Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain)

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations/deletions in the GCH1 gene. The finding of the mutation Q89X in the GCH1 gene in 23 patients from two pedigrees in an are...

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Bibliographic Details
Published in:Journal of neurology 2009-11, Vol.256 (11), p.1816-1824
Main Authors: López-Laso, Eduardo, Ochoa-Sepúlveda, Juan José, Ochoa-Amor, Juan José, Bescansa-Heredero, Enrique, Camino-León, Rafael, Gascón-Jiménez, Francisco Javier, Mateos-González, Maria Elena, Pérez-Navero, Juan Luis, Lao-Villadóniga, José Ignacio, Ormazabal, Aida, Artuch, Rafael, Beyer, Katrin
Format: Article
Language:English
Subjects:
Adult
Aged
Asymptomatic
Biological and medical sciences
Child
Child development
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
DNA Mutational Analysis
Dyskinesia
Dystonia
Dystonic Disorders - genetics
Dystonic Disorders - physiopathology
Family Health
Female
Founder Effect
Gait
Glutamine - genetics
GTP Cyclohydrolase - genetics
Haplotypes
Humans
Male
Medical sciences
Medicine
Medicine & Public Health
Microsatellite Repeats - genetics
Middle Aged
Mutation
Neurologic Examination - methods
Neurology
Neuroradiology
Neurosciences
Original Communication
Patients
Polymorphism, Single-Stranded Conformational - genetics
Spain
Walking
Young Adult
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Summary:Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency is an inborn error of neurotransmitter metabolism, with a prevalence of 0.5 per million, caused by mutations/deletions in the GCH1 gene. The finding of the mutation Q89X in the GCH1 gene in 23 patients from two pedigrees in an area inhabited by a population of 800,000 prompted us to consider that our cohort may have descended from a single founder. Twelve Q89X mutation-positive cases belonging to two families and 100 unrelated control subjects from the same geographical region were studied. Six microsatellite markers located near GCH1 were analyzed to validate a possible mutation-related founder haplotype. Haplotype analysis revealed two different haplotypes for six microsatellite markers that segregated with the Q89X mutation. A common haplotype in 10 out of 12 mutation carriers studied was identified. Two subjects carried a second haplotype, most probably because of a recombination event. However, at least 186 different haplotypes were established in the control subjects. In contrast with the frequencies of 83.3% and 16.7%, respectively, found for both mutation-segregating haplotypes, the frequency of none of the control haplotypes exceeded 1.5%. Dystonia was the most frequent symptom in our series, and parkinsonism was present in five patients. The large number of Q89X mutation carriers in our community is because of a founder effect. The same mutation in GCH1 causes a wide phenotypic spectrum of clinical variability occurring in this population of affected patients.
ISSN:0340-5354
1432-1459
DOI:10.1007/s00415-009-5198-z