High Mitochondrial DNA T8993G Mutation (>90%) Without Typical Features of Leigh's and NARP Syndromes

Abstract

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome and maternally inherited Leigh's syndrome have been associated with T8993G point mutations in the mitochondrial adenosine triphosphatase 6 gene. Typically, NARP syndrome is characterized by developmental delay, seizures, dementia, retinitis pigmentosa, ataxia, sensory neuropathy, and proximal weakness. Usually, there is a correlation between the percentage of mutated mitochondrial DNA and clinical severity, and when mutated mitochondrial DNA is > 90%, it is often seen with Leigh's syndrome. We now report a family with mitochondrial DNA T8993G mutation in eight living members, five with mutant mitochondrial DNA >90% and one with 20% mutant mitochondrial DNA. However, their clinical features include variable combinations of seizures, behavior problems, learning disability, mental retardation, sensorineural deafness, cerebellar ataxia, and proximal muscle weakness. No retinitis pigmentosa was found in all eight living members, including a 56-year-old grandmother. Only one dead female relative was diagnosed with Leigh's syndrome on the neuropathologic examination at age 22 years, when she died of an accident. High mitochondrial DNA T8993G mutation is not always associated with typical features of Leigh's and NARP syndromes. (J Child Neurol 2001;16:533-535).

Get full access to this article

View all access options for this article.

References

Holt IJ , Harding AE , Petty Rkh , morgan-Hugnes JA : A new mitochondrial disease associated with mitochondrial DNA heteroplasmy . Am J Hum Genet 1990;46:428-433.

Tatuch Y. , Pagon RA , Vlcek B. , et al: The 8993 mtDNA mutation: Heteroplasmy and clinical presentation in three families. Eur J Hum Genet 1994;2:35-43.

Fryer A. , Appleton R. , Sweeney MG , et al: Mitochondrial DNA 8993 (NARP) mutation presenting with a heterogeneous phenotype including cerebral palsy. Arch Dis Child 1994;71:419-422.

Shoffner JM , Fernhoff PM , Krawiecki NS , et al: Subacute necrotizing encephalopathy: Oxidative phosphorylation defects and the ATPase 6 point mutation. Neurology 1992;42:2168-2174.

Robinson BH , Tatuch YM : Four families with variable presentation of the 8993 mtDNA mutation within the ATPase 6 gene, abstract. Am J Hum Genet 1992;51:A175.

Ciafaloni E. , Santorelli FM , Shanske S. , et al: Maternally inherited Leigh's syndrome . J Pediatr 1993;122:419-422.

Sakuta R. , Goto Y. , Horai S. , et al: Mitochondrial DNA mutation and Leigh's syndrome. Ann Neurol 1992;32:597-598.

Santorelli FM , Shanske S. , Macaya A. , et al: The mutation at nt8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann Neurol 1993;34:827-834.

Vilarinho L. , Leao E. , Barbot C. , et al: Clinical and molecular studies in three Portuguese mtDNA T8993G families. Pediatr Neurol 2000;22: 29-32.

10.

Tatuch Y. , Christodoulou J. , Feigenbaum A. , et al: Heteroplasmic mtDNA mutation (T ⇨ G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992;50:852-858.

11.

Silvestri G. , Bertini E. , Servidei S. , et al: Maternally inherited cardiomyopathy: A new phenotype associated with the A to G at nt 3243 of mitochondrial DNA (MELAS) mutation. Muscle Nerve 1997;20: 221-225.

12.

Moraes CT , Ciacci F. , Silvestri G. , et al: Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromuscul Disord 1993;3:43-50.

13.

Torroni A. , Petrozzi M. , D'Urbano L. , et al: Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14848. Am J Hum Genet 1997;60:1107-1121.

14.

Cock HR , Tabrizi SJ , Cooper JM , Schapira Ahv : The influence of nuclear background on the biochemical expression of 3460 Leber's hereditary optic neuropathy. Ann Neurol 1998;44:187-193.

15.

Hao H. , Morrison LE , Moraes CT : Suppression of a mitochondrial tRNA gene mutation phenotype associated with changes in the nuclear background. Hum Mol Genet 1999;8:1117-1124.