Adrenoleukodystrophy (ALD), also known as X-linked adrenoleukodystrophy (X-ALD), is a rare genetic brain disorder that affects about 1 in 15,500 males (and roughly 1 in every 18,000 people if both sexes are included). The disease is characterized by the accumulation of a compound known as saturated very long chain fatty acids (VLCFAs) that, in excess, destroys myelin (a protective sheath that insulates nerve cells in the brain) and damages the adrenal glands (small hormone-producing glands that are located above the kidneys).
Patients with ALD usually display symptoms of neurologic dysfunction and adrenocortical insufficiency, a condition where the adrenal glands are not able to produce enough steroid hormones.
Causes of ALD
ALD is caused by a mutation in the ABCD1 gene, which is located on the X-chromosome. Several mutations in the ABCD1 gene are known to cause ALD; in some patients, parts of the gene are deleted. Specific mutations or large deletions can even result in the complete absence of the protein this gene works to produce. Currently, it is not known if the type of mutation correlates with the condition’s clinical subtypes or severity.
Because men have only one X-chromosome, they are more severely affected by the disease than women. Women have two X-chromosomes, and the second healthy copy of the gene partially compensates for the loss of function in the mutated copy.
The ABCD1 gene provides instructions to build a protein — called the adrenoleukodystrophy protein, or ALDP — that plays a crucial role in the transport of VLCFAs into the peroxisome. Peroxisomes are small compartments within the cell that are important for energy metabolism and the breakdown of many molecules, among them VLCFAs.
The insufficient transport of VLCFAs into peroxisomes leads to an abnormal buildup of VLCFA in the blood and central nervous system. The exact mechanism by which VLCFAs cause damage is not entirely understood, but they appear to be toxic to the myelin sheath and the adrenal cortex or the outer layer of the adrenal gland.
Research suggests that the accumulation of VLCFAs triggers an inflammatory response in the brain that leads to the breakdown of myelin (demyelination).
Damage to the adrenal cortex causes a shortage of steroid hormones (mainly cortisol and aldosterone), a phenomenon known as adrenal insufficiency or Addison’s disease. These hormones are needed for various bodily functions, such as metabolism and stress regulation, reduced inflammation, and blood pressure regulation.
Symptoms of ALD
Symptoms that occur in ALD can be divided into two groups: those that are the cause of neurologic dysfunction, and those that are caused by adrenal insufficiency. Neurologic abnormalities include changes in behavior, learning, and motor skills. Adrenal insufficiency symptoms are vomiting, weakness, weight loss, coma, and increased skin pigmentation.
The severity and onset of symptoms depend on the type of ALD.
Types of ALD
Three distinct types of adrenoleukodystrophy have been identified:
Childhood cerebral ALD (CALD)
CALD is the one of the most common types of ALD, representing about 45 percent of all cases. Affected individuals typically begin to show learning and behavioral difficulties between ages 4 and 10. Further symptoms include aggressive behavior, difficulty swallowing, vision problems, poor coordination, and impaired adrenal gland function. The rate at which CALD progresses varies, but it can progress very quickly, often leading to total disability within a few years.
AMN, also known as adult-onset ALD, is another common form of this disease with signs and symptoms that appear in early adulthood, although they can become evident in middle age. It is usually less severe and progresses more slowly than CALD, although some of these patients will have cognitive and emotional as well as physical difficulties. AMN’s main symptoms are a stiff gait and weakness in the legs, and problems with control over the bowel and bladder.
Most individuals with ALD develop symptoms of Addison’s disease but some (about 10 percent) initially only develop adrenocortical insufficiency symptoms that can appear any time between childhood and adulthood. Most individuals develop additional symptoms of the AMN by the time they reach middle age. The severity of symptoms varies, but it is typically the mildest of the three forms.
Women with ALD
Women with ALD usually develop a mild form of AMN, in which symptoms are much less severe and occur later in life. Symptoms in childhood are extremely rare and develop over several decades. Common symptoms include weakness, disturbed sensation and spasticity (continuous muscle contraction) of the legs, and impaired control over the bladder and bowel. Adrenal insufficiency is hardly known in females.
Theoretically, both copies of the ABCD1 gene on each X-chromosome can be mutated. But reports of this occurring are very few.
Diagnosis of ALD
It is important to diagnose ALD as early as possible, because available treatments only work during a narrow window before symptoms develop or very shortly after their onset. The reason for this is that the loss of myelin is irreversible, and there is currently no possibility of restoring what is lost.
Clinical presentation plays a role in the diagnosis of ALD, but because symptoms vary greatly and other conditions — such as attention deficit and hyperactivity disorder (ADHD), autism, and epilepsy — can have similar symptoms, they are not very useful in the diagnostic process. Neurologic symptoms usually lead to the decision to perform a magnetic resonance imaging (MRI) scan of the brain. Damage to myelin is easily recognized on an MRI scan, and most patients demonstrate characteristic MRI findings.
