Academic Medical Centre, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Department of Paediatrics/Emma Children's Hospital, Amsterdam, The Netherlands.
J Med Genet. 2010 Sep;47(9):608-15. doi: 10.1136/jmg.2009.074302. Epub 2010 Jul 20.
Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different PEX genes. This includes PEX16, which encodes an integral peroxisomal membrane protein involved in peroxisomal membrane assembly. PEX16-defective patients have been reported to have a severe clinical presentation. Fibroblasts from these patients displayed a defect in the import of peroxisomal matrix and membrane proteins, resulting in a total absence of peroxisomal remnants.
To report on six patients with an unexpected mild variant peroxisome biogenesis disorder due to mutations in the PEX16 gene. Patients presented in the preschool years with progressive spastic paraparesis and ataxia (with a characteristic pattern of progressive leucodystrophy and brain atrophy on MRI scan) and later developed cataracts and peripheral neuropathy. Surprisingly, their fibroblasts showed enlarged, import-competent peroxisomes.
Plasma analysis revealed biochemical abnormalities suggesting a peroxisomal disorder. Biochemical variables in fibroblasts were only mildly abnormal or within the normal range. Immunofluorescence microscopy revealed the presence of import-competent peroxisomes, which were increased in size but reduced in number. Subsequent sequencing of all known PEX genes revealed five novel apparent homozygous mutations in the PEX16 gene.
An unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene, with a relatively mild clinical phenotype and an unexpected phenotype in fibroblasts, was identified. Although PEX16 is involved in peroxisomal membrane assembly, PEX16 defects can present with enlarged import-competent peroxisomes in fibroblasts. This is important for future diagnostics of patients with a peroxisomal disorder.
泽尔韦格综合征谱障碍是由至少 12 种不同 PEX 基因中的突变引起的。这包括 PEX16，它编码一种参与过氧化物酶体膜组装的完整过氧化物酶体膜蛋白。已经报道过 PEX16 缺陷的患者具有严重的临床表现。这些患者的成纤维细胞显示出过氧化物酶体基质和膜蛋白导入的缺陷，导致过氧化物酶体残余物完全缺失。
报告六例由于 PEX16 基因突变导致的意外轻度变异过氧化物酶体生物发生障碍。患者在学龄前出现进行性痉挛性截瘫和共济失调（MRI 扫描显示特征性的进行性白质营养不良和脑萎缩模式），随后发展为白内障和周围神经病。令人惊讶的是，他们的成纤维细胞显示出增大的、导入功能正常的过氧化物酶体。
血浆分析显示生化异常提示过氧化物酶体障碍。成纤维细胞中的生化变量仅轻度异常或在正常范围内。免疫荧光显微镜显示存在导入功能正常的过氧化物酶体，其大小增加但数量减少。随后对所有已知的 PEX 基因进行测序，发现 PEX16 基因中有 5 个新的明显纯合突变。
确定了一种由 PEX16 基因突变引起的不寻常的变异过氧化物酶体生物发生障碍，其临床表现相对较轻，成纤维细胞的表型出乎意料。虽然 PEX16 参与过氧化物酶体膜的组装，但 PEX16 缺陷可导致成纤维细胞中出现增大的导入功能正常的过氧化物酶体。这对于过氧化物酶体障碍患者的未来诊断很重要。
