Therapy of X-linked adrenoleukodystrophy

Abstract

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. Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. Therapy of X-linked Adrenoleukodystrophy Future Drugs Ltd: Peer Review PaperPlease return your comments for the attention of the Commissioning Editor at l.tipton@expert-reviews.com Many thanks in advance for your kind assistance. et al 1963 [6]. In 1981 the X-ALD locus was mapped to chromosome Xq28 [7], and twelve years later, the X-ALD gene (ABCD1) was identified [8,9]. Today X-ALD has been identified in most countries worldwide and in most ethnic groups. The minimum frequency of hemizygotes in the UnitedStates was determined to be 1:42,000 and the one of hemizygotes plus heterozygotes 1:16,800, suggesting X-ALD as the most common inherited leukodystrophy [10]. X-ALD phenotypesX-ALD is characterized by a highly variable clinical spectrum, from early progressive childhood to mild adulthood disease with only slow symptom progre...

Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms

“…The clinical features of symptomatic women were similar to those previously reported, mainly characterized by spastic paraplegia, lower limb sensory disturbances, and neurogenic bladder (Table 2) [3,9]. The age at evaluation was significantly higher in the symptomatic than in asymptomatic females (62.0 ± 12.1 vs .…”

“…Indeed, it would be a valuable parameter to early identify the subgroup of X-ALD female carriers with a higher-risk of becoming symptomatic and for whom a possible preventive therapy would be warranted [9]. With the aim of shedding light on this topic, we assessed the XCI pattern in 30 X-ALD female carriers and evaluated its relation with clinical findings.…”

Disease specific therapies in leukodystrophies and leukoencephalopathies

“…Use of Lorenzo’s Oil appears to offer a modest reduction in the risk of developing cerebral X-ALD, although it has no impact on the progression of cerebral X-ALD once the disease process has begun [11]. Its consumption carries health risks [13] and it’s availability in the US is currently restricted to X-ALD boys aged 3–10 under an expanded access trial (Clinical Trials.gov, NCT02233257).…”

Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy

“…The clinical constellation of a spastic paraparesis hints at first at a chronic inflammatory or neurodegenerative disorder, and patients are often misdiagnosed as having multiple sclerosis or hereditary spastic paraparesis [5,6]. During diagnostic workup, exclusion of vitamin E or vitamin B12 deficiency as well as of other leukodystrophies should be part of the diagnostic procedure.…”

“…Besides symptomatic treatment of spasticity, hormone therapy of adrenal and testicular insufficiency and hematopoietic cell transplantation in childhood-onset ALD [5,8], different nutritional regiments including the application of Lorenzo's oil have been recommended in the past [9]. Recently, some authors have also recommended the use of Lorenzo's oil in female carriers [5].…”