Myopathy, Mitochondrial Progressive, With Congenital Cataract, Hearing Loss, And Developmental Delay

A number sign (#) is used with this entry because of evidence that mitochondrial progressive myopathy with congenital cataract, hearing loss, and developmental delay is caused by homozygous mutation in the GFER gene (600924) on chromosome 16p13. One such family has been reported.

Clinical Features

Di Fonzo et al. (2009) reported a consanguineous Moroccan family including 3 children with congenital cataract, muscular hypotonia, sensorineural hearing loss, and developmental delay. The first child presented in the first month of life with congenital cataract and axial hypotonia. He did not learn to walk until 2 years of age or speak until 3 years of age. At the age of 12 he developed progressive hearing loss and bilateral ptosis. At age 17, neurologic examination revealed generalized hypotonia and hypotrophy, especially in the lower limbs. He could walk only with assistance and was unable to fix his gaze; rotatory nystagmus was noted. Proximal and distal muscle strength was normal. Upper and lower extremity deep tendon reflexes were weak or absent. Audiologic examination showed severe bilateral hearing loss. ECG and echocardiography were normal. Ferritin was low. Amylase and serum lactate were somewhat elevated. MRI showed a thin corpus callosum. His 2 brothers had similar manifestations. Muscle biopsies from the first 2 sibs showed scattered COX-negative fibers. Biochemical studies revealed a constant moderate reduction (30 to 50% of normal mean values) of complex IV activity in multiple tissues from both probands. Interestingly, the older proband displayed a multicomplex alteration including a complex I and II defect in both muscle and myoblasts, whereas an analysis of the younger proband's fibroblasts revealed only reduced complex IV activity. Ultrastructural analysis of muscle tissue showed abnormally enlarged mitochondria with electron-dense vacuolizations and thickened cristae. In addition, all manifested accelerated time-dependent accumulation of multiple mitochondrial DNA deletions.

Molecular Genetics

In 3 sibs from a consanguineous Moroccan family with a combined mitochondrial complex deficiency, Di Fonzo et al. (2009) detected homozygosity for a missense mutation in the GFER gene (600924.0001). The consequences of the mutation at the level of the patients' muscle tissues and fibroblasts were a reduction in complex I, II, and IV activity, a lower cysteine-rich protein content, and abnormal ultrastructural morphology of the mitochondria with enlargement of the mitochondrial intermembrane space.