Genetic landscape of Segawa disease in Spain. Long-term treatment outcomes
Autor
Fernández Ramos, Joaquín Alejandro
Torre‑Aguilar, M. J. de la
Quintáns, Beatriz
Pérez Navero, Juan Luis
Beyer, Katrin
López-Laso, Eduardo
Editor
ElsevierFecha
2021Materia
Dopa-responsive dystoniaAutosomal dominant Segawa disease
GCH1
GTPCH
Autosomal dominant GTPCH deficiency
Dystonia
Parkinsonism
Parkinson's disease
Levodopa
Dyskinesias
Founder mutation
Dopamine
METS:
Mostrar el registro METSPREMIS:
Mostrar el registro PREMISMetadatos
Mostrar el registro completo del ítemResumen
Introduction
In 2009, we described a possible founder effect of autosomal dominant Segawa disease in Córdoba (Spain) due to mutation c.265C>T (p. Q89*) in the GCH1 gene. We present a retrospective multicentre study aimed at improving our knowledge of Segawa disease in Spain and providing a detailed phenotypic-genotypic description of patients.
Methods
Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals.
Results
Eighty subjects belonging to 24 pedigrees had heterozygous mutations in GCH1. Seven genetic variants have been described only in our cohort of patients, 5 of which are novel mutations. Five families not previously described with p. Q89* were detected in Andalusia due to a possible founder effect. The median latency to diagnosis was 5 years (IQR 0–16). The most frequent signs and/or symptoms were lower limb dystonia (38/56, 67.8%, p = 0.008) and diurnal fluctuations (38/56, 67.8%, p = 0.008). Diurnal fluctuations were not present in the phenotypes other than dystonia. Fifty-three of 56 symptomatic patients were treated with a levodopa/decarboxylase inhibitor for (mean ± SD) 12.4 ± 8.12 years, with 81% at doses lower than 350 mg/day (≤5 mg/kg/d in children). Eleven of 53 (20%) patients had nonresponsive symptoms that affected daily life activities. Dyskinesias (4 subjects) were the most prominent adverse effects.
Conclusion
This study identifies 5 novel mutations and supports the hypothesis of a founder effect of p. Q89* in Andalusia. New insights are provided for the phenotypes and long-term treatment responses, which may improve early recognition and therapeutic management.
Descripción
Embargado hasta 12/02/2044