NORD gratefully acknowledges Ali Fatemi, MD, Department of Neurogenetics, Kennedy Krieger Institute, for assistance in the preparation of this report.
SummaryX-linked adrenoleukodystrophy (ALD) is a rare genetic disorder that affects the white matter of the nervous system and the adrenal cortex. White matter is made up of nerve fibers called axons that relay nerve impulses from one cell to another. These nerve fibers are covered by myelin, an insulating layer or sheath that protects the nerve fibers. Myelin is made up of proteins and fats and gives white matter its white color. Without myelin, the signals between nerve cells cannot be transmitted properly, resulting in neurological symptoms. The adrenal cortex is the outer layer of cells of the adrenal glands. The adrenal glands sit atop the kidneys and produce hormones that are vital to proper health and development including cortisol and the sex hormones. Many of those affected experience serious neurological problems either during childhood or during adulthood with rather different types of disabilities. Some affected individuals also have adrenal insufficiency, which means that reduced amounts of certain hormones such as adrenaline and cortisol are produced, leading to abnormalities in blood pressure, heart rate, sexual development and reproduction. ALD is an X-linked recessive disorder that is caused by variations (mutations) in the ABCD1 gene. Because it is an X-linked disorder males develop more serious complications than females, while some females will have no symptoms. ALD can be broken down into different types based on symptoms and age of onset.
The signs and symptoms of can vary widely, even among members of the same family. Some individuals have serious complications in infancy or childhood while others develop symptoms as adults. Some individuals do not develop symptoms (asymptomatic) until adulthood. The progression of the disorder can also vary. There are different forms of ALD.
Childhood Cerebral ALD
35% of affected males develop neurological symptoms between three and ten years of age. It almost never occurs before approximately two and a half to three years of age. Affected males will develop normally and then start to show a loss (regression) of previously acquired skills. Before the loss of skills, affected males may exhibit behavioral problems including attention deficit and hyperactivity disorder (ADHD) and learning disabilities. Affected individuals usually develop cognitive deficits which means that they may have impairment of their mental processes and have difficulty acquiring information and knowledge. This means affected children may show a decline in performance at school. They may “space out” in school or at various times, have difficulty understanding speech, difficulty reading or understanding written words, difficulty with spatial references, and show a deterioration in handwriting skills.
Later on, they will develop additional symptoms including diminished clarity of vision (diminished visual acuity), hearing loss, gait difficulty, and eventually weakness and stiffness of limbs, convulsions or seizures. Eventually, affected children loose most neurological function and become totally disabled with blindness, deafness and inability to move voluntarily. The disorder will further progress to result in a vegetative state and death typically within 2-3 years from onset of neurological symptoms.
Affected males may also have adrenal insufficiency. The adrenal glands are located on top of the kidneys and produce two hormones called cortisol and aldosterone. Other hormones produced by the adrenal glands help to regulate the fluid and electrolyte balance in the body. When the adrenal glands fail to produce these hormones the term primary adrenal insufficiency is used. Symptoms can include fatigue, unintended weight loss, nausea, vomiting, gastrointestinal issues, weakness, morning headaches, low blood pressure (hypotension), and low blood sugar levels (hypoglycemia). These symptoms are reminiscent of Addison’s disease. Many affected males may develop tanning of skin including areas not exposed to sunlight (hyperpigmented skin).
Adrenomyeloneuropathy is a specific form of ALD characterized by onset in the late 20s to middle ages in affected men. It eventually affects almost all males who do not present in childhood. Initial symptoms are usually progressive stiffness and weakness in the legs (spastic paraparesis). Affected men may develop problems walking or walk in an unusual manner (abnormal gait). Numbness and pain from polyneuropathy are also common symptoms. Polyneuropathy is a general term for degeneration of the peripheral nerves, which are the nerves outside of the brain and spinal cord (i.e. central nervous system).
