Wisniewski K E, Kida E, Connell F, Zhong N
Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314, USA.
Neurol Sci. 2000;21(3 Suppl):S49-56. doi: 10.1007/s100720070040.
This study describes the phenotype/genotype analysis of 159 probands with neuronal ceroid lipofuscinosis (37 CLN1, 72 classic CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR). Phenotype/genotype comparison showed that mutations in the CLN1 gene were associated with different phenotypes: infantile, late infantile, and juvenile. Two common mutations (223A-->C and 451C-->T) were found in 26 of 37 CLN1 subjects (64% of alleles examined). A nonsense point mutation, 451C-->T, was the most common in CLN1 subjects with infantile onset at 0-2 years, accounting for 50% of alleles studied. A missense point mutation, 223A-->C, was the most common among CLN1 subjects with juvenile onset older than 4 years, accounting for 45% of alleles examined. Twenty-one other CLN1 mutations were identified in 4 of 37 subjects with infantile onset, 6 of 37 with late-infantile onset, and 6 of 37 with juvenile onset. All CLN1 probands were palmitoyl-protein thioesterase (PPT)-deficient and showed granular osmiophilic deposits (GROD) at the electron microscopic (EM) level. In the group of classic CLN2 (72 probands), two common mutations were found: an intronic 3556G-->C transversion in the invariant AG of 3' splice junction in 55% of probands, and a nonsense mutation 3670C-->T in 30% of probands. Classic late-infantile onset (2-4 years) was found in 68 of 72 (95%) cases, whereas juvenile onset (> 4 years) occurred only in 4 of 72 (5%) cases. All probands had deficiency of tripeptidyl-peptidase I (TPP1) activity and, at the EM level, curvilinear profiles. Ten probands with late-infantile onset did not show mutations in the CLN2 gene, had normal TPP1 activity, and at the EM level had mixed profiles. Further studies are in progress to identify genetic defect(s) in these subjects. The CLN3 group (40 probands) was divided into two categories: classic or typical presentation, and delayed classic or atypical presentation. All CLN3 patients had onset of symptoms after 4 years of age. In 40 probands, the 1.02-kb common deletion was found in one or two alleles of the CLN3 gene. Homozygotes for the common CLN3 deletion showed the classic phenotype. The phenotype in compound heterozygotes was either the classic or the delayed classic or atypical form. Thus, our study indicates that some mutations in the CLN1 and CLN2 genes may be associated with juvenile onset of the disease process and a more benign clinical course. Interfamilial and intrafamilial variations also were found, especially in the speed of becoming blind and neurologically disabled.
本研究描述了在纽约州发育障碍基础研究所以色列（IBR）收集的159例神经元蜡样脂褐质沉积症先证者（37例CLN1、72例经典CLN2、10例变异型LINCL和40例CLN3）的表型/基因型分析。表型/基因型比较显示，CLN1基因突变与不同表型相关：婴儿型、晚婴儿型和青少年型。在37例CLN1受试者中的26例（所检测等位基因的64%）发现了两个常见突变（223A→C和451C→T）。无义点突变451C→T在0至2岁婴儿期起病的CLN1受试者中最为常见，占所研究等位基因的50%。错义点突变223A→C在4岁以上青少年期起病的CLN1受试者中最为常见；占所检测等位基因的45%。在37例婴儿期起病的受试者中的4例、37例晚婴儿期起病的受试者中的6例和37例青少年期起病的受试者中的6例中鉴定出另外21种CLN1突变。所有CLN1先证者均缺乏棕榈酰蛋白硫酯酶（PPT），并在电子显微镜（EM）水平显示嗜锇颗粒沉积（GROD）。在经典CLN2组（72例先证者）中，发现了两个常见突变：55%的先证者在3'剪接位点的不变AG中有内含子3556G→C颠换，30%的先证者有3670C→T无义突变。72例中的68例（95%）出现经典晚婴儿期起病（2至4岁），而72例中仅4例（5%）出现青少年期起病（>4岁）。所有先证者均缺乏三肽基肽酶I（TPP1）活性，在EM水平呈曲线状形态。10例晚婴儿期起病的先证者未显示CLN2基因突变，TPP1活性正常，在EM水平呈混合形态。正在进行进一步研究以确定这些受试者的基因缺陷。CLN3组（40例先证者）分为两类：经典或典型表现，以及延迟经典或非典型表现。所有CLN3患者在4岁以后出现症状。在40例先证者中，在CLN3基因的一个或两个等位基因中发现了1.02 kb的常见缺失。常见CLN3缺失的纯合子表现出经典表型。复合杂合子的表型为经典型、延迟经典型或非典型型。因此，我们的研究表明，CLN1和CLN2基因中的一些突变可能与疾病过程的青少年期起病和更良性的临床病程相关。还发现了家族间和家族内的变异，尤其是在失明和神经功能障碍的发展速度方面。
