Institute for Human Genetics, University Clinic Freiburg, Freiburg, Germany.
Eur J Hum Genet. 2010 Oct;18(10):1100-6. doi: 10.1038/ejhg.2010.79. Epub 2010 May 26.
Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.
沃伯格微综合征是一种罕见的常染色体隐性遗传综合征，其特征为小头畸形、小眼球、小角膜、先天性白内障、视神经萎缩、皮质发育不良，特别是胼胝体发育不全、严重智力障碍、痉挛性双瘫和性腺功能减退。我们在七个疑似微综合征患者中发现了五个新的 RAB3GAP1 基因突变，这些患者来自土耳其、巴勒斯坦、丹麦和危地马拉的家庭。对患者进行全面的临床调查，有助于确定微综合征患者的一致症状，以便将来对微综合征患者进行鉴别诊断。所有患者均有出生后小头畸形、小眼球、小角膜、双侧先天性白内障、短睑裂、视神经萎缩、严重智力障碍和先天性低张力，随后出现痉挛性瘫痪。只有一名患者出生时即有小头畸形，这突出表明先天性小头畸形并非微综合征的一致特征。大脑磁共振成像（MRI）分析显示额顶叶多小脑回、宽大脑裂、胼胝体发育不全且薄、硬脑膜下间隙增宽的一致模式。所有患者均为检测到的突变纯合子，所有突变均预测导致 RAB3GAP1 蛋白截短。对 RAB3GAP1 基因侧翼的九个多态性标记的分析表明，丹麦患者纯合的突变 c.1410C>A（p.Tyr470X）位于与患者无关的杂合父母共有的单倍型上。这表明该突变在丹麦人群中可能存在一个共同的起源。
