Diseases title

X-linked cerebral adrenoleukodystrophy )

Orpha Number: 139396

X-linked cerebral adrenoleukodystrophy (X-CALD), a subtype of X-linked adrenoleukodystrophy (X-ALD, see this term), is a peroxisomal disease characterized by severe inflammatory demyelination in the brain, and often associated with adrenal insufficiency.X-CALD manifests in 70% of male and 2% of female cases of X-ALD, whose estimated birth incidence (male and female) is 1/20,000.X-CALD may occur in healthy boys (2.5-10 years old, 50% of cases), in symptomatic male adrenomyeloneuropathy (AMN, see this term) cases (35%), in adult males as the initial manifestation of X-ALD (~12%) and most rarely in adult women (2%). Adrenocortical insufficiency (AI, 65% of cases) is often latent, lacking melanoderma, presenting as fatigue, nausea or even acute primary adrenal insufficiency (see this term). AI sometimes precedes neurologic symptoms that are limited to mild cognitive dysfunction mimicking attention deficit disorder (ADD) in children. An active phase follows: emotional lability, cognitive decline and either visuospatial impairment or frontal syndrome are rapidly accompanied by deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures. Patients may lose the ability to understand language and to walk within weeks. Some patients (10%) remain in a chronic or arrested X-CALD and often develop marked visual-spatial and cognitive deficits. Disturbances resembling schizophrenia or psychosis may occur, particularly in adolescents and adults.X-CALD is due to mutations of ABCD1 (Xq28,) encoding ALDP, a peroxisomal transmembrane protein involved in the transport of very long chain fatty acid CoA-esters (VLCFA) into the peroxisome; perturbing VLCFA homeostasis in glial cells contributes to myelin destabilization. This leads to severe neuroinflammation with impairment of the neuro-vascular unit followed by rapid functional decline.Genetic testing must be preceded in men by testing for high plasma concentrations of VLCFA. Initially, brain MRI reveals characteristic abnormal white matter signals, often in the splenium or genu of the corpus callosum. Then, the extent of demyelinating lesions progresses, as revealed by peripheral injection of gadolinium.Initial symptoms in boys may ressemble ADD. AI symptoms may resemble congenital or acquired forms of Addison disease (see this term).Gestational chorionic villus sampling (10-13 weeks), amniocentesis (15-18 weeks) and pre-implantation genetic testing are feasibleTransmission is X-linked, with less than 8% de novo mutations. Genetic testing of parents and male extended family is mandatory to permit early detection by brain MRI and to propose therapeutic intervention. Systematic testing of women at risk to be carriers is also warranted to propose genetic counseling.Brain MRI is the sole means to detect demyelination prior to symptomatic onset and must be performed every 6 months from 3-12 years, and then annually up to 50 years for all X-ALD males. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only therapeutic intervention that can halt cerebral demyelination, but only when performed at a very early stage. Appropriate donors (HLA-identical non-affected siblings, HLA-matched unrelated donors or cord blood) must be identified rapidly. Autologous HSCT, genetically corrected ex vivo, had a similar efficacy to allogeneic HSCT in the first 4 treated patients. AI and hypogonadism are not cured by HSCT. Plasma testosterone, cortisol, mineralocorticoids, ACTH levels and ACTH stimulation reponses must be tested regularly. Replacement therapy may be required.Left untreated, all but 10% of patients are bedridden, blind, lacking speech and require fulltime care, dying within 2-5 years. Arrested X-CALD may enter a phase of rapid neurological deterioration at any time.
source: Orphanet