, 612453.0006). The mutations were found by whole genome sequencing. Screening of this gene in 272 additional patients with unexplained myopathy found 1 who was heterozygous for a missense mutation (R71W; 612453.0008) that was inherited from an unaffected parent; however, a second pathogenic mutation could not be identified in the patient. Boyden et al. (2012) suggested that the milder phenotype in their patients compared to the patients reported by Logan et al. (2011) may be due to some residual MEGF10 function from missense mutations, as opposed to the frameshift or truncating mutations identified in the latter patients. Given the role of mouse Megf10 in satellite cells (Holterman et al., 2007), Boyden et al. (2012) hypothesized that excessive differentiation of satellite cells in patients with MEGF10 mutations may deplete the population of self-renewing cells available to regenerate damaged muscle fibers.