Mitochondrial Myopathy With Lactic Acidosis

A number sign (#) is used with this entry because of evidence that mitochondrial myopathy with lactic acidosis (MMLA) is caused by compound heterozygous mutation in the PNPLA8 gene (612123) on chromosome 7q31. One such family has been reported.

Clinical Features

Saunders et al. (2015) reported a 7-year-old girl, born of unrelated parents, with a mitochondrial myopathy. She had normal early development, with the exception of toe-walking, but began to show severe progressive proximal muscle weakness resulting in loss of ambulation by age 3 years. Independent sitting became difficult due to fatigue. Her fine motor skills declined, speech became dysarthric, and hypotonicity progressed to spasticity. Other features included complex partial seizures, lactic acidosis, and increased serum pyruvate. Skeletal muscle biopsy showed abnormal mitochondria with disarray of cristae and dense globular osmiophilic inclusions on electron microscopy. Ragged-red fibers were not observed, but there was an increase in secondary lysosomes containing residual bodies that appeared to be derived from mitochondria. Mitochondrial oxidative enzyme analysis was normal, suggesting normal function of the electron transport chain. The patient's cognitive function was difficult to assess due to seizures and oromotor dystonia, but she attended elementary school.

Inheritance

The transmission pattern of MMLA in the family reported by Saunders et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a girl with MMLA, Saunders et al. (2015) identified compound heterozygous truncating mutations in the PNPLA8 gene (612123.0001-612123.0002). The mutations, which were found by exome sequencing, were predicted to result in a loss of function, and Western blot analysis of patient muscle biopsy showed a dramatic decrease in immunoreactivity for the PNPLA8 protein. Saunders et al. (2015) noted that the phenotype in this patient replicated that of the Pnpla8-null mouse (Mancuso et al., 2009).

Animal Model

Mancuso et al. (2009) found abundant expression of the Pnpla8 gene in multiple regions of the mouse brain, including the cortex, cerebellum, hippocampus, and brainstem. Pnpla8-null mice showed a neurodegenerative disorder phenotype characterized by impaired spatial learning and memory. There were morphologic alterations in the hippocampus, including enlarged mitochondria, heteromorphic membrane structures, and inclusion bodies containing sheets and whorls of membranes that were identified as degenerating mitochondria. Analysis of lipid extracts from the hippocampus of mutant mice showed increased cardiolipin content and altered molecular species distribution, consistent with altered mitochondrial phospholipid homeostasis.

History

Hackett et al. (1973) described 2 sisters with signs of growth failure, severe muscle weakness, and moderate neural deafness. Light microscopy of skeletal muscle showed areas of 'granular necrosis,' which, by electron microscopy, were found to be produced by large and numerous mitochondria. Hyperalaninemia and hyperalaninuria were demonstrated, and an oral alanine load was more slowly cleared than normal. The patients also had elevated pyruvate concentration in the blood and severe lactic acidosis, which in 1 girl was fatal at age 11 years. The girls were asymptomatic until ages 6 and 8 years. One sister was alive at age 20. No statement about parental consanguinity was made.