Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy(X-ALD),an inborn error of peroxisomalβ-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 adrenoleukodystrophy 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.

Adrenal Insufficiency by Adrenoleukodystrophy

The X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder due to mutations in the ABCD1 gene. Objective: To report a case of a 19-year-old man with adrenal insufficiency due to adrenoleukodystrophy. Method: Case report and literature review. Result: A previously healthy 19-year-old male patient was admitted to the emergency room with nausea and vomiting for 5 days, who progressed to abdominal pain, severe asthenia, and fever (38.5°C). He referred progressive darkening of the skin, oral mucosa, tongue and nail bed of the hands and feet, observed in the last 6 years. Emergency laboratory evaluation showed severe hyponatremia and hyperkalemia, which, together with decreased plasma cortisol, directed the investigation to causes of adrenal insufficiency. High ACTH (Adrenocorticotropic hormone) and very long chain fatty acid levels closed the diagnosis. Discussion: ALD is characterized by progressive demyelination in the central and peripheral nervous system and adrenal insufficiency consequence to the accumulation of very long chain fatty acids (VLCFA) in the adrenal. The overall incidence of ALD is 1:17,000. Adrenal insufficiency may be the first symptom of ALD in boys and adults. The diagnosis is based on the measurement of VLCFA plasma levels. Allogeneic bone marrow transplantation is the only treatment that provides a permanent cure when the procedure is performed at an early stage of brain demyelination, i.e. when patients are asymptomatic, although brain magnetic resonance imaging (MRI) is abnormal. Treatment of Addison’s disease is obligatory, but does not change the course of neurological symptoms.