Neuropathy, Ataxia, And Retinitis Pigmentosa

A number sign (#) is used with this entry because of evidence that NARP syndrome is caused by mutation in the gene encoding subunit 6 of mitochondrial H(+)-ATPase (MTATP6; 516060).

Clinical Features

Holt et al. (1990) described a family in which 4 members showed a variable combination of developmental delay, retinitis pigmentosa, dementia, seizures, ataxia, proximal neurogenic muscle weakness, and sensory neuropathy, in a pedigree pattern consistent with maternal transmission. There was no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained 2 populations of mitochondrial DNA, one of which had a previously unreported restriction site for AvaI. Sequence analysis showed that this new restriction site was the consequence of a point mutation at nucleotide 8993 of the MTATP6 gene, resulting in an amino acid change from a highly conserved leucine to arginine in mitochondrial H(+)-ATPase (8993T-G; 516060.0001). There was some correlation between clinical severity and the amount of mutant mitochondrial DNA in the patients; this was present in only small amounts in the blood of healthy elderly relatives in the same maternal line. The index case was a 47-year-old female who developed night blindness at the age of 12 years and was diagnosed as having retinitis pigmentosa. She was almost blind by the age of 30 years. At the age of 24 years, she had a generalized seizure and was treated with phenytoin. In her early thirties, she suddenly noticed unsteadiness on walking which subsequently progressed; there had been no evidence of anticonvulsant toxicity. Sensory action potentials were reduced in amplitude, indicating an axonal sensory neuropathy. Quadriceps-muscle biopsy showed mild chronic partial denervation with collateral reinnervation. The patient's sister was asymptomatic at the age of 52 years but had a few clumps of retinal pigment and proximal muscle weakness. Her daughter noticed reduced peripheral vision at the age of 25 years and was diagnosed as having retinitis pigmentosa. The daughter of this daughter was severely affected and at the age of 3 years spoke only single words, had a pigmentary retinopathy, and limb and gait ataxia.

Kerrison et al. (2000) described the progression of retinopathy in NARP. Prior to the onset of visual field constriction, ophthalmoscopy revealed salt-and-pepper retinopathy. After the visual fields had become constricted, fundus examination showed diffuse peripheral bone spicule formation, optic nerve pallor, and arteriolar attenuation. The authors stressed that mild mottling of the peripheral retinal pigment epithelium (salt-and-pepper retinopathy or retinitis pigmentosa sine pigmento) does not represent a specific entity but is an early stage of the retinitis pigmentosa, whether the patient has NARP or isolated retinitis pigmentosa.

Lopez-Gallardo et al. (2009) reported a 40-year-old man with NARP syndrome. He had delayed development, psychomotor retardation, and irritability in childhood, and later developed other neurologic signs, including hearing loss, blindness due to optic atrophy and retinitis pigmentosa, ataxia, and clonic spasms. Genetic analysis identified a novel truncating mutation in the MTATP6 gene (516060.0009). The mutation was heteroplasmic, present in 26% and 85% of blood and muscle, respectively.

Pathogenesis

Sgarbi et al. (2009) demonstrated that human fibroblasts containing the NARP-associated 8993T-G mutation could be protected from cell death when treated with alpha-ketoglutarate/aspartate to boost mitochondrial substrate-level phosphorylation (70% vs 5%; treated vs untreated survival after 72 hours). Homoplasmic 8993T-G cybrids showed similar results (75% vs 15%; treated vs untreated survival after 72 hours). In untreated fibroblasts and cybrids, the decrease in ATP content paralleled cell death, but ATP content returned to control levels after treatment. The findings indicated that ATP synthase-deficient cells can be rescued by increasing mitochondrial substrate-level phosphorylation, suggesting a potential therapeutic option for patients with such disorders.