PDF(Pubmed)
Abstract：
Alexander disease (AxD) is a rare inherited autosomal dominant (AD) disease with different clinical phenotypes according to the age of onset. It is caused by mutations in the glial fibrillary acid protein (GFAP) gene, which causes GFAP accumulation in astrocytes. A wide spectrum of mutations has been described. For some variants, genotype-phenotype correlations have been described, although variable expressivity has also been reported in late-onset cases among members of the same family. We present the case of a 19-year-old girl who developed gait ataxia and subtle involuntary movements, preceded by a history of enuresis and severe scoliosis. Her mother has been affected by ataxia since her childhood, which was then complicated by pyramidal signs and heavily worsened through the years. Beyond her mother, no other known relatives suffered from neurologic syndromes. The scenario was further complicated by a complex brain and spinal cord magnetic resonance imaging (MRI) pattern in both mother and daughter. However, the similar clinical phenotype made an inherited cause highly probable. Both AD and autosomal recessive (AR) ataxic syndromes were considered, lacking a part of the proband\'s pedigree, but no causative genetic alterations were found. Considering the strong suspicion for an inherited condition, we performed clinical exome sequencing (CES), which analyzes more than 4,500 genes associated with diseases. CES evidenced the new heterozygous missense variant c.260 T > A in exon 1 of the glial fibrillary acidic protein (GFAP) gene (NM_002055.4), which causes the valine to aspartate amino acid substitution at codon 87 (p. Val87Asp) in the GFAP. The same heterozygous variant was detected in her mother. This mutation has never been described before in the literature. This case should raise awareness for this rare and under-recognized disease in juvenile-adult cases.
摘要：
亚历山大病（AxD）是一种罕见的遗传性常染色体显性遗传（AD）疾病，根据发病年龄具有不同的临床表型。它是由胶质纤维酸性蛋白（GFAP）基因突变引起的，这导致GFAP在星形胶质细胞中积累。已经描述了广泛的突变。对于某些变体，已经描述了基因型-表型相关性，尽管在同一家族成员的迟发性病例中也有不同的表达能力。我们介绍了一个19岁女孩的案例，她出现了步态共济失调和微妙的不自主运动，之前有遗尿症和严重脊柱侧凸的病史。她的母亲从小就受到共济失调的影响，然后由于金字塔的迹象而变得复杂，多年来严重恶化。除了她的母亲，没有其他已知的亲属患有神经综合征。母亲和女儿的复杂的大脑和脊髓磁共振成像（MRI）模式使这种情况更加复杂。然而,相似的临床表型使遗传原因很可能。考虑了AD和常染色体隐性遗传（AR）共济失调综合征，缺少一部分先证者的血统，但没有发现致病基因改变。考虑到对遗传性疾病的强烈怀疑，我们进行了临床外显子组测序（CES），分析了4,500多个与疾病相关的基因。CES证明了神经胶质纤维酸性蛋白（GFAP）基因（NM_002055.4）外显子1的新杂合错义变异c.260T>A，这导致缬氨酸在密码子87处取代天冬氨酸氨基酸（p。Val87Asp）在GFAP中。在她的母亲中检测到相同的杂合变体。这种突变以前从未在文献中描述过。此病例应提高对这种罕见且未得到充分认可的疾病的认识。
