Women with ALD

Authors: Marc Engelen, M.D., Ph.D., Stephan Kemp, Ph.D. & Björn M. van Geel, M.D., Ph.D.

Introduction

For many years, adrenoleukodystrophy was thought to be a disease that only affected boys and men. However, it has become clear that females carrying a defective ABCD1 gene also develop neurological symptoms. Very rarely do women with ALD develop adrenal insufficiency or the cerebral form of the disease. Females with ALD are therefore a distinct group of adrenoleukodystrophy patients. This page discusses the complaints and symptoms that women with ALD may develop and what can be done about them.

Contrary to earlier concepts, it has now been clearly demonstrated that disorders linked to the X chromosome do not only affect males, but to a lesser extent also females with the defective gene. Adrenoleukodystrophy is no exception. Females with ALD are also patients, but this is less well known. Symptoms are often attributed to other causes, and symptomatic treatment may be delayed. In our experience in the Netherlands, undiagnosed women with ALD have undergone surgical procedures (hip replacement, cervical spine surgery), some more than once, for what  later turned out to be symptoms of spinal cord disease due to adrenoleukodystrophy. Worse, the failure to recognize the adrenoleukodystrophy carrier prevented genetic counseling and appropriate diagnosis and treatment of other family members.

A carrier’s story

When she was 38 years old, Dutch-born Mrs. H. was living in the United States with her family. She had noticed that it was becoming increasingly difficult for her to keep her balance. Her legs were also starting to feel a little stiff. She had been having problems with her bladder function for several years, but thought this was due to the birth of her two children. One of her cousins, who was initially thought to have a brain tumor, died at the age of 13. Another cousin, who had progressive walking problems, was diagnosed with multiple sclerosis. After reading an article about adrenoleukodystrophy in a popular magazine in 1985, she recognized her symptoms and those of her cousins and decided to contact Dr. Hugo Moser at the Kennedy Krieger Institute in Baltimore, MD. A blood sample was taken, and analysis revealed elevated levels of very long-chain fatty acids (VLCFAs), confirming the diagnosis of adrenoleukodystrophy.

When Mrs. H. was 55 years old, 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 had not yet been tested for adrenoleukodystrophy. Some chose not to be tested, but many had never been offered the biochemical test to measure very long-chain fatty acids. On physical examination, there was increased tone in the leg muscles and some weakness. Sensation was abnormal, as light touch, vibration, and positional sensation were all impaired in the legs and feet. Tendon reflexes were brisk in the legs and plantar responses were extensor.

Magnetic resonance imaging (MRI) of the brain and spinal cord were both normal. Genetic counseling and blood testing were offered to relatives.

Retrospectively, childhood cerebral adrenoleukodystrophy and spinal cord variant of adrenoleukodystrophy (myelopathy) were diagnosed in her cousins. She was referred to a rehabilitation physician and physical therapist.

Together with her husband, the director of the Dutch patient organization, she supported newly diagnosed families and patients for many years. Until she died suddenly and unexpectedly from a disease unrelated to ALD.

The symptoms of women with ALD

It has been known since the 1980s that women with ALD can develop symptoms. In 2014, a large systematic study was conducted to systematically investigate this. In a study conducted at the AMC in the Netherlands, it was shown the frequency of symptomatic women with ALD increases with age (Figure 1). More than 80% of women with ALD will develop signs of neurological dysfunction by the age of 60.

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 ALD. The black dots show each individual in the cohort classified as either symptomatic or pre-symptomatic.

It is very important to note that symptoms in childhood are extremely rare. Also, brain disease in older women with spinal cord involvement is very rare. Symptoms in affected women are mainly due to abnormalities in the spinal cord and nerves in the legs, just as in men with the spinal cord form (myelopathy). Over decades, weakness and spasticity of the legs, loss of sensation in the lower limbs, and impaired bladder and bowel control develop. Unlike men, women are very unlikely to develop adrenal insufficiency, although it has been described in 1% of a large group. None of the Dutch women with ALD from the 2014 publication showed signs of adrenal dysfunction.

It is unclear what prevents women with ALD from developing the cerebral form of adrenoleukodystrophy. The ALD gene is located on the X chromosome (see the Facts about ALD page for more information). During embryonic development, one of the two X chromosomes that each female has in her tissue cells is randomly inactivated. It is hypothesized, and partially supported by laboratory studies, that in females who develop the cerebral form of adrenoleukodystrophy, the X chromosomes are not randomly inactivated, but that for some reason the normal X chromosome, the one without the pathogenic variant in the ABCD1 gene, is inactivated in all cells. This results in a situation similar to that of boys with cerebral adrenoleukodystrophy.

Why women with ALD should be identified

Many women with ALD who have mild symptoms remain undiagnosed for many years. As a result, specific treatment for spasticity, lower back or joint pain, and bladder and bowel dysfunction may be withheld. Once diagnosed, these symptoms are easier to treated. Most importantly, once a woman is diagnosed as a heterozygote for the pathogenic variant of adrenoleukodystrophy, her children and relatives can be screened 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. Affected boys and men with previously unrecognized adrenal dysfunction can be identified. If left untreated, adrenal dysfunction can lead to serious complications and even death. Boys with the disease can be monitored closely, and if brain involvement develops, they can undergo bone marrow or stem cell transplantation. This has been shown to be beneficial in boys with only mild brain involvement. Daughters of women with ALD who wish to have children may also be offered VLCFA and DNA testing.