Affected men may also exhibit erectile dysfunction and problems with bowel and bladder control due to sphincter dysfunction. Sphincters are muscles which control the narrowing or widening certain passageways in the body. The urinary sphincters are two muscles that control the passage of urine from the bladder through the tiny tube that carries urine out of the body (urethra). Poor control of the urinary sphincter leads to urinary dysfunction. In addition, many men also develop premature balding and thinning of hair.
Adult Cerebral ALD
At least 20 percent of all affected men develop cognitive decline similar to that seen in boys with childhood cerebral forms. These patients develop progressive neurological symptoms similar to childhood cerebral ALD and typically result in severe neurological impairment, and eventually vegetative state or death.
In a small percentage of people, adrenocortical insufficiency reminiscent of Addison’s disease may be the only symptom. Sometimes, these individuals are said to have Addison’s-only ALD; they account for about 10% of people with ALD. Most of these individuals eventually develop additional symptoms during middle-age, although adrenal insufficiency may develop years or often decades before neurological problems.
Women with ALD
Women who are carriers (see Causes section below) for ALD often develop adrenomyeloenuropathy in adulthood although the symptoms are often less severe compared to males.
Approximately 20% of female ALD carriers under 40 develop symptoms. By the age of 60 that percentage reaches about 90%. Adrenal insufficiency and involvement of the brain are rare in women, but can occur.
ALD is caused by a variation (mutation) in the ABCD1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
The ABCD1 gene contains instructions for creating a protein called X-linked adrenoleukodystrophy protein or ALDP. This is a transporter protein; it helps to transport fat molecules called very long-chain fatty acids into structures called peroxisomes. Peroxisomes are small membrane-bound structures or sacs within the gel-like fluid (cytoplasm) of cells that play a vital role in numerous biochemical processes in the body. Very long-chain fatty acids are then broken down (metabolized). Because these is a deficiency of ALDP, the transport and, ultimately, the breakdown of very long-chain fatty acids are disrupted and, consequently, these fatty molecules build up in the tissues of the body. Two specific areas affected are the myelin of nerve cells and the adrenal cortex. Originally, it was believed that these fatty molecules were directly toxic to brain tissue. However, some research suggests that the abnormal accumulation of very long-chain fatty acids in the brain sets off an inflammatory response by the immune system that damages the myelin leading to the neurological symptoms associated with x-linked adrenoleukodystrophy.
In the adrenal cortex, abnormal accumulation of very long-chain fatty acids is associated with dying of the hormone producing cells while the exact mechanism are not yet known. It is also possible that damage to adrenal cortex results from an abnormal immune system response to fatty accumulation.
X-linked genetic disorders are caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
In some females, known as heterozygotes, who inherit a single copy of the disease gene for ALD, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit symptoms associated with ALD.
The prevalence of ALD is estimated to be between 1 in 10,000 and 1 in 17,000 individuals in the general population. Prevalence refers to the number of people in the general population who have a disorder at any given time. Rare disorders like ALD often go undiagnosed or misdiagnosed making it difficult to determine the true frequency of the disorder in the general population. The condition occurs throughout the world in all ethnic groups.
A diagnosis of ALD is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.
Some infants may be diagnosed through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. This screening is primarily done through the examination of dried blood spots. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has a disease. Often, a repeat test must be done to confirm the diagnosis. If a newborn screen is positive, then a genetic test may be ordered to identify the specific gene change (mutation) that causes ALD.
In 2016, ALD was added to the Recommended Uniform Newborn Screening Panel (RUSP) in the United States. However, each state determines what specific disorders are included in its newborn screening program within that state. As of October 2019, only a dozen of states test for ALD through newborn screening, although more states are planning on adding the disorder to testing programs.
