No abstract

Relative carnitine deficiency is important in the pathophysiology of several disorders, including Reye's syndrome and organic acidemias. In acute clinical crises, carnitine serves as a "buffer," trapping toxic acyl compounds. Mitochondrial failure develops in carnitine deficiency when there is insufficient tissue carnitine available to buffer toxic acyl-CoA metabolites. Toxic levels of acyl-CoA impair the citrate cycle, gluconeogenesis, the urea cycle, and fatty-acid oxidation. Carnitine replacement therapy is safe and induces excretion of toxic acyl groups in the urine.

Familial vitamin E deficiency (AVED) causes ataxia and peripheral neuropathy that resembles Friedreich's ataxia. AVED is thought to be caused by a defect in the transport of vitamin E in liver cells, which is the probable function of alpha-tocopherol transfer protein (alphaTTP). We have cloned the cDNA and several genomic phage clones covering the entire human alphaTTP gene and determined the junctions between the five exons and four introns that composed the gene for human alphaTTP. Three mutations in three unrelated North American families with AVED were identified. Two mutations, 485delT and 513insTT, cause a frame shift and a premature stop codon and the third mutation 574G-->A would substitute Arg192 to His in alphaTTP. The 2 patients with a severe form of AVED were homozygous with 485delT and 513insTT, respectively, while the patient with a mild form of the disease was compound heterozygous with 513insTT and 574G-->A. These findings have identified the underlying genetic defect in AVED and have confirmed the role of alphaTTP in AVED.

Perinatal hypoxia-ischemia remains a significant cause of neonatal mortality and neurodevelopmental disability. Numerous lines of evidence indicate that cerebral ischemic insults disrupt normal respiratory activity in mitochondria. Carnitine (3-hydroxy-4-N-trimethylammonium-butyrate) has an essential role in fatty acid transport in the mitochondrion and in modulating potentially toxic acyl-CoA levels in the mitochondrial matrix. There are no naturally occurring esterases available to reduce the accumulation of acyl-CoA but this process can be overcome by exogenous carnitine. We used a newborn rat model of perinatal hypoxia-ischemia to test the hypothesis that treatment with Lcarnitine would reduce the neuropathologic injury resulting from hypoxia-ischemia in the developing brain. We found that treatment with L-carnitine during hypoxia-ischemia reduces neurologic injury in the immature rat after both a 7-and 28-d recovery period. We saw no neuroprotective effect when L-carnitine was administered after hypoxia-ischemia. Treatment with D-carnitine resulted in an increase in mortality during hypoxia-ischemia. Carnitine is easy to administer, has low toxicity, and is routinely used in neonates as well as children with epilepsy, cardiomyopathy, and inborn errors of metabolism. L-Carnitine merits further investigation as a treatment modality for the asphyxiated newborn or as prophylaxis for the at-risk fetus or newborn. Hypoxic-ischemic injury in the developing brain is characterized by a cascade of cellular events that evolve for hours or days, a distinct clinical syndrome manifest as encephalopathy, a combination of ischemia superimposed on hypoxia, and specific regional brain vulnerability to injury (1-3). Cerebral ischemia in the adult (4) and hypoxia-ischemia in the newborn (5) disrupt mitochondrial function leading to a collapse in cell energy metabolism.The amino acid derivative carnitine (3-hydroxy-4-Ntrimethylammonium-butyrate) is required for the maintenance of normal mitochondrial function. Carnitine has three major functions: facilitating transport of acyl moieties between organs and across the mitochondrial inner membrane and the buffering of potentially toxic intracellular acyl-CoA moieties (6, 7). High levels of acyl-CoA esters impair numerous mitochondrial processes (Fig. 1) (8 -10). There are no endogenous esterases available to reduce the accumulation of acyl-CoA esters. This process can be overcome by the addition of exogenous carnitine. Carnitine may function therefore in acute metabolic crises to trap toxic acyl-CoA moieties that impair fatty acid oxidation, urea cycle function metabolism, and gluconeogenesis (6,7,11).Carnitine has been tested as a neuroprotective therapy in adult animal models of cerebral ischemia (12-14). However, there are no data directly addressing the effect of L-carnitine treatment on cerebral ischemic injury in the newborn. LCarnitine is potentially an attractive therapeutic modality for perinatal asphyxia given the extensive pediatric clinical experience with the use of th...

CSF B- and T-cell recruitment is linked to neurologic signs in pediatric OMS, which may relate to relapses and disease progression.