Article (Scientific journals)
A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.
RAMAEKERS, Vincent; Senderek, J.; Hausler, M. et al.
2001In Molecular Genetics and Metabolism, 73 (2), p. 179-87
Peer Reviewed verified by ORBi
 

Files


Full Text
A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.pdf
Publisher postprint (1.78 MB)
Request a copy

All documents in ORBi are protected by a user license.

Send to



Details



Keywords :
5-Hydroxytryptophan/cerebrospinal fluid/therapeutic use; Abnormalities, Multiple/drug therapy/genetics/pathology; Carbidopa/therapeutic use; Child; Child, Preschool; DNA/chemistry/genetics; DNA Mutational Analysis; Developmental Disabilities/pathology; Drug Therapy, Combination; Follow-Up Studies; Homovanillic Acid/cerebrospinal fluid; Humans; Hydroxyindoleacetic Acid/cerebrospinal fluid; Infant; Learning Disorders/pathology; Male; Methylenetetrahydrofolate Reductase (NADPH2); Mutation, Missense; Oxidoreductases Acting on CH-NH Group Donors/genetics; Syndrome; Tetrahydrofolates/cerebrospinal fluid; Treatment Outcome; Tryptophan Hydroxylase/genetics
Abstract :
[en] 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.
Disciplines :
Neurology
Pediatrics
Author, co-author :
RAMAEKERS, Vincent ;  University Hospital Aachen > Paediatrics > Paediatric Neurology
Senderek, J.;  University Hospital Aachen > Human Genetics
Hausler, M.;  University Hospital Aachen > Paediatrics > Paediatric Neurology
Haring, M.;  University Hospital Aachen > Clinical Chemistry
Abeling, N.;  Academic Medical Center Amsterdam, The Netherlands > Laboratory Genetic Metabolic Diseases
Zerres, K.;  University Hospital Aachen > Human Genetics
Bergmann, C.;  University Hospital Aachen > Human Genetics
Heimann, G.;  University Hospital Aachen > Paediatrics > Paediatric Neurology
Blau, N.;  University Children's Hospital, 8032 Zürich, Switzerland > Clinical Chemistry and Biochemistry
Language :
English
Title :
A novel neurodevelopmental syndrome responsive to 5-hydroxytryptophan and carbidopa.
Publication date :
July 2001
Journal title :
Molecular Genetics and Metabolism
ISSN :
1096-7192
eISSN :
1096-7206
Publisher :
Elsevier, Atlanta, Georgia
Volume :
73
Issue :
2
Pages :
179-87
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright 2001 Academic Press.
Available on ORBi :
since 07 June 2014

Statistics


Number of views
33 (0 by ULiège)
Number of downloads
0 (0 by ULiège)

Scopus citations®
 
19
Scopus citations®
without self-citations
16
OpenCitations
 
12

Bibliography


Similar publications



Contact ORBi