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X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder resulting in cerebral demyelination, axonal dysfunction in the spinal cord leading to spastic paraplegia, adrenal insufficiency and in some cases testicular insufficiency.
X-ALD is the most common peroxisomal disorder with an estimated birth incidence is 1/20,000 (male and female). It has been reported throughout the world.
X-ALD most severely affects male hemizygotes and less severely affects 60% of female heterozygotes. The age of onset and morbidity are highly variable and progression is unpredictable. Male hemizygotes may initially present with neurological symptoms in two different forms: X-linked cerebral adrenoleukodystrophy (X-CALD) and adrenomyeloneuropathy (AMN). X-CALD is the most devastating manifestation of X-ALD, affecting 2.5-12 year old boys in about 35% of X-ALD cases. It may more rarely present as the initial manifestation of X-ALD in adolescent (<7%) or adult (<5%) males. Primary manifestations of X-CALD are moderate cognitive deficits followed by diminished visual acuity, central deafness, cerebellar ataxia, hemiplegia, convulsions and dementia leading to a neurovegetative state or death within several years. AMN is characterized by the onset of spastic paraparesia in adult men (mean age of 30) associated with gait disturbances due to sensory ataxia, urinary disorders and sexual dysfunction. In 35% of cases, over a 10 year period AMN progresses towards severe paraplegia complicated by cerebral demyelinization (X-CALD). Adrenocortical insufficiency (AI) is reported in 70% of all male X-ALD patients and may be the initial presentation years or even decades prior to the onset of neurological symptoms. AI in X-ALD is reminiscent of Addison disease, manifesting with fatigue, nausea, weight loss, hypotension and hypoglyacemia. Acute primary adrenal insufficiency, or adrenal crisis, may be the first manifestation of X-ALD. In 10% of X-ALD males AI may be the exclusive manifestation of the disease for years. However, all patients with initially isolated AI are at risk to develop X-CALD, AMN or both. Hypogonadism has also been reported in adult males with X-ALD. Many female carriers of X-ALD (>60%) show signs of AMN, albeit generally less severe than men and with a later onset (>40 years). In these AMN symptomatic women, X-CALD and AI are rare (2% and 1%, respectively).
X-ALD is caused by mutations of ABCD1 (Xq28). More than 1,200 different mutations in the gene have been reported. No direct correlation has been made between the different mutations and phenotype. The gene codes for ALDP, a peroxisomal transmembrane protein involved in the transport of very long-chain fatty acid CoA-esters (VLCFA) from the cytosol into the peroxisome. Ablation or dysfunction of ALDP leads to an accumulation of these hydrophobic VLCFA in various lipid fractions as well as in proteins acylated with fatty acids. Perturbed VLCFA homeostasis in glial cells may contribute to the destabilization of the myelin sheath and impairment of axonal function. In males the diagnosis can be performed upon the measurement of VLCFA in plasma. A significant percentage of heterozygous women for X-ALD have normal levels of plasmatic VLCFA.
Antenatal ABCD1 mutational analysis may be performed and pre-implantation genetic diagnosis is available in some countries.
Transmission is X-linked with complete penetrance in male hemizygotes and 60% of female heterozygotes develop some less severe neurological symptoms later in life. Genetic counseling must be offered to the parents and extended family of those affected with X-ALD, and genetic testing both to detect carriers and to follow the presymptomatic boys or adult males is mandatory.