戈谢病Ⅲ型同胞患儿临床及GBA基因突变分析

Clinical features and GBA gene mutation in two siblings with type Ⅲ Gaucher disease

目的探讨戈谢病Ⅲ型的临床表现、脑电图特点及致病基因突变。方法分析戈谢病Ⅲ型-家系中姐弟2例同胞患儿的临床资料,以及采用PCR-直接测序方法检测的患儿及其父母外周血白细胞β-葡糖苷酶GBA基因结果。结果先证者,弟弟,9岁,肝脾显著肿大,血小板减少(68×109/L),无神经系统症状,智力、运动正常,脑电图异常,醒睡各期广泛性中低波幅棘慢波、多棘慢波频繁阵发,清醒期放电明显。白细胞β-葡糖苷酶活性显著降低(1.5 nmol·h-1·mg-1Pr),符合戈谢病Ⅲ型。姐姐,12岁,自7岁起反复癫痫发作,呈强直阵挛、肌阵挛表现,多种抗癫痫药物治疗效果差,伴语言、智力、运动倒退,病情进行性加重,肝肋下2.5 cm,脾脏无肿大,脑电图显示多灶异常放电,并频繁泛化全导,白细胞β-葡糖苷酶活性亦显著降低(1.8 nmol·h-1·mg-1 Pr)。两例患儿的GBA基因突变相同,为c.680A>G(p.N188S)/c.1342G>C(p.D409H),分别来自其父母。结论两例同胞患儿具有相同的基因突变,但临床表现差异显著,可能随着病情进展症状加重。戈谢病Ⅲ型为慢性神经病变型,以神经系统症状如癫痫发作、肌阵挛等为主要表现起病,肝脾肿大及脾功能亢进可不显著。

Objective To report clinical manifestations, electroencephalogram（EEG）, and the genotypes of two siblings with type Ⅲ Gaucher disease. Methods Two patients with different features were siblings. Their clinical data, signs, peripheral leukocytes acid β-glucosidase activity, and GBA gene were analyzed. Results（1） The proband was a boy. He visited us at the age of nine years old because of hepatosplenomegaly, thrombocytopenia and growth retardation without any neurologic symptoms. He had normal intelligence but abnormal EEG findings. The activity of acid β-glucosidase in his leucocytes decreased to 1.5 nmol h^-1·mg^-1 Pr（normal range 6.0-16.7 nmol h^-1·mg^-1 Pr）, supporting the diagnosis of type Ⅲ Gaucher disease.（2） The elder sister of the proband was 12 years old. She had tonic-clonic seizure and myoclonus seizure from the age of seven years old. Mild hepatomegaly, abnormal EEG, poor effect for antiepileptics, and progressive deterioration of psychomotor abilities were found. Her blood leucocytes acid β-glucosidase activity decreased to 1.8 nmol h^-1·mg^-1 Pr（normal range 6.0-16.7 nmol h^-1·mg^-1 Pr）. Two heterozygous missense mutations, c.680A〉G,（p.N188S） and c.1342G〉C（p.D409H） were detected from the two siblings, respectively. Conclusions Patients with type Ⅲ Gaucher disease usually have the onset in childhood with typical features of Gaucher disease without neurologic involvement. Abnormal EEG may be helpful to the differential diagnosis of type I or type Ⅲ. On the other hand, neurologic manifestations could be presented as the first symptom in some patients without viscera enlargement. The patients of type Ⅲ Gaucher disease with the same genotype could have different phenotypes, even between the siblings.