Chapter 14 - Nuclear Genetic Causes of Leigh and Leigh-Like Syndrome

Abstract

Leigh syndrome and Leigh-like syndrome are mitochondrial encephalopathies caused by mutations in either nuclear or mitochondrial DNA. The diagnostic pipeline described in this chapter can pinpoint specific genetic causation for children with overlapping clinical phenotypes. A family history suggestive of autosomal recessive inheritance raises the suspicion of a nuclear cause for the clinical phenotype. Initial clinical, biochemical, and neuroradiologic features, and tissue-based enzyme assays including muscle respiratory chain enzyme analysis, can suggest potential candidate genes. Selective use of whole exome sequencing also plays an important role in identifying candidate gene mutations. The list of nuclear genes known to be implicated in Leigh syndrome is rapidly expanding and currently numbers >50, including genes encoding subunits and assembly factors of oxidative phosphorylation enzymes, as well as proteins involved in maintaining the integrity and expression of the mitochondrial DNA and the mitochondrial membranes, and cofactor biosynthesis and transport.