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.

Neuropsychiatric symptoms and intelligence quotient in autosomal dominant Segawa disease

“…Clinical neurophysiological studies have revealed the heterogeneity of pathophysiologies of this disorder [25]. We consider that the families investigated (family A and family B) belong to the action dystonia type, due to the presentation of some patients of family A during adulthood with focal dystonia and parkinsonism (data not shown) [19], though there was marked variation in the age at onset of symptoms. Furthermore, this was supported because the side predominance of the hypertonus between the sternocleidomastoideus and the muscles of the extremities was ipsilateral in all the cases in which this information was available (patients V-6, V-7, VI-8, and VI-10 of family A; and patients II-2 and III-2 of family B), and the response to levodopa of the action dystonia was sometimes not complete (patient V-6 of family A; and patient III-2 of family B).…”

“…A large number of GCH1 gene mutation carriers were detected in our community due to a possible founder effect, as described elsewhere [19]. The same mutation in GCH1 causes a wide phenotypic spectrum of clinical variability occurring in this population of affected patients.…”

“…1). In this pedigree, 17 individuals harboring the mutation Q89X in exon 1 of GCH1 in heterozygosity have been identified [19]. Twelve carriers and patients with this mutation underwent the IQ and neuropsychiatric symptoms assessment.…”

“…Clinical details of 12 of these patients belonging to the same family have been described elsewhere [19]. A history combined with a neurological examination was performed in all subjects by one adult neurologist or by one pediatric neurologist before biochemical and molecular analysis.…”

Clinical Features and Pharmacotherapy of Childhood Monoamine Neurotransmitter Disorders

“…The mechanism of action is likely to be a central antimuscarinic effect [73]. It is frequently used in AADC deficiency and also sometimes in the management of GCH deficiency, especially for those who have experienced l -dopa-related dyskinesia [17, 26, 74, 75]. The side effects are dose related and include drowsiness, confusion, hallucinations, urinary retention, constipation, dry secretions, anorexia, confusion, and psychosis [75].…”