What is Adrenoleukodystrophy?
Adrenoleukodystrophy (ALD) is a rare genetic disorder that causes trouble breaking down very long-chain fatty acids (VLCFAs). When these VLCFAs can’t be metabolized, they start to accumulate in various body tissues, especially in the nervous system and adrenal glands. The buildup is caused by mutations in the ABCD1 gene, which usually helps transport and break down VLCFAs.
The first signs of this disease were noted in early 1900s, but the exact name and understanding of how it works weren’t reported until the 1970s. The brain, spinal cord, adrenal glands, and testes are usually most affected by this disorder. Symptoms of ALD vary widely, but they often include progressively worsening nervous system problems and issues with the adrenal glands.
Most of the time, ALD is passed down through an X-linked pattern, meaning it’s often linked to the X chromosome and hence referred to as “X-ALD”. There’s also a unique newborn form of ALD that’s tied to Zellweger syndrome, and is inherited in an autosomal recessive pattern; it’s referred to as “N-ALD”. Because ALD can affect multiple organs, it’s highly recommended to include a team of various health professionals when it comes to treatment and care.
What Causes Adrenoleukodystrophy?
X-ALD disease is related to a change in the ABCD1 gene. This gene is important in moving VLCFA (very long chain fatty acids) in tiny structures in our cells called peroxisomes, where these fats can be further broken down. When the ABCD1 gene changes, it messes up this process, leading to an unhealthy build-up of VLCFA in various organs in the body. This build-up can interfere with the normal functioning of these organs.
A change in genes named PTS1 receptor, PXR1, PEX1, PEX10, or PEX13 causes the version of the disease that appears in newborn babies. The disease can look different depending on which organs are affected and how old the person is when the disease starts. The four main types of X-ALD disease are the newborn version, the childhood brain version, a version that affects the nerves and adrenal gland (known as adrenomyeloneuropathy), and a version that impacts the adrenal gland.
Risk Factors and Frequency for Adrenoleukodystrophy
ALD (Adrenoleukodystrophy) is a genetic disease that mainly affects the peroxisomes, parts of the cells that break down fats and detoxify the cell. It’s the most common disease of its type, and it affects roughly 1 in every 20,000 people. Higher incidence of ALD is noticed in people with Latino or African heritage. There’s a specific variety of ADL known as N-ALD, which affects 1 in 50,000 people.
Signs and Symptoms of Adrenoleukodystrophy
N-ALD and X-ALD are two types of a disease that can manifest differently based on the person’s age and the severity of the condition. N-ALD usually appears immediately after birth, but symptoms can be mild, which might delay diagnosis. The list below details the typical signs and symptoms of N-ALD:
- Seizures, muscle weakness, and hearing problems
- Loss of vision, cataracts, and issues with the optic nerve
- Jaundice and an enlarged liver
- Failure to grow at the expected rate and specific facial features
X-ALD has three forms which manifest based on age and the affected organs: childhood cerebral ALD, Addison disease, and adrenomyeloneuropathy.
Childhood cerebral ALD generally starts between the ages of 3 and 10 years. Symptoms include developmental issues, sensory problems, and severe neurological issues usually resulting in severe disability, coma, and sometimes death. Notably, a few adults may present symptoms similar to this form of the disease.
Addison disease, another form of X-ALD, primarily affects the adrenal gland. Its manifestations are due to decreased production of aldosterone and cortisol hormones. Symptoms include low sodium levels, fatigue, low blood pressure, dehydration, low blood-sugar levels, and general weakness. In some cases, the skin might darken.
Adrenomyeloneuropathy, which is a mild form of X-ALD, typically starts in the third decade of life. People with this condition usually have difficulty walking, an unsteady gait, and problems with bowel or bladder control.
Females who have X-ALD may experience mild symptoms like unbalanced gait, nerve disease, and mild paralysis. Rarely, this form of the disease may affect the adrenal glands and brain.
Testing for Adrenoleukodystrophy
Typically, doctors begin examining for adrenoleukodystrophy (ALD) through noting some key symptoms, signs, and any family history of the condition. Some places have even started screening newborns for X-ALD, a form of ALD, to spot it early and start treatment before symptoms show up.
Lab tests are done to get more insights. An abnormal liver function or a reduced response to a specific hormone might hint at ALD. However, real clues of ALD come from different tests: high levels of a type of fat (VLCFA) in the blood, low levels of a certain compound (plasmalogen) in red blood cells, and high levels of pipecolic and phytanic acid in the blood and fibroblasts.
Brain imaging through a magnetic resonance imaging (MRI) is also very important. ALD often appears on an MRI as a certain pattern of white matter degradation, small, irregular formations on the brain, and particular cysts found in the caudothalamic groove. If these clues align, doctors can then use genetic testing to find the specific mutation causing the disorder and confirm the diagnosis.
