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Leukodystrophy

The word leukodystrophy comes from the Greek words leuko (meaning white), trophy (meaning growth), and dys (meaning ill). Putting these pieces together, the word leukodystrophy describes a set of diseases that affect the growth or maintenance of the white matter (myelin).

Leukodystrophies are a group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and often the peripheral nerves. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can’t function normally without it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems.

Causes

Leukodystrophies are genetic disorders caused by specific gene abnormalities that lead to abnormal development or destruction of the myelin sheath in the nervous system or white matter in the brain. Each type of leukodystrophy follows a particular pattern of inheritance such as autosomal recessive, X-linked recessive or autosomal dominant. Some dominantly inherited conditions result from a de novo mutation. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Related Disorders

Symptoms of the following disorder can be similar to those of leukodystrophy. Comparisons may be useful for a differential diagnosis:

Multiple sclerosis (MS) is a chronic inflammatory disease affecting the myelin sheath of the brain and spinal cord (central nervous system). It may be progressive, relapsing and remitting, or stable. MS consists of small lesions called plaques that form randomly throughout the brain and spinal cord. These plaques on the myelin sheath prevent proper transmission of nervous system signals. Symptoms may include visual and speech problems, numbness, walking difficulty and loss of bladder or bowel control. MS affects adults, and its cause is unknown.

Standard Therapies

Treatment of most leukodystrophies is symptomatic and supportive. Medications and physical therapy may be helpful for spasticity and motor difficulties. Anti-epileptic medications should be provided for seizures and burning paresthesia from peripheral neuropathy may respond to medications for neuropathic pain. Please review the NORD report on the specific type of leukodystrophy for information about successful therapies. Genetic counseling is beneficial for affected individuals and their families.

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Nonketotic hyperglycinemia (NKH)

NKH is a rare genetic disorder that affects 1 child in every 60,000 born. Children with this condition have a problem breaking down the amino acid glycine. This is caused by a defect in the genetic code for the machinery that is responsible for the glycine breakdown (called glycine cleavage enzyme). Amino acids are natural components of our body. Because glycine is not broken down, it accumulates in the body. Glycine is an important molecule in the brain where it has various functions such as transmitting signals from one brain cell to another. Excessive glycine disrupts the function of the brain.

Children with NKH usually present as newborns, but 1 in 5 children presents in infancy. Typical symptoms include seizures, low tone, and severe problems with learning and development. This can profoundly affect a child’s ability to learn and to do normal things such as eating, sitting, and walking. The seizures can be so severe that they are hardly controlled despite the use of several medications for seizures. Not all children are equally affected. Most commonly children are severely affected and do not make developmental progress and have difficult to control seizures. Some children, about 1 in 6, are more mildly affected. They make progress in their development, and have seizures that can be controlled more easily. Current treatment is limited.

We assume, but have not completely proven, that the difference between severely affected children and more mildly affected children relates to the genetic defect. There is also some early evidence that the condition involves a loss of function that occurs in the first year of life. If so, then this indicate that the problems are not due to defects present before birth, but reinforce our hope that understanding this process will provide an opportunity to prevent the harm to the brain of these children from occurring. This process seems to happen in the more severely affected children.
In our current studies, we first aim to analyze what predicts if children are severely or more mildly affected with the condition. We try to provide the link between the genetic defect and the severity and to develop a practical method to study this difference. Second, we aim to look for clues to the mechanism that causes this disease. Only when we understand how the defect in the metabolism of glycine leads to the observed problems, can we develop rational interventions that will change the course of the disease. Such studies will involve analyzing samples from affected children. We also aim to study and animal that has this disease and that will allow us to directly investigate how this diseases affects the brain. Finally, we aim to review what the impact has been of the current existing treatment on the patients. We hope that this will provide the way with which we can develop a treatment that changes the course of the disorder for these unfortunate children.

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