5-methyltetrahydrofolate and Syndrome

Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the first rate-limiting step of serotonin biosynthesis by converting l-tryptophan to 5-hydroxytryptophan. Serotonin controls multiple vegetative functions and modulates sensory and alpha-motor neurons at the spinal level. We report on five boys with floppiness in infancy followed by motor delay, development of a hypotonic-ataxic syndrome, learning disability, and short attention span. Cerebrospinal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end-metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched median values. In one out of five patients a low CSF 5-methyltetrahydrofolate (MTHF) was present probably due to the common C677T heterozygous mutation of the methylenetetrahydrofolate reductase (MTHFR) gene. Baseline 24-h urinary excretion showed diminished 5HIAA values, not changing after a single oral load with l-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryptophan administration (1 mg/kg). Treatment with 5-hydroxytryptophan (4-6 mg/kg) and carbidopa (0.5-1.0 mg/kg) resulted in clinical amelioration and normalization of 5HIAA levels in CSF and urine. In the patient with additional MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G529A) of the TPH gene caused an exchange of valine by isoleucine at codon 177 (V177I). This has been interpreted as a rare DNA variant because the pedigree analysis did not provide any genotype-phenotype correlation. In the other four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptophan and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivating the TPH enzyme, or selective loss of serotonergic neurons.

Topics: 5-Hydroxytryptophan; Abnormalities, Multiple; Carbidopa; Child; Child, Preschool; Developmental Disabilities; DNA; DNA Mutational Analysis; Drug Therapy, Combination; Follow-Up Studies; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Infant; Learning Disabilities; Male; Methylenetetrahydrofolate Reductase (NADPH2); Mutation, Missense; Oxidoreductases Acting on CH-NH Group Donors; Syndrome; Tetrahydrofolates; Treatment Outcome; Tryptophan Hydroxylase

Cerebral folate deficiency (CFD) is increasingly recognized in various neurological conditions, raising the question of whether it might represent a clear-cut clinical syndrome.. Retrospective analysis of patients with low cerebral spinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) values was performed.. 58 pediatric patients with low (-2nd to -3rd standard deviation) and 45 patients with very low 5MTHF values (<3rd standard deviation) were identified, including 22 patients with defined underlying neurological conditions. The leading symptoms were mental retardation (n=84), motor retardation (n=75), epilepsy (n=53), ataxia (n=44) and pyramidal tract signs (n=37). There was no relationship between 5MTHF levels and the severity of clinical disease, the duration of clinical disease, distinct neurological symptoms and antiepileptic drug treatment, respectively. Genetical analysis for mutations in the folate receptor 1 gene proved normal in all 16 children studied.. For the majority of patients CFD is not a clear-cut neurometabolic syndrome but the common result of different genetic, metabolic or unknown processes. Nevertheless, CFD may represent a treatable disease-modifying factor which should therefore be addressed in prospective studies.

Topics: Abnormalities, Multiple; Adolescent; Ataxia; Child; Child, Preschool; Epilepsy; Female; Folic Acid Deficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pyramidal Tracts; Retrospective Studies; Syndrome; Tetrahydrofolates; Young Adult

Topics: Antiparkinson Agents; Atrophy; Basal Ganglia; Brain Diseases, Metabolic; Carbidopa; Cerebellum; Demyelinating Diseases; Dystonia; Female; Folic Acid Deficiency; Humans; Leucovorin; Levodopa; Male; Syndrome; Tetrahydrofolates; Treatment Outcome; Vitamin B Complex