X连锁肾上腺脑白质营养不良的携带者筛查及产前诊断探讨

目的探讨X连锁肾上腺脑白质营养不良(X linkedadrenoleukodystrophy,X ALD)的携带者筛查及产前诊断方法。方法应用气相色谱质谱联用法对83例X ALD可疑携带者血浆、9例高危孕妇羊水细胞及其中5例胎儿出生后的血浆中极长链脂肪酸(VLCFAs)水平进行了检测。应用PCR、测序方法对31例X ALD可疑携带者及羊水细胞VLCFAs增高的男性及女性各1例进行了基因突变分析。结果83例X ALD可疑携带者中,51例血浆VLCFAs水平增高,31例ABCD1基因突变分析,29例有突变。9例胎儿中,7例羊水细胞VLCFAs水平正常,2例增高(1例男性,1例女性)。5例出生后进行了血浆VLCFAs水平检测,结果与产前诊断结果相一致。2例羊水细胞VLCFAs水平增高的胎儿,均有ABCD1基因突变,其核苷酸与氨基酸的改变分别为871G>A(E291K)和726G>A(W242X)。结论血浆及羊水细胞中VLCFAs水平检测结合基因突变分析可以准确地进行X ALD携带者筛查及产前诊断。

Screening for carrier and prenatal diagnosis of X-linked adrenoleukodystrophy

OBJECTIVE: X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by progressive demyelination of the central nervous system, adrenal cortex insufficiency and accumulation of saturated very long chain fatty acids (VLCFAs) in tissues and body fluids due to the impaired beta-oxidation in peroxisomes. X-ALD shows a wide range of phenotypic variation. Childhood cerebral form (CCER) is the most common phenotype with severe neurological symptoms and often the average interval from onset to total disability or death is 3 years. So far no effective treatment is available for the underlying defect. Screening for carriers of mutated relevant gene and prenatal diagnosis are very important for the prevention of the disease. In this study, the authors explored the method of carrier screening and prenatal diagnosis of X-ALD. METHODS: The plasma VLCFAs levels of 83 suspected carriers for ALD were determined by using GC/MS and ABCD1 gene mutational analysis was performed in 31 of them. Amniocentesis was performed in 9 suspected carriers for ALD during 18 - 30 gestational weeks. The VLCFAs level of cultured amniocytes was tested with GC/MS. ABCD1 gene mutational analysis was performed on two cases (one was a male and the other a female) whose VLCFAs levels of amniocytes were found elevated. The plasma VLCFAs levels were measured in five of the nine prenatally diagnosed children when they were 1 day to 3.5 years old. RESULTS: Fifty-one of 83 suspected carriers had high plasma VLCFAs levels; 29 of 31 suspected carriers showed ABCD1 gene mutation. Among the nine fetuses, four were males and five were females. The VLCFAs levels of the cultured amniocytes were high in two cases, one was female and the other a male. ABCD1 gene mutational analysis of these two cases showed a 871G > A (E291K) mutation and a 726G > A (W242X) mutation, respectively, which confirmed the biochemical result. The VLCFAs levels were normal in the rest of cases and five of them were confirmed by postnatal plasma VLCFAs assay. CONCLUSION: The carrier screening and prenatal diagnosis are very important for prevention of the X-ALD. Only the combined use of plasma VLCFAs level analysis and ABCD1 gene mutational analysis could detect X-ALD carriers correctly. ABCD1 gene mutational analysis and postnatal plasma VLCFAs level test verified that amniocytes VLCFAs level analysis is a reliable prenatal diagnostic method for this disease.