Females with ALD
Authors: Marc Engelen, M.D., Ph.D., Stephan Kemp, Ph.D. & Björn M. van Geel, M.D., Ph.D.
For many years adrenoleukodystrophy has been regarded as a disease that only affects boys and men. However, it has become clear that females carrying a defective ABCD1 gene develop neurological symptoms as well. Only very rarely females with ALD develop deficient function of the adrenal glands or the cerebral form of the disease. Females with ALD are, therefore, a distinct group of adrenoleukodystrophy patients. This page addresses the complaints and symptoms females with ALD may develop, and what can be done about it.
Contrary to earlier concepts, it has now clearly been demonstrated that X-chromosome linked disorders not only affect males, but to a lesser extent, females with the defective genes as well. Adrenoleukodystrophy is no exception. Females with ALD are patients as well, but this is less well known. Frequently, symptoms are attributed to other causes, and therefore symptomatic treatment may be delayed. In our experience in the Netherlands, undiagnosed females with ALD had undergone surgical procedures (hip replacement, cervical spine operations), some more than once, for what was later shown to be symptoms of spinal cord disease due to adrenoleukodystrophy. Even worse, failing to recognize carriership of adrenoleukodystrophy prevented genetic counseling and appropriate diagnosis and therapy of other family members.
A carrier’s story
When she was 38 years of age, Mrs. H., born in the Netherlands, lived in the US together with her family. She had noticed that keeping her balance gradually became more and more difficult. Also, her legs started to feel a little stiff. She had problems with her bladder function for several years, but assumed that giving birth to her two children had caused this. One of her cousins, who at first was thought to have a brain tumor, died at the age of 13 years. Another cousin, who had progressive problems with walking, was diagnosed with multiple sclerosis. Having read an article on adrenoleukodystrophy in a popular magazine in 1985, she recognized her symptoms and those of her cousins, and she decided to contact Dr. Hugo Moser at the Kennedy Krieger Institute in Baltimore, MD. A blood sample was taken, and analysis revealed an elevation of the very long-chain fatty acids (VLCFAs), thus confirming the diagnosis adrenoleukodystrophy.
When Mrs. H. was 55, she visited the Academic Medical Center in Amsterdam, the Netherlands. It appeared that some of her relatives had been reported in the medical literature, but apparently many were not yet tested for adrenoleukodystrophy. Some chose not to be screened, but many had never been offered the biochemical test to measure very long-chain fatty acids. On physical examination the tone in the leg muscles was increased, and there was some weakness. Sensation was abnormal, as light touch, vibration and position sense were all impaired in the legs and feet. The tendon reflexes were brisk in the legs, and the plantar responses were extensor.
Magnetic resonance imaging (MRI) investigation of the brain and spinal cord were both normal. Genetic counseling and blood tests were offered to relatives.
Retrospectively, childhood cerebral adrenoleukodystrophy and the spinal cord variant of adrenoleukodystrophy (myelopathy) were diagnosed in her cousins. She was referred to a rehabilitation physician and a physiotherapist.
Together with her husband, the director of the Dutch patient organization, she supported newly diagnosed families and patients for many years. Until she passed away suddenly and unexpectedly, due to a disease unrelated to adrenoleukodystrophy.
The symptoms of females with ALD
It has been known since the 1980s that females with ALD can develop symptoms. Only recently was a large systematic study performed to study this systematically. In a study conducted at the AMC in the Netherlands, it was demonstrated that with increasing age, the frequency of females with adrenoleukodystrophy that are symptomatic increases (Figure 1). Over 80% of females with ALD will develop signs of neurological dysfunction by the age of 60 years.
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.
It is very important to point out that symptoms in childhood are extremely rare. Also, brain disease in older females with spinal cord involvement is very uncommon. The symptoms in affected females are mainly due to abnormalities in the spinal cord and nerves in the legs, just like in males affected with the spinal cord form (myelopathy). Over decades, weakness and spasticity of the legs, disturbed sensation of the lower limbs, and impaired control over bladder and bowel develop. Unlike the affected men, it is very unlikely that females develop adrenal insufficiency, although it has been described in 1% in a large group. None of the Dutch females with ALD studied had signs of adrenal dysfunction.
It is unclear what prevents females with ALD from developing the cerebral form of adrenoleukodystrophy. The adrenoleukodystrophy gene is located on the X-chromosome (see the Facts on adrenoleukodystrophy page for more info). Normally, one of the two X-chromosomes that every females has in her tissue cells is inactivated at random. It is hypothesized and partially supported by laboratory studies that in females who develop the cerebral form of adrenoleukodystrophy the X-chromosomes are not inactivated randomly, but that for some reason the normal X-chromosome, the one without the mutation in the ABCD1 gene, is inactivated a all cells. This results in a situation similar to the boys with cerebral adrenoleukodystrophy.
Why females with ALD should be identified
Many females with ALD having mild symptoms remain unrecognized for many years. This may result in withholding specific treatment for spasticity and lower back or joint pain, and bladder and bowel dysfunction. Once diagnosed, these symptoms can be treated more easily. Most importantly, once a female is diagnosed as a heterozygote of the adrenoleukodystrophy mutation, her children and relatives can be screened, in order to diagnose boys and men with adrenal insufficiency. In addition, prenatal testing (using amniotic fluid or chorionic villus biopsy) allows early identification of an affected fetus. Boys and men who are affected and who have a yet unrecognized dysfunction of the adrenal glands can be identified. If left untreated, adrenal dysfunction can result in serious complications, and even death. Boys affected by the disease can be monitored closely; when they develop brain involvement, they can undergo bone marrow or stem cell transplantation. This has been proven to be beneficial in boys with only mild brain involvement. Daughters of women with adrenoleukodystrophy who desire to have children can also be offered VLCFA and DNA testing.
