Leukodystrophy

What Causes Leukodystrophy?

Leukodystrophies are caused by abnormal changes (mutations) in genes. These mutations affect myelin, a fatty substance that coats specific nerve cells in the brain and spinal column. Myelin protects the nerve cells and helps them communicate with each other. The gene mutations associated with leukodystrophies cause an abnormal production of proteins that results in either underdevelopment or destruction of myelin.

Each of the leukodystrophies is caused by a unique mutation or mutations that affect different parts of the myelin sheath that surrounds nerve cells. Because of this, each disorder has a unique set of symptoms.

Examples of the genetic causes of leukodystrophy include:

• Adrenoleukodystrophy, the most common leukodystrophy, is caused by a mutation in the ABCD1 gene. The gene carries instructions for making X-linked adrenoleukodystrophy protein (ALDP). ALDP is involved in the process of transporting substances called very long-chain fatty acids (VLCFAs) into cell structures called peroxisomes, where the VLCFAs are broken down. When ABCD1 mutations impair the production of ALDP, leading to an abnormal accumulation of VLCFAs inside cells. The build-up of these substances leads to myelin damage.
• Canavan disease is caused by mutations in a gene called the ASPA gene. This gene is responsible for the production of an enzyme called aspartoacylase. Aspartoacylase is responsible for breaking down a naturally occurring chemical called N-acetylaspartic acid (NAA). Certain mutations in the ASPA gene lead to abnormally low levels of aspartoacylase in cells which, in turn, allows NAA to accumulate to unusually high levels. An elevated level of the chemical in nerve cells seems to interfere with myelin production.
• Metachromatic leukodystrophy is usually caused by a mutation in a gene called the ARSA gene, which carries instructions for making compounds that break down fatty waste substances inside cells. The mutation causes the waste-processing compounds to be incorrectly produced or not produced at all. As a result, the fatty substances build up to toxic levels inside the cells. In nerve cells, the toxic effect causes the myelin coating surrounding cells in the brain and elsewhere in the nervous system to break down.

Is Leukodystrophy Hereditary?

The gene mutations that cause leukodystrophy sometimes occur spontaneously and are not inherited by a child from their parents. However, in many cases, the mutations are passed from parent to child.

Leukodystrophies are often inherited in an autosomal recessive pattern, meaning that the child must inherit two copies of the mutated gene, one from each parent, to develop the disorder. People with only one copy of the mutation usually don’t have symptoms of the disease, but they are carriers who may pass the mutation to their children. When two carriers have children, they have a 25 percent chance of having an affected child with each pregnancy. They have a fifty percent chance of having a child who is a carrier. Twenty-five percent of the time, their child will inherit two normal copies of the disease-causing gene and be entirely unaffected by the disorder.

Some types of leukodystrophy, such as adrenoleukodystrophy and Pelizaeus-Merzbacher disease, are X-linked disorders, meaning the affected gene lies on the X chromosome. Females have two copies of the X chromosome, one inherited from each parent, but males have only one copy of the chromosome. Females are likely to have only one copy of the mutated gene, so they typically have mild symptoms of the disorder or no symptoms at all. However, males who inherit a mutated gene have no normal copy to compensate, so they develop more severe symptoms.

A form of leukodystrophy that affects adults called adult-onset autosomal dominant leukodystrophy (ADLD) is inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

How Is Leukodystrophy Detected?

Early signs of leukodystrophy vary depending on the disorder. General early symptoms include:

• Delays in acquiring skills such as walking
• Loss of skills already acquired
• Seizures
• Decline in cognitive skills
• Feeding difficulties
• Speech difficulties
• Hearing or vision problems

In some states, all newborns are screened for some types of leukodystrophy, including Krabbe disease, adrenoleukodystrophy, and metachromatic leukodystrophy.

How Is Leukodystrophy Diagnosed?

A doctor may suspect MLD if a patient shows neurological symptoms that worsen in a pattern characteristic of the disease. The diagnostic process will usually include an evaluation of the patient’s medical history, along with physical, cognitive, and neurological exams. Further diagnostic steps may consist of:

• Blood tests and urine tests
• Imaging exams such as magnetic resonance imaging (MRI) or computerized tomography (CT) to look for evidence of demyelination in the brain
• Nerve conduction test to measure nerve cells’ function
• Psychological exams to rule out other possible causes for behavioral symptoms
• Genetic testing to look for the disease-causing gene mutations

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Leukodystrophy Treated?

