The mitochondrial 8993 mutation associated with Leigh disease that explains 20 percent of cases is also discussed below in relation to the NARP syndrome. The close relationship between the two processes reemphasizes the point that several mitochondrial mutations rise to the clinical and pathologic picture of a necrotizing encephalopathy. However, it has been recently pointed out that many cases of Leigh disease are associated with nuclear mutations, including in RANBP2 that codes for a component of the nuclear pore.
Neuropathy, Ataxia, Retinitis Pigmentosa Syndrome (NARP)
As just indicated, Leigh syndrome exemplifies to a remarkable degree the heterogeneity of abnormalities that may be associated with cytochrome oxidase deficiency caused by a single mitochondrial gene mutation. A minor transversion error, the substitution of one nucleotide in the mitochondrial DNA at position 8993, the same site implicated in Leigh syndrome, also gives rise to a maternally inherited syndrome of sensory NARP. The mutation creates a defective ATPase-6 of complex V of the mitochondrial respiratory chain. Included in some cases of NARP are developmental delay, seizures, and proximal muscle weakness.
The severity of the NARP syndrome corresponds to the amount of aberrant DNA in the mitochondrial genome; mutations involving more than 90 percent of mitochondrial DNA produce the more severe phenotype of the necrotizing encephalopathy.
Santorelli and colleagues found that 12 of 50 patients with Leigh syndrome from 10 families displayed the 8993 point mutation. Within one kindred, the mitochondrial aberration may vary from a mild developmental delay, to NARP, to the full-blown Leigh syndrome, or early death with lactic acidosis. These differences in severity are thought to result from the mosaicism of mitochondrial genetics and specifically to the protective effect of even small amounts of the normal mitochondrial genome. The first manifestations of disease may not appear until adulthood, although it only rarely begins after age 20 years.
Further confounding the clinical classification of this disease complex is the observation that many patients with the Leigh syndrome have a pyruvate dehydrogenase (usually X-linked) or pyruvate decarboxylase deficiency or a cytochrome oxidase deficiency. These are common to many mitochondrial disorders and inherited usually as an autosomal recessive trait. However, patients with Leigh syndrome and the 8993 mutation tend not to have these enzymatic deficiencies. Bridging these complex cases to the typical ones are instances with cytochrome oxidase deficiency with psychomotor retardation, slowed growth, and lactic acidosis, many without the striatal or brainstem spinal necroses of Leigh syndrome.