X-linked Adrenoleukodystrophy (XALD)

In Ontario, every baby has a few drops of blood taken from their heel when they are about a day old. The blood is tested for more than 25 treatable diseases, including X-linked adrenoleukodystrophy (XALD). The target of screening for XALD is the most severe form which is called childhood cerebral adrenoleukodystrophy (CCALD). A pilot program screening for XALD will start in a small, random subset of the population in March 2025. Therefore, some infants will be screened for XALD during this time period. If a screened sample is positive, infants will be referred for follow up. It is expected that in August 2025, XALD will officially be added to the newborn screening panel in Ontario.  After this date, all samples received at NSO will be screened for XALD. 

A screen positive result means that the baby is at risk for XALD but more tests are needed to know for sure. It does not mean that a baby has XALD. Babies identified at a young age through screening can be monitored for symptoms and treated early to help prevent health problems.

• X-linked adrenoleukodystrophy (XALD) is a rare inherited (genetic) disease that affects the central nervous system and the adrenal glands. 
• XALD is caused by variants in the ABCD1 gene which is located on the X chromosome (‘X-linked’). Individuals with one X chromosome (typically males) who have a genetic change in their ABCD1 gene will be at risk of developing the severe form of XALD (CCALD).  Individuals with two X chromosomes (typically females) are usually not at risk of developing XALD as they have two copies of the ABCD1 gene, and it is unlikely both copies will have a genetic change. 
• The adrenal glands produce important chemical signals (hormones) that regulate our metabolism.  When these hormones are not produced at adequate levels, it can result in a condition called adrenal insufficiency.
• Leukodystrophy refers to conditions that affect the white matter of the central nervous system.
• There are 3 main types of XALD:
• Cerebral (CCALD): This is the most severe form of XALD.  Brain (neurological) changes typically appear in childhood (typically 4-8 years of age). Adrenal insufficiency can occur at any time starting in early childhood (typically age 2 and onward). Approximately 40% of males with XALD will have this form.
• Adrenal insufficiency: Adrenal insufficiency with no other symptoms accounts for ~10% of cases of XALD. It can present from age 2 to adulthood.
• Adrenomyeloneuropathy: symptoms are adult onset (20s-30s) and result in slow progression of muscle and nerve changes in the body (leg weakness, muscle control problems) and adrenal insufficiency.  This form accounts for ~45% of XALD cases.
• The goal of newborn screening for XALD is to detect the cerebral form of the disease (CCALD).  For babies who screen positive for XALD, careful monitoring is required to detect the possible development of CCALD or adrenal insufficiency. There is no way to predict the disease type or severity in the newborn period.

• A screen positive result means that the baby is at risk to have XALD, but more testing is needed to be sure.   
• It is natural for parents and guardians to feel worried and have questions when their baby has a screen positive result.
• A health care provider at a newborn screening regional treatment centre or the baby’s healthcare provider will discuss the screening results with the baby’s family.
• Follow-up blood tests and an assessment with a metabolic or genetic specialist are arranged as soon as possible
• It can take a few weeks to find out if a baby truly has XALD or not. This waiting period can be hard for families. 

• Normal – the follow-up test results show that the baby does not have XALD.
• Abnormal – the baby does have XALD and will need monitoring. The family will be supported by a team of caring specialists.
• Inconclusive – more testing is required in order to determine if the baby does or does not have XALD.  The baby will be followed closely by a specialist to ensure that he/she receives optimal care.

Babies with XALD usually do not have any symptoms at birth. Symptoms can appear in the first few years of life due to adrenal insufficiency.  Symptoms of the cerebral form of the disorder usually don’t appear until mid-childhood (typically 4-8 years of age).  Symptoms of CCALD can include:

• Behavioral changes
• Cognitive decline
• Loss of skills (regression)
• Muscle weakness
• Seizures
• Decreased appetite
• Fatigue

Children with CCALD can benefit from being identified early, being monitored for signs/symptoms and getting treatment sooner when needed.

If your baby is found to have XALD, your baby’s healthcare team will discuss management and treatment options available to your child.

• Regular follow-up tests are used to monitor for signs/symptoms of adrenal insufficiency or CCALD.
• Babies with XALD have their health and development checked regularly.

Through continued monitoring, treatment can be started as early as possible when symptoms appear, to avoid adrenal crisis and changes to the nervous system.