Reducing Body Myopathy, X-Linked 1a, Severe, With Infantile Or Early Childhood Onset

A number sign (#) is used with this entry because severe X-linked reducing body myopathy-1 with infantile or early childhood onset (RBMX1A) is caused by mutation in the FHL1 gene (300163) on chromosome Xq26.

Description

Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death, and a less severe form has onset in late childhood or adulthood (RBMX1B; 300718) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).

Clinical Features

Brooke and Neville (1972) reported 2 unrelated girls with a severe, progressive, fatal muscle disorder. One girl had onset before age 8 weeks of hypotonia, contractures, and respiratory muscle weakness. She died at age 2.5 years. The second child had onset of hypotonia a few days after birth and died at age 9 months. Both had progressive myopathy and decreased deep tendon reflexes. Skeletal muscle biopsy showed fiber size variation without inflammation and intracytoplasmic dark inclusion bodies that reduced nitroblue tetrazolium (NBT), indicating the presence of sulfhydryl-containing compounds. Electron microscopy showed that these 'reducing bodies' were at the edge of muscle fibers near the sarcolemma and were composed of dense osmiophilic material consisting of closely packed fibrillar particles.

Kiyomoto et al. (1995) reported 2 unrelated girls with normal development until just over 2 years of age, when they showed progressive hypotonia and proximal muscle weakness. Initial symptoms included frequent falls, Gowers sign, and neck muscle weakness. Serum creatine kinase was elevated. Both had a rapidly progressive course with death from respiratory failure just before age 5 and 4 years, respectively. Muscle biopsy showed variation in fiber size, internal nuclei, mild inflammation, rimmed vacuoles, and numerous reducing bodies in almost all degenerating fibers. Electron microscopy showed that these inclusions consisted of fine granular material, usually located around the degenerating nucleus. Myofibrils with reducing bodies had disorganized cross-striations. These bodies occasionally stained positive for ubiquitin (UBB; 191339).

Schessl et al. (2008) reported 2 unrelated girls with classic, severe, early-onset reducing body myopathy. One child presented with weakness leading to loss of ambulation at age 3 years, followed by respiratory insufficiency. At 8 years, she had a tracheostomy and feeding tube with no antigravity strength. In a follow-up of this patient, Schessl et al. (2009) noted that she had mildly delayed motor development and learned to walk at 18 months, but was never able to run or stand up from a sitting position. The disease progressed at age 2 years, with poor head control and neck weakness, leading to wheelchair dependency at age 3. She had proximal muscle weakness, progressive spinal rigidity, and scoliosis. There was no apparent cardiac involvement. The second girl reported by Schessl et al. (2008) had onset of progressive weakness at age 2 years, followed by loss of ambulation at 4.5 years, and death from respiratory failure at 6.5 years. In both girls, serum creatine kinase was increased, and skeletal muscle biopsies showed inclusion bodies that stained with NBT. Schessl et al. (2008) isolated the material from the inclusion bodies and used mass spectrometry and immunohistochemical analysis to determine that FHL1 was the primary protein component. In fibers with reducing bodies, FHL1 was present in inclusions and closely associated with the nuclei, but decreased at the I band/Z disc contractile apparatus compared to normal fibers. Other protein components of the reducing bodies included desmin, actin, and ubiquitin.

Schessl et al. (2009) reported 5 additional patients with severe, early-onset FHL1-related reducing body myopathy. All patients had sporadic disease without a relevant family history. Onset ranged from 13 months to 4 years. Common features included frequent falls, abnormal gait, progressive proximal muscle weakness, contractures, and scoliosis. There were 4 girls and 1 boy, who was the most severely affected. A detailed report of the boy stated that he had normal development and no difficulties walking at age 13 months. By age 17 months, he had developed significant proximal muscle weakness with inability to rise from the floor, climb stairs, or roll over in bed, as well as axial and cervical muscle weakness with head drop. The disorder was rapidly progressive, and he lost ambulation, had no antigravity strength, and required continuous ventilatory support by age 3. He had severe joint contractures, mild scoliosis, and increased serum creatine kinase.

Molecular Genetics

In 2 unrelated girls with severe, early-onset reducing body myopathy, Schessl et al. (2008) identified a de novo heterozygous mutation in the FHL1 gene (300163.0004 and 300163.0005, respectively).

In 1 of the patients reported by Kiyomoto et al. (1995), Shalaby et al. (2009) identified a heterozygous mutation in the FHL1 gene (300163.0008).

In 5 patients with early-onset reducing body myopathy, Schessl et al. (2009) identified de novo mutations affecting the same residue in second LIM domain of the FLH1 gene (H123Y, 300163.0004; H123L, 300163.0015; H123Q, 300163.0016).