Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.

Keywords: Adrenomyelo-neuropathy; Cerebral adrenoleukodystrophy; Modifiers; Phenotypic variation; X-adrenoleukodystrophy.

Figure 1

Possible modifiers associated with disease phenotypic variability. Phenotypic heterozygosity observed in a monogenic disorder can be due to the association of modifying factors such as genetic, epigenetic, and/or environmental factors, commonly termed as “modifiers.”

Figure 2

Factors determining the onset of symptoms of cerebral demyelination. Migration of immune cells into the brain could be a rate-limiting step in the appearance of symptoms of cerebral demyelination. Onset of the migration across the blood brain barrier could be precipitated by environmental triggers, genetic or epigenetic factors and ATP Binding Cassette Subfamily D Member 1 (ABCD1) deficiency acting either alone or in concert, marking the onset of brain inflammation leading to cerebral symptoms.