Research On Clinic Presentation And Molecular Biology Of Patients With Adrenoleukodystrophy

Adrenoleukodystrophy is an X-linked disease , The characteristic biochemical abnormality of ALD is the accumulation of very-long-chain fatty acides(VLCFA). The disease have different phenotypes and high mortality rate. It is important for us to diagnose the disease and treat it in early stage. Resently,the other country's workers have been researching into the causes of ALD and have found the method of diagnosing the disease. In the aspect of molecular biology, ALD gene has been mapped to Xq28 and contains ten exons. Many kinds of mutations have been found in ALD gene. Now , we have less reports concerning the disease and have not research into the ALD gene in china.Objective To explore the method of diagnosis and molecular mechanism of X-linked adrenoleukodystrophy,and to provide the method and the experimental evidence of diagnosis and treatment of ALD. Methods (1) Provide the method of diagnosis with physical examination, coronal MRI and biochemical measure. (2) Direct DNA sequencing and polymerase chain reaction in exons and their flanking sequences of ALD gene were performed in four patients and their mothers . Result (1) We can diagnose the disease with clinic presentation, brain MRI and increased levels of VLCFA. (2) A splice mutation were identified in interface of exon 5 and intron 5(1875+G?A). The splice mutation due to the change of splice signal on 5 end of ALD gene and leads to abnormal splice in exonS and exon6. This mutation causes unstable and abnormal ALD protein. (3) A missense mutation were identified in exon6(Va!517Tle G -A). The other missense mutation were identified in exon7(Gln556Arg AG).The ALD gene is predicted to encode a protein of 745 amino acide consisting of six-membrane-spanning segments and a ATP-binding domain on the membrane of peroxisome. The exon 6, 7, 8 encode ATP-binging domain of ALD gene. The mutations in exon6 and exon7 lead to abnormal ALDP. The lignoceroyl COA ligase can not transport into peroxisome and can not develop his normal function. Defective 3 -oxidation of VLCFA in peroxisome has been shown to lead to an accumulation of VLCFA in the central nerve systems, adrenal gland and blood.Conclusion (1) Adrenoleukodystrophy is an X^linked disease and caused by the gene mutation. We can diagnose the disease with clinic presentation and laboratory data. (2) The splice mutation in 5 end of intron 5 leading to abnormal splice in exonS and exonG , two missense mutation in exon6( Val517Ile G-A) and in exon7(Gln556Arg Aæ¡®) appear to be causes of X-linked recessive adrenoleukodystrophy.