Infantile Presentation of the mtDNA A3243G tRNA^{Leu (UUR)} Mutation

Mitochondrial DNA (mtDNA) disorders are clinically very heterogeneous, ranging from single organ involvement to severe multisystem disease. One of the most frequently observed mtDNA mutations is the A-to-G transition at position 3243 of the tRNA^{Leu (UUR)} gene. This mutation is often related to MELAS syndrome. However, not all patients with the A3243G mutation share the same clinical disease expression and, on the contrary, patients clinically exhibiting MELAS syndrome may have other mtDNA mutations. Here we describe two patients with a very early infantile presentation of disease associated with the A3243G mutation. Patient 1 presented with hypotonia, feeding difficulties and failure to thrive (FTT) at the age of 3 months. Laboratory investigations showed persistent hyperlactic acidemia, elevated lactate/pyruvate ratios and elevated alanine concentrations in blood. Developmental delay was progressive and he developed cardiomyopathy and seizures. Death occurred at the age of 3.5 years. Patient 2 was born prematurely and had persistent, severe lactic acidosis from birth on. Moderate biventricular hypertrophy was seen on ultrasound studies of the heart and, suffering from progressive lactic acidosis, he died at the age of 13 days. Because of the rarity of this very early presentation, we searched the literature for other infantile cases associated with the A3243G mutation and found 8 additional ones. In infants presenting with lactic acidosis/hyperlactic acidemia, failure to thrive, hypotonia, seizures and/or cardiomyopathy, mtDNA mutational analysis, also for the disease entities, usually only observed in juveniles or adults is warranted.

