Adrenoleukodistrophy (ALD) is a chromosome X-linked rare inherited neurodegenerative disorder that affects the brain, nerves, and adrenal glands.
The disease is caused by mutations of the ABCD1 gene that result in loss of function of the encoded ALD protein (ALDP), an ABCD transporter located in the peroxisomal membrane.
The pathogenic variants in ABCD1 gene lead to deficient β-oxidation of saturated very-long-chain fatty acids (VLCFAs), being VLCFAs in plasma a diagnostic marker of the disease.
Additionally, mutations in the ABCD1 gene also cause changes in adhesion molecules and tight junctions in the brain endothelium, which in turn promote an increase in Blood-Brain- Barrier (BBB) permeability, independently of VLCFA accumulation.
As a result, ALD causes severe axonal damage in central and peripheral nervous system, resulting in a chronic progressive myelopathic and neuropathic Adrenomieloneuropathy (AMN) in adulthood.
In addition to chronic neurodegeneration, acute inflammatory brain demyelination can appear, either in childhood or in adults, which is known as cerebral ALD (cALD), leading to rapid death or vegetative state.
cALD is therefore the most rapidly progressive, and the most devastating form of X-linked adrenoleukodystrophy (’X-ALD’), affecting the brain, which causes progressive loss of mental and physical abilities. As a X chromosome linked disease, cALD typically affects boys and men and is characterized by the presence of demyelinating brain lesions. Progressive cALD onset can occur at any time.
X-ALD has an estimated birth incidence of 1 in 20,000 worldwide (male and female), and neither ethnicity nor country of birth is thought to have any impact on this.
The estimated prevalence is 0.35 per 10,000 people in the EU.
Childhood cALD occurs in 31-35% of ALD patients with onset typically between age 2 and 12 years of age. Recent literature reports that most of adult ALD men, i.e., up to 60%, will develop cALD over time, in addition to their myeloneuropathy (50% in an observation period of 15.1 years; 63% with a mean of 10 years from myeloneuropathy symptoms onset).
cALD is a genetic disease.
cALD can affect both paediatric and adult individuals.
Approximately 60% of male X-ALD patients develop cerebral involvement during their lifetime. It occurs in approximately one-third of affected boys between the ages of 3 and 11 years and in less than 10% of adolescents (11 – 21 years). Approximately 20% of adult males with AMN, a chronic manifestation of X-ALD, experience progression to cALD. cALD is extremely rare in women, and few confirmed or suspected cALD cases have been reported in women.
According to recently published guidelines for the diagnosis and management of patients with ALD, cALD should be considered in boys and men with white matter abnormalities on brain magnetic resonance imaging (MRI) with or without cognitive and neurological symptoms, as these MRI abnormalities precede and predict symptoms and ultimately death.
Progressive cALD is characterized by severe and rapidly increasing cerebral demyelination, breakdown of the blood-brain barrier with subsequent infiltration of immune cells, and a consequent increase in inflammation in the brain and associated brain lesions. When such lesions become progressive, they show rapid growth, which is followed by acute neurological decline and death in three to four years. The symptoms often begin as early as elementary school age period. While initial child development is still age-appropriate, the very first signs of behavioural, personality changes and learning difficulties might occur very suddenly.
If progressive cALD does not occur until adulthood, the first symptoms are usually psychiatric in nature. Due to the unexpected symptom onset, progressive cALD is often not recognized at its early stage and misdiagnosis is common (attention deficit hyperactivity disorder, depression, psychosis).
Because of the severe and rapidly progressing inflammatory process in the brain, more severe symptoms soon follow. Thus, visual, and auditory disturbances may initially occur, accompanied by weakness in the extremities, coordination disorders and cramps. Gait difficulties, as well as a lack of postural control, are correspondingly common.
Children may lose the ability to walk or speak or communicate meaningfully within a few months. Even in adulthood, after initial behavioral and neurological deficits, an equally massive symptom progression occurs.
The gold standard for diagnosis of cALD uses Magnetic Resonance Imaging (MRI) scans. At the onset of the disease, typical MRI findings include detectable demyelination of the splenium corporis callosum and adjacent parieto-occipital white matter or the genu corporis callosum and adjacent frontal white matter. Even before the onset of typical symptoms, i.e. even mild cognitive deficits, MRI can detect cerebral demyelination.
Later, active demyelinating lesions increase in extension, detectable after peripheral gadolinium injection, and correlate with disease progression.
Therefore, regular MRI examinations are recommended with gadolinium-containing contrast agents in childhood boys, as progression to cALD is most common between 3 and 12 years of age. If the MRI findings are initially normal, the examination should be repeated every six months in this age group and later annually, until the age of 50 years.
An MRI-based scoring system, called the Loes system, records the location and extent of lesions and the presence of focal and/or global brain atrophy. It can, therefore, quantify the extent of cerebral neuronal degeneration.
Clinical status – typical symptoms and imaging findings, is the initial diagnostic finding in patients without a family history of X-ALD. In cases of familial history or negative clinical status, ABCD1 gene analysis is recommended directly.
Genetic testing (ABCD1 analysis) is the gold standard to have a diagnostic confirmation. For biochemical testing, plasma C26:0-lysophosphatidylcholine (C26:0-lysoPC) has superior diagnostic performance.
If unavailable, fasting plasma VLCFAs (C26:0; C26:0/C22:0; C24:0/C22:0) should be obtained. Diagnostic algorithms are gender specific because VLCFA may be (near) normal in women.
Currently, there is no pharmacological curative treatment. To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only available therapeutic option with life-prolonging potential and potentially curative therapeutic approach in cALD.
In general, for patients for whom allogeneic HSCT is not an option, the only remaining option is “best supportive care”. The aim here is to alleviate symptoms and, if necessary, to achieve the best possible quality of life through psychological support.
Currently, there is no way to prevent cALD.
Alzheimer's
Alzheimer's
Alzheimer's
Join our mailing list
Get the latest updates from the Neuraxpharm.