Chinese patients with adrenoleukodystrophy and Zellweger spectrum disorder presenting with hereditary spastic paraplegia
Chinese patients with adrenoleukodystrophy and Zellweger spectrum disorder presenting with hereditary spastic paraplegia
复制标题
中国肾上腺脑白质营养不良和齐薇格谱系障碍患者，表现为遗传性痉挛性截瘫
DOI：
10.1016/j.parkreldis.2019.06.008
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发表时间：
2019-08-01
影响因子：
4.1
通讯作者：
Chen, Wan-Jin
中科院分区：
文献类型：
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作者：
Chen, Yi-Jun;Wang, Meng-Wen;Chen, Wan-Jin
前言X连锁肾上腺脑白质营养不良(ALD)和Zellweger谱系障碍(Zellweger Spectrics，ZSD)是以超长链脂肪酸(VLCFA)在血浆和组织中积聚为特征的过氧酶体疾病。由于ALD和不典型ZSD的临床表现千差万别，临床上易误诊为遗传性痉挛截瘫(HSP)。在这里，我们的目的是确定过氧化酶体疾病的频率，并将其表型谱与热休克蛋白进行比较。方法：我们首先对120个痉挛截瘫家系进行了靶向测序，随后确定了74个热休克蛋白家系。然后，我们对其余46个缺乏已知HSP致病基因的家系的先证者进行了完整的外显子组测序。结果：发现7个伴有ABCD1突变的ALD家系和1个含有PEX16双等位基因突变的ZSD家系。临床上，除了痉挛截瘫外，4名ALD先证者还表现出肾上腺皮质功能不全，ZSD先证者和她受影响的妹妹都出现了甲状腺问题。VLCFA分析显示ALD先证者C24/C22和C26/C22比值明显升高。结论：本研究报道了中国首例表现为痉挛性截瘫的ZSD病例，并强调了过氧化体疾病在痉挛性截瘫实体中所占比例很大(8/120)。这些发现扩展了我们目前对ALD和ZSD疾病的理解。
Introduction X-linked adrenoleukodystrophy (ALD) and Zellweger spectrum disorder (ZSD) are peroxisomal diseases characterized by accumulation of very long chain fatty acids (VLCFA) in plasma and tissues. Considering the wide variability of manifestation, patients of ALD and atypical ZSD are easily misdiagnosed as hereditary spastic paraplegia (HSP) on their clinical grounds. Here, we aimed to determine the frequency of peroxisome diseases and compare their phenotypic spectra with HSP.Methods: We first applied targeted sequencing in 120 pedigrees with spastic paraplegia, and subsequently confirmed 74 HSP families. We then performed whole exome sequencing for the probands of the 46 remaining pedigrees lacking known HSP-causal genes. Detailed clinical, radiological features, and VLCFA analyses are presented.Results: Seven ALD pedigrees with ABCD1 mutations and one ZSD family harboring bi-allelic mutations of PEX16 were identified. Clinically, in addition to spastic paraplegia, four ALD probands presented adrenocortical insufficiency, and the ZSD proband and her affected sister both developed thyroid problems. VLCFA analysis showed that ratios of C24/C22 and C26/C22 were specifically increased in ALD probands. Moreover, three ALD probands and the ZSD proband had abnormalities in brain or spinal imaging.Conclusions: Our study reports the first ZSD case in China that manifested spastic paraplegia, and emphasized the finding that peroxisomal diseases comprise a significant proportion (8/120) of spastic paraplegia entities. These findings extend our current understanding of the ALD and ZSD diseases.