Wiśniewski K E, Zhong N, Kida E, Kaczmarski W, Kaczmarski A, Connell F, Brooks S S, Brown W T
Department of Pathological Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, USA.
Folia Neuropathol. 1997;35(2):73-9.
We have collected 122 late-infantile neuronal ceroid lipofuscinosis (LINCL, CLN2) and 191 juvenile NCL (JNCL, CLN3) cases, diagnosed on the basis of age-at-onset, clinical symptomatology, and pathological findings and representing the most common forms of NCL in the United States, and Europe. However, careful analysis of available data revealed that about 80% of cases show typical and 20% show atypical clinical course and/or pathological findings and thus, may represent variants of LINCL and JNCL, respectively. Recent progress in the biochemistry and molecular genetics of NCL inclined us to reevaluate these atypical NCL cases. The gene responsible for LINCL has not yet been identified, except for the Finnish variant. Accumulation of subunit c of mitochondrial ATP synthase, to curvilinear profiles, is found in LINCL cases. A novel variant of LINCL, with predominantly granular profiles in the lysosomal storage, as well as normal excretion of subunit c in urine samples, was found in five cases. When the palmitoyle-protein thioesterase (PPT) was studied in these five cases, it was found that the level was deficient, suggesting that they are not LINCL, but the infantile form of neuronal ceroid lipofuscinosis (INCL). Using molecular genetic techniques in the typical JNCL cases, common 1.02 kb deletion to CLN3 was found in 23/27 (homozygotes) and in one allele 4/27 (heterozygotes) in affected pedigrees. In atypical JNCL pedigrees, it was found in 5/16 heterozygotes, while in 1/5 pedigrees, a novel mutation of one atypical JNCL where a single amino acid substitution at 295 E-->K was found in one allele. None of the atypical JNCL cases was homozygote. In atypical JNCL cases where mutation in CLN3 has not been identified (11/16 probands), several possibilities may exist. The phenotype may be caused by a yet undefined mutation in CLN3 or may be due to phenotypically overlapping with other forms of NCL. Pheno/genotypic correlation and the diagnostic difficulties are discussed.
我们收集了122例晚发性婴儿神经元蜡样脂褐质沉积症（LINCL，CLN2）和191例青少年型神经元蜡样脂褐质沉积症（JNCL，CLN3）病例，这些病例是根据发病年龄、临床症状和病理结果诊断的，代表了美国和欧洲最常见的神经元蜡样脂褐质沉积症形式。然而，对现有数据的仔细分析显示，约80%的病例表现为典型症状，20%表现为非典型临床病程和/或病理结果，因此，可能分别代表LINCL和JNCL的变异型。神经元蜡样脂褐质沉积症在生物化学和分子遗传学方面的最新进展促使我们重新评估这些非典型神经元蜡样脂褐质沉积症病例。除了芬兰变异型外，LINCL的致病基因尚未确定。在LINCL病例中发现线粒体ATP合酶亚基c积累至曲线状形态。在5例病例中发现了一种新型的LINCL变异型，其溶酶体储存中主要为颗粒状形态，且尿样中亚基c排泄正常。对这5例病例研究棕榈酰蛋白硫酯酶（PPT）时，发现其水平不足，提示它们并非LINCL，而是婴儿型神经元蜡样脂褐质沉积症（INCL）。在典型的JNCL病例中使用分子遗传学技术，在23/27例（纯合子）和4/27例（杂合子）受影响家系的一个等位基因中发现了常见的1.02 kb CLN3缺失。在非典型JNCL家系中，在5/16例杂合子中发现了该缺失，而在1/5例家系中，在一个非典型JNCL的一个等位基因中发现了一个新的突变，即295位氨基酸E→K的单氨基酸替换。没有非典型JNCL病例是纯合子。在未发现CLN3突变的非典型JNCL病例（11/16例先证者）中，可能存在几种情况。其表型可能由CLN3中尚未确定的突变引起，也可能是由于与其他形式的神经元蜡样脂褐质沉积症表型重叠所致。文中讨论了表型/基因型相关性及诊断困难。
