X-linked adrenoleukodystrophy (ABCD1 gene): inheritance, adrenal and brain effects

Adrenoleukodystrophy, usually shortened to ALD, is a rare inherited disorder. Great Ormond Street Hospital (GOSH) describes it as a condition that can affect the adrenal glands, causing adrenal insufficiency, as well as the nerves of the spinal cord, known as adrenomyeloneuropathy or AMN, and sometimes the white matter of the brain, known as cerebral ALD or cALD.

The underlying cause is a problem with peroxisomes, tiny structures in cells that help to break down very long chain fatty acids. GOSH explains that in ALD the process of transporting these fatty acids into the peroxisomes is faulty. This damages the adrenal glands, the nerves of the spinal cord and the myelin, the insulating material around nerve fibres in the brain, although it is not fully understood why the damage occurs.

The condition used to be called Addison-Schilder disease, after the doctor who first recognised it in 1923. The name is still seen in older records.

ALD is an X-linked recessive disorder. The ABCD1 gene is on the X chromosome, one of the two sex chromosomes. Males have one X chromosome and one Y, so a male with a changed ABCD1 gene has no second working copy. GOSH says males who have the changed gene are at risk of all the features of ALD developing.

Females have two X chromosomes and the fault can be completely or partially overcome by the healthy copy. GOSH notes the condition tends to be milder in females who do not develop the brain disease, but they may still be at risk of AMN and adrenal insufficiency later in life.

A boy with ALD will usually have inherited the changed X chromosome from his mother, although occasionally the change happens for the first time in the baby. If a woman carries the changed gene, each son has a 50 per cent chance of being affected and each daughter a 50 per cent chance of being a carrier. If a man with ALD has children, his sons will be unaffected because they receive his Y chromosome, while all of his daughters will inherit the changed X and be carriers.

Prenatal testing is possible by chorionic villus sampling early in pregnancy, and GOSH says advice about this is provided through the clinical genetics service.

GOSH stresses that many people with ALD are asymptomatic and may not know they have the condition. Sometimes the first sign relates to adrenal insufficiency, which can cause low blood glucose and problems that become evident during illness or infection. It adds that if adrenal insufficiency is diagnosed, ALD should be considered as one of the possible causes, especially if the insufficiency is not caused by autoimmune processes.

In around one in three boys with ALD the brain disease may develop during childhood. These boys have probably been well for the first few years of life. Between the ages of four years and early teens, hyperactivity may develop with disruptive behaviour, and memory and learning skills may cause concern. Increasing unsteadiness, loss of developmental skills, problems with vision and communication, seizures and later problems with feeding and swallowing can follow. GOSH says that if the condition continues to deteriorate and cannot be treated it will lead to death, sometimes within a few years of cerebral ALD developing.

For those who do not develop cerebral ALD, there is a longer-term risk of symptoms from the spinal cord disease, AMN, which can affect walking, mobility, and bladder and bowel function. Women who carry the gene can also develop AMN-type symptoms later in life.

The NHS describes Addison's disease as a rare condition where the adrenal glands do not work properly, and its symptoms include extreme tiredness, darker skin areas, loss of appetite, weight loss, feeling sick, dizziness on standing and cravings for salty foods. In ALD the cause is the underlying fatty acid problem rather than the more common autoimmune process.

The NHS says there is no cure, but the main treatment is steroid replacement, with medicines such as hydrocortisone, prednisolone or fludrocortisone usually taken every day for life, with extra doses when unwell or before surgery. It advises carrying a steroid emergency card and says adrenal crisis, which can be triggered by infection, injury or surgery, is a medical emergency that is usually treated with an injection of steroid medicine.

GOSH explains that if ALD is suspected a blood test is done that shows increased levels of very long chain fatty acids. Sometimes a blood test measuring a chemical called lyso-C26 phosphatidylcholine is also used, and genetic testing of the ABCD1 gene confirms the diagnosis.

The same page notes that in a few countries, but not the UK, the condition is tested for on the routine newborn heel-prick screening test. That means that in the UK diagnosis usually follows symptoms, adrenal insufficiency, or testing of relatives after a family member has been diagnosed. When one person is diagnosed, a clinical genetics service can offer testing to relatives who may carry the same gene change.

Care is shared by a team. GOSH lists the inherited metabolic disorders clinic, endocrinology for adrenal care, neurology for cerebral ALD and AMN, the bone marrow transplant team if needed, physiotherapy, speech and language therapy, dietitians and psychologists. For boys with advanced cerebral ALD, specialist symptom care or palliative care teams also give input.

Cerebral ALD can be effectively treated if it is detected at a very early stage, using bone marrow transplant, also called haematopoietic stem cell transplant. GOSH says there is also a gene therapy available in some countries, though not currently in the UK, that can treat early stages. If ALD is diagnosed, careful evaluation looks for cerebral disease, and if it has not developed there are regular check-ups including regular MRI brain scans to look for early signs.

For boys who already have advanced cerebral ALD when the diagnosis is made, transplant and gene therapy are not suitable, and high-quality symptom care becomes the priority. Research into new treatments for different aspects of ALD is ongoing.