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At a glance

A peroxisomal metabolic disorder characterized by progressive demyelinization of the central nervous system and peripheral adrenal insufficiency resulting from adrenal gland atrophy.

Synonyms

Adrenomyeloneuropathy; Addison Disease and Cerebral Sclerosis; Siemerling-Creutzfeldt Disease; Bronze Schilder Disease; Melanodermic Leukodystrophy.

Nature

Genetic disorder, mainly affecting males but 50% of female heterozygotes have symptoms.

Incidence

1:15,000 to 1:100,000 in general population, 1:21,000 in males.

Genetic inheritance

X-linked inherited with 4% de novo mutation. All patients carry a mutation in ABCD1 gene. Manifesting either as rapidly progressive cerebral demyelination in childhood (X-adrenoleukodystrophy childhood form, most severe) or as progressive myelopathy in adulthood (adrenomyeloneuropathy, AMN). Gene locus is the long arm of X chromosome at position 28 (Xq28), which codes for an 80-kDa transmembrane transporter protein. Mutation can be missense, frameshift, nonsense, or deletion. This syndrome is distinct from neonatal adrenoleukodystrophy (autosomal recessive).

Pathophysiology

Very-long-chain fatty acids (VLCFA) are metabolized by VLCFA-CoA synthetases in peroxisomes or mitochondria. Adrenoleukodystrophy gene mutation may impair the peroxisomal import of this synthetase, leading to VLCFAs (>C22) accumulation especially in nervous system, adrenal glands, and testis. Whether these long, rigid, acyl fatty acids reduce membrane fluidity, causing an inflammatory response in the nervous system (demyelination), and reduce steroid synthesis in the adrenal glands remains unresolved.

Diagnosis

Clinical course with demyelinization signs and association of peripheral adrenal insufficiency in 80% of children forms and 65% of adult forms. Diagnosis is confirmed by abnormally high saturated VLCFAs and C26:C22 ratio in blood or accessible tissues. Radiologic imaging reveals symmetrical hypodense corpus callosum and periventricular white matter. ABCD1 mutation analysis recommended in women with adrenoleukodystrophy. Prenatal (chorion villus biopsy) and female heterozygotes (VLCFA profiles) diagnosis available.

Clinical aspects

There are three forms of XLA that consists of:

  • X-Adrenoleukodystrophy Childhood Form: Normal childhood development until a mean age of 7 years, followed by parietal-occipital demyelination with rapidly progressive dementia, behavioral changes, visual/auditory defect, and seizures; 90% of patients have an adrenal insufficiency. Average life span is 9.4 years.

  • Adrenomyeloneuropathy: Milder form with adult onset. Near 100% lifetime penetrance: virtually all men and up to 80% of women with the disease develop myelopathy. Spinal cord involvement (paraparesis/sphincter problems) is more common than cerebral (50% of cases) or adrenal (30% of cases) dysfunction.

  • Female Heterozygotes: Similar clinical picture as adrenomyeloneuropathy; however, presenting normal adrenal glands (99% of cases). Often misdiagnosed as multiple sclerosis.

Early diagnosis of boys, especially at birth, allows for detection of adrenal insufficiency and timely initiation of treatment with adrenal steroid replacement medications. Curative treatment with either hematopoietic stem cell transplantation or Lenti-D gene therapy (lentiviral vector that contained manufactured ABCD1gene). Lorenzo’s oil (oleic acid ...

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