Clinical presentations

Authors: Stephan Kemp, Ph.D., Hugo Moser, M.D. and Marc Engelen, M.D., Ph.D.


X-linked adrenoleukodystrophy (ALD) is a disease that can present itself in many different forms (phenotypes). Symptoms range from a progressive disease of the spinal cord in men and females (myelopathy) to a fatal brain disease in boys and men (cerebral ALD). Adrenoleukodystrophy is caused by a genetic defect (a pathogenic variant) in the ABCD1 gene. All adrenoleukodystrophy patients have a pathogenic variant in the ABCD1 gene. Over 900 different pathogenic variants have been found so far – most of these are collected in this database. Unfortunately, pathogenic variants have no predictive value with respect to the disease severity in a specific individual. Although all babies born with adrenoleukodystrophy have a pathogenic variant in the ABCD1 gene, the clinical course of an individual patient remains entirely unpredictable, even among family members who share the same pathogenic variant. Until today no predictive markers have been identified; not the blood levels of the very long-chain fatty acids (VLCFA), not the pathogenic variant in the gene, not the family history with respect to adrenoleukodystrophy, not the presence or absence of ALD protein in cultured cell lines.

Prevalence of adrenoleukodystrophy

The overall incidence for adrenoleukodystrophy is about 1 in 17.000 newborns. Adrenoleukodystrophy has been identified in all European and Latin American countries, China, Japan, India, Israel, Saudi-Arabia, and in all ethnic groups, including Afro-Americans, Native Americans and Maori.

Females with ALD

Pre-symptomatic: Adrenoleukodystrophy has been demonstrated by one of the following criteria: demonstration of elevated levels of VLCFA, a pathogenic variant identified in the ABCD1 gene, she has a father with adrenoleukodystrophy, or she has given birth to at least two children with adrenoleukodystrophy. The number of pre-symptomatic females with ALD diminishes with age. The majority of females younger than 30 years are free of neurological symptoms.
We recommend that females who are at risk of being heterozygous for adrenoleukodystrophy 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.

Myelopathy: As in many X-linked diseases, it was originally assumed that the majority of females with ALD remain free of symptoms. However, in a recent study it was shown that more than 80% of females with ALD develop symptoms after the age of 60 years. The full text of this study can be viewed and downloaded (as a pdf). In general, the onset of neurologic symptoms occurs at a later age than in men with adrenoleukodystrophy; typically between 40 to 50 years of age (Fig 1). Motor disability and disease progression are generally less severe but some females with ALD are as severely impaired as male patients with adrenoleukodystrophy. It is important to note that females with ALD are often misdiagnosed as having multiple sclerosis. Although there are many females affected with adrenoleukodystrophy, many of them remain undiagnosed, because most females with ALD remain without symptoms until middle age. In addition, many females with symptoms often remain undiagnosed unless they have a symptomatic affected male relative. A study from the Kennedy Krieger Institute demonstrated that from 616 families identified with adrenoleukodystrophy, in only 16 cases the first patient identified in the family was a female. The vast majority of female adrenoleukodystrophy patients are identified only after a male in their family has been diagnosed (through extended family screening programs). The best method to establish whether a female has adrenoleukodystrophy is through genetic analysis of the ABCD1 gene. But for this to be most reliable the pathogenic variant in that family must be determined in an affected male relative or an obligate carrier. An obligate carrier is a female either with a father diagnosed with adrenoleukodystrophy or a female with two children with genetically proven adrenoleukodystrophy.
We recommend that females who are at risk of carrying the adrenoleukodystrophy gene 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.

Cerebral involvement: This is rarely seen in females with ALD, only some isolated cases are known.

Clinically evident primary adrenal insufficiency: Adrenal insufficiency or Addison’s disease (see below) is very rare in females with ALD at any age, less than 1%.

Figure 1: Correlation between the symptomatic status and age in a cohort of 46 females with ALD. The green bars indicate the percentage of females within each age group that have developed clinical symptoms related to adrenoleukodystrophy. The black dots show each individual in the cohort, classified as either symptomatic or pre-symptomatic.

