ABCD1 and X‐linked adrenoleukodystrophy: A disease with a markedly variable phenotype showing conserved neurobiology in animal models

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a phenotypically heterogeneous disorder involving defective peroxisomal β-oxidation of very long-chain fatty acids (VLCFAs), due to mutation in the ABCD1 gene. X-ALD is the most common peroxisomal inborn error of metabolism and confers a high degree of morbidity and mortality.Remarkably, a subset of patients exhibit a cerebral form with inflammatory invasion of the central nervous system and extensive demyelination, while in others only dyingback axonopathy or even isolated adrenal insufficiency is seen, without genotypephenotype correlation. X-ALD's biochemical signature is marked elevation of VLCFAs in blood, a finding that has been utilized for massive newborn screening for early diagnosis. Investigational gene therapy approaches hold promises for improved outcomes. However, the pathophysiological mechanisms of the disease remain poorly understood, limiting investigation of targeted therapeutic options. Animal models for the disease recapitulate the biochemical signature of VLCFA accumulation and demonstrate mitochondrially generated reactive oxygen species, oxidative damage, increased glial death, and axonal damage. Most strikingly, however, cerebral invasion of leukocytes and demyelination were not observed in any animal model for X-ALD, reflecting upon pathological processes that are yet to be discovered. This review summarizes the current disease models in animals, the lessons learned from these models, and the gaps that remained to be filled in order to assist in therapeutic investigations for ALD.

De novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila

“…Glial dysfunction has been implicated in a growing number of late-onset neurodegenerative diseases, including Alzheimer disease (46)(47)(48), amyotrophic lateral sclerosis and frontotemporal dementia (49) as well as in early onset Mendelian disorders, such as Rett syndrome (50), Mitchell syndrome (36), Alexander disease (51), X-linked adrenoleukodystrophy (52), metachromatic leukodystrophy (53) and Pelizaeus-Merzbacher disease (54). Moreover, genetic defects resulting in glial dysfunction have been shown to underlie cerebellar defects (55), similar to the phenotype seen in humans with EMC1 variants.…”

Modern gene therapy drugs

“…Описано три варианта проявления болезни: детская церебральная форма, адреномиелонейропатия и изолированная надпочечниковая недостаточность. Детская церебральная форма считается самой тяжёлой, обычно проявляется в возрасте 4-8 лет и может приводить к серьёзным неврологическим нарушениям и смерти [55]. Теоретически ранняя диагностика заболевания у мальчиков из группы риска и аллогенная трансплантация ГСК могут остановить демиелинизацию головного мозга, если провести все необходимые мероприятия задолго до появления неврологических симптомов и до развития прогрессирующего заболевания головного мозга [56].…”

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

“…In addition, various animal models with both advantages and drawbacks were used to study the mechanism of X-ALD (74,75). ABCD1 knockout mice that exhibit delayed (20 months) onset axonopathy in the spinal cord without cerebral inflammatory demyelination (76), which are considered to mimic AMN, are often used to evaluate changes in biochemical markers.…”