Reducing Body Myopathy, X-Linked 1b, With Late Childhood Or Adult Onset

A number sign (#) is used with this entry because X-linked reducing body myopathy-1 with late childhood or adult onset (RBMX1B) 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 (RBMX1A; 300717), and a less severe form has onset in late childhood or adulthood (RBMX1B) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).

Clinical Features

Kiyomoto et al. (1995) described a 42-year-old woman with distal myopathy in whom skeletal muscle biopsy showed rimmed vacuoles and nitroblue tetrazolium reducing bodies in the cytoplasm.

Goebel et al. (2001) reported a boy who developed decreased mobility of the spine and contractures at age 7. He had left-sided scoliosis and an inability to reduce physiologic cervical lordosis. Serum creatine kinase was increased. The disorder was rapidly progressive, leaving him wheelchair-bound at age 8. He developed progressive muscle weakness in the hips and shoulders and loss of deep tendon reflexes. His maternal grandmother developed slowly progressive weakness of the legs at age 50. Skeletal muscle biopsy of the boy showed fiber size variation, internal nuclei, multiple inclusion bodies, reducing bodies, and rimmed vacuoles. Some inclusion bodies reacted with anti-desmin and anti-ubiquitin. Electron microscopy showed 2 types of inclusion bodies: cytoplasmic with granular material at the core and fine filaments in the periphery, and reducing bodies with granular appearance. Goebel et al. (2001) classified this patient as having reducing body myopathy with cytoplasmic bodies, a 'mixed' congenital myopathy.

Ohsawa et al. (2007) reported a boy, born of a Japanese father and Filipino mother, who developed lower limb weakness and frequent falls at age 10 years. He had proximal muscle weakness and atrophy, winging of the scapulae, lumbar lordosis, and spinal rigidity. He could walk on his toes but on not his heels; he had Gowers sign and decreased deep tendon reflexes. His mother developed foot drop at age 29 and became wheelchair-bound within 5 years. Both mother and son had increased serum creatine kinase. Skeletal muscle biopsy in both showed clusters of atrophic fibers containing reducing bodies that stained bright red with hematoxylin and eosin. In a detailed study of the muscle biopsies of the patients reported by Ohsawa et al. (2007), Liewluck et al. (2007) determined that the reducing bodies contained virtually all membrane-associated proteins tested, including those of nuclei, sarcoplasmic reticulum, Golgi apparatus, lysosome, and plasma membrane. Reducing bodies also had features of aggresomes, including positive immunoreactivity for ubiquitin and other chaperones, indicating activation of the unfolded protein response. Liewluck et al. (2007) concluded that accumulation of various misfolded membrane proteins could be a primary event in this disorder, which results in activation of the unfolded protein response and subsequent aggresome formation.

Schessl et al. (2008) reported 2 unrelated boys with childhood-onset progressive muscle weakness associated with NBT-positive reducing bodies on skeletal muscle biopsy. One boy had onset at age 5 years, followed by loss of ambulation at age 8, and respiratory failure requiring ventilatory support at age 11. Dilated cardiomyopathy was detected at age 18. His mother began to have weakness in her early thirties and required a wheelchair in her forties. The second boy developed weakness and a rigid spine at age 10 years. This was followed by progressive weakness and contractures with loss of ambulation by age 16. His mother had proximal muscle weakness beginning in her mid-thirties. Both had normal cardiac examinations.

Shalaby et al. (2008) reported a 16-year-old boy with late childhood onset of X-linked reducing body myopathy. He had been a good runner during childhood and was noted to have scoliosis at age 13 years. He then developed progressive walking and running difficulties. By age 16, he had difficulty in bending his body and in neck flexion, atrophy and weakness of the proximal muscles, and joint contractures. He was diagnosed with rigid spine syndrome. Serum creatine kinase was mildly elevated, and he had mild respiratory insufficiency. Skeletal muscle biopsy showed intracytoplasmic inclusions, rimmed vacuoles, and decreased protein levels of FHL1.

Molecular Genetics

In 2 unrelated boys with childhood-onset reducing body myopathy, Schessl et al. (2008) identified hemizygous mutations in the FHL1 gene (300163.0006 and 300163.0007, respectively). Both mutations affected the second LIM domain. Both mothers had a less severe phenotype and were heterozygous for the respective FHL1 mutations.

In the mother and son reported by Ohsawa et al. (2007), Shalaby et al. (2009) identified a mutation in the FHL1 gene (300163.0009). in the second LIM domain.

In a 16-year-old boy with late childhood onset of X-linked reducing body myopathy, Shalaby et al. (2008) identified an in-frame 9-bp deletion in the FHL1 gene affecting the second LIM domain (300163.0017).