Lethal Infantile Mitochondrial Disease or Congenital Lactic Acidosis

The oxidative phosphorylation defects associated with extreme neonatal lactic acidosis involve defects in multiple complexes (mostly complex I and IV but also III) and various cytochromes. There are probably several genetic mechanisms of lethal infantile mitochondrial disease (LIMD): tissue-specific depletions of mtDNA, mtDNA mutations, and abnormal expression of specific complex I or IV subunits. The genetics of the mtDNA depletion syndromes could be autosomal recessive or dominant with variable expressivity. Three hypotheses could explain these: (1) there is a defect in a nuclear gene that controls mtDNA

replication and copy number; (2) there is abnormal timing of mtDNA replication (delayed) in embryogenesis; (3) an mtDNA point mutation interacts with specific nuclear alleles and replication is impaired.

These are rare diseases, and the epidemiology is unknown. Because the respiratory chain is influenced by mitochondrial and nuclear genomes, inheritance is either mendelian or maternal.

Presentation is usually in or shortly after the neonatal period, with marked hypotonia and weakness, failure to thrive, respiratory difficulty, and severe lactic acidosis. The hypotonia/weakness is due to a myopathy with lipid and glycogen accumulation and abnormally shaped mitochondria without inclusions but only rare, ragged red fibers. Death occurs ordinarily by 5 months, usually because of the uncorrectable lactic acidosis. Hepatic dysfunction is highly associated, with lesser involvement of kidneys (proximal tubule abnormalities and generalized aminoaciduria) and a myocardiopathy. The brain itself is rarely involved, but when it is, bilateral basal ganglial abnormalities are shown on neuroimaging.

The differential diagnosis includes other infantile causes of lactic acidosis: primary defects of pyruvate metabolism, such as pyruvate dehydrogenase deficiency, or secondary disturbances, such as in various organic acidurias and fatty acid oxidation defects; Krebs' cycle defects; and defects of gluconeogenesis. y Before the serum lactic acid levels are known, the clinical picture resembles the hyperammonemia syndromes due to urea cycle defects.

Important tests to order include blood levels of amino acids; urine levels of organic acids; serum and CSF levels of lactate, pyruvate, and ammonia; liver and renal function tests, blood creatine kinase (skeletal and cardiac fractions); ultrasound evaluation of the heart; neuroimaging of the brain; and electroencephalography to document a toxic/ metabolic encephalopathy.

Supportive treatment of liver, renal, and cardiac failure is important, along with consultation with a center using experimental protocols. For respiratory chain defects, megadoses of vitamins K and C, coenzyme Q10, L-carnitine, and folic acid have all been tried with controversial benefit. If PDH deficiency is the cause, thiamine and lipoic acid may be therapeutic, because PDH requires these as cofactors. If biotinidase deficiency or multiple carboxylase deficiency is the cause, 50 mg of biotin daily can be given. Fructose-1,6-biphosphatse deficiency and glucose-6-phosphatase deficiency, both gluconeogenic defects, respond to frequent daily and continuous nocturnal feedings to prevent hypoglycemia. There is no effective treatment for pyruvate carboxylase deficiency or partial defects of the Krebs cycle. Correction of the metabolic acidosis and lowering of serum lactic acid is most effective with sodium dichloroacetate (DCA), 15 to 200 mg/kg/day administered intravenously or orally. DCA crosses the blood-brain barrier and inhibits the pyruvate dehydrogenase specific kinase, activating the PDHC and lowering brain and blood lactate levels.

LIMD is lethal. If definite nuclear gene mutations are identified in the future, prenatal diagnosis using chorionic villus sampling or amniocentesis should be feasible. The prognosis of the other congenital lactic acidoses depends on the underlying biochemical defects--best with biotinidase deficiency and the gluconeogenic defects, less with PDH, pyruvate carboxylase (PC), and Krebs' cycle defects.

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