Metachromatic Leukodystrophy

What Causes Metachromatic Leukodystrophy?

MLD is most commonly caused by an abnormal change (mutation) in a gene called the ARSA gene. Sometimes the disease is caused by a mutation in the PSAP gene. Both of these genes carry 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, impairing the nerve cells’ ability to send and receive signals from one another.

Is Metachromatic Leukodystrophy Hereditary?

MLD is inherited when parents pass the disease-causing gene mutations to their children. The condition is 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.

How Is Metachromatic Leukodystrophy Detected?

The earliest signs of MLD often vary depending on the age of onset:

• Late-infantile form. The earliest sign of this form is often difficulty walking or an unusual gait, such as dragging the feet or walking on the toes.
• Juvenile form. In this form, early signs may be cognitive declines that interfere with school.
• Adult form. In this form, the first signs are often behavioral or personality changes manifesting in difficulties at work or school or substance abuse.

How Is Metachromatic 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 evaluating the patient’s medical history and physical, cognitive, and neurological exams. Further diagnostic steps may consist of:

• Blood tests to measure enzyme levels
• Urine test to look for accumulation of the fatty substances associated with MLD
• 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 Metachromatic Leukodystrophy Treated?

MLD has no cure, and no treatment will reverse symptoms once they appear. However, 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 MLD, especially when administered early in the course of the disease.

Other treatment options 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 Metachromatic Leukodystrophy Progress?

The rate of MLD progression often varies depending on the age of onset. Early-onset forms typically progress more rapidly than later-onset forms. For example, children with the late-infantile form usually survive only a few years after onset. Still, people with the adult-onset form often survive for decades after symptoms first appear.

Later symptoms of the disorder may 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

How Is Metachromatic Leukodystrophy Prevented?

People with a family history of MLD should consult a genetic counselor to assess their risks before becoming pregnant. Parents who have had a child with MLD should also seek genetic counseling before having more children.

Metachromatic Leukodystrophy Caregiver Tips

• Learn all you can about MLD. The disease and its effects on children living with it are complex. You’ll best be able to care for your child when you know what to expect from the disorder’s progression.
• Stay up-to-date on research developments. New therapies and treatments for MLD 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 MLD, including links to education, medical referrals, and financial assistance programs.

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

• People with MLD may be at increased risk for mood disorders such as depression.
• At least half of people with MLD experience symptoms similar to those of schizophrenia, including hallucinations and delusions.

Metachromatic Leukodystrophy Brain Science

The most common cause of MLD is a mutation in the ARSA gene. This gene contains instructions for making the enzyme arylsulfatase A. The enzyme works in cell structures called lysosomes to break down fatty substances called sulfatides, byproducts of normal cell processes.

In a small number of cases, the disease is caused by a mutation in the PSAP gene. This gene carries instructions for making several proteins, including saposin B. Saposin B works with arylsulfatase A to break down sulfatides.

The mutations cause insufficient production of the waste-reducing chemicals, resulting 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 myelin production, a substance that coats the cells and allows them to transmit nerve impulses. As myelin degrades, nerve cells in the brain and the central nervous system cannot communicate with the rest of the body. Eventually, the demyelination leads to cell loss, and symptoms get progressively worse.

Metachromatic 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”) 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

The 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 most 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 during infancy begin to exhibit disease manifestations, 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 the progression of the disease.

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 serve as an adjunctive therapy to a standard UCB transplant. The goal of this therapy is 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, as a result of 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 primary 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 uses 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 a 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.

The purpose of this study is 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 better survival rate, less organ toxicity, and improved quality of life following the RIC compared to the myeloablative regimen.