Leukodystrophy and genetics
Leukodystrophy is a rare genetic disorder characterized by the progressive degeneration of myelin, the protective insulation around nerve fibers in the brain. This decline in myelin affects how signals are transmitted within the nervous system, leading to a range of neurological symptoms. There are various types of leukodystrophies, including metachromatic leukodystrophy, Krabbé disease, and adrenoleukodystrophy, which can manifest in infancy, childhood, adolescence, or early adulthood. The condition is typically inherited in an autosomal recessive manner, meaning that both parents must be carriers of the mutated gene for a child to be affected.
Mutations in the ARSA gene and the PSAP gene are primarily responsible for the disease, leading to the accumulation of toxic substances that damage nerve cells. Symptoms can vary widely and may include motor skill decline, seizures, and developmental delays, as well as potential complications affecting other organ systems. Diagnostic procedures often involve MRI scans, blood tests, and comprehensive medical evaluations.
While treatment focuses on symptom management and may include therapies like physical or occupational therapy, the research community is actively exploring advanced options such as gene therapy and bone marrow transplants. As there is currently no known prevention for leukodystrophy, genetic counseling may be advisable for affected families considering future pregnancies.
Leukodystrophy and genetics
DEFINITION Leukodystrophy is a rare disease that results in the progressive decline of the myelin, or “white matter,” of the brain. Myelin works to insulate and protect axons, which transmit signals from the brain throughout the body.
Types of leukodystrophies include metachromatic leukodystrophy, Krabbé disease, adrenoleukodystrophy, adrenomyelopathy, Pelizaeus-Merzbacher disease, Canavan disease, childhood ataxia with central nervous system hypomyelination (CACH, also called vanishing white matter disease), Alexander disease, Refsum disease, and cerebrotendinous xanthomatosis. Most leukodystrophies begin in infancy or childhood. However, there are several types that may not begin until adolescence or early adulthood.
Risk Factors
Individuals with a family history of leukodystrophy are at risk for the disease.
Etiology and Genetics
Leukodystrophy is inherited as an autosomal recessive disorder, which means that both copies of a particular gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected. If one parent has metachromatic leukodystrophy and the other is a carrier, there is a 50 percent probability that each child will be affected. A simple blood test is available to screen for and identify the most common carrier phenotype.
Mutations in two separate genes are known to cause this disease. Most affected individuals have mutations in the ARSA gene, found on the long arm of chromosome 22 at position 22q13.31-qter, which encodes an known as arylsulfatase A. This enzyme catalyzes an essential step in the breakdown of sulfatides, a group of sphingolipids that are important components of cell membranes. Nerve cells surrounded by myelin sheaths are particularly rich sources of sulfatides. In the absence of functional arylsulfatase A activity, sulfatides can accumulate to toxic levels in these tissues that will eventually destroy the cells forming the myelin sheath. This in turn leads to nerve cell destruction and the loss of nervous system function that is characteristic of leukodystrophy.
A minority of patients have mutations in the PSAP gene, found on the long arm of chromosome 10 at position 10q21-q22. This gene specifies the synthesis of a large protein known as prosaposin. Prosaposin is subsequently cleaved into four smaller proteins called saposin A, B, C, and D. Each of these serves to assist other proteins in the breakdown of various sphingolipids. Saposin B is the one that interacts with arylsulfatase A to recycle sulfatides. If mutations in the PSAP gene result in an inactive saposin B, sulfatides will accumulate in nerve cells and cause the cell destruction that leads to leukodystrophy.
Symptoms
Symptoms of leukodystrophy may include a gradual decline of the health of an infant or child who previously appeared well, a loss or an increase in muscle tone, a change in movements, seizures, abnormal eye movements, and a change in gait. Additional symptoms may include a loss of speech, a loss of the ability to eat, a loss of vision, a loss of hearing, a change in behavior, and a slowdown of mental and physical development.
Some leukodystrophies are accompanied by involvement of other organ systems, resulting in blindness; heart disease; enlargement of the liver and spleen; skeletal abnormalities, such as short stature, coarse facial appearance, and joint stiffness; respiratory disease leading to breathing problems; bronzing of the skin; and the formation of cholesterol nodules on tendons.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. The doctor will also perform a magnetic resonance imaging (MRI) scan to produce detailed images of the brain, which can help in the diagnosis of leukodystrophy.
Other tests include urine analysis; a nerve biopsy; a blood test; a biopsy, which is the removal of a sample of skin tissue; a computed tomography (CT) scan, a type of X ray that uses a computer to make pictures of structures inside the skull; a lumbar puncture, a procedure to collect cerebrospinal fluid; and nerve conduction testing, a test that measures the speed and degree of electrical activity in a nerve to determine if it is functioning normally.
Treatment and Therapy
Individuals should talk with their doctors about the best plans for them. Treatment options include management of a patient’s symptoms. Depending on the type of leukodystrophy and the symptoms, this management may include medications; physical, occupational, and/or speech therapy; nutritional programs; education; and recreational programs.
In a few of the leukodystrophies, a bone marrow transplant may help stop the progression of the disease. Replacement of the abnormal or absent enzyme is being explored for a few of the leukodystrophies. Research is being done in this area. Gene therapy interventions have reached clinical application for some leukodystrophies, including X-linked adrenoleukodystropy and metachromatic leukodystrophy, and stem cell gene therapy is being performed. One area of study is in vivo application of recombinant adeno-associated viral (rAAV) vectors to target affected cells. Individuals should talk to their doctors to find out what treatments may be right for them.
Prevention and Outcomes
There is no known way to prevent leukodystrophy. For parents who have had a child with leukodystrophy, may be beneficial to find out the chances of having another child with the disease.
Bibliography
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