Newborn screening is the only known way of diagnosing the condition before the appearance of symptoms. Several U. S. states routinely screen newborns for ALD. The screen includes a biochemical analysis of VLCFA levels in the blood. They are elevated in all male ALD patients, regardless of ALD type. Elevated levels are also seen in 85 percent of females. However, high VLCFA levels are not specific to ALD, and a blood test cannot be used to reach a definite diagnosis. Genetic tests that confirm the presence of mutations in the ABCD1 gene are required for a final diagnosis. When a family history of ALD is known, mutations can also be detected through prenatal screening.
Treatment of ALD
Available treatments for ALD can inhibit the progression of the disease by arresting demyelination of nerve cells. So far, there is however no possibility to restore myelination.
Adrenal insufficiency can be treated with corticosteroid replacement therapy, while neurological dysfunction can be treated with stem cell therapy, which involves the use of stem cells from the bone marrow of a donor that develop into nerve cells in the brain. Transplanted cells compensate for the ABCD1-deficient brain cells and arrest the demyelination of nerve cells.
Stem cell therapy is currently the standard of care for patients with CALD. It is effective when used in boys with early-stage CALD that have a Loes score below 10. Loes score is a rating of the severity of abnormalities in the brain found on MRI.
The problem with this approach is that it requires the severe weakening of the immune system. The immune system’s function is to protect the body from harmful foreign substances. Because cells from a donor are considered as foreign and potentially harmful, the body’s immune cells attack these cells and prevent successful engraftment without suppression of the immune system. As a consequence, the patient is extremely vulnerable to severe illness from otherwise harmless infections.
A further complication develops when the donor’s bone marrow cells attack the recipient’s body, a phenomenon known as graft versus host disease. For these reasons, stem cell therapy involving cells from a donor is considered risky and carries a high mortality rate. Gene therapy, still in early research stages and discussed below, is seen as a possible alternative approach.
There is also a treatment called Lorenzo’s oil, which is a 4:1 mix of oleic acid and erucic acid, two fatty acids that are extracted from olive oil and rapeseed oil. It is thought to inhibit the production of VLCFAs, so to prevent CALD when the therapy is started before disease onset and to slow the progression of AMN. However, its efficacy has never been shown in controlled randomized clinical trials. One larger placebo-controlled trial (NCT00545597) was discontinued due to adverse reactions in the control group.
There are a number of experimental treatments that are currently being developed to treat ALD. These are summarized below.
Oxidative stress is thought to play an important role in the demyelination of nerve cells in ALD.
OP-101 is an experimental medication developed by Orpheris that works by reducing oxidative stress and inflammation. The company recently completed a Phase 1 safety study (NCT03500627) in healthy volunteers.
Inflammation that occurs as a result of VLCFS accumulation is thought to play a major role in the pathology of ALD. Lowering inflammation levels may arrest the demyelination in ALD.
Minoryx developed MIN-102, a compound designed to reduce inflammation. The company showed, in a Phase 1 clinical trial, that MIN-102 is safe and well-tolerated. Following these positive data, Minoryx started a Phase 2/3 randomized and placebo-controlled clinical trial (NCT03231878) assessing the efficacy of MIN-102 in slowing AMN progression. The trial is ongoing, and results are expected at the end of 2020.
ABCD2 is another gene with a very similar function to ABCD1. As ABCD1, it also provides instructions to build a protein that transports VLCFAs into peroxisomes. The upregulation of the activity of the ABCD2 gene could, therefore, compensate for the loss of function in the ABCD1 gene.
Following this approach, the startup company NeuroVia developed NV1205. A multicenter Phase 1/2 (NCT03196765) open-label and dose-escalation study, aiming to determine the most effective dose of the NV1205, is currently recruiting patients in Argentina, Australia, Chile, Colombia, France, the Russian Federation, Ukraine, and the U.K. The dose-escalation part 1 of this study will be followed by a long-term treatment phase.
Gene therapy is an advancement of standard stem cell therapy that uses a patient’s own stem cells instead of stem cells taken from a matched donor. These immature cells are isolated from the patient’s bone marrow, and engineered (or modified) to give them a working copy of the ABCD1 gene using a virus, one that is able to produce a functional ALD protein (ALDP). The modified cells are then returned to the patient, where they might develop into nerve cells in the brain. Because this therapy uses a patient’s own cells, the risk that the body rejects the cells is very low.
Using this approach, the company Bluebird Bio is developing Lenti-D. The U.S. Food and Drug Administration (FDA) designated Lenti-D a breakthrough therapy designation in May 2018. The designation was based on promising preliminary data from a Phase 2/3 clinical trial (NCT01896102) assessing the efficacy and safety of Lenti-D in treating CALD.
Two additional clinical trials using the same approach are currently recruiting patients in Guangdong, China. A Phase 1/2 clinical trial (NCT02559830) at the Shenzhen Second People’s Hospital aims to assess the efficacy and safety of transplanting genetically modified patient-derived bone marrow stem cells. Another Phase 1/2 clinical trial (NCT03727555) at the Shenzhen Geno-Immune Medical Institute is aiming to evaluate the safety and efficacy of a lentiviral vector (TYF-ABCD1) injected directly into the patient’s brain for the treatment of ALD.
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