Myopathy, Myofibrillar, 8
A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-8 (MFM8) is caused by homozygous or compound heterozygous mutation in the PYROXD1 gene (617220) on chromosome 12p12.Description
Myofibrillar myopathy-8 is an autosomal recessive myopathy characterized by childhood onset of slowly progressive proximal muscle weakness and atrophy resulting in increased falls, gait problems, and difficulty running or climbing stairs. Upper and lower limbs are affected, and some individuals develop distal muscle weakness and atrophy. Ambulation is generally preserved, and patients do not have significant respiratory compromise. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization (summary by O'Grady et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).Clinical Features
O'Grady et al. (2016) reported 9 patients from 5 unrelated families with childhood onset of slowly progressive muscle weakness and atrophy mainly affecting the proximal muscles. Early gross motor skills were largely normal, and all started walking between 9 and 20 months of age. However, some patients had poor head control associated with generalized hypotonia and feeding difficulties in infancy. All patients were still ambulant at 7 to 31 years of age, but had difficulty running and climbing stairs. Some patients had distal muscle involvement, including 2 brothers in their twenties who had marked wasting of the intrinsic hand muscles. Additional variable features included neck weakness, facial weakness, ptosis, high-arched palate, nasal speech, dysphagia, and hypo- or areflexia. Some patients had recurrent respiratory infections and mild restrictive pulmonary function. Only 1 older patient had evidence of cardiac involvement in his late twenties. Cognition was normal, except for 1 patient who had learning difficulties. Laboratory studies showed increased serum creatine kinase. Muscle biopsy, performed in 5 patients, showed variation in fiber size, internal nuclei, increased interstitial connective tissue, central core-like zones devoid of mitochondria, large myofibrillar inclusions, and rare nemaline rods. Electron microscopy showed sarcomeric disorganization and Z-band streaming. Nerve conduction studies of 2 older sibs showed decreased compound muscle action potentials (CMAPs) and decreased sural sensory potentials, suggestive of a mild length-dependent axonal neuropathy.Inheritance
The transmission pattern of MFM8 in the families reported by O'Grady et al. (2016) was consistent with autosomal recessive inheritance.Molecular Genetics
In 9 patients from 5 unrelated families with MFM8, O'Grady et al. (2016) identified homozygous or compound heterozygous mutations in the PYROXD1 gene (617220.0001-617220.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 2 splice site mutations, 1 frameshift mutation, and 2 missense mutations, including 1 that showed a founder effect in the Turkish families (N155S; 617220.0003). Complementation experiments in yeast showed that the missense mutations caused impaired reductase activity. The findings suggested that altered redox regulation may be a primary cause of congenital muscle disease.Animal Model
O'Grady et al. (2016) reported that knockout of Pyroxd1 in mouse was embryonic lethal. Morpholino-mediated knockdown of the zebrafish ortholog, ryroxd1, reduced swimming performance, with lower maximal acceleration in touch-evoked response, compared with controls. Knockdown of ryroxd1 disrupted muscle structure, with mitochondrial infiltration of disintegrated myofibrils, loss of Z-disk and sarcomeric structures, and formation of electron dense bodies. Overexpression of 2 human missense mutations (N155S and Q372H) in zebrafish muscle resulted in occasional thickening of the Z-disk, suggesting the formation of abnormal aggregates.