Men with adrenoleukodystrophy

Pre-symptomatic: Some patients, in particular those identified by family screening, may neither have neurologic nor endocrinologic abnormalities. Adrenoleukodystrophy has been diagnosed by one of the following criteria: demonstration of elevated levels of VLCFA or a pathogenic variant identified in the ABCD1 gene. But there is no evidence for adrenal or neurologic involvement yet. The number of pre-symptomatic males diminishes with age. It is important that a physician sees these patients frequently. Follow-up in pre-symptomatic boys and men with adrenoleukodystrophy is important for two reasons: 1) early detection of adrenal insufficiency, and 2) early detection of cerebral ALD by brain MRI to propose allogeneic hematopoietic stem cell transplantation (HSCT) if a HLA-matched donor or cord blood is available.. The risk for these patients to develop neurologic symptoms or endocrinologic abnormalities is high. Pre-symptomatic adrenoleukodystrophy is common in boys under 3 years of age and very rare in males over 40 years of age.

Adrenal insufficiency: A prospective evaluation of adrenal function in 49 neurologically presymptomatic boys with adrenoleukodystrophy showed that 80% already had impaired adrenal function. Unrecognized adrenal insufficiency is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early identification of impaired adrenal reserve, and timely initiation of hormone replacement therapy. It is often the first manifestation of adrenoleukodystrophy, frequently before the onset of neurologic symptoms. The most common signs of adrenal insufficiency are chronic, or long lasting, fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain and unexplained vomiting. Other symptoms may include nausea, diarrhea, low blood pressure (that drops further when a person stands up, causing dizziness or fainting), irritability and depression, craving salty foods, hypoglycemia, or low blood sugar, headache, or sweating. Individuals may or may not have increased skin pigmentation resulting from excessive adrenocorticotropin hormone (ACTH) secretion.

Cerebral ALD (childhood, adolescent and adult): Symptoms of cerebral ALD are in general rapidly progressive. The specific symptoms depend on age of presentation. Cerebral ALD occurs often in early childhood (childhood cerebral ALD; CCALD), but never before the age of 3 years. Usually, affected boys initially have behavioral problems or learning deficits, often diagnosed as attention deficit disorder or hyperactivity. 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 double-vision; 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 extremely rapid with total disability in six months to two years, followed by death at varying ages. Most individuals already have impaired adrenal function at the time that neurological disturbances are first noted. A newborn male patient has a 35–40% risk to develop cerebral ALD between the ages of 3 and 18 years, but cerebral ALD can also occur in adulthood. In adult patients the presentation and progression of cerebral ALD is similar, with behavioral changes and/or psychiatric symptoms. Adults who develop cerebral ALD often already have signs of AMN and adrenal insufficiency.

Myelopathy: Virtually all patients with adrenoleukodystrophy who reach adulthood develop spinal cord disease (myelopathy). Symptoms are limited to the spinal cord and the peripheral nerves. The diagnosis of adrenoleukodystrophy is rarely made during the first 3–5 years of clinical symptoms, unless other cases of adrenoleukodystrophy have been identified in the same family. The typical presentation is a man in his twenties or middle age who develops progressive stiffness and weakness of his legs, impaired vibration sense in the lower limbs, sphincter disturbances, and sexual dysfunction. All symptoms are progressive over decades. Hair of affected males is often thin and sparse; these patients often show balding already in their twenties. Most men with this presentation of adrenoleukodystrophy have impaired adrenal function at the time that neurological symptoms are first noted. The combination of myelopathy and adrenal dysfunction is also referred to as adrenomyeloneuropathy (AMN). Men with myelopathy are at risk to also develop cerebral ALD. The exact risk is not known and the initiation of cerebral ALD can not be predicted. The risk for developing cerebral ALD secondary to myelopathy is estimated to be at least 20% over a period of 10 years.

Last modified | 2022-01-22