Establishing the diagnosis

Historically, adrenoleukodystrophy has been diagnosed by analyzing VLCFA in blood samples or cultured skin cells (fibroblasts). In boys and men, an abnormally elevated level of VLCFA in blood plasma or cultured fibroblasts confirms the diagnosis of adrenoleukodystrophy. However, at least 10 to 15% of women with ALD have VLCFA levels within normal limits. Apparently, cells expressing normal (unaffected) ALD protein have sufficient residual activity to mask the biochemical deficiency. Therefore, it is impossible to exclude that a female in an affected family does not have adrenoleukodystrophy based on finding normal VLCFA levels in blood or cultured cells! On the other hand, finding elevated levels of VLCFA confirms the diagnosis.
In 2020, C26:0-lysoPC levels were found to be elevated in all men and more than 99% of women with ALD [Jaspers et al 2020]. Even women with ALD with normal VLCFA levels had elevated levels of C26:0-lysoPC levels in dried blood spots and plasma. Therefore, C26:0-lysoPC is considered a superior diagnostic biomarker for ALD compared to VLCFA analysis.

Today, DNA diagnostics (genetic testing) is the gold standard for identifying women with ALD. It should never be omitted in females from affected families in whom VLCFA levels are in the normal range. More than 950 different pathogenic variants have been identified in the ABCD1 gene. DNA analysis can be performed on blood or other tissue samples, including chorionic villus biopsies and amniotic fluid cells, or previously cultured cells.

Diagnostic strategy

When adrenoleukodystrophy is diagnosed in a family, it cannot be emphasized enough how important it is that the family be thoroughly screened. This can prevent unnecessary new cases and help 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, VLCFA analysis and DNA analysis should be performed as soon as adrenoleukodystrophy is diagnosed in a family with no history of the disease. Once the pathogenic variant has been found, genetic testing of relatives is much easier because the test can be focused on that specific abnormality (pathogenic DNA variant). DNA analysis should be performed in specialized centers.

Hormonal dysfunction

Although endocrine dysfunction has been described in women with ALD, it is very rare. Approximately 1% have some evidence of impaired adrenal function. Abnormal thyroid function has been reported, but is also common in the general population, so it is difficult to say whether it is related to adrenoleukodystrophy. In general, endocrine tests should only be performed when endocrine insufficiency is suspected.

Neuroimaging and electrophysiology

Very rarely severe white matter abnormalities have been reported in women with ALD. Suspected brain involvement may be demonstrated by MRI. Electrophysiologic examination, such as electroencephalogram (EEG) or evoked response studies, may also be abnormal in these cases. When peripheral nerves are involved, nerve conduction studies and electromyography (EMG) may also be abnormal.

These tests are interesting for research purposes, but it is not necessary to perform them on every affected woman, unless there are clear abnormalities on physical examination that warrant further investigation.

Treatment and management

Curative treatment
Many therapies have been tried in adrenoleukodystrophy over the past decades. Treatment with Lorenzo’s oil, ß-interferon, intravenous immunoglobulins, immunosuppression with cytostatic drugs, and plasma exchange have not been able to halt or delay disease progression once neurological symptoms are present. In boys with mild brain involvement, bone marrow or stem cell transplantation is the only treatment that has been shown to be beneficial.

However, bone marrow or stem cell transplantation should not be performed in men and females with symptoms related to the myelopathy. This treatment s specific to cerebral ALD. It is not effective for the slowly progressive loss of nerve cell function in the spinal cord (myelopathy) and peripheral nerves, that occurs in women with ALD.

Symptomatic treatment
Spasticity can be treated with medications that reduce muscle tone or sometimes with injections of botulinum toxin into the affected muscles.

Many women with ALD experience lower back pain or pain in the ankles, knees and hips caused by the increased muscle tone in the legs and resulting abnormal gait. Non-opioid analgesics, such as acetaminophen and non-steroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen or diclofenac), may be particularly useful in treating pain.

Medication is available to reduce the discomfort of urge incontinence, but this is often not effective if the symptoms are severe. Incontinence products are often needed.

A multidisciplinary approach
Women with ALD who present 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 may be consulted to help with coping. Finally, the clinical geneticist should not be forgotten to discuss the mode of inheritance of adrenoleukodystrophy, the availability of prenatal testing, and the need for family screening.

Final remarks

Many, if not most, women with ALD will develop neurological symptoms caused by damage to the spinal cord and peripheral nerves. It is important to recognize these symptoms for effective symptomatic treatment. It should be noted that very reliable and powerful diagnostic tools are now available to detect or exclude female carriers of adrenoleukodystrophy. It cannot be emphasized enough that the gold standard for diagnosis in women is DNA analysis, as the VLCFA test may well be normal in 10 to 15% of women with ALD. Importantly, C26:0-lysoPC is elevated in all men and more than 99% of women with ALD and is considered a superior diagnostic biomarker for ALD compared to VLCFA analysis. Once the diagnosis of adrenoleukodystrophy has been made, the family should be screened and affected relatives identified. These tests and family screening should preferably be performed in specialized centers.

Adapted and translated with permission from: van Geel BM. Draagsterschap van X-gebonden adrenoleukodystrofie (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 | 2024-06-24