Neudorfer Orit, Pastores Gregory M, Zeng Bai J, Gianutsos John, Zaroff Charles M, Kolodny Edwin H
Division of Neurogenetics, Department of Neurology, New York University School of Medicine, New York, NY, USA.
Genet Med. 2005 Feb;7(2):119-23. doi: 10.1097/01.gim.0000154300.84107.75.
The purpose of this study was to describe the phenotype (and corresponding genotype) of adult patients with late-onset Tay-Sachs disease, a clinical variant of the GM2-gangliosidoses.
A comprehensive physical examination, including neurological assessments, was performed to establish the current disease pattern and severity. In addition, the patients' past medical histories were reviewed. The patients' alpha-subunit mutations (beta-Hexosaminidase A genotype) were determined and correlated with their corresponding clinical findings and disease course.
Twenty-one patients (current mean age: 27.0 years; range: 14-47 years) were identified. The pedigree revealed a relative with the "classic" infantile or late-onset form of Tay-Sachs disease in four (out of 18) unrelated families. The patients were predominantly male (15/21 individuals) and of Ashkenazi Jewish ancestry (15/18 families). Mean age at onset was 18.1 years; balance problems and difficulty climbing stairs were the most frequent presenting complaints. In several cases, the diagnosis was delayed (mean age at diagnosis: 27.0 years). Analysis of the beta-hex A gene revealed the G269S mutation as the most common disease allele; found in homozygosity (N = 1) or heterozygosity (N = 18; including 2 sib pairs). Disease onset (age 36 years) was delayed and progression relatively slower in the homozygous G269S patient. Two siblings (ages 28 and 31 years), of non-Jewish ancestry, were compound heterozygotes (TATC1278/W474C); their clinical course is dominated by psychiatric problems. Brain imaging studies revealed marked cerebellar atrophy in all patients (N = 18) tested, regardless of disease stage.
Late-onset Tay-Sachs disease is an infrequent disorder and the diagnosis is often missed or delayed (by approximately 8 years). Early on, the majority of patients develop signs of either cerebellar or anterior motor neuron involvement. Affected individuals may also develop psychotic episodes. In most cases, the later-onset of expression results from the presence of at least one allele (usually the G269S mutation), associated with residual enzyme (beta-hexosaminidase A) activity. A positive family history is a valuable clue, enabling early diagnosis. Nonspecific cerebellar atrophy on brain imaging is another important finding. This entity should be considered among patients presenting with speech, gait, and balance problems, and those with psychiatric disorders even when focal neurologic deficits may be initially absent. Accurate diagnosis will permit appropriate genetic counseling regarding disease prognosis and reproductive risks.
本研究旨在描述成人迟发性泰-萨克斯病（GM2神经节苷脂贮积症的一种临床变异型）的表型（及相应基因型）。
进行全面的体格检查，包括神经学评估，以确定当前的疾病模式和严重程度。此外，回顾了患者的既往病史。确定患者的α亚基突变（β-己糖胺酶A基因型），并将其与相应的临床发现和病程相关联。
共识别出21例患者（当前平均年龄：27.0岁；范围：14 - 47岁）。家系分析显示，在18个无关家庭中的4个家庭有亲属患“经典”婴儿型或迟发性泰-萨克斯病。患者以男性为主（15/21），且多为阿什肯纳兹犹太裔（15/18家庭）。发病平均年龄为18.1岁；平衡问题和爬楼梯困难是最常见的主诉。在几例病例中，诊断被延迟（诊断时平均年龄：27.0岁）。β-己糖胺酶A基因分析显示，G269S突变是最常见的致病等位基因；在纯合子（N = 1）或杂合子（N = 18；包括2对同胞）中发现。纯合G269S患者发病延迟（36岁），病情进展相对较慢。两名非犹太裔同胞（年龄分别为28岁和31岁）为复合杂合子（TATC1278/W474C）；他们的临床病程以精神问题为主。脑部影像学研究显示，所有接受检测的患者（N = 18）均有明显的小脑萎缩，无论疾病处于何阶段。
迟发性泰-萨克斯病是一种罕见疾病，诊断常被漏诊或延迟（约8年）。早期，大多数患者会出现小脑或前运动神经元受累的体征。患者也可能出现精神病发作。在大多数情况下，发病较晚是由于至少存在一个与残余酶（β-己糖胺酶A）活性相关的等位基因（通常是G269S突变）。阳性家族史是一个有价值的线索，有助于早期诊断。脑部影像学上非特异性的小脑萎缩是另一重要发现。对于出现言语、步态和平衡问题的患者，以及那些有精神障碍的患者，即使最初可能没有局灶性神经功能缺损，也应考虑到这种疾病。准确的诊断将有助于就疾病预后和生殖风险进行适当的遗传咨询。