Treatment Options for Adrenoleukodystrophy
There currently isn’t a cure for ALD (adrenoleukodystrophy), a rare genetic disease that affects the brain and adrenal glands. However, there are ways to help manage the symptoms. This can include good nutrition, physical therapy, and support for breathing problems.
If ALD affects the patient’s adrenal glands, doctors may recommend hormone replacement therapy with corticosteroids and mineralocorticoids. These hormones help the body deal with stress, keep blood pressure normal, and balance salt and water levels.
There is also some evidence that cell transplantation treatment (allogeneic hematopoietic cell transplantation, or HCT) may be beneficial in some cases. This therapy tends to work best in people who do not have symptoms yet or only mild symptoms.
Moreover, recent research trials have been conducted on the use of a compound called docosahexaenoic acid. This compound is thought to help trigger an increase in specialized compartments in cells (peroxisomes). Still, the results have been mixed so far.
Since ALD impacts many organs and each patient may have different needs, it is best to have a team of various medical professionals involved in the care. This team could include endocrinologists (hormone doctors), neurologists (brain and nervous system doctors), geneticists (genetic disorder specialists), and psychologists.
What else can Adrenoleukodystrophy be?
When trying to diagnose N-ALD, a type of genetic disorder that can show signs and symptoms in newborn babies, doctors may need to consider other similar conditions. These might include:
- Hypoxic-ischemic encephalopathy, a type of brain damage that occurs when the brain doesn’t receive enough oxygen or blood flow
- Angelman, Rett, and Prader-Willi syndromes, which are all genetic disorders that can affect a child’s development and cause various physical and mental challenges
- Metabolic disorders, which affect the body’s ability to process certain nutrients and cause various health problems
- Myotonic dystrophy, a type of muscular disorder that can cause muscle weakness and other symptoms
On the other hand, when diagnosing X-ALD, another rare genetic disorder, doctors might need to consider conditions that cause damage to the protective covering of nerve fibers in the brain, known as demyelination. These could include:
- Acute disseminated encephalomyelitis, an inflammation of the brain and spinal cord
- Multiple sclerosis, a lifelong condition that can affect the brain and/or spinal cord
What to expect with Adrenoleukodystrophy
The outlook for N-ALD and most forms of X-ALD isn’t very hopeful. Typically, the treatment is focused on easing the symptoms. Replacement therapy can work well for patients with Addison disease. Meanwhile, Hematopoietic Cell Transplantation (HCT) might be beneficial for patients who do not yet show any symptoms, are identified through newborn screening or incidental imaging, or have mild symptoms. Unfortunately, individuals with N-ALD and X-ALD are often left with severe disabilities and generally have reduced life spans.
Preventing Adrenoleukodystrophy
Adrenoleukodystrophy is a health condition that typically arises from birth (in cases of N-ALD) and affects both children and adults (for X-ALD). This condition can impact many parts of the body, but it particularly targets the brain and adrenal glands, which are situated just above the kidneys. It’s crucial that patients and their families understand several key points about the disease:
- N-ALD is passed down from parents to children through genes, requiring a copy of the faulty gene from both parents.
- X-ALD is also genetic but is more commonly found in men as it’s linked to the X-chromosome.
The symptoms of adrenoleukodystrophy can look different in different people. Some might experience problems with muscle tone, strength, growth, and thinking abilities. Others may also have issues with blood pressure regulation, tiredness, and blood sugar levels. These are typically due to the brain dysfunction and poor adrenal gland performance caused by the disease.
To know if someone has this disease, doctors need to look closely at the person’s medical history, conduct a physical examination, and perform various tests. This could include measuring very long-chain fatty acids (VLCFA) in the blood, taking images of the brain (MRI), and doing specific genetic tests.
Unfortunately, there’s currently not a lot of definitive treatments available for most people with this condition. Doctors often focus on relieving symptoms as they come up. In some cases, replacing certain hormone-like substances in the body (corticosteroids and mineralocorticoids), or doing a certain kind of transplant (hematopoietic cell transplantation or HCT), can be helpful. But, overall, the long-term outlook (prognosis) for individuals with adrenoleukodystrophy is not very promising – many patients face severe health problems and a short lifespan. However, researchers are currently testing new gene therapies that might provide some hope for these patients in the future.
Obviously, this condition has significant repercussions for the entire family. That’s why genetic testing is very important – it can help female carriers and the families of patients better understand what the future holds. With this knowledge, they can take steps to manage potential risks, consider different prenatal testing options, and make well-informed decisions about family planning.
