Rozenberg R, Kok F, Burin M G, Sá Miranda M C, Vasques C, Henriques-Souza A M M, Giugliani R, Vainzof Mariz, Pereira L V
Centro de Estudos do Genoma Humano, Instituto de Biociências, Depto. Biologia/Genética, Universidade de São Paulo, Rua do Matão, Travessa 13 no. 106, CEP 05508-900 São Paulo-SP, Brazil.
J Child Neurol. 2006 Jun;21(6):540-4. doi: 10.1177/08830738060210061101.
Molecular analysis of five Brazilian families, including eight patients presenting with nonclassic Tay-Sachs disease, was performed to identify frequent causative mutations and their correlation with clinical course. Three patients were affected by the B1 subacute variant and were shown to carry the R178H mutation (the DN allele), which is also common among Portuguese patients. Two of them were compound heterozygotes, whereas the third presented with the mutation in both alleles. Since Brazil was a Portuguese colony for over two centuries, common ancestry might be the probable explanation. The fourth patient presented with a juvenile phenotype and carries the R499H mutation, which has been reported only once worldwide and is associated with residual enzyme activity, responsible for a slower clinical course. The fifth family, of an Ashkenazi Jewish background, showed an extensive intrafamilial clinical variability among three affected sibs presenting with muscle atrophy, ataxia, and psychiatric symptoms. They were first diagnosed as having atypical spinal muscular atrophy and, subsequently, spinocerebellar ataxia, but, recently, the diagnosis of late-onset Tay-Sachs disease was confirmed based on reduced plasma hexosaminidase A activity and the G269S/InsTATC1278 genotype. It is therefore highly recommended to test patients with a similar clinical history for Tay-Sachs disease. In the same family, one first cousin committed suicide at the age of 24 years, presenting with a clinical phenotype that suggested an undiagnosed case and highlighting the effect of the intrafamilial clinical variability in delaying a prompt diagnosis. It is now recognized that his parents are, in fact, a carrier couple. Additionally, another relative had been previously identified as a heterozygote in a Tay-Sachs disease screening program, but the information was not shared among the family. Since this information might anticipate diagnosis and genetic counseling, it is advisable that heterozygote screening programs encourage families to share genetic information.
对五个巴西家庭进行了分子分析，其中包括八名患有非典型泰-萨克斯病的患者，以确定常见的致病突变及其与临床病程的相关性。三名患者受B1亚急性变异型影响，被证明携带R178H突变（DN等位基因），该突变在葡萄牙患者中也很常见。其中两名是复合杂合子，而第三名患者两个等位基因均存在该突变。由于巴西曾是葡萄牙殖民地两个多世纪，共同的祖先可能是合理的解释。第四名患者表现为青少年型表型，携带R499H突变，该突变在全球仅报道过一次，与残余酶活性相关，导致临床病程较慢。第五个家庭具有阿什肯纳兹犹太背景，在三名受影响的同胞中表现出广泛的家族内临床变异性，这些同胞出现肌肉萎缩、共济失调和精神症状。他们最初被诊断为非典型脊髓性肌萎缩症，随后又被诊断为脊髓小脑共济失调，但最近根据血浆己糖胺酶A活性降低和G269S/InsTATC1278基因型确诊为迟发性泰-萨克斯病。因此，强烈建议对有类似临床病史的患者进行泰-萨克斯病检测。在同一个家庭中，一名一级表亲在24岁时自杀，其临床表型提示有未确诊病例，突出了家族内临床变异性对延迟及时诊断的影响。现在认识到他的父母实际上是携带者夫妇。此外，另一名亲属此前在泰-萨克斯病筛查项目中被确定为杂合子，但该信息未在家族中共享。由于这些信息可能有助于早期诊断和遗传咨询，杂合子筛查项目建议鼓励家族共享遗传信息。
