Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD) is a rare inherited disorder treated at Great Ormond Street Hospital (GOSH) led by the inherited metabolic disorder (IMD) service. ALD can affect the adrenal glands, causing “adrenal insufficiency”, as well as the nerves of the spinal cord (called “adrenomyeloneuropathy (AMN)”), and sometimes affecting the white matter of the brain as well (cerebral adrenoleukodystrophy (cALD).

ALD is one of a group of disorders caused by a defect of peroxisomes, which are essential for the breakdown of very long chain fatty acids in cells. In ALD the process of transporting the very long chain fatty acids into the peroxisomes is faulty. This results in the damage to the adrenal glands, and the nerves of the spinal cord, and the myelin of the brain cells (the substance around nerve fibres that is essential for transmission of messages between brain cells and the rest of the body). It is not fully understood why the damage occurs.

If ALD is suspected, a blood test is done that will show increased levels of the very long chain fatty acids (VLCFA). Sometimes a blood test measuring a specific chemical (lyso-C26 phosphatidylcholine) may also be used. Genetic testing to look at the ALD gene (ABCD1 gene) will also be done to confirm the diagnosis.

In a few countries (but not the UK) the condition is tested for on the routine newborn heel-prick screening test.

The condition used to be called Addison-Schilder’s disease, after the doctor who first recognised it in 1923.

ALD is a genetic or inherited disorder. It is an X-linked recessive disorder. The ABCD1 gene is located on the X chromosome, which is one of the sex chromosomes. Females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). In males, who only have one X, there is not another X to provide a functioning gene. Males who have the faulty ABCD1 gene are at risk of all features of ALD developing.

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

A boy with ALD will usually have inherited the faulty X-chromosome from his mother, although occasionally the genetic change occurs for the first time in the baby (a de novo genetic change). If a female has the faulty ABCD1 gene in one of the X chromosomes she is termed a “carrier” for the condition. Any male child that she has will have a 50% chance of inheriting the faulty X-chromosome with the faulty ABCD1 gene and so will be affected by ALD, and a 50% chance of inheriting the healthy X-chromosome and healthy ABCD1 gene and not having ALD. Any female child that she has will have a 50% chance of inheriting the faulty X-chromosome with the faulty ABCD1 gene and so also being a carrier for the condition.

If a male with ALD has a child, any male children will be unaffected as only the Y chromosome is passed on from father to son, while all female children will inherit the faulty X-chromosome and ABCD1 gene and so be a carrier for ALD.

Prenatal testing is possible by chorionic villus sampling early in pregnancy, and advice regarding this is provided via the Clinical Genetics service.

It affects approximately one in every 20,000 males.

Care of children with ALD will require the input from many different health care professionals. Patients with ALD are managed in the inherited metabolic disorders clinic by specialists in metabolic medicine. Input from endocrinology teams in monitoring and treating adrenal insufficiency will be important. Neurology teams will provide input for those who have problems from cALD and (later in life) from adrenomyeloneuropathy. The Bone Marrow Transplant (BMT) team will be involved if this treatment is required. Input from other teams including physiotherapy, speech and language therapy, dietitians and psychologists will also be important.

For boys who develop advanced forms of cerebral ALD, input from specialist symptom care or palliative care teams will also be important.

Many people with ALD are “asymptomatic” and do not know that they have the condition.

Sometimes the first sign of the condition relates to adrenal insufficiency, which can lead to problems including low blood glucose (hypoglycaemia), and problems that become evident during illness or infection. If adrenal insufficiency is diagnosed, it is important that ALD is considered as one of the potential causes (especially if the adrenal insufficiency is not caused by the autoimmune processes).

In around one in three boys with ALD, the brain disease (cerebral ALD) may develop during childhood. For boys who develop cALD, they will probably have 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. If cALD occurs, there may be increasing problems with unsteadiness, and loss of developmental skills. Problems with vision and communication may develop, and there is the risk of seizures (epilepsy). If the condition progress, there can be problems with feeding and swallowing. Sadly, if the condition continues to deteriorate and cannot be treated, ALD will lead to death, sometimes within a few years of cALD developing.

For patients who do not develop cALD, there is still a longer term risk of developing symptoms relating to the spinal cord disease (AMN), which can affected walking, mobility and bladder/bowel function.

Adrenal insufficiency can be treated by giving replacement hormones (which are essential for life).

Cerebral ALD (cALD) can be effectively treated if it is detected at a very early stage, using bone marrow transplant (BMT, also called haematopoietic stem cell transplant (HSCT)). There is also a gene therapy transplant available in some countries (not currently the UK) that can treat early stages of cALD.

If ALD is diagnosed, careful evaluation will be made to see if cALD has already developed. If it has not, ongoing regular check-ups including with regular MRI brain scans will be undertaken to look out for early signs of cALD.

For boys who already have advanced stages of cALD when the diagnosis is first made, BMT/HSCT and gene therapy will not be suitable. In that situation, high-quality symptom care management will be important to address all the problems that ALD can cause.

There is a lot of ongoing research exploring new potential treatments for the different aspects of ALD.

Further information can be obtained from the GOSH metabolic team, and also from Alex, The Leukodystrophy Charity.