Early diagnosis of Adrenoleukodystrophy in patients with Idiopathic Primary Adrenal Insufficiency
Adrenoleukodystrophy (ALD) is a rare, X-linked neurodegenerative disorder primarily affecting males, though females can experience milder symptoms later in life. It is characterised by the inability to metabolise Very Long Chain Fatty Acids (VLCFAs), leading to their accumulation in the brain and irreversible demyelination which may lead to loss of life if not treated early. The condition presents in several key phenotypes:
- Asymptomatic ALD: Often identified through family screening, most patients will develop symptoms, with 80% of males developing primary adrenal insufficiency (PAI) which can be life-threatening if undiagnosed.
- Childhood Cerebral ALD (CCALD): Affects 35-40% of boys aged 4-10, typically presenting with behavioural issues, vision/hearing problems, and rapid neurological decline. Hematopoietic stem cell transplant (HSCT) can halt progression if administered early, but success is contingent on early detection.
- Arrested ALD: Approximately 10% of boys or young adult males with cerebral ALD may not develop the rapidly progressive disease. The same may occur in men with ACALD or in men with AMN. This is often referred to as arrested cerebral X-ALD. The cerebral demyelinating process arrests spontaneously and the patient can remain stable for many years, but there can be sudden onset of rapid neurologic deterioration even after many years of stable disease.
- Adrenomyeloneuropathy (AMN): Occurs in nearly all adult males with ALD, symptoms typically start between the ages of 30-40 years, affecting the spinal cord and peripheral nerves. Patients develop gradually progressive spastic paraparesis, sensory ataxia with impaired vibration sense, bladder disfunction, pain in the legs and impotence.
- Adult-Onset Cerebral ALD: Similar prognosis to CCALD in children, but treatment options are limited. Early intervention may involve Hematopoietic stem cell transplant.
- Females: Over 80% of females with the ALD gene develop symptoms by age 60 caused by demyelination of the spinal cord. Symptoms are similar to those seen in men with AMN including impaired walking, balance and bladder and bowel irregularities. It is very rare for females to have cerebral disease or primary adrenal insufficiency.
What is the problem?
Adrenoleukodystrophy patients often go through a long diagnostic odyssey. The early detection of ALD, before symptom onset, is key to improving treatment eligibility and patient outcomes. 80% of males with ALD are diagnosed with primary adrenal insufficiency (PAI) and it is often one of the first symptoms patients experience.
ALD is mentioned as a rare co-existing condition in the NICE Guideline Adrenal insufficiency: identification and management, though the current care pathway for these co-occurring conditions is underdeveloped. The identification of ALD in the PAI diagnostic pathway remains insufficient.
What are we trying to do?
Alex TLC are trying to bring awareness to the critical link between adrenoleukodystrophy and primary adrenal insufficiency.
We have established a working group of healthcare professionals, researchers, and other key stakeholders who are committed to advancing early detection strategies for ALD. Together, this group form a collaborative network to drive improvements in clinical practices and research, ensuring timely interventions and better outcomes for ALD patients.
What have we found so far?
As of April 2026, we have coordinated several Freedom of Information (FOI) requests from UK trusts with 62% of responding trusts confirming they have not tested any males with unexplained PAI for ALD. Testing for ALD at this stage is a simple, affordable diagnostic blood test to identify Very Long Chain Fatty Acid (VLCFA) levels. Male patients with ALD have elevated VLCFAs in the brain and adrenal glands which cause neurological problems and PAI. This illustrates a potentially life threatening gap in knowledge and awareness around the critical link between PAI and ALD.
Our goal
This project seeks to address the critical need for early ALD diagnosis in patients with idiopathic PAI by advocating for the integration of ALD testing into the PAI diagnostic pathway. We believe integrating ALD testing into routine PAI diagnosis where the cause is unknown will help facilitate early intervention and better clinical outcomes.
Interested in supporting our project?
We invite healthcare professionals, endocrinologists, researchers, and other stakeholders to join this vital initiative. By participating in the working group, you will contribute to advancing the clinical and research frameworks for ALD and PAI diagnosis, ultimately improving outcomes for patients across the healthcare system.
Please contact Alex TLC for further details and to express interest in participating in this important project. Your expertise and support are crucial to achieving these goals.
Contact details: Kristina Backlund, Research Analyst – kristina@alextlc.org