Crow Yanick J
Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France
Manchester Centre for Genomic Medicine, University of Manchester, Manchester, United Kingdom
Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known.
DIAGNOSIS/TESTING: The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes); AND/OR by identification of one of the following: Biallelic pathogenic variants in , , , , , or Specific heterozygous autosomal dominant pathogenic variants in and A variety of heterozygous autosomal dominant pathogenic variants in
Chest physiotherapy and treatment of respiratory complications; attention to diet and feeding methods to assure adequate caloric intake and avoid aspiration; management of seizures using standard protocols. Monitoring for signs of diabetes insipidus in the neonatal period; repeat ophthalmologic examinations at least for the first few years of life to evaluate for evidence of glaucoma; monitoring for evidence of scoliosis, insulin-dependent diabetes mellitus, and hypothyroidism.
AGS is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific or inherited autosomal dominant pathogenic variants in or , and a variety of heterozygous autosomal dominant pathogenic variants in . At conception, each sib of an affected individual with autosomal recessive AGS has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Individuals with AGS do not typically reproduce. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk for AGS, and preimplantation genetic testing are possible.
最典型的是，艾卡迪 - 古铁雷斯综合征（AGS）表现为早发性脑病，通常（但并非总是）导致严重的智力和身体残疾。一部分患有AGS的婴儿出生时就有异常的神经系统表现、肝脾肿大、肝酶升高和血小板减少，这一情况高度提示先天性感染。否则，大多数受影响的婴儿在出生后几周的不同时间出现症状，通常是在一段明显正常的发育阶段之后。典型情况下，他们会出现严重脑病的亚急性发作，其特征为极度易激惹、间歇性无菌性发热、技能丧失和头围生长减缓。随着时间推移，多达40%的患者会在手指、脚趾和耳朵出现冻疮样皮肤病变。越来越明显的是，存在非典型的、有时症状较轻的AGS病例，因此与AGS相关基因的致病变异相关的真实表型范围尚不清楚。
诊断/检测：AGS的诊断在具有典型临床症状以及头颅CT（基底节和白质钙化）和MRI（脑白质营养不良性改变）特征性异常的先证者中得以确立；和/或通过识别以下情况之一：在 、 、 、 、 或 中存在双等位基因致病变异；在 和 中存在特定的杂合常染色体显性致病变异；在 中存在多种杂合常染色体显性致病变异。
胸部物理治疗和呼吸并发症的治疗；注意饮食和喂养方法以确保足够的热量摄入并避免误吸；使用标准方案管理癫痫发作。在新生儿期监测尿崩症迹象；至少在生命的头几年重复进行眼科检查以评估青光眼证据；监测脊柱侧弯、胰岛素依赖型糖尿病和甲状腺功能减退的证据。
AGS最常以常染色体隐性方式遗传；在少数情况下，该疾病可由 或 中的特定 或遗传常染色体显性致病变异以及 中的多种杂合常染色体显性致病变异引起。在受孕时，常染色体隐性AGS患者的每个同胞有25%的几率患病，50%的几率为无症状携带者，25%的几率未患病且不是携带者。患有AGS的个体通常不生育。一旦在受影响的家庭成员中确定了致病变异，就可以对有风险的亲属进行携带者检测、对AGS风险增加的妊娠进行产前检测以及进行植入前基因检测。