Clinical Testing and Workup
The initial diagnostic test is usually a blood test to measure the levels of very long-chain fatty acids in the blood plasma. If these levels are notably high or if the ratio of these fatty molecules in the blood is off, physicians will order genetic testing to confirm a diagnosis. Some women who are carriers for ALD can have normal levels of very long-chain fatty acids in the blood. Women who are suspected of having the disorder may require genetic testing to definitely rule out the diagnosis.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the ABCD1 gene known to cause ALD, but is available only as a diagnostic service at specialized laboratories.
Physicians will also test the function of the adrenal glands through a test called ACTH stimulation test. ACTH stands for adrenocorticotropic hormone and is produced by the pituitary gland. An increase in the concentration of ACTH leads to an increase in the production of adrenal hormones. Specifically, there should be a rise in cortisol in the blood plasma.
A specialized imaging technique called magnetic resonance imaging (MRI) may be recommended to assess how ALD has affected the brain. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues including the brain. This allows physicians to see whether the brain has been damaged, including the loss of myelin in the cerebral white matter.
Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, physicians who specialize in diagnosing and treating disorders of the brain and nervous system (pediatric neurologists), adult neurologists, physicians who specialize in diagnosing and treating disorders of the urinary system (urologists), physicians who specialize in diagnosing and treating disorders of the endocrine system (endocrinologists), psychiatrists, physical therapists, and other healthcare professionals may need to systematically and comprehensively plan treatment.
Genetic counseling is recommended for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Boys without symptoms (asymptomatic) should be closely monitored for signs of cerebral disease. This group tends to be boys identified through newborn screening or were diagnosed early because of a previous affected family member. Treatment such as hematopoietic stem cell transplantation should only be considered in boys with abnormal MRI changes who do not yet have neurological symptoms.
For individuals with adrenal insufficiency, corticosteroid replacement therapy is essential. Management of spinal cord disease, urinary complications, polyneuropathy tend to follow routine or standard guidelines.
Following an initial diagnosis in infants or children, a neurodevelopmental assessment may be performed, and affected boys need to undergo repeated MRI studies on a routine basis for disease surveillance. It is important to identify the brain MRI changes as early as possible, since individuals with early MRI changes prior to neurological symptoms have the best outcome when undergoing therapy. Periodic reassessments and adjustment of services should be provided with all children and adults. Additional medical, social, and/or vocational services including specialized learning programs may be necessary.
Allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of certain individuals, particularly young boys or adolescents with evidence of central nervous system involvement who are early in the course of the disease and have no neurological symptoms is currently standard of care and only existing effective therapy to stop progression of neurological symptoms in childhood.
Hematopoietic stem cells are special cells found in bone marrow that grow or mature into different types of cells. In allogenic stem cell transplantation, affected individuals, receive hematopoietic stem cells from a healthy person, referred to as the donor. A series of studies conducted over the last two decades have shown that a HSCT stops the progression of neurological disease in ALD, although it does not improve adrenal insufficiency. HSCT is a major medical procedure that carries significant risk. Since Allogeneic HSCT is only effective in early stages of the disease, it is pertinent that newborn screening is expanded to all states and that all boys diagnosed with ALD undergo repeated brain MRI studies and follow up routinely with a neurologist.
HSCT is also being studied as a potential treatment for affected adults with significant disability due to ALD. Studies have only been conducted on a small number of affected individuals. More research is necessary to determine the long-term safety of HSCT for adults with ALD.
Gene therapy is also being studied as another approach to therapy for affected individuals. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce working protein at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure.” Initial studies are ongoing to determine the long-term safety and effectiveness of gene therapy for certain individuals with ALD.
Lorenzo’s oil is an experimental treatment for ALD. Studies have shown that, in some children, Lorenzo’s oil lowered the risk of neurological symptoms developing in children who do not have any symptoms yet (asymptomatic). However, it is not effective in children who already display neurological symptoms of the disorder. In general, dietary modifications like Lorenzo’s oil or restricting the intake of fatty foods have not demonstrated clinical effectiveness and remain investigational therapies.
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