X-linked adrenoleukodystrophy (X-ALD) is a disease that can present itself in many different forms (phenotypes); seven different phenotypes have been described in male patients and five in female patients. All these phenotypes are caused by genetic defects (mutations) in the ABCD1 gene. All X-ALD patients have a mutation in the ABCD1 gene. Within a single family, all X-ALD patients have the same mutation. Over 500 different mutations have been found so far – most of these are collected in this database. Unfortunately, mutations have no predictive value with respect to the clinical outcome of an asymptomatic patient. Until today no predictive markers have been identified; not the blood levels of the very long-chain fatty acids (VLCFA), not the mutation in the gene, not the family history with respect to X-ALD, not the presence or absence of ALD protein in cultured cell lines.
Prevalence of X-ALD: A large study from the Kennedy Krieger Institute and the Mayo Clinic indicates that, at least in the United States, X-ALD is found in about 1 in 21.000 new born males and approximately 1 in 14.000 new born females are carrier for this disease. This data is in agreement with frequencies reported previously from France. The overall frequency for X-ALD is about 1 in 17.000 live births. X-ALD has been identified in all European and Latin American countries, China, Japan, India, Israel, Saudi-Arabia, and all ethnic groups, including Afro-Americans, Native Americans and Maori.
Women with X-ALD: Although there is a high number of females with X-ALD (carriers), many of them remain undiagnosed, because most carriers remain without symptoms until middle age. In addition, many women with symptoms often remain undiagnosed unless they have a symptomatic affected male relative. A recent study from the Kennedy Krieger Institute demonstrated that from 616 families identified with X-ALD, in only 16 cases the first patient identified in the family was a female. The vast majority of carriers are identified only after a male in their family has been diagnosed (through extended family screening programs). The best method to establish carrier status in women suspected for X-ALD is through genetic analysis of the gene causing X-ALD. But for this to be most reliable the mutation in that family must be determined in an affected male relative or an obligate carrier. An obligate carrier is a woman either with a father diagnosed with X-ALD or a woman with two children with genetically proven X-ALD.
We recommend that women who are at risk of being heterozygous for X-ALD be informed about the availability of genetic testing when they reach reproductive age. They can then make an informed decision whether they wish to be tested and also be offered the opportunity to establish contact with a genetic counselor.
asymptomatic: X-ALD has been demonstrated by one of the following criteria: demonstration of elevated levels of VLCFA, a mutation identified in the ABCD1 gene, she has a father with X-ALD, or she has given birth to at least two children with X-ALD. But there is no evidence for adrenal or neurological involvement. The number of asymptomatic carriers diminishes with age. The majority of women younger than 30 years are free of neurological symptoms.
mild myelopathy: Mild impaired vibration sense and some increased, involuntary, reflexes in the legs. This is caused be mild damage to myelin (the insulation around the nerves). This myelin damage affects the signal transduction of the axons (long nerve fibers that send signals from the spinal cord to muscles and other parts). Present in approximately 50% of carriers over the age of 40 years.
moderate to severe myeloneuropathy: Symptoms resemble those found in male patients with adrenomyeloneuropathy (AMN: see below), but they are milder. This form is found in approximately 15% of carriers over the age of 40 years.
cerebral involvement: This form resembles childhood cerebral ALD (see below). It is rarely seen in females, only some isolated cases are known.
clinically evident adrenocortical insufficiency: Addisons disease (see below). Very rare in carriers at any age, less than 1%.
asymptomatic or presymptomatic: Some patients, in particular those identified by family screening, may neither have neurologic nor endocrinologic abnormalities. X-ALD has been demonstrated by one of the following criteria: demonstration of elevated levels of VLCFA or a mutation identified in the ABCD1 gene. But there is no evidence for adrenal or neurologic involvement. The number of asymptomatic males diminishes with age. It is important that these patients are seen frequently by a physician and the adrenal function must be monitored. The risk for these patients to develop neurologic symptoms is high. This form is common in boys under 4 years of age and very rare in males over 40 years of age.
childhood cerebral ALD: Presentation occurs most commonly between four and eight years of age with a peak at seven years. This form virtually never occurs before three years of age and very rarely after 15 years. Affected boys present with behavioral or learning deficits, often diagnosed as attention deficit disorder or hyperactivity, which may respond to stimulant medication. These behaviors may persist for months or longer, but are then followed by symptoms suggestive of a more serious underlying disorder. These symptoms may include “spacing out” in school: inattention, deterioration in handwriting skills, and diminishing school performance; difficulty in understanding speech (though sound perception is normal); difficulty in reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally diplopia; and aggressive or disinhibited behavior. Brain MRI examination performed at this time can be strikingly abnormal even when symptoms are relatively mild. In some boys, seizures may be the first manifestation. The rate of progression is variable. It may be rapid with total disability in six months to two years, followed by death at varying ages. Most individuals have impaired adrenocortical function at the time that neurological disturbances are first noted. Approximately, 35% of X-ALD patients develops CCALD.
adolescent cerebral ALD: Resembles CCALD. The age of onset is between 11 and 21 years of age. The progression is somewhat slower. Present in 4 to 7% of patients.
adult cerebral ALD: This form develops in 2 to 5% of patients. These patients may be misdiagnosed as having paranoid psychosis, schizophrenia or other psychiatric disorders. This form is not preceded by AMN (see below). A white matter inflammatory response is present (visible on MRI). The progression parallels that of the childhood cerebral form.
adrenomyeloneuropathy (AMN): The typical presentation is a man in his twenties or middle age who develops progressive stiffness and weakness of his legs, abnormalities of sphincter control, and sexual dysfunction. All symptoms are progressive over decades. Approximately 40-45% of individuals with AMN show some degree of brain involvement on MRI or clinical examination. In 10-20% of individuals with AMN, brain involvement becomes severely progressive and leads to serious cognitive and behavioral disturbances that may progress to total disability and death. About 70% of men with adrenomyeloneuropathy have impaired adrenocortical function at the time that neurological symptoms are first noted. About 45% of these patients are at risk for developing cerebral involvement.
Addison-only phenotype: These males present with signs of adrenal insufficiency between two years of age and adulthood, but most commonly by 7 1/2 years of age. These signs include unexplained vomiting and weakness or coma, leading to the diagnosis of Addison disease. Individuals may or may not have increased skin pigmentation resulting from excessive ACTH secretion. Most individuals who present initially with adrenocortical insufficiency only develop evidence of AMN by middle age. About 10% of X-ALD patients have the Addison-only phenotype.