Study on Pathophysiology, Prevention and Gene Therapy of Adrenoleukodystrophy

对X-连锁肾上腺脑白质营养不良(ALD)的病理生理、防治进行了研究。1)阐明了15例日本儿童和成人ALD的自然病程。平均发病年龄为8.5岁。虽然最常见的首发症状是视力障碍(n=7)，但精神衰退进展迅速。卧床和吞咽困难的出现明显晚于智力低下的出现。2)描述了4例日本患者接受骨髓移植治疗儿童ALD的效果。两名智商水平相对维持的老年患者效果良好。两名较年轻的患者病程较快，骨髓移植时智商水平无法测量，显示神经功能恶化。3)研究了PMP70，一种与ALD蛋白同源的过氧体膜蛋白的作用。当PMP70在CHO细胞中表达时，棕榈酸酯的氧化速率增加，而木质油酸的氧化速率降低。PMP70参与了长链脂肪酸的代谢转运，并可能与ALD蛋白形成异二聚体。4)研究了几种过氧化体膜蛋白的基因和功能。PEX13是过氧化物酶体生物发生障碍H组的致病基因，在C组中发现了PEX6基因结构和11个新的突变。PEX1的G843D点突变是导致第1组过氧化物酶体生物发生障碍的温度敏感性突变。

Pathophysiology, prevention and treatment of X-linked adrenoleukodystrophy (ALD) were investigated.1) Natural course of 15 Japanese patients with childhood and adrescent ALD was clarified. Average onset was 8.5 years of age. Though the most common first symptom was visual disturbance (n=7), mental deterioration rapidly progressed. The appearance of bed-ridden and dysphagia were significantly later than that of mental retardation.2) The effects of BMT in Childhood ALD were described in four Japanese patients. Two elder patients with relatively maintained IQ levels had favorable results. Two younger patients with a rapid course and unmeasurable IQ levels at BMT showed deterioration of neurological functions.3) The role of PMP70, a peroxisomal membrane protein which has a homology to ALD protein, was investigated. When PMP70 was expressed in CHO cells, the oxidation rate of palmitate was increased, however, the oxidation of lignocerate was decreased. PMP70 is involved in metabolic transport of long chain fatty acids and may form a heterodimer with ALD protein.4) Genes and functions of several peroxisomal membrane protein were investigated. PEX13 was the pathogenic gene of peroxisomal biogenesis disorders group H. Gene structure and novel 11 mutations of PEX6 were identified in group C peroxisome biogenesis disorders. A point mutation G843D in PEX1 was the temperature-sensitivity causing mutation in group 1 peroxisome biogensis disorder.