Very long chain fatty acids are common throughout the body and brain. VLCFAs have at least 22 carbons and are too long to be metabolized in the mitochondria, a specialized sac of a eukaryotic cell. Instead, the peroxisome sacs, also in the eukaryotic cells, must metabolize these acids. People with adrenoleukodystrophy (ALD) have a defect in this process that results in a build-up of VLCFAs that invade the brain and adrenal cortex. This defect damages the myelin sheath, which insulates the brain’s nerve cells. ALD affects 1 in 18,000 people, with painful results.
An abnormality of the ABCD1 gene on the X chromosome, which is responsible for producing the adrenoleukodystrophy protein in the peroxisomes, causes adrenoleukodystrophy. Because it’s an X-linked recessive genetic disorder, women are better protected due to their extra X chromosome, while men endure more severe effects. The symptoms of the condition vary depending on the subtype, but because ALD affects the white matter of the central nervous system and adrenal cortex, neurological abnormalities are common.
As a subtype of X-linked adrenoleukodystrophy, childhood-onset cerebral ALD or X-CALD represents 45 percent of all ALD cases. The disease shows up between the ages of four and ten, where healthy boys display signs of some cognitive dysfunction as well as withdrawal. Symptoms worsen to include deafness and blindness and deteriorate into dementia. In most cases, X-CALD proves fatal within two to five years of the development of symptoms. Antenatal genetic testing, and testing plasma for VLCFA concentrations, helps with detection.
Also known as hypoadrenocorticism, Addison’s disease happens when adrenal glands don't produce enough of the hormones cortisol and aldosterone. Cortisol affects how the body responds to stress, while aldosterone is responsible for electrolyte balance, which is vital in cardiovascular function. While a good number of Addison’s cases go undiagnosed, it’s the only clinical sign of ALD in 10 percent of cases. Often, the condition is easily handled through lifestyle changes as well as a daily steroid pill.
Not all who are born with the damaged gene show symptoms at birth. Adult-onset ALD, known as adrenomyeloneuropathy or AMN, starts in the late twenties and includes speech difficulties, sexual dysfunction, seizures, and adrenal insufficiency. In women who carry the mutated gene but don’t develop the disease, milder symptoms may develop after age 35, including urinary problems and joint pain. Treatments vary and can include physical therapy for building muscle strength and steroid replacement therapy for those with adrenal insufficiency. Between 40 and 45 percent of those with AMN have neurological effects, and between 10 and 20 percent of those cases become fatal.
Leukodystrophy is an umbrella of disorders characterized by degeneration of the brain’s white matter, which makes diagnosing a particular subtype challenging. Understanding certain related disorders helps doctors put the pieces together. Like ALD, Metachromatic leukodystrophy is an inherited disorder characterized by an arylsulfate A enzyme deficiency. This leads to the accumulation of sulfatide, a molecule that assists with memory and neural plasticity, and destroys the myelin sheath of the peripheral and central nervous systems.
Another related disorder that can help with the differential diagnosis of adrenoleukodystrophy is Krabbe disease. This genetic disorder is seen mostly in infants at around six months of age, where the deficiency of galactocerebrosidase (GALC) causes a problem with lipid storage. GALC is a metabolizing enzyme that helps create myelin, and when it fails to do its job, demyelination ensues. Symptoms include mental deficits, blindness, and paralysis of some facial muscles. Most infants with Krabbe do not live beyond two years.
Multiple sclerosis is a disease that leads to lesions on the myelin sheath of the brain and spinal cord, resulting poor signal transmission throughout the central nervous system. Symptoms include visual, speech, and mobility problems, similar to some manifestations of ALD. Unlike ALD, MS is a chronic disease with stages of remission, relapse, and stability. In 2011, scientists discovered the first case of a female X-ALD carrier who presented with sensorimotor symptoms that were actually symptoms of MS.
The Zellweger spectrum is a group of conditions with overlapping signs and symptoms. One such condition is neonatal adrenoleukodystrophy or NALD. The less severe condition may not manifest until late infancy or early childhood. Hearing loss and development delays are also symptoms of NALD, but scientists insist that NALD is not to be confused with ALD. One fundamental reason is that NALD is the mutation of one of 13 PEX genes responsible for peroxisome development, while ALD deals with the abnormality of a specific protein.
There is no cure for adrenoleukodystrophy, but treatment options are available. Bone marrow transplants replace cells missing the protein with healthy stem cells that can break down VLCFAs. While this protects the central nervous system from more damage, treatments cannot correct the existing damage. Allogeneic transplants comprise cells from a healthy donor, but patients first undergo chemotherapy to kill unhealthy cells. Patients receive donated cells intravenously, and these cells travel to bones to make healthy cells.
The critically-acclaimmed 1992 movie Lorenzo’s Oil was based on the true story of Augusto and Michaela Odone’s fight to treat their son Lorenzo’s ALD. Lorenzo’s Oil is a 4:1 mixture of oleic acid and erucic acid, which comes from mustard and rape seeds. Studies showed that paired with a moderately low-fat diet, the oil reduced the production of VLCFAs in individuals with ALD. This treatment is effective at halting the progression of childhood-onset cerebral adrenoleukodystrophy when administered at the earliest stages or before symptoms manifest.
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