X-linked adrenoleukodystrophy is the most common leukodystrophy in males of all ages.
Summary
Cause
X-linked adrenoleukodystrophy (ALD, OMIM #300100) is a peroxisomal metabolic disorder linked to the X chromosome, involving both neurological and adrenal impairments. ALD results from pathogenic variants in the ABCD1 gene and the consequent loss of function of the ALD protein (a peroxisomal transmembrane protein). This leads to abnormal degradation and accumulation of very long-chain fatty acids (VLCFAs) in plasma and tissues.
The most common biochemical marker of the disease is elevated plasma levels of VLCFAs. Biochemical developments in ALD have identified another biomarker in ALD: C26:0-lysophosphatidyl-CoA (C26:0-LysoPC). C26:0-LysoPC shows comparable (or even greater) analytical performance to VLCFAs in men but offers better diagnostic accuracy for women.
Symptoms
ALD is the most common genetic leukodystrophy in males of all ages, with an incidence of 1 in 17,000. Affected males can develop three main clinical syndromes, with no clear genotype-phenotype correlation:
- Adrenomyeloneuropathy (AMN): A slowly progressing myeloneuropathy that begins between 20 and 40 years of age, with complete penetrance usually by age 60 in men; AMN can also occur in heterozygous women.
- Adrenal insufficiency: Often starts in childhood but can occur at any age, affecting 80% of male patients.
- Cerebral form (CALD): A rapidly progressing inflammatory leukodystrophy that can occur at any age in male patients.
CALD is the most severe manifestation of ALD. It typically presents insidiously, followed by rapid neurological deterioration that can lead to premature death within months to a few years. CALD can appear in childhood, between ages 3 and 12, affecting 35-40% of boys.
In adults, over 50% of AMN patients are at risk of developing CALD within 10 years. Therefore, the majority of males with ALD will eventually develop CALD. Cerebral forms in adults can either occur in asymptomatic men (often with adrenal impairment) or in men with AMN. Cerebral demyelination may manifest as either rapidly progressive motor and/or cognitive impairment or as worsening motor symptoms, psychiatric deterioration, and/or cognitive decline in AMN patients.
In a male with a pathogenic variant in the ABCD1 gene, warning signs that require urgent investigation for the cerebral form (including an emergency MRI) include (but are not limited to):
- The onset of behavioral changes, such as depression or addictive behaviors;
- Cognitive decline, potentially starting with executive dysfunction, leading to difficulties at work or noticeable impact on daily life as observed by family;
- Motor symptoms not typical of AMN, particularly cerebellar syndrome and/or extrapyramidal manifestations;
- Rapid worsening of pyramidal involvement, unusual for AMN;
- Auditory or visual symptoms.
Treatment
The gold standard for CALD is hematopoietic stem cell transplantation (HSCT), preferably using bone marrow. If performed early, when cerebral demyelination and clinical symptoms are minimal or absent, HSCT can halt neuroinflammation, stabilize the neurological disease, and improve long-term survival with excellent quality of life in affected boys or men. Unlike in children, clinical benefits can still be observed in adults with moderate lesion load. Consequently, it is essential for all boys and men with X-ALD to undergo regular brain MRI follow-ups to detect early brain lesions—every six months between 2 and 12 years of age, and annually after age 12, with no upper age limit in adults.
Unfortunately, many men with CALD are ineligible for HSCT due to age (>50-55 years), lack of a compatible donor, or corticospinal tract lesions progressing too quickly for HSCT to have an effect on the brain. A small molecule called leriglitazone offers promising therapeutic options for men with CALD. In a double-blind, randomized controlled trial of 116 men with AMN, leriglitazone significantly reduced the incidence of cerebral forms over two years compared to placebo. A French compassionate study has shown that leriglitazone appears to halt the progression of CALD and allows for clinical and radiological stabilization in patients at early to moderate stages of CALD. A randomized controlled trial is currently underway for men with CALD who are not eligible for HSCT.