For decades, families facing a diagnosis of adrenoleukodystrophy (ALD) in their young sons have confronted a devastating reality.
This uncommon genetic disorder progressively destroys the protective fatty (myelin) sheath surrounding nerve and brain cells, often leading to rapid neurological decline and early death.
However, a promising advance in stem cell transplantation is transforming that outlook and offering new hope where once little existed.
Also known as X-linked ALD, this rare disease is caused by mutations in the ABCD1 gene, which is located on the X chromosome.
The most severe form, known as cerebral ALD, typically appears in affected boys between the ages of four and 10 years.
This mutation leads to the inability to metabolise dietary very long chain fatty acids (VLCFA) in the brain, nerves and adrenal glands, resulting in toxic accumulation in the body.
Without timely intervention, inflammatory damage in the brain can progress swiftly, robbing children of their ability to function.
Children with untreated ALD often decline to a vegetative state before dying within 10 years of developing symptoms.
Historically, the only established treatment capable of halting cerebral ALD has been haematopoietic stem cell transplantation.
Donor-derived stem cells can migrate into the brain and differentiate into microglial cells, which can help halt the inflammatory destruction of myelin, thus stabilising detrimental brain changes and preserving neurological function.
When performed at an early stage – before major neurological symptoms develop – this transplantation can slow or stop the inflammatory process.
However, finding a suitable donor is often a major obstacle.
For many families, a perfectly-matched sibling donor simply does not exist.
Unrelated donor matches, sourced through international registries, can take precious months to identify, in addition to overwhelming financial cost.
Now, the growing use of haploidentical, or “half-matched”, stem cell transplantation is changing the landscape.
In these procedures, stem cells from a parent can be used instead.
Stopping it early
Public awareness of ALD first heightened in the early 1990s with the release of the film Lorenzo’s Oil.
It chronicled the real-life struggles of Italian-American parents Augusto and Michaela Odone to save their son, Lorenzo, after his ALD diagnosis.
At the time, treatment options were limited.
The experimental dietary therapy known as “Lorenzo’s Oil” – a mixture of fatty acids designed to reduce harmful VLCFAs in the blood – generated both hope and controversy.
While it did not reverse established neurological damage, research suggested that the oil could delay disease onset, albeit temporarily, in boys who had not yet developed symptoms.
In the film, a physician offers a sobering assessment: “The oil may slow the accumulation (of VLCFAs), but it cannot undo what is already destroyed.”
That line, voicing decades of scientific frustration, underscored the urgent need for therapies capable of stopping brain inflammation once it begins.
Today, stem cell transplantation – especially when performed early – offers precisely that potential.
It started with seizures
Muhamad Faaeq Muhd Fitrizuhaili first presented with seizures at the age of five years.
He had been well until that point in time and the fits were initially thought to be related to Covid-19.
Over subsequent months, he had two further epileptic episodes that required hospital admission.
Despite repeated blood and radiological investigations, the diagnosis of ALD was only established 18 months later, reflecting the rarity of the condition.
He was then referred to Universiti Malaya Medical Centre (UMMC) in Kuala Lumpur for stem cell transplantation.
At that point, Muhamad Faaeq already had some neurological changes involving his vision and gait.
He underwent a “half-matched” stem cell transplant using his father as the donor.
Muhamad Faaeq’s younger brother, four-year-old Aqil Fahmi, was also screened for the disease.
Unfortunately, he was found to have inherited the mutation as well.
Although he appeared completely well, an MRI (magnetic resonance imaging) scan of Aqil’s brain showed early changes consistent with ALD.
The UMMC team expedited the transplant for Aqil, also using his father’s stem cells, which was done five months after his elder brother.
Today, nearly two years after their respective transplants, Faaeq uses glasses and has minor mobility issues, but Aqil remains symptom-free.
Both brothers are otherwise well and are attending normal school.
The earlier, the better
Haploidentical transplantation allows physicians to use stem cells from a biological parent, who is always at least a 50% match as each child would have received half their genes.
Advances in graft engineering and immune suppression have significantly reduced the risk of graft-versus-host disease (GVHD).
GVHD is a potentially life-threatening complication that historically limited the use of partially-matched donors.
This approach essentially ensures that nearly every child has a donor immediately available, and that immediacy, especially for boys with ALD, can be lifesaving.
Because ALD progression can accelerate within months, eliminating the delay associated with donor searches is critical.
Early transplantation – before severe neurological symptoms develop – remains the key to preserving cognitive and motor function.
Clinicians consistently point to early diagnosis as the single most important factor in altering the course of ALD.
Often, affected children are not diagnosed until they attend school.
Early symptoms of ALD in primary school-aged boys include behavioural problems and learning disabilities.
These findings may mimic other conditions such as attention-deficit/hyperactivity disorder (ADHD), delaying the diagnosis of ALD.
In the United States, ALD is included in nationwide newborn screening.
This allows affected boys to be identified in infancy and monitored closely with regular MRI scans and laboratory testing before neurological symptoms develop.
In Malaysia, however, ALD is not currently part of the standard newborn heel prick screening panel.
Even so, early detection is still readily achievable.
Screening for elevated VLCFAs, followed by confirmatory genetic testing, can be arranged through many private hospitals and specialised diagnostic centres.
Expanding access to early testing, whether through public health initiatives or private healthcare providers, increases the likelihood of identifying boys before irreversible brain damage occurs.
This then creates the opportunity for timely stem cell transplantation and far better long-term outcomes.
From deadly to a normal life
Currently, the two most decisive interventions in altering the course of ALD are early detection and timely stem cell transplantation.
For families who once faced ALD with few options and overwhelming uncertainty, the opportunity for a parent to become their child’s stem cell donor through haploidentical haematopoietic stem cell transplantation represents more than medical progress – it is a profoundly personal act of hope.
More than three decades after Lorenzo’s Oil introduced ALD to global audiences, the narrative has shifted.
What was once a story marked largely by desperate experimental dietary therapies is now increasingly defined by early screening, rapid intervention and measurable clinical success.
For boys like Muhamad Faaeq and Aqil Fahmi, the outlook is increasingly promising.
With timely referral and early therapeutic access, as well as medical advances such as haploidentical transplantation, ALD is progressively shifting from a uniformly-devastating diagnosis to a condition in which meaningful stabilisation and long-term survival are achievable clinical outcomes.
Prof Dr Hany Ariffin is the UMMC Paediatric Blood and Marrow Transplant Unit head. Dr Goh Jun Yan is a Clinical Fellow at the Unit. For more information, email starhealth@thestar.com.my. The information provided is for educational and communication purposes only, and should not be considered as medical advice. The Star does not give any warranty on accuracy, completeness, functionality, usefulness or other assurances as to the content appearing in this article. The Star disclaims all responsibility for any losses, damage to property or personal injury suffered directly or indirectly from reliance on such information.
