Adrenoleukodystrophy (ALD) is a genetic disorder caused by a mutation in the ABCD1 gene, which is situated on the X chromosome. Because women have two X chromosomes, even if the ABCD1 gene on one of the X chromosomes is mutated, the healthy copy of the gene on the other X chromosome can balance the defect. This is why ALD mostly affects men, who only have one X chromosome.
Women with one mutated copy of the ABCD1 gene are so-called ALD carriers. These individuals usually do not show any symptoms or have milder symptoms, but have a 50 percent risk of passing the mutated gene on to their children. In some very rare cases, both copies of the ABCD1 gene can be mutated, and women can be affected by ALD in the same way as men.
Symptoms of ALD in female carriers
The symptoms of ALD are usually absent or very mild in female carriers. Thus, it is very hard to tell that they are carriers.
When present, commonly observed symptoms include chronic leg muscle weakness affecting gait, spasticity, or muscle stiffness, and bowel and bladder dysfunction. Adrenal gland malfunction is usually rare, affecting only about 1 percent of female ALD carriers.
A study published in the scientific journal Brain found that, in 46 female ALD carriers older than 18, peripheral neuropathy — tingling and numbness in the hands and feet — and spinal cord injury, or myelopathy, were the two leading symptoms. Poor bowel and bladder control was also reported. Other symptoms included abnormal muscle reflexes and gait disorders. Elevated levels of very long chain fatty acids (VLCFA), a biomarker of the disease, were found in 98% of the participants in the study. However, only women older than 40 showed ALD-like symptoms.
Similarly, a study published in Case Reports in Neurological Medicine described the case of a 35-year-old woman who was identified as an ALD carrier as part of a family genetic screening when her brother was diagnosed with the condition. Although family history helped in her diagnosis, her initial symptoms were vague. She reported balance issues, knee pain, heaviness in her hands and feet, and problems in normal activities such as running, jumping, or climbing stairs. However, muscle strength was normal, and no gait disorders were seen. Her brain MRI did not reveal any abnormalities either. Seven years after her genetic testing, her blood VLCFA levels were elevated, which was attributed to her ALD carrier status, but no adrenal insufficiency was reported.
Some studies describe clinical symptom variability that ranges from no symptoms or slow-progressing muscle spasticity to aggressive neurological impact, highlighting the need for further in-depth investigations.
A unique case described severe and progressive dementia in a 79-year-old female ALD carrier.
Risk of ALD carriers passing on the disease
Women ALD carriers have a 50 percent risk of passing the defective gene on to their children. If this happens and the child is a girl, she will be a carrier like her mother, and if it is a boy, he will have ALD.
Men with ALD can only pass their X chromosome to their daughters who then have a 50 percent chance of being carriers and 50 percent chance of developing the disease if the mother was an ALD carrier.
For people with a known family history of ALD, genetic testing can help identify carriers and affected children before the development of any symptoms.
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