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 in many different forms (phenotypes). Symptoms range from a progressive disease of the spinal cord in men and women (myelopathy) to a fatal brain disease in boys and men (cerebral ALD). Adrenoleukodystrophy is caused by a genetic defect (pathogenic variant) in the ABCD1 gene. All patients with adrenoleukodystrophy have a pathogenic variant in the ABCD1 gene. Over 950 different pathogenic variants have been identified – most of which are included in this database. Unfortunately, pathogenic variants have no predictive value regarding the severity of the disease in a particular individual. Although all babies born with adrenoleukodystrophy have a pathogenic variant in the ABCD1 gene, the clinical course of an individual patient remains completely unpredictable, even among family members who share the same pathogenic variant. To date, no predictive markers have been identified; not blood levels of very long-chain fatty acids (VLCFA), not the pathogenic variant in the gene, not family history of adrenoleukodystrophy, not the presence or absence of ALD protein in cultured cell lines.

Prevalence of adrenoleukodystrophy

The overall incidence of adrenoleukodystrophy is approximately 1 in 17,000 newborns. Adrenoleukodystrophy has been reported in all European and Latin American countries, China, Japan, India, Israel, Saudi Arabia, and in all ethnic groups, including African Americans, Native Americans, and Maori.

Women with ALD

Pre-symptomatic: Adrenoleukodystrophy has been demonstrated by one of the following criteria: evidence of elevated levels of VLCFA, a pathogenic variant identified in the ABCD1 gene, having a father with adrenoleukodystrophy, or having given birth to at least two children with adrenoleukodystrophy. The number of pre-symptomatic women with ALD decreases with age. The majority of women under the age of 30 are free of neurological symptoms.
We recommend that women 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 about whether to be tested and also be offered the opportunity to contact a genetic counselor.

Myelopathy: As with many X-linked diseases, it was originally thought that the majority of women with ALD would remain asymptomatic. However, a 2014 study showed that more than 80% of women with ALD develop symptoms after the age of 60. The full text of this study can be viewed and downloaded (as a pdf). In general, the onset of neurological symptoms occurs later than in males with adrenoleukodystrophy, typically between 40 and 50 years of age (Figure 1). Motor disability and disease progression are generally less severe, but some women with ALD are as severely impaired as male patients with adrenoleukodystrophy. It is important to note that women with ALD are often misdiagnosed as having multiple sclerosis. Because most women with ALD remain asymptomatic until middle age, many women remain undiagnosed. In addition, many women with symptoms often remain undiagnosed unless they have a symptomatic affected male relative. A study from the Kennedy Krieger Institute showed that of 616 families identified with adrenoleukodystrophy, only 16 had a female as the first patient identified in the family. The vast majority of female adrenoleukodystrophy patients are identified after a male in the family is diagnosed (through extended family screening programs). The best way to determine whether a female has adrenoleukodystrophy is through genetic analysis of the ABCD1 gene. However, for this to be most reliable, the pathogenic variant in the family must be identified in an affected male relative or obligate carrier. An obligate carrier is either a female with a father diagnosed with adrenoleukodystrophy or a female with two children with genetically proven adrenoleukodystrophy.
We recommend that women 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 about whether to be tested and also be offered the opportunity to contact a genetic counselor.

Cerebral involvement: This is rarely seen in women with ALD, only a few isolated cases are known.

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

Figure 1: Correlation between symptomatic status and age in a cohort of 46 women with ALD. The green bars show the percentage of women within each age group who 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, particularly those identified by family screening, may have no neurologic or endocrinologic abnormalities. Adrenoleukodystrophy has been diagnosed by one of the following criteria: evidence of elevated VLCFA levels or a pathogenic variant identified in the ABCD1 gene. However, there is still no evidence of adrenal or neurological involvement. The number of presymptomatic men decreases with age. It is important that a physician see these patients frequently. Follow-up of 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 an HLA-matched donor or cord blood is available. These patients are at high risk of developing neurologic symptoms or endocrinologic abnormalities. Presymptomatic adrenoleukodystrophy is common in boys under the age of 3 and very rare in men over the age of 40.

Adrenal insufficiency: A prospective evaluation of adrenal function in 49 neurologically pre-symptomatic 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 recognition of impaired adrenal reserve, and timely initiation of hormone replacement therapy. It is often the first manifestation of adrenoleukodystrophy, often before the onset of neurological symptoms. The most common signs of adrenal insufficiency are chronic or prolonged fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, and unexplained vomiting. Other symptoms may include nausea, diarrhea, low blood pressure (which drops further when a person stands up, causing dizziness or fainting), irritability and depression, craving salty foods, hypoglycemia or low blood sugar, headaches, or sweating. Individuals may or may not have increased skin pigmentation due to excessive secretion of adrenocorticotropic hormone (ACTH).

Cerebral ALD (childhood, adolescent and adult): Symptoms of cerebral ALD are generally rapidly progressive. The specific symptoms depend on the age of onset. Cerebral ALD often occurs in early childhood (childhood cerebral ALD; CCALD), but never before the age of 3. Typically, affected boys first present with behavioral or learning problems, often diagnosed as attention deficit disorder or hyperactivity. These behaviors may persist for months or longer, but are then followed by symptoms that indicate a more serious underlying disorder. These symptoms may include “dropping out” of school: inattention, deterioration of handwriting skills, and declining school performance; difficulty understanding speech (although sound perception is normal); difficulty reading, spatial orientation, and comprehension of written material; clumsiness; visual disturbances and occasionally double vision; and aggressive or disinhibited behavior. Brain MRI scans performed at this time may 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 can be extremely rapid, with complete disability in six months to two years, followed by death at various ages. Most individuals have impaired adrenal function by the time neurologic deficits are first noted. A newborn male patient has a 35-40% risk of developing 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 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 peripheral nerves. The diagnosis of adrenoleukodystrophy is rarely made during the first 3 to 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 the legs, impaired vibratory sensation in the lower limbs, sphincter dysfunction, and sexual dysfunction. All symptoms progress over decades. The hair of affected men is often thin and sparse; these patients are often bald by their twenties. Most men with this presentation of adrenoleukodystrophy have impaired adrenal function by the time neurological symptoms are first noted. The combination of myelopathy and adrenal dysfunction is called adrenomyeloneuropathy (AMN). Men with myelopathy are at risk for developing cerebral ALD. The exact risk is not known and the onset of cerebral ALD cannot be predicted. The risk of developing cerebral ALD secondary to myelopathy is estimated to be at least 20% over a 10-year period.

Last modified | 2024-06-24