title: Segawa syndrome due to mutation Q89X in the GCH1 gene: a possible founder effect in Córdoba (southern Spain).
abstract: 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.
authors.affiliation: Pediatric Neurology Unit, Department of Pediatrics, University Hospital Reina Sofia, University of Córdoba, Av. Menéndez Pidal s/n, 14004 Córdoba, Spain. elolaso@gmail.com
authors.forename: Eduardo
authors.initials: E
authors.lastname: López-Laso
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ochoa-Sepúlveda
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ochoa-Amor
authors.forename: Enrique
authors.initials: E
authors.lastname: Bescansa-Heredero
authors.forename: Rafael
authors.initials: R
authors.lastname: Camino-León
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gascón-Jiménez
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Mateos-González
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Pérez-Navero
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Lao-Villadóniga
authors.forename: Aida
authors.initials: A
authors.lastname: Ormazabal
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.forename: Katrin
authors.initials: K
authors.lastname: Beyer
mesh_terms: D000328:Adult; D000368:Aged; D002648:Child; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics* / Q000503:physiopathology; D005192:Family Health; D005260:Female; D018703:Founder Effect; D006136:GTP Cyclohydrolase / Q000235:genetics*; D005973:Glutamine / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D009460:Neurologic Examination / Q000379:methods; D018807:Polymorphism, Single-Stranded Conformational / Q000235:genetics*; D013030:Spain; D055815:Young Adult
chemical_list: D005973:Glutamine; D006136:GTP Cyclohydrolase