A new adrenoleukodystrophy-causing mutation in the ABCD1 gene was described in the case report of a 20-year-old Korean man.
The report, “Novel ABCD1 Gene Mutation in a Korean Patient with X-Linked Adrenoleukodystrophy Presenting with Addison’s Disease,” was published in the journal Endocrinology and Metabolism.
Adrenoleukodystrophy (ALD), also called X-linked ALD (X-ALD), is caused by mutations in the gene ABCD1 (ATP-binding cassette sub-family D member 1) located on the X-chromosome. These mutations lead to a buildup of saturated very long chain fatty acids (VLCFAs), compounds that, in excess, can damage multiple organ systems, including the brain, kidneys, and adrenal glands.
As genetic technologies have advanced in recent decades, so has knowledge about the kinds of ABCD1 mutations that can cause ALD.
The new report describes the case of a 20-year-old male patient who was referred to an endocrinology and metabolism clinic with a diagnosis of adrenal insufficiency (also known as Addison’s disease, wherein the adrenal glands do not make enough of certain hormones). The diagnosis had been made four months prior, when the patient developed adrenal crisis (acute adrenal insufficiency) and pneumonia while in the military service.
The patient underwent a series of diagnostic tests, and among the most relevant findings, researchers identified high levels of VLCFAs, indicative of ALD.
The man’s DNA was analyzed through whole-exome sequencing (WES) — a technique in which the protein-coding parts of the genome (called the exome) are sequenced.
WES analysis revealed a mutation dubbed c.1991G>A. This was determined to be a nonsense mutation, which is a mutation where a “stop” signal occurs within the sequence of a gene, typically resulting in truncated proteins that are unable to function. At the protein level, this mutation is denoted p.Trp664*.
This particular mutation has not been reported before, but because it was a nonsense mutation identified in a person with increased VLCFAs, there was “very strong evidence” it is pathogenic — that is, a disease-causing mutation that leads to ALD.
This same mutation also was identified in the patient’s biological mother, who had no symptoms of ALD. This is presumably because the disease is X-linked, and females have two X chromosomes, whereas males have one; that’s why, in females, there are two copies of the ABCD1 gene, and one can compensate if the other is mutated.
The patient’s mother and biological siblings elected not to undergo VLCFAs analysis. However, the patient’s older sister — who, being female, could be an unknowing carrier — was informed that genetic testing would be advisable prior to attempting to become pregnant.
The patient was placed on corticosteroids, and is reported to be “doing well.”
“In conclusion, we report the case of a patient with X-ALD presenting with adrenal insufficiency, and have identified a novel ABCD1 gene mutation (p.Trp664*, c.1991G>A) using whole-exome sequencing,” the researchers wrote.
