Department of Paediatrics, University Hospital Reina Sofia, University of Córdoba, Spain.
Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-U711), Santiago de Compostela, Spain.
Parkinsonism Relat Disord. 2022 Jan;94:67-78. doi: 10.1016/j.parkreldis.2021.11.014. Epub 2021 Nov 25.
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.
Clinical-genetic information were obtained from standardized questionnaires that were completed by the neurologists attending children and/or adults from 16 Spanish hospitals.
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.
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.
2009 年，我们描述了在西班牙科尔多瓦（西班牙）可能存在常染色体显性遗传 Segawa 病的起源效应，原因是 GCH1 基因中的突变 c.265C>T（p. Q89*）。我们进行了一项回顾性多中心研究，旨在提高我们对西班牙 Segawa 病的认识，并对患者进行详细的表型-基因型描述。
临床遗传信息是从由 16 家西班牙医院的神经科医生填写的标准化问卷中获得的。
80 名属于 24 个家系的患者携带 GCH1 的杂合突变。7 种遗传变异仅在我们的患者队列中被描述，其中 5 种是新的突变。由于可能的起源效应，在安达卢西亚发现了 5 个以前未描述的携带 p. Q89*的家族。诊断的中位潜伏期为 5 年（IQR 0-16）。最常见的体征和/或症状是下肢肌张力障碍（38/56，67.8%，p=0.008）和日间波动（38/56，67.8%，p=0.008）。除了肌张力障碍以外的表型没有日间波动。56 名有症状的患者中有 53 名接受了左旋多巴/脱羧酶抑制剂治疗（平均±SD，12.4±8.12 年），其中 81%的患者剂量低于 350mg/天（≤5mg/kg/d 在儿童中）。53 名有症状的患者中有 11 名（20%）的症状无反应，影响日常生活活动。运动障碍（4 例）是最突出的不良反应。
本研究鉴定了 5 种新的突变，并支持 p. Q89*在安达卢西亚起源效应的假说。为表型和长期治疗反应提供了新的见解，这可能有助于早期识别和治疗管理。
