溶酶体神经氨酸酶基因缺乏小鼠听觉和耳形态学改变初步研究

目的研究溶酶体神经氨酸酶基因（Neul）敲除小鼠听功能和耳形态学改变，探讨唾液酸沉积症听力损害的病理生理机制。方法应用听性脑干反应测试和常规颞骨连续切片观察3周、2个月和4个月龄的Neul敲除纯合子（Neul-／-）和野生型（Neul＋／＋）小鼠听阈和光镜下外耳、中耳及内耳形态。结果3周龄的Neul-／-小鼠，短声和短音8、16及32kHz听阈（声压级）较Neul＋／＋提高50—55dB；2个月和4个月龄小鼠听阈提高60—68dB。Neul-／-小鼠3周龄即有明显的中耳和内耳改变，特别是2个月和4个月龄有显著的外耳道堵塞和严重中耳炎，听小骨和耳蜗骨壁细胞、血管纹边缘层和中间层细胞、耳蜗螺旋神经节细胞、螺旋缘纤维细胞、前庭膜、基底膜及沿前庭阶外淋巴隙的间皮细胞明显囊泡化，但Corti器细胞正常。前庭神经节细胞、壶腹嵴及球囊毛细胞和支持细胞也呈现明显囊泡化。结论溶酶体神经氨酸酶的缺乏可导致较严重的听力损害和耳形态改变；外耳道阻塞或中耳炎和听骨改变可能引起传导性聋；耳蜗螺旋神经元、血管纹、螺旋缘、前庭膜和基底膜等细胞的溶酶体储积可能导致感音神经性聋。     

Biochemical definition of the mucopolysaccharidoses

The excretion pattern of urinary acid mucopolysaccharides was determined in 72 patients with different clinical types of mucopolysaccharidoses and mucolipidoses. Using a chromatographic fractionation method, characteristic excretion patterns were found in the six classical types of mucopolysaccharidoses. Patients with Hunter's disease excreted relatively more heparansulfate and less dermatansulfate than patients with Hurler's disease. In Sanfilippo's disease the excretion of heparansulfate only was increased. In Morquio's disease abnormal amounts of substances with characteristics of chondroitin-4(6)-sulfate were found in addition to keratansulfate. In one patient with Ullrich-Scheie's disease and six patients with Maroteaux's disease relatively large amounts of substances with characteristics of dermatansulfate were present. There was very little overlap between the excretion patterns of different types of mucopolysaccharidoses. In the types of mucolipidoses investigated, the urinary excretion of acid mucopolysaccharides was normal. The intrafamilial variability in eight pairs of related children was small. Our data suggest that the excretion pattern of urinary acid mucopolysaccharides, as determined by the Dowex Column Chromatography Method, is a valuable aid in the definition of the mucopolysaccharidoses.Supported by Grants No. WI 80 of the Deutsche Forschungsgemeinschaft.     

I-cell disease and pseudo-Hurler polydystrophy: Heterozygote detection and characteristics of the altered N-acetyl-glucosamine-phosphotransferase in genetic variants

The human disorders I-cell disease and pseudo-Hurler polydystrophy (also known as mucolipidosis II and III, respectively) are caused by an inherited deficiency of UDP-GlcNAc: lysosomal enzyme precursor GlcNAc-P transferase activity. The most common genetic variants of these diseases (complementation group A) can be identified in homozygotes and heterozygotes using a GlcNAc-P transferase assay with artificial acceptors and commercially available radiochemicals. The kinetic characteristics of the residual GlcNAc-P transferase activity in complementation group A fibroblasts indicates that the low activity is due to a low V_max. The measured Michaelis-Menten constants for the substrates UDP-GlcNAc and -methyl mannoside are in the normal range. Homozygotes and heterozygotes of another less common variant of pseudo-Hurler polydystrophy (complementation group C) have normal activity and normal kinetic characteristics with this assay using -methyl mannoside as the acceptor substrate. Several PHP variants with unusual characteristics are discussed.     

溶酶体贮积病

Lysosomesaresinglemembrane boundorganellescontaining manyhydrolyticenzymesinvolvedinthedegradationofavarietyofbiologicalmacromolecules.Ifoneormoreenzymeisdeficient,theaccumulationofthesemoleculesisinevitable.Lysosomalstoragedisorders(LSDs)representagroupo…     

非活性型脂蛋白脂酶在动脉粥样硬化早期病变形成中的作用

目的探讨兔动脉壁高表达非活性型脂蛋白脂酶(LPL)在动脉粥样硬化发生中的作用。方法新西兰兔24只,以腺病毒基因转移技术转染基因,随机分为3组,以碱性磷酸酶(AP)基因作对照(对照组),通过球囊导管损伤兔颈总动脉造模后,实验组在血管壁高表达活性型人LPL(hLPL组),非活性型人LPL_(194)基因(hLPL_(194)组)。1周后通过油红O染色及免疫组化对血管壁的形态进行分析。结果 hLPL_(194)组血管壁内膜下有明显的脂质沉积,定量分析显示较对照组增高(0.0545±0.0097比0.012±0.0004)(P<0.01),但较hLPL组少(0.1043±0.0462)(P<0.01)。同时发现hLPL_(194)组的动脉壁内膜下局部巨噬细胞浸润与hLPL组一样也有增多。而3组动物的血浆总胆固醇、三酰廿油及高密度脂蛋白胆固醇水平差异均无统计学意义(均为P>0.05)。结论非活性型LPL和活性型LPL一样,在血管壁内膜下过表达时,能引起内膜下脂质沉积,并伴有巨噬细胞浸润,促进动脉粥样硬化早期病变的形成。     

MR findings in mannosidosis

Summary MR findings are reported in three patients presenting mannosidosis. Among a family of 8 children, 4 presented typical clinical and biological abnormalities related to mannosidosis. Brain MR examinations including sagittal T1 and axial T2 sections were obtained in three patients of this family (one 25-year-old male, one 34-year-old female, and one 35-year-old female). MR scans demonstrate seven types of modifications: (1) brachycephaly, (2) thick calvaria, (3) verticalization of the chiasmatic sulcus, (4) poor pneumatization of the sphenoid body, (5) partial empty sella turcica (6) cerebellar atrophy, and (7) white matter signal modifications. High signal abnormalities involving the parieto-occipital white matter are identified on axial T2-weighted scans in the three patients and are probably related to demyelination and associated gliosis as described previously by several authors on specimens.