Semmler Alexander, Köhler Wolfgang, Jung Hans H, Weller Michael, Linnebank Michael
University Hospital Zürich, Department of Neurology, Frauenklinikstr. 26, CH-8091 Zürich, Switzerland.
Expert Rev Neurother. 2008 Sep;8(9):1367-79. doi: 10.1586/14737175.8.9.1367.
X-linked adrenoleukodystrophy (X-ALD; OMIM #300100) is caused by defects of the ABCD1 gene on chromosome Xq28, resulting in an impairment of peroxisomal beta-oxidation and the accumulation of saturated very long chain fatty acids (VLCFAs). Primary manifestations occur in the CNS, the adrenal cortex and the testes' Leydig cells. The clinical presentation shows a marked variability which is not explained by the different X-ALD genotypes. Phenotypes range from rapidly progressive cerebral disease with childhood (childhood cerebral ALD [CCALD]) or adulthood (adult cerebral ALD [ACALD]) onset leading to death within a few years, over adult-onset adrenomyeloneuropathy (AMN) with or without focal CNS demyelination, AMN converting into a rapidly progressive, cerebral demyelinating phenotype resembling CCALD, to slow disease progression over decades, or adrenal insufficiency only. Approximately 50% of female heterozygotes develop moderate spastic paresis resembling the AMN phenotype. This review focuses on current experiences with different therapeutic approaches. Lorenzo's oil did not prove to be effective in cerebral inflammatory disease variants, but asymptomatic patients, and speculatively AMN variants without cerebral involvement, as well as female carriers may benefit from early intake of oleic and erucic acids in addition to VLCFA restriction. Hormone-replacement therapy is necessary in all patients with adrenal insufficiency. Hematopoietic stem cell transplantation has been reported to be effective in presymptomatic or early symptomatic CCALD, and may well also be a final therapeutic option in early ACALD patients. Early detection of mutation carriers and timely initiation of therapy is important for the effectiveness of all therapeutic efforts. Gene therapy of endogenous hematopoietic stem cells, pharmacological upregulation of other genes encoding proteins involved in peroxisomal beta-oxidation, reduction of oxidative stress, and possibly lovastatin are candidates for future X-ALD therapies.
X连锁肾上腺脑白质营养不良（X-ALD；OMIM #300100）由位于Xq28染色体上的ABCD1基因缺陷引起，导致过氧化物酶体β氧化受损以及饱和极长链脂肪酸（VLCFA）蓄积。主要表现在中枢神经系统、肾上腺皮质和睾丸的Leydig细胞。临床表现具有显著变异性，不同的X-ALD基因型无法解释这种现象。其表型范围从儿童期（儿童脑型ALD [CCALD]）或成年期（成年脑型ALD [ACALD]）起病的快速进展性脑病，在数年内导致死亡，到成年起病的肾上腺脊髓神经病（AMN），伴有或不伴有局灶性中枢神经系统脱髓鞘，AMN转变为类似CCALD的快速进展性脑脱髓鞘表型，再到病程长达数十年的缓慢疾病进展，或仅表现为肾上腺功能不全。约50%的女性杂合子会出现类似AMN表型的中度痉挛性轻瘫。本综述聚焦于不同治疗方法的当前经验。洛伦佐油在脑炎性疾病变体中未被证明有效，但无症状患者以及推测无脑部受累的AMN变体，还有女性携带者，除限制VLCFA外，早期摄入油酸和芥酸可能有益。所有肾上腺功能不全患者都需要进行激素替代治疗。据报道，造血干细胞移植对症状前或早期有症状的CCALD有效，对早期ACALD患者也很可能是最终的治疗选择。早期检测突变携带者并及时开始治疗对所有治疗措施的有效性都很重要。内源性造血干细胞的基因治疗、对参与过氧化物酶体β氧化的其他蛋白质编码基因进行药理学上调、降低氧化应激以及可能的洛伐他汀是未来X-ALD治疗的候选方法。