Key words

A3243G mutation - Infantile - Mitochondrial encephalomyopathy - OXPHOS

References

• 1 Afifi K, Ibrahim M ZM, Bergman R A. et al . Morphologic features of hypermetabolic mitochondrial disease: a light microscopic, histochemical and electron microscopic study.  J Neurol Sci. 1972;  15 271-290
• 2 Anderson S, Bankier A T, Barrell B G. et al . Sequence and organization of the human mitochondrial genome.  Nature. 1981;  290 457-465
• 3 Bentlage H, Wendel U, Schagger H, ter Laak H, Janssen A, Trijbels F. Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts with combined complex I and IV deficiencies in muscle.  Neurology. 1996;  47 243-248
• 4 Bourgeron T, Rustin P, Chretien D, Birch-Machin M, Bourgeois M, Viegas-Pequignot E. et al . Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain deficiency.  Nat Genet. 1995;  11 144-149
• 5 Chinnery P F, Turnbull D H. Mitochondrial DNA and disease.  Lancet. 1999;  354 (Suppl I) 17-21
• 6 Chomyn A, Enriquez J A, Micol V, Fernandez-Silva P, Attardi G. The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial tRNA^Leu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes.  J Biol Chem. 2000;  275 19198-19209
• 7 Cooperstein S J, Lazarow A. A microspectrophotometry method for the determination of cytochrome c oxidase.  J Biol Chem. 1951;  189 665-670
• 8 Damian M S, Seibel P, Schachenmayr W, Reichmann H, Dorndorf W. VACTERL with the mitochondrial NP 3243 point mutation.  Am J Med Genet. 1996;  62 398-403
• 9 DiMauro S, Moraes C. Mitochondrial encephalomyopathies.  Arch Neurol. 1993;  50 1197-1208
• 10 Feigenbaum A, Chitayat D, Robinson B, MacGregor D, Myint T, Arbus G. The expanding clinical phenotype of the tRNA^{Leu (UUR)} A → G mutation at np 3243 of mitochondrial DNA: Diabetic embryopathy associated with mitochondrial cytopathy.  Am J Med Genet. 1996;  62 404-409
• 11 Fischer J C, Ruitenbeek W, Berden J A, Trijbels J M, Veerkamp J H, Stadhouders A M. et al . Differential investigation of the capacity of succinate oxidation in human skeletal muscle.  Clin Chim Acta. 1985;  153 23-26
• 12 Fischer J C, Ruitenbeek W, Gabreëls F JM, Janssen A JM, Renier W O, Sengers R CA. et al . Mitochondrial encephalomyopathy: the first case with an established defect at the level of coenzyme Q.  Eur J Pediatr. 1986;  144 441-444
• 13 Fischer J C, Ruitenbeek W, Trijbels J M, Veerkamp J H, Stadhouders A M, Sengers R C. et al . Estimation of NADH oxidation in human skeletal muscle mitochondria.  Clin Chim Acta. 1986;  155 263-273
• 14 Fukuhara N, Tokiguchi S, Shirakawa K. et al . Myoclonus epilepsy associated with ragged red fibers (mitochondrial abnormalities): disease entity or a syndrome? Light- and electron microscopic studies of two cases and review of literature.  J Neurol Sci. 1980;  47 117-133
• 15 Goto Y-I, Nonaka I, Horai S. A mutation in the tRNA^Leu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies.  Nature. 1990;  348 651-653
• 16 Goto Y-I, Horai S, Matsuoka T. Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS): a correlative study of he clinical features and mitochondrial DNA mutation.  Neurology. 1992;  42 545-550
• 17 Hilton G. MELAS; a mitochondrial encephalomyopathy syndrome.  J Neurosci Nurs. 1995;  27 278-282
• 18 Kishnani P S, Van Hove J LK, Shoffner J S, Kaufman A, Bossen E H, Kahler S G. Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNA^{Leu (UUR)} gene.  Eur J Pediatr. 1996;  155 898-903
• 19 Koga Y, Akita Y, Takane N, Sato Y, Kato H. Heterogeneous presentation in A3243G mutation in the mitochondrial tRNA^Leu(UUR) gene.  Arch Dis Child. 2000;  82 407-411
• 20 Koo B, Becker L E, Chuang S, Merante F, Robinson B H, MacGregor D. et al . Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological and genetic observations.  Ann Neurol. 1993;  34 25-32
• 21 van Laack H, Ruitenbeek W, Trijbels J M, Sengers R C, Gabreëls F J, Janssen A J. et al . Estimation of pyruvate dehydrogenase (E1) activity in human skeletal muscle; three cases with E1 deficiency.  Clin Chim Acta. 1988;  171 109-118
• 22 Leonard J V, Schapira A HV. Mitochondrial respiratory chain disorders I; mitochondrial DNA defects.  Lancet. 2000;  355 389-394
• 23 Li Y Y, Hengstenberg C, Maisch B. Whole mitochondrial genome amplification reveals basal level multiple deletions in mtDNA of patients with dilated cardiomyopathy.  Biochem Biophys Res Commun. 1995;  210 211-218
• 24 Loeffen J, Smeitink J AM, Trijbels J MF, Janssen A J, Triepels R, Sengers R C. et al . Isolated complex I deficiency in children: clinical, biochemical and genetic aspects.  Hum Mut. 2000;  15 123-134
• 25 Macmillan C, Lach B, Shoubridge E A. Variable distribution of mutant mitochondrial DNAs (tRNA^Leu[3243]) in tissues of symptomatic relatives with MELAS; the role of mitotic segregation.  Neurology. 1993;  43 1586-1590
• 26 Mariotti C, Savarese N, Suomalainen A, Rimoldi M, Comi G, Prelle A. et al . Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243 G mutation of mitochondrial DNA.  J Neurol. 1995;  242 304-312
• 27 Nissenkorn A, Zeharia A, Lev D, Watemberg N, Fattal-Valevski A, Barash V. et al . Neurologic presentations of mitochondrial disorders.  J Child Neurol. 2000;  15 44-48
• 28 Pavlakis S G, Philips P C, DiMauro S. et al . Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: A distinctive clinical syndrome.  Ann Neurol. 1984;  16 481-488
• 29 Srere P A. Citrate synthase EC 4. 1. 3. 7 citrate oxaloacetate lyase (co-A-acetylating).  Method Enzymol. 1969;  13 3-11
• 30 Sue C M, Bruno C, Andreu A L, Cargan A, Mendell J R, Tsao C-Y. et al . Infantile encephalopathy associated with the MELAS A3243G mutation.  J Pediatr. 1999;  134 696-700
• 31 Taanman J W. The human mitochondrial genome: structure, transcription, translation and replication.  Biochim Biophys Acta. 1999;  1410 103-123
• 32 Tritschler H J, Packer L, Medori R. Oxidative stress and mitochondrial dysfunction in neurodegeneration.  Biochem Mol Biol Int. 1994;  34 169-181
• 33 de Vries D, de Wijs, Ruitenbeek W, Begeer J, Smit P, Bentlage H. et al . Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G-mutation.  J Neurol Sci. 1994;  124 77-82