Leukodystrophies have no cure, and in most cases, no treatment will reverse symptoms once they appear. The only type of leukodystrophy currently treatable is cerebrotendinous xanthomatosis, which can be effectively treated with chenodeoxycholic acid (CDCA) replacement therapy if the disorder is diagnosed early.

Promising research has shown that therapies such as bone marrow transplants, stem cell therapy, gene therapy, and enzyme replacement may be effective at slowing the progression of metachromatic leukodystrophy, especially when administered early in the course of the disease.

Treatment options for most types of leukodystrophy focus on lessening the severity of symptoms, preventing complications, and improving quality of life. Common treatments include:

• Anti-seizure medications
• Medications to treat behavioral issues and other physical complications
• Feeding assistance
• Physical therapy
• Occupational therapy
• Speech therapy

How Does Leukodystrophy Progress?

Leukodystrophies are progressive diseases. The damage to nerve cells and the resulting symptoms get worse over time. The rate of progression may vary depending on the type of disorder and factors such as the age of onset. The diseases are usually fatal, with many children not surviving past adolescence. However, in some cases, survival into adulthood is possible.

Potential long-term complications of the disorders include:

• Loss of mobility and the ability to walk
• Severe cognitive decline
• Loss of speech
• Loss of ability to swallow
• Loss of vision and/or hearing
• Loss of gall bladder function
• Loss of bowel and/or bladder control
• Brittle bones
• Heart disease
• Lung disease
• Intellectual impairment
• Dementia
• Hallucinations
• Depression

How Is Leukodystrophy Prevented?

There is no known way to prevent leukodystrophy. People with a family history of leukodystrophies should consult a genetic counselor to assess their risks before becoming pregnant. Parents who have had a child with leukodystrophy should also seek genetic counseling before having more children.

Leukodystrophy Caregiver Tips

• Stay up-to-date on research developments. New therapies and treatments for leukodystrophy are the subjects of active research, and results so far are promising. Keep abreast of the latest studies so you can be an informed part of your child’s medical team.
• Remember that there is a community of people who know what you’re going through, and they can help. The United Leukodystrophy Foundation maintains a directory of resources for families living with leukodystrophy, including links to education, medical referrals, and financial assistance programs.

Many people with leukodystrophies also suffer from other brain-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with leukodystrophies:

• People with leukodystrophies may be at increased risk for mood disorders such as depression.
• Some people with certain forms of leukodystrophy experience symptoms similar to those of schizophrenia, including hallucinations and delusions.
• Obsessive-compulsive disorder (OCD) may be more common in people with forms of leukodystrophy.
• People with leukodystrophy may be at increased risk of dementia.

Leukodystrophy Brain Science

All types of leukodystrophy affect the myelin-sheathed cells of the brain and central nervous system, cells called white matter, but different types of leukodystrophy affect white matter in very different ways. Some of the diseases also affect other parts of the body.

• Adrenoleukodystrophy results when very-long-chain fatty acids (VLCFAs) accumulate inside cells in various parts of the body. White matter nerve cells seem to be particularly sensitive to VLCFA accumulation. Recent research has suggested that damage to these cells comes not from a direct effect of VLCFAs but possibly from an immune response to the presence of the fatty acids. The immune system reaction causes inflammation that may be responsible for white matter deterioration.

VLCFA accumulation also damages the adrenal gland. Scientists don’t yet know why this happens, but a similar autoimmune response may be to blame there, too.

• Metachromatic leukodystrophy is caused by a deficiency of an enzyme called arylsulfatase A (ARSA). The enzyme works in cell structures called lysosomes to break down fatty substances called sulfatides, byproducts of normal cell processes. Insufficient production of ARSA results in an accumulation of sulfatides inside cells in the kidneys, testes, and the nervous system. When sulfatides accumulate in nerve cells, they create a toxic effect that impairs the production of myelin.

The progression of metachromatic leukodystrophy may be slowed or stopped if the disease is diagnosed early and treated with umbilical cord blood or bone marrow transplants. These procedures replace ARSA in the child’s cells and help reduce myelin damage. However, this therapy will not reverse existing myelin damage.

