A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.
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.
Ramaekers
V T
VT
Division of Paediatric Neurology, Department of Pediatrics, University Hospital Aachen, 52074 Aachen, Germany. vramaekers@post.klinikum.rwth-aachen.de
Senderek
J
J
Häusler
M
M
Häring
M
M
Abeling
N
N
Zerres
K
K
Bergmann
C
C
Heimann
G
G
Blau
N
N
D006916:5-Hydroxytryptophan / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D000015:Abnormalities, Multiple / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002230:Carbidopa / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000473:pathology*; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D007223:Infant; D007859:Learning Disabilities / Q000473:pathology*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D020125:Mutation, Missense; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics; D013577:Syndrome; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D014365:Tryptophan Hydroxylase / Q000235:genetics
D013763:Tetrahydrofolates; D006897:Hydroxyindoleacetic Acid; D004247:DNA; D006916:5-Hydroxytryptophan; D014365:Tryptophan Hydroxylase; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002230:Carbidopa; C005984:5-methyltetrahydrofolate; D006719:Homovanillic Acid