一个X-连锁肾上腺脑白质营养不良家系的临床特征及致病基因分析

Clinical features and genetic mutation analysis in a family of X-linked adrenoleukodystrophy

目的对1例以肾上腺皮质功能减低症起病的X-连锁肾上腺脑白质营养不良(X-ALD)患儿及其家系的临床特征、ATP结合盒转运子超家族成员D1(ABCD1)基因突变进行分析。方法纳入1个2代中有2例发病的汉族X-ALD家系,收集该患者家系成员的临床资料,并运用二代测序技术对先证者及其父母、弟弟行ABCD1基因测序分析。结果2例发病患儿均为男性,先证者表现为原发性肾上腺皮质功能减退和神经系统功能异常,大脑白质广泛脱髓鞘改变,血极长链脂肪酸浓度明显升高。先证者弟弟2岁10个月时出现原发性肾上腺皮质功能减低症状,目前无神经系统症状。先证者及其弟弟基因测序结果均显示:ABCD1基因第7号外显子区域(Exon7)存在c.1666C>T杂合突变,经家系验证,该突变遗传自其母亲。结论ABCDl基因c.1666C>T突变可导致肾上腺脑白质营养不良,原发性肾上腺皮质功能减退和神经系统异常为X-ALD典型临床表现。

Objective To analyze the clinical features of a kindred of X-linked adrenoleukodystrophy(X-ALD)with the onset of primary adrenocortical insufficiency,and to detect the mutation of ATP-binding cassette,sub-family D,member l(ABCD1)gene.Methods A Chinese X-ALD kindred with two affected males from two-generations was studied.The clinical data of the proband′s family members were collected.The sequences of ABCD1 of the proband,his parent and young brother were detected by next-generation sequencing.X-ALD was diagnosed according to clinical manifestations,cranial MRI image,and serum level of very long chain fatty acid(VLCFA).Results The two cases were all males.The proband was characteristic of primary adrenocortical insufficiency and neurological dysfunction,with extensive cerebral white matter demyelination and high serum VLCFA level.At the age of 2 years and 10 months,the younger brother of the proband presented with primary adrenocortical dysfunction,without neurological symptoms.Gene sequencing results of two patients showed a novel missense substitution(c.1666C>T)in exon 7 of ABCD1 inherited from their mother.Conclusion The new mutation of ABCDl gene c.1666C>T may lead to adrenoleukodystrophy.Primary adrenocortical insufficiency and neurological dysfunction are the typical manifestations of X-ALD.