Leukodystrophy Research

Title:  The Natural History of Metachromatic Leukodystrophy Study (HOME Study)

Stage: Recruiting

Principal investigator: Vanessa Boulanger, MSc

National Organization for Rare Disorders

Danbury, CT

The HOME Study is a web-based natural history study for patients with metachromatic leukodystrophy. It is hosted by the National Organization for Rare Disorders (NORD), an independent non-profit patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them.

The study collects information from participants (or their authorized respondents, previously referred to collectively as “participants”) who are affected by metachromatic leukodystrophy.

Data are collected at pre-baseline, baseline, 3, 6, 9, and 12 months through online surveys, telephone Interviews, web-based virtual assessments with a clinical study coordinator, and a (optional – only for U.S. residents) mobile application. Data entered into this study includes name, date of birth, diagnosis, treatments, medical history, family history, quality of life, disease progression, treatment – past and proposed, general medical information, genetic test results and mutations, blood level results, and upload of medical records.

Title: UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (DUOC-01)

Stage: Recruiting

Principal investigator: Joanne Kurtzberg, MD

Duke University Medical Center

Durham, NC

Inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, most of which involve a single gene mutation resulting in an enzyme defect. In the majority of cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or interfere with normal cellular function. Often, patients may appear normal at birth but begin to exhibit disease manifestations during infancy, frequently including progressive neurological deterioration due to absent or abnormal brain myelination. The ultimate result is death in later infancy or childhood.

Currently, the only effective therapy to halt the neurologic progression of the disease is allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed engraftment of donor cells in the CNS when administered through the intravenous route, which is associated with ongoing disease progression over 2-4 months before stabilization. The engraftment of donor cells in a patient with an IMD provides a constant source of enzyme replacement, thereby slowing or halting disease progression.

This study will evaluate the safety of a potential new treatment for patients with certain IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention, intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01), will be an adjunctive therapy to a standard UCB transplant. This therapy aims to accelerate the delivery of donor cells to the CNS, thereby bridging the gap between systemic transplant and engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and cells used for HSCT will be derived from the same UCB donor unit.

Title: Reduced Intensity Conditioning for Non-Malignant Disorders Undergoing UCBT, BMT or PBSCT (HSCT+RIC)

Stage: Recruiting

Principal investigator: Paul Szabolcs, MD

UPMC Children’s Hospital of Pittsburgh

Pittsburgh, PA

For some non-malignant diseases (NMD; i.e., thalassemia, sickle cell disease, most immune deficiencies), a hematopoietic stem cell transplant may be curative by healthy donor stem cell engraftment alone. HSCT in patients with NMD differs from that in malignant disorders for two important reasons: 1) these patients are typically naïve to chemotherapy and immunosuppression. This may potentially lead to difficulties with engraftment. And 2) RIC with subsequent bone marrow chimerism may be beneficial even in mixed chimerism and result in decreased transplant-related mortality (TRM). Nevertheless, any previous organ damage resulting from the underlying disease may remain present after the HSCT.

For other diseases (metabolic disorders, some immunodeficiencies, etc.), a transplant is not curative. For these diseases, the main intent of the transplant is to slow down, or stop, the progress of the disease. In a select few cases/diseases, the presence of healthy bone marrow-derived cells may even prevent progression and prevent neurological decline.

In this research study, instead of using the standard myeloablative conditioning, the study doctor is using RIC, in which significantly lower doses of chemotherapy will be used. The lower doses may not eradicate every stem cell in the patient’s bone marrow. However, in the presented combination, the intention is to eliminate already formed immune cells and provide maximum growth advantage to healthy donor stem cells. This paves the way to the successful engraftment of donor stem cells. Engrafting donor stem cells can outcompete, and donor lymphocytes could suppress the patients’ surviving stem cells. With RIC, the side effects on the brain, heart, lung, liver, and other organ functions are less severe, and late toxic effects should also be reduced.

This study aims to collect data from the patients undergoing reduced-intensity conditioning before HSCT and compare it to the standard myeloablative conditioning. It is expected there will be therapeutic benefits, paired with a better survival rate, less organ toxicity, and improved quality of life, following the RIC compared to the myeloablative regimen.