X-Linked Adrenoleukodystrophy (X-ALD)

1. DEFINITION AND ETIOLOGY

Definition: The most common Peroxisomal Disorder, characterized by impaired peroxisomal beta-oxidation of Very Long Chain Fatty Acids (VLCFA).
Inheritance: X-Linked Recessive.
Gene: ABCD1 gene located on chromosome Xq28.
Protein Defect: Deficiency of the Adrenoleukodystrophy Protein (ALDP), a peroxisomal transmembrane transporter protein.
Pathophysiology:
- Defective transport of VLCFA into the peroxisome prevents their breakdown.
- Accumulation: Massive accumulation of saturated VLCFAs (specifically C26:0 and C24:0) in tissues and plasma.
- Target Tissues:
  - CNS White Matter: Inflammatory demyelination (leading to leukodystrophy).
  - Adrenal Cortex: Cytotoxicity to adrenocortical cells (leading to atrophy/insufficiency).
  - Leydig Cells: Testicular dysfunction.

Phenotypic expression is highly variable even within the same family. There is no genotype-phenotype correlation.

Onset: 4–8 years of age (Boys).
Course: Rapidly progressive inflammatory demyelination.
Symptoms:
- Early: ADHD-like behavior, school failure, auditory processing problems, vision loss.
- Late: Spasticity, seizures, vegetative state, cortical blindness/deafness.
Outcome: Death or permanent disability within 2–5 years of onset without treatment.

Onset: Young adulthood (20s–30s).
Pathology: Non-inflammatory distal axonopathy involving the spinal cord.
Symptoms: Progressive spastic paraparesis, sensory ataxia, sphincter dysfunction (neurogenic bladder/bowel).
Note: Many CCALD patients who survive or slow-progressors evolve into AMN.

Presentation: Primary Adrenal Insufficiency without neurological signs at onset.
Risk: Most will eventually develop AMN or cerebral involvement.
Clinical Tip: Any boy with idiopathic Addison's disease must be screened for X-ALD.

Carrier females may develop mild spastic paraparesis (AMN-like) in later life (>40 years).

Biochemical Screening (Gold Standard):
- Plasma VLCFA: Elevated levels of Hexacosanoic acid (C26:0) and high ratios of C26:0/C22:0 and C24:0/C22:0.
Imaging (MRI Brain):
- Pattern: Symmetrical T2-hyperintensity in the Parieto-Occipital white matter (posterior zones).
- Contrast: Enhancement at the leading edge indicates active inflammation (Active Cerebral ALD).
- Loes Score: A 34-point scale used to grade severity of MRI involvement; critical for transplant decisions.
Endocrine Function:
- Elevated ACTH (often the earliest sign of adrenal dysfunction).
- Blunted cortisol response to ACTH stimulation (Synacthen test).
Molecular Genetics: ABCD1 gene sequencing (confirmatory).

Multidisciplinary approach is required.

Corticosteroid replacement (Hydrocortisone/Fludrocortisone) for adrenal insufficiency.
Note: Does not alter the progression of neurological disease.

Indication: Early-stage Childhood Cerebral ALD (Loes score < 9) with Gadolinium enhancement.
Mechanism: Replaces defective microglial cells, arrests inflammation and demyelination.
Efficacy: Only effective if performed before significant neurological symptoms appear. Contraindicated in advanced disease.

Composition: 4:1 mixture of Glyceryl Trioleate (GTO) and Glyceryl Trierucate (GTE).
Effect: Normalizes plasma VLCFA levels by inhibiting the elongase enzyme.
Clinical Utility:
- Does NOT improve neurological symptoms in established cerebral ALD.
- May have a preventive role in asymptomatic boys to delay onset (controversial).

Untreated Cerebral Form: Fatal within years.
AMN: Chronic progression over decades.
Early Transplant: Can result in long-term survival with arrested disease progression.