Genetic diseases are due to inherited changes in their DNA sequence, which we call mutations. Our DNA is organized in genes that produce specific proteins. Some mutations prevent the production of a functional protein and this may cause disease. In the nucleus of our cells, we have two copies of most DNA sequences. One of the copies comes from our father and another one comes from our mother. Although an affected parent can pass along a disease-causing mutation to their child, diseases that are caused by DNA mutations that can be passed on from parent to child are called genetic diseases. Today we're going to focus on ALD, which stands for X-linked Adreno-Lucodistrophy. ALD affects one in 17,000 people of all ethnic backgrounds. This disease is caused by a mutation in the ABCD1 gene that produces the ALD protein. Degrees in the ABCD1 gene prevent the production of a functional ALD protein. The disease affects men more than women, who experience a less severe disease later in life. This is because of a very interesting genetic fact. I just mentioned that we have two DNA copies of all genes. Well that's not entirely true. Men only have one copy of the genes found on chromosome X, while women have two copies. That is what determines whether you are male or female. It turns out that the ABCD1 gene is located on the X chromosome. So women with a mutation in one copy of the ABCD1 gene still have a normal copy of the gene that can make a functional ALD protein. Men however, only have one copy of the ABCD1 gene, so if this copy is mutated, there is no normal ALD protein produced. So what effect does an ABCD1 mutation have on the cell? In a cell, ALD is normally present on the surface of structures that we call peroxisms. ALD is responsible for transporting specific kinds of fats called very long-chain fatty acids, or VLCFA's, into the peroxisone where they are broken down. When a cell doesn't produce functional ALD protein, very long-chain fatty acids can't get broken down in the peroxisms, so they accumulate. The very large quantities of VLCFA's can be toxic to certain cells, including cells that produce blood cells, cells that produce hormones, and cells that produce myelin in the nervous system, which is required for neurons to function. Therefore, patients with ALD develop very severe symptoms associated with the malfunction of these cells. Although all ALD patients share a genetic problem, or genotype, the symptoms ALD patients' experience can vary greatly, and are grouped into phenotypes. The ALD genotype has four unique phenotypes, which can overlap during lifetime. The four phenotypes are asymptomatic, adrenal myelonoropathy, AMN, adrenal insufficiency, and cerebral demyelination. The onset and severity of the phenotypes can vary from patient to patient. Let's explain how this works by talking about each of the ALD phenotypes in more detail. Let's start with the asymptomatic phenotype. All patients with ALD are completely asymptomatic for the first few years of life. During childhood and adolescence, men may begin developing symptoms, and by age 50, essentially 100% of men with the ALD genotype will have developed at least one of the ALD phenotypes or symptoms. On the other hand, women with the ALD genotype rarely develop symptoms before reaching adulthood, and then the symptoms are usually limited only to one phenotype, adrenal myelonoropathy, or AMN. Adrenal myelonoropathy, or AMN, is the most common ALD phenotype. It affects all men and most women by the time they reach their late 40s. In this sense, it is considered the default form of ALD. In other words, whether you are a man or a woman with ALD, if you live long enough, you will eventually develop AMN. AMN results from slow and progressive injury to the myelon and axons of the spinal cord and nerves because of VLCFA accumulation. Myelons serves as a sheath to protect and insulate the axons of neurons in the spinal cord, responsible for movement and sensation, which are among the largest and longest cells in the body, leaving them vulnerable and harder for the body to repair. When myelon is damaged in ALD, neurons in the spinal cord and nerves malfunction. As a result, symptoms often begin as stiffness or tingling in the feet, but they always worsen over time and result in difficulty with walking, balance, and strength, as well as bowel, bladder, and sexual functions. Fortunately, the AMN phenotype appears to spare brain function. Unfortunately, we don't yet have an effective treatment for AMN. The next most common phenotype is adrenal insufficiency, which eventually affects most men with the ALD genotype, but is rare in women. Symptoms include weakness and fatigue, nausea, and low blood pressure. In ALD, adrenal insufficiency occurs when the cells that produce hormones in their adrenal gland are injured. This injury is irreversible, and the resulting symptoms of low blood pressure and fatigue can be life-threatening if untreated. Fortunately, if diagnosed promptly, adrenal insufficiency can be safely and easily treated using daily hormone supplements. This is why all boys and men, with the ALD genotype, should be tested regularly for adrenal insufficiency. The most dreaded symptom of ALD is cerebral demyelinating ALD, or cerebral ALD. About two-thirds of men with ALD will experience cerebral ALD. It is very rare in women. This is the most devastating of all ALD symptoms, and is lethal unless it is promptly diagnosed and treated. The biology underlying cerebral ALD is similar to AMN, in that damage is mild in axons. However, whereas AMN progresses slowly and affects the spinal cord and nerves, cerebral ALD progresses much more rapidly and affects the brain. The damage to axons in cerebral ALD appears to originate with this function of the white blood cells in the brain, which become injured when VLCFA is accumulated in ALD. This leads to massive inflammation that typically starts near the center of the brain and radiates outward. This inflammation damages the brain's myelin, axons, and eventually the neurons. This leads to myriad of different symptoms that may include problems with vision, attention, behavior, and coordination. Unfortunately, many boys with ALD are diagnosed late because symptoms do not appear until a damage to the brain is already quite large. So regular brain scans help doctors detect the onset of the brain damage early. When diagnosed early, cerebral ALD can be stopped with a bone marrow transplant from a matched donor. The donor's bone marrow contains stem cells that don't have an ABCD1 mutation. These stem cells can replace the patient's defective white blood cells and stop the brain inflammation. This procedure only stops the progression of cerebral ALD if it has started very early in the course of disease within a few months. This is why monitoring for cerebral ALD in boys and men is very important. Lastly, because bone marrow transplant carries the potential for serious side effects, it should only be used in patients with cerebral ALD. Unfortunately, there is no definitive cure for ALD. Although some effective treatments do exist for cerebral ALD, bone marrow transplant, and adrenal insufficiency, hormone supplements. We can also treat individual symptoms like muscle stiffness and fatigue depending on the patient's condition. In ALD, earlier diagnosis allows for better treatment. To diagnose ALD, we begin by measuring blood levels of very long chain fatty acids, which accumulate in ALD patients. This test can easily be performed at birth and is being added to the newborn screening panel in a growing number of states. The final diagnosis of ALD is made by identifying mutations in the ABCD1 gene, which can be done after birth or as part of a prenatal diagnosis. So it lies ahead for ALD patients. There are many exciting advances already in progress. Newborn screening for ALD is being implemented in a growing number of US states. Scientists have found several drugs that may reduce levels of VLCFA's. There are also several exciting treatments currently in clinical trials. In fact, ALD is one of the first diseases to show promising results to a gene therapy in clinical trials. But there's still much we don't know about ALD. For example, we still cannot predict which patients will develop cerebral ALD or adrenal insufficiency. Researchers are trying to identify biological markers that can predict which patients are more likely to experience each symptom. This video has been produced by Ureca Science in collaboration with ALD Connect. 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