Adrenoleukodystrophy (ALD), also called X-linked ALD, is a genetic condition caused by a mutation in the ABCD1 gene that is situated on the X-chromosome. The disease primarily affects the nervous system and the adrenal glands. The ABCD1 gene carries the information to make a protein called the adrenoleukodystrophy protein (ALDP), a key player in the transport of very long-chain fatty acids (VLCFA) to a compartment inside cells called the peroxisomes, where they are broken down.
Mutation in the ABCD1 gene results in little or no ALDP being produced, leading to an accumulation of VLCFAs inside cells that is toxic. The buildup of VLCFA causes the deterioration of the protective myelin sheath around the nerve cells in the brain and the spinal cord, affecting their ability to communicate. The accumulation of VLCFA in the adrenal glands, which produce many vital hormones, causes a hormone deficiency called adrenocortical insufficiency and leads to several symptoms observed in ALD patients.
ALD is an inherited condition that primarily affects males. Because men carry one X and one Y chromosome, if they inherit a mutated copy of the ABCD1 gene, they will develop the disease. Women carry two X chromosomes, so a healthy copy of the ABCD1 gene on one X chromosome can balance the other mutated one.
Based on the age of onset and severity of its symptoms, ALD is classified into three main types: childhood cerebral adrenoleukodystrophy (CALD), adrenomyeloneuropathy (AMN), and Addison’s disease.
In this type of ALD, children, between ages 4 and 10, start exhibiting symptoms that include hyperactivity and learning difficulties, and behavioral changes such as increased aggression. Rapid leukodystrophy or progressive breakdown of the myelin sheath occurs over time, resulting in a worsening of symptoms.
Early diagnosis is vital for CALD because, depending on its severity and rate of progression, the disease can be fatal within five to 10 years if left untreated. In addition, available treatments only work before the symptoms fully develop, or for a short while after they develop, because the loss of the myelin sheath is irreversible.
Patients with AMN, also called adult-onset ALD, develop symptoms in early to mid-adulthood, and usually in their 20s or 30s. Neurological symptoms and progressive lower limb weakness and stiffness are common. These patients may also exhibit bowel and bladder dysfunction. Behavioral changes start to develop as the condition progresses. In severe cases, brain and spinal cord involvement could impact life expectancy.
Compared to CALD, AMN progression is slower. However, most AMN patients experience a decline in physical and mental abilities.
In about 10 percent of ALD patients, the only symptom is adrenocortical insufficiency. In such cases, the disease is referred to as Addison’s disease. Adrenal hormones regulate metabolism and help in responding to stress. Abnormal levels of these hormones can be life-threatening. Proper diagnosis can help manage the condition with the help of hormone supplements.
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