5-methyltetrahydrofolate and Developmental-Disabilities

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

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Topics: Atrophy; Brain; Brain Diseases, Metabolic, Inborn; Child Development Disorders, Pervasive; Child, Preschool; Consanguinity; Developmental Disabilities; Early Diagnosis; Electroencephalography; Epilepsies, Myoclonic; Female; Folate Receptor 1; Folic Acid Deficiency; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Mutation, Missense; Point Mutation; Pyridoxine; Siblings; Tetrahydrofolates

We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.

Topics: Adolescent; Autistic Disorder; Brain; Child; Child, Preschool; Developmental Disabilities; Dyskinesias; Epilepsy; Female; Folic Acid; Folic Acid Deficiency; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Pregnancy; Psychomotor Disorders; Reference Values; Regression, Psychology; Tetrahydrofolates

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

Topics: Adaptation, Physiological; Autistic Disorder; Cerebral Cortex; Child; Developmental Disabilities; Disease Progression; Female; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intellectual Disability; Leucovorin; Mutation; Recovery of Function; Reduced Folate Carrier Protein; Seizures; Tetrahydrofolates; Transcription Factors; Treatment Outcome