A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa

Citation
Vt. Ramaekers et al., A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa, MOL GEN MET, 73(2), 2001, pp. 179-187
Citations number
37
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MOLECULAR GENETICS AND METABOLISM
ISSN journal
1096-7192 → ACNP
Volume
73
Issue
2
Year of publication
2001
Pages
179 - 187
Database
ISI
SICI code
1096-7192(200106)73:2<179:ANNSRT>2.0.ZU;2-D
Abstract
Tryptophan hydroxylase (TPH; EC 1.14.16.4) catalyzes the first rate-limitin g step of serotonin biosynthesis by converting L-tryptophan to 5-hydroxytry ptophan. Serotonin controls multiple vegetative functions and modulates sen sory and alpha-motor neurons at the spinal level. We report on five boys wi th floppiness in infancy followed by motor delay, development of a hypotoni c-ataxic syndrome, learning disability, and short attention span, Cerebrosp inal fluid (CSF) analysis showed a 51 to 65% reduction of the serotonin end -metabolite 5-hydroxyindoleacetic acid (5HIAA) compared to age-matched medi an 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 urinar y excretion showed diminished 5HIAA values, not changing after a single ora l load with L-tryptophan (50-70 mg/kg), but normalizing after 5-hydroxytryp tophan 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 no rmalization of 5HIAA levels in CSF and urine. In the patient with additiona l MTHFR heterozygosity, a heterozygous missense mutation within exon 6 (G52 9A) 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 pedig ree analysis did not provide any genotype-phenotype correlation. In the oth er four patients the TPH gene analysis was normal. In conclusion, this new neurodevelopmental syndrome responsive to treatment with 5-hydroxytryptopha n and carbidopa might result from an overall reduced capacity of serotonin production due to a TPH gene regulatory defect, unknown factors inactivatin g the TPH enzyme, or selective loss Of serotonergic neurons. (C) 2001 Acade mic Press.