J Korean Med Sci.  2010 Jan;25(1):180-184. 10.3346/jkms.2010.25.1.180.

Pediatric-Onset Dystonia Associated with Bilateral Striatal Necrosis and G14459A Mutation in a Korean Family: A Case Report

• Kim IS
• Ki CS
• Park KJ

• KMID: 1713855
• DOI: http://doi.org/10.3346/jkms.2010.25.1.180

Abstract

We describe a Korean family presenting with pediatric-onset, progressive, generalized dystonia with bilateral striatal necrosis and the homoplasmic G14459A mutation in the mitochondrial ND6 gene. The G14459A mutation has been reported in families presenting with Leber hereditary optic neuropathy (LHON) alone, LHON plus dystonia, or pediatric-onset dystonia. The proband had shown dysarthria, progressive generalized dystonia, and spasticity at 5 yr. Brain MRI demonstrated bilateral striatal necrosis. Additional investigation of family members revealed the presence of homoplasmic G14459A mutation in asymptomatic individuals. The clinical manifestation of the homoplasmic G14459A mtDNA mutation within the same family showed asymptomatic or pediatric-onset dystonia, without optic neuropathy. This study reemphasizes that the G14459A mutation is a candidate mutation for maternally inherited dystonia, regardless of optic neuropathy, and supports the hypothesis that nuclear genes may play a role in modifying the clinical expression of mitochondrial disease.

Keyword

Mitochondrial Diseases; Basal Ganglia; Necrosis; Dystonia; Nucleotide Position 14459

MeSH Terms

Adult
Asian Continental Ancestry Group/*genetics
Base Sequence
Brain/pathology
Dystonia/complications/diagnosis/*genetics
Female
Humans
Magnetic Resonance Imaging
Male
Mitochondrial Diseases/complications/diagnosis/*genetics
NADH Dehydrogenase/*genetics
Necrosis
Optic Atrophy, Hereditary, Leber/genetics
Pedigree
*Point Mutation
Republic of Korea
NADH Dehydrogenase

Figure

• 

  Fig. 1 (A) Pedigree of a Korean family with maternally inherited, pediatric-onset dystonia carrying the G14459A mutation. (B) Direct sequencing analyses of the mitochondrial DNA for the G14459A mutation. Circle, female; square, male; black symbol, affected; dot, asymptomatic carrier; diagonal line, deceased.

• 

  Fig. 2 Brain MRI of the proband (A, B) and his nephew (C, D). (A) The T2 weighted image of the proband show bilateral striatal hyperintensities with necrosis. (B) The T1 weighted image of the proband show bilateral hypointensities with necrosis. (C) The T2 weighted image of his nephew shows bilateral putaminal hyperintensities without necrosis. (D) The T1 weighted image of his nephew shows bilateral putaminal hypointensities without necrosis.

Reference

1. Jun AS, Trounce IA, Brown MD, Shoffner JM, Wallace DC. Use of transmitochondrial cybrids to assign a complex I defect to the mitochondrial DNA-encoded NADH dehydrogenase subunit 6 gene mutation at nucleotide pair 14459 that causes Leber hereditary optic neuropathy and dystonia. Mol Cell Biol. 1996. 16:771–777.

2. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci USA. 1994. 91:6206–6210.

3. Shoffner JM, Brown MD, Stugard C, Jun AS, Pollock S, Haas RH, Kaufman A, Koontz D, Kim Y, Graham JR, Smith E, Dixon J, Wallace DC. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol. 1995. 38:163–169.

4. Funalot B, Reynier P, Vighetto A, Ranoux D, Bonnefont JP, Godinot C, Malthiery Y, Mas JL. Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy. Ann Neurol. 2002. 52:374–377.

5. Gropman A, Chen TJ, Perng CL, Krasnewich D, Chernoff E, Tifft C, Wong LJ. Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. Am J Med Genet A. 2004. 124:377–382.

6. Tarnopolsky MA, Baker SK, Myint T, Maxner CE, Robitaille J, Robinson BH. Clinical variability in maternally inherited leber hereditary optic neuropathy with the G14459A mutation. Am J Med Genet A. 2004. 124:372–376.

7. Watanabe M, Mita S, Takita T, Goto Y, Uchino M, Imamura S. Leber's hereditary optic neuropathy with dystonia in a Japanese family. J Neurol Sci. 2006. 243:31–34.

8. Campos Y, Martin MA, Rubio JC, Gutierrez del Olmo MC, Cabello A, Arenas J. Bilateral striatal necrosis and MELAS associated with a new T3308C mutation in the mitochondrial ND1 gene. Biochem Biophys Res Commun. 1997. 238:323–325.

9. Sakuta R, Honzawa S, Murakami N, Goto Y, Nagai T. Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. Pediatr Neurol. 2002. 27:397–400.

10. De Meirleir L, Seneca S, Lissens W, Schoentjes E, Desprechins B. Bilateral striatal necrosis with a novel point mutation in the mitochondrial ATPase 6 gene. Pediatr Neurol. 1995. 13:242–246.

11. Makino M, Horai S, Goto Y, Nonaka I. Confirmation that a T-to-C mutation at 9176 in mitochondrial DNA is an additional candidate mutation for Leigh's syndrome. Neuromuscul Disord. 1998. 8:149–151.

12. Solano A, Roig M, Vives-Bauza C, Hernandez-Pena J, Garcia-Arumi E, Playan A, Lopez-Perez MJ, Andreu AL, Montoya J. Bilateral striatal necrosis associated with a novel mutation in the mitochondrial ND6 gene. Ann Neurol. 2003. 54:527–530.

13. Kirby DM, Kahler SG, Freckmann ML, Reddihough D, Thorburn DR. Leigh disease caused by the mitochondrial DNA G14459A mutation in unrelated families. Ann Neurol. 2000. 48:102–104.