levoleucovorin and Phenylketonurias

Plasma and CSF concentrations of endogenous L-DOPA, catecholamines, and metabolites of monoamines were assayed in a patient with atypical phenylketonuria due to absent dihydropteridine reductase (DHPR), before and during treatment with folinic acid, Sinemet, and 5-hydroxytryptophan. The patient had low but detectable levels of L-DOPA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 3,4-dihydroxyphenylglycol (DHPG) in plasma and low but detectable levels of these compounds and of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in CSF, with approximately normal plasma and CSF levels of norepinephrine [noradrenaline (NA)]. Folinic acid treatment approximately doubled plasma levels of L-DOPA, NA, DOPAC, and DHPG, compared with values during dietary phenylalanine restriction alone. Detection of L-DOPA, catecholamines, and monoamine metabolites in this patient indicates that monoamine synthesis in humans does not absolutely require DHPR. The results are consistent with the existence of an alternative biochemical pathway, with folinic acid treatment augmenting activity along this pathway. Low plasma levels of L-DOPA, DOPAC, and DHPG may reflect decreased catecholamine synthesis and turnover in sympathetic nerves, with compensatory increases in exocytotic release normalizing plasma NA levels.

Topics: 5-Hydroxytryptophan; Biogenic Monoamines; Humans; Infant; Leucovorin; Levodopa; Male; Phenylketonurias

Hyperphenylalaninemia in infants and children may be caused by a deficiency of dihydropteridine reductase (DHPR). Recommended therapy includes folinic acid as a source of tetrahydrofolate, a phenylalanine-restricted diet, and both dopamine and serotonin precursors. We report a child with progressive basal ganglia and other subcortical calcifications prior to the use of folinic acid. Six other reported cases of DHPR deficiency demonstrated similar calcifications prior to folinic acid therapy. Since this pattern of calcification also resembles that seen in CNS folate deficiency caused by both congenital folate deficiency and that which is methotrexate-induced, we propose that intracranial calcification in DHPR deficiency is caused by inadequate CNS tetrahydrofolate and may be prevented by the use of folinic acid. Our patient achieved excellent seizure control following the use of folinic acid, suggesting either a direct or indirect anticonvulsant effect of this compound in patients with DHPR deficiency.

Topics: Brain; Brain Diseases; Calcinosis; Female; Humans; Infant, Newborn; Leucovorin; NADH, NADPH Oxidoreductases; Phenylketonurias; Seizures; Tomography, X-Ray Computed

We gave folinic acid to three siblings, and to a fourth child, who have or had dihydropteridine reductase (DHPR) deficiency. The youngest began folinic acid therapy in addition to neurotransmitter precursors and a phenylalanine-restricted diet at age 2 months, and at 2 years of age has near normal development without evidence of neurologic impairment. His older brother began similar treatment at 5 1/2 months of age, when early neurologic findings were evident. At age 6 years his mental retardation and neurologic impairment are less severe than reported in most patients with DHPR deficiency. Little improvement occurred in their sister, who first received treatment at 2 years of age, when she already had severe neurologic impairment. An unrelated boy with profound neurologic impairment showed subtle signs of improvement after he began treatment with folinic acid alone at age 9 years. These results provide evidence that folinic acid is important in the treatment of DHPR deficiency and, if begun early in infancy, may prevent irreversible neurologic damage. The mechanism of folinic acid action in DHPR deficiency may be to increase indirectly the synthesis of 5-methyltetrahydrofolate.

Topics: 5-Hydroxytryptophan; Brain; Carbidopa; Drug Therapy, Combination; Female; Folic Acid; Humans; Infant; Infant, Newborn; Leucovorin; Levodopa; Male; NADH, NADPH Oxidoreductases; Neurotransmitter Agents; Phenylketonurias

Topics: Biopterins; Child; Child, Preschool; Chromatography, High Pressure Liquid; Diagnosis, Differential; Diet; Humans; Infant; Leucovorin; Phenylalanine Hydroxylase; Phenylketonurias; Pterins

Topics: Animals; Ascorbic Acid; Biopterins; Child, Preschool; Humans; Hydroxocobalamin; In Vitro Techniques; Infant; Leucovorin; Male; NADH, NADPH Oxidoreductases; Phenylketonurias; Rats; Tetrahydrofolates

Topics: Adolescent; Child; Female; Folic Acid; Humans; Lactates; Leucovorin; Male; Mixed Function Oxygenases; Phenylalanine; Phenylketonurias; Phenylpyruvic Acids; Urine