Aging Raises Risk of Women Developing ALD Symptoms or More Severe Disease, Study Suggests

Aging Raises Risk of Women Developing ALD Symptoms or More Severe Disease, Study Suggests

Age is the major risk factor for adrenoleukodystrophy (ALD) symptoms and their severity in women carrying one mutated copy of the ABCD1 gene — the gene associated with ALD, an Italian study suggests.

These findings add to the natural history of ALD in women, and suggest that underlying disease mechanisms are particularly vulnerable to aging, starting around middle age. They may also help in the early diagnosis and development of appropriate treatments for women.

The study, “Natural history of a cohort of ABCD1 variant female carriers,” was published in the European Journal of Neurology.

ALD is a X-linked disorder, meaning that the mutated gene that causes it — the ABCD1 gene — is located on the X chromosome, one of the two sex chromosomes that play a part in determining gender.

Since men only have one X chromosome, those who inherit a mutated ABCD1 gene will develop the disease, while in women — who have two X chromosomes — a healthy ABCD1 gene copy partly compensates for a mutated one. Women with a mutated copy of the ABCD1 gene are called ALD carriers, and usually develop no or only milder symptoms of the disease.

Mutations in the ABCD1 gene lead to a deficient production of adrenoleukodystrophy protein (ALDP), which is involved in the breakdown of very-long-chain fatty acids (VLCFAs) inside a cellular structure called the peroxisome. ALDP deficiency leads to the toxic build-up of VLCFAs, and to the loss of myelin (the protective sheath around nerve cells), and progressive dysfunction of the adrenal glands (small hormone-producing glands located above the kidneys).

While ALD is well-characterized in men, information is limited regarding the clinical symptoms and disease progression in ALD carriers.

Researchers in Italy evaluated the natural history of ALD and potential factors associated with clinical features in 32 untreated women with a mutated copy of the ABCD1 gene. These women were relatives of men with ALD, followed at the Bambino Gesu Children’s Hospital in Rome.

The scientists retrospectively analyzed the women’s demographic and clinical data, levels of VLCFAs (the conventional diagnostic marker for ALD), and the adult ALD clinical score (AACS) — a specific scale measuring motor, bladder, sensory, and brain functions in adults with ALD — assessed at up to three visits over seven years.

Mean age for these women was 42.8, and 19 of them (59.4%) were symptomatic at the beginning of the study. Of these, a total of 14 (73.7%) had symptoms of adrenomyeloneuropathy (AMN, the adult-onset form of ALD), including walking/balance problems, urinary incontinence, sensory complaints, and psychological disturbances, while the other five (26.3%) had only signs of motor deficits.

Results showed that symptomatic women were significantly older than those without ADL symptoms, and age was the most significant risk factor for the development of ADL symptoms and the main determinant of disease severity.

ADL carriers were mainly asymptomatic (or with few symptoms) up to their 30s or 40s, when they developed disease symptoms and a progressive decline began, the researchers wrote. The rate of decline was calculated as a 0.24-point annual increase on the AACS scale.

Thus, in ALD carriers “aging was crucial for the onset and progression of symptoms,” the researchers wrote.

They also noted that “the estimated annual increase of the AACS will be useful for future interventional studies,” adding that, based on this AACS rate, future controlled trials evaluating treatment effectiveness in halting disease progression would likely need 272 women (136 per treatment and control group).

Results also found that VLCFA levels did not differ between symptomatic and asymptomatic women or change over time, indicating that VLCFA levels are not effective biomarkers for ADL diagnosis or monitoring of disease progression in ADL carriers.

Overall, “this study provides data on the natural disease progression of untreated ABCD1 heterozygous female carriers, demonstrating the relevance of aging,” the researchers wrote. The findings “lead to a reconsideration of the clinical approach to this condition, providing early diagnosis and possibly appropriate therapeutic options,” they added.