NARP-MILS syndrome caused by 8993 T > G mitochondrial DNA mutation: a clinical, genetic and neuropathological study

Abstract

The 8993 T>G mutation in mitochondrial DNA has been associated with variable syndromes of differing severity ranging from maternally inherited Leigh's syndrome (MILS) to neuropathy, ataxia, retinitis pigmentosa (NARP), depending on the mutation loads in affected patients. We report a kindred with several members in the same generation suffering NARP or Leigh's syndrome due to a 8993 T>G mutation. Post-mortem studies of the brain in one affected member clinically presenting with a neurological disorder intermediate between adult Leigh's syndrome and NARP showed symmetrical lesions of the basal ganglia and brainstem closely resembling those usually described in typical Leigh's syndrome. Analysis of mtDNA in different tissues showed a high proportion of mutant genome in brainstem, cerebral cortex, putamen, cerebellum and thalamus. These observations illustrate the continuum of clinical and neuropathological manifestations associated with the 8993 T>G mutation of the mtDNA.

Mitochondrial Regulation of Neuronal Plasticity

“…The 8993 T > G mutation in mitochondrial DNA has been established as the cause of neurological disorders that vary in their severity and phenotype depending upon the mutation load in the affected patient. Leigh's syndrome and neuropathy, ataxia, retinitis pigmentosa (NARP) are two such syndromes in which neurons in the basal ganglia and brainstem become dysfunctional and degenerate [63]. IOSCA (infantile onset spinocerebellar ataxia) is a severe autosomal recessively inherited developmental neurological disorder characterized by progressive dysgenesis of the cerebellum, brain stem and spinal cord.…”

Rostral brain lesions of Leigh syndrome associated with the mitochondrial DNA 8993T>G mutation

“…As for the 8993T NG mutation, the mutation load affects the clinical phenotype, i.e., more than 90% results in Leigh syndrome, and less than 90% results in neuropathy, ataxia, and retinitis pigmentosa (NARP) [4]. Given that the m.8993TN G mutation load of the present patient was nearly 100%, and she exhibited no ataxia or retinal lesions, she was diagnosed genetically and clinically as Leigh syndrome, and not NARP.…”

Infantile mitochondrial disorder associated with subclinical hypothyroidism is caused by a rare mitochondrial DNA 8691A>G mutation

“…The majority of frequently reported mutations in the ATPase 6 gene include heteroplasmic transversion 8993T > C and 8993T > G, which are associated with neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome, and maternally inherited Leigh syndrome; the latter is also known as infantile subacute necrotizing encephalomyelopathy, with characteristic bilateral symmetric lesions in the basal ganglia and subcortical brain regions [13][14][15][16][17][18]. In addition, the ATPase 6 8851T > C mutation, ATPase 6 9176T > C mutation, ATPase 6 9185T > C mutation, and ATPase 6 8597T > C mutation can result in a change of leucine to proline, which also leads to Leigh syndrome or bilateral striatal necrosis [14,[19][20][21][22].…”