Establishing the diagnosis
Adrenoleukodystrophy used to be diagnosed by analysis of VLCFA in blood samples or cultured skin cells (fibroblasts). In boys and men, an abnormally elevated level of VLCFAs in blood plasma or cultured fibroblasts confirms the diagnosis adrenoleukodystrophy. But in at least 10 to 15% of the females with ALD, VLCFA levels are within normal limits. Apparently, their unaffected X-chromosomes have enough residual activity and are able to mask the biochemical deficiency. Therefore, it is impossible to exclude that a female in an affected family does not have adrenoleukodystrophy based upon finding normal VLCFA concentrations in blood or cultured cells! On the other hand, once elevated levels of VLCFA are found, this confirms the diagnosis.
Nowadays, DNA diagnostics (mutation analysis) is the golden standard for the identification of females with ALD or suspected to have adrenoleukodystrophy. It should never be omitted in females of affected families in which VLCFA analysis is within normal limits. So far, more than 800 different mutations in the ABCD1 gene have been identified. DNA analysis can be performed in blood or other tissue samples, including chorionic villus biopsies and amniotic fluid cells, or previously cultured cells.
When adrenoleukodystrophy is diagnosed in a family, it cannot be emphasized enough how important it is that the family is screened thoroughly. This may prevent unnecessary new cases, and helps to identify those relatives with adrenal insufficiency and those who may benefit from bone marrow or stem cell transplantation. To make identification of affected relatives easier and more reliable, not only VLCFA analysis and DNA analysis should be carried out once adrenoleukodystrophy is diagnosed in a family previously unknown with the disease. Once the mutation has been found, mutational analysis in relatives is much easier, as the test can be focused on that specific abnormality. The DNA analysis should be performed in specialized centers.
Although endocrine dysfunction has been described in females with ALD, it is very rare. Approximately 1% has some signs of impaired function of the adrenals. Abnormal function of the thyroid gland has been reported, but is encountered frequently in the overall population as well, making it difficult to say whether there is any relation with adrenoleukodystrophy. In general, endocrine tests should only be carried out when endocrine insufficiency is suspected.
Neuroimaging and electrophysiology
Only very occasionally severe white matter abnormalities in females with ALD have been reported. Suspected brain involvement can be demonstrated with MRI investigations. Electrophysiological examinations, such as the electroencephalogram (EEG) or evoked response investigations, may be abnormal in these cases as well. When the peripheral nerves are involved, nerve conduction studies and electromyography (EMG) may be abnormal as well.
For research purposes these investigations are interesting, but it is not essential to carry out these tests in every affected female, unless there are clear abnormalities on physical examination that warrant further investigation.
Treatment and management
Over the last decades many therapies have been tried in adrenoleukodystrophy. Treatment with Lorenzo’s oil, ß-interferon, intravenous immunoglobulins, immunosuppression with cytostatic drugs, and plasma exchange so far have not been able to arrest or delay the disease progression once neurological symptoms are present. So far, bone marrow or stem cell transplantation in boys with mild brain involvement is the only treatment that has been shown to be beneficial.
In men and females with symptoms related to the myelopathy however, bone marrow or stem cell transplantation should not be performed. This aggressive treatment is directed against the brain inflammation. It is not effective for the slowly progressive loss of function of the nerve cells in the spinal cord (myelopathy) and peripheral nerves, which occurs in females with ALD.
Spasticity can be treated with drugs that reduce the muscle tone or sometimes injections with botulin toxin in affected muscles.
Many females with ALD experience lower back pain, or pain in the ankles, knees and hips, caused by the increased muscle tone in the legs and consequent abnormal walking. Nonopioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (e.g. ibuprofen, naproxen or diclofenac) may be particularly useful in the treatment of pain.
Medication is available to reduce complaints of urge incontinence, but this will often not be effective if symptoms are severe. Incontinence materials are often necessary.
A multidisciplinary approach
Females with ALD with neurological symptoms may benefit from a multidisciplinary approach. The neurologist can treat some of the symptoms but referral to a rehabilitation physician or urologist is often necessary. If necessary a psychologist can be consulted for coping. Last but not least, the clinical geneticist should not be forgotten, as the mode of inheritance of adrenoleukodystrophy, the availability of prenatal testing, and the need for family screening must be discussed.
Many if not most of the females with ALD will develop neurological symptoms caused damage to the spinal cord and peripheral nerves. It is important to recognize these symptoms for effective symptomatic treatment. It should be kept in mind that at present very reliable and powerful diagnostic tools are available to demonstrate or exclude female carriership of adrenoleukodystrophy. It cannot be emphasized enough that the golden standard for the diagnosis in females is DNA analysis, as the VLCFA test may very well be normal in 10 to 15% of females with ALD. Once the diagnosis adrenoleukodystrophy has been established, the family should be screened and affected relatives must be identified. These tests and family screening preferably should be performed in specialized centers.
With permission adapted and translated from: van Geel BM. Draagsterschap van X-gebonden adrenoleukodystrofie (The carrier state for X-linked adrenoleukodystrophy). Ned Tijdschr Geneeskd (2000) 144:1764-1768. Updated and combined with new data from: Engelen et al., X-linked adrenoleukodystrophy in women: A cross-sectional cohort study. Brain. (2014) 137(Pt 3):693-706 (free paper).
Last modified | 2019-03-19