X-Linked Adrenoleukodystrophy · X-ALD

Description

X-linked adrenoleukodystrophy is an inherited disorder of peroxisomal fatty acid metabolism. Pathogenic variants in ABCD1 disrupt the adrenoleukodystrophy protein, a peroxisomal transporter required for import of very long-chain fatty acids (VLCFAs) for beta-oxidation. VLCFAs accumulate in plasma, adrenal cortex, testis, and the white matter of the brain and spinal cord. Inheritance is X-linked. ABCD1 sits at Xq28.

The disorder presents along a spectrum that varies even within a single family. Cerebral ALD is the most aggressive form. Inflammatory demyelination begins most often between ages 4 and 10 in boys, and untreated cerebral disease progresses to severe disability or death within a few years of symptom onset. Adrenomyeloneuropathy, the adult-onset form, presents in the third or fourth decade with a slowly progressive spastic paraparesis, sphincter and sexual dysfunction, and adrenal insufficiency. Primary adrenal insufficiency, sometimes called Addison disease, develops in roughly 80 percent of affected males by adulthood and may be the first sign. Heterozygous females develop neurologic symptoms with age, often in midlife.

Detection is by newborn screening on the dried blood spot. The screening assay measures C26:0-lysophosphatidylcholine, a lysophosphatidylcholine species elevated in ABCD1 deficiency, by tandem mass spectrometry. Confirmation uses plasma VLCFA profiling and ABCD1 sequencing. X-ALD was added to the Recommended Uniform Screening Panel in February 2016 after New York State began statewide screening in December 2013. Reported incidence on screening is roughly 1 in 14,700 male births in pooled US data.

Treatments to date

Pre-symptomatic identification permits a structured surveillance program. Boys with ABCD1 variants enter serial brain MRI surveillance, typically every six months from around age 3, to detect the earliest inflammatory white matter lesions. Adrenal function is monitored with morning cortisol and ACTH, and corticosteroid replacement begins when adrenal insufficiency is documented. Adrenal replacement does not alter neurologic course.

Allogeneic hematopoietic stem cell transplant halts cerebral ALD when performed early in the inflammatory phase, defined by limited MRI burden and preserved neurologic function. Outcomes depend on disease stage at transplant; advanced cerebral disease at the time of transplant carries far worse outcomes. The procedure carries the standard risks of allogeneic HSCT, including graft-versus-host disease and treatment-related mortality.

Elivaldogene autotemcel, marketed as Skysona, was approved by the FDA in September 2022 for boys ages 4 to 17 with early active cerebral ALD. The therapy is an autologous CD34-positive cell product transduced ex vivo with a lentiviral vector carrying functional ABCD1, returned to the recipient after myeloablative conditioning. The label carries a boxed warning for hematologic malignancy following treatment, reflecting cases of myelodysplastic syndrome reported in clinical development.

Lorenzo's oil, a 4-to-1 mixture of glyceryl trioleate and glyceryl trierucate, lowers plasma VLCFA but has limited evidence for prevention of cerebral disease and is not FDA-approved for ALD. Adrenomyeloneuropathy is managed symptomatically; no therapy halts the spinal cord disease. Leriglitazone, a selective PPAR gamma agonist, has been studied in adrenomyeloneuropathy with mixed clinical results.