Metachromatic leukodystrophy is one of a group of inherited metabolic storage disorders in which the lack of an enzyme affects various organs and tissues, including the brain. Enzymes are proteins that play many roles, including to metabolize (break down) substances in the body. In metabolic storage disorders, the body lacks an enzyme needed to metabolize a substance, such as a sugar. Instead, the substance builds up in the body and causes damage.
A type of leukodystrophy
MLD is one of a subgroup of metabolic disorders called the leukodystrophies. The leukodystrophies are caused by a variety of gene mutations (mistakes). Genes carry an inherited code of instructions that tells the body how to make every cell and substance in the body. In the leukodystrophies, the gene mutations lead to damage of the myelin.
Myelin is the fatty substance that forms a sheath around the axons that carry signals to and from nerves in the central nervous system (brain and spinal cord). The myelin sheath is similar to the insulation on a wire. It enables the axons to carry signals very quickly. When the myelin sheath is damaged, the signals slow down or may stop completely.
If the signals from the brain and spinal cord have trouble getting to the rest of the body, a person can have problems controlling the body's movements. If the signals between nerves in the brain are slowed or stopped, a person can have problems with memory, learning, speaking and understanding speech, and other mental functions.
Metachromatic leukodystrophy
In people with MLD, the gene mutation affects an enzyme called arylsulfatase A. This enzyme breaks down substances called sulfatides. Sulfatides are one of the ten substances that make up myelin. Without the arylsulfatase A enzyme, sulfatides build up and damage the myelin sheath, causing problems with the central nervous system and peripheral nervous system. The peripheral nervous system is the nerves throughout the body that carry signals to and from the central nervous system.
A person gets MLD when he or she inherits a gene with the mutation from both parents. MLD appears most often in babies and young toddlers, but it also occurs in older children and adults. MLD is rare. About 1 in 100,000 people has this disorder.
Signs and symptoms of MLD
Late-infantile MLD
The most common and severe form of MLD is the late-infantile form. The symptoms of the late-infantile form of MLD appear when children are 6 to 24 months old. The first symptoms include problems with walking or other motor skills. Symptoms get worse quickly. Painful muscle cramps and problems with speech, movement and the ability to learn get worse until the child becomes paralyzed and blind. Children with this form of MLD usually die before 10 years of age.
Juvenile MLD
The juvenile form of MLD appears in children between the ages of 4 to 12, sometimes earlier. Early symptoms include problems with learning or with walking. As the disease progresses, symptoms include behavior problems, trouble following directions, and worsening problems with walking and speech. Eventually the child becomes paralyzed and blind. Some children with juvenile MLD survive into adulthood, though others die sooner.
Adult MLD
The adult form of MLD can appear in teenagers or adults of any age. The first symptoms are often changes in personality and poor school or job performance. Adult MLD is often mistaken for other disorders such as schizophrenia or depression. As the disorder progresses, problems with memory and other mental skills, speech, controlling movement and eating get worse slowly. People with adult MLD may sometimes live 10 to 30 years or more after symptoms appear.
Diagnosis
Tests a doctor may use to help diagnose MLD include:
Blood or skin tests to check for low levels of arylsulfatase A enzyme activity
Brain scans using magnetic resonance imaging (MRI) to check for abnormalities
Lumbar puncture (spinal tap) to check the fluid around the spinal cord for high levels of protein
Urine tests to check for high levels of sulfatides and other signs of possible MLD
Tests to check the function of the nerves (nerve velocity conduction studies)
Families affected by MLD may want to talk with a genetic counselor about family planning and the chances of having children with the disorder. Early diagnosis may enable early treatment before symptoms occur, which can be important to outcomes.
Transplant for MLD
The only known treatment that can affect the progression of MLD is a bone marrow or cord blood transplant (also called a BMT). The healthy cells received in a transplant can make the arylsulfatase A the body was missing.
Though it has serious risks and is not an option for all patients, a transplant can be life-saving. It can stop damage to the central nervous system, preventing severe mental disability for some people with MLD. A transplant is most likely to benefit a person early in the course of MLD who shows few or no symptoms. Some of the limits of transplant for MLD include:
Problems that have already appeared will remain after transplant. Damage the disease has already done is not reversed.
Patients who already have severe symptoms are unlikely to benefit from transplant. Their symptoms are likely to continue to get worse.
A transplant cannot stop damage to the peripheral nervous system. Problems with controlling movement are likely to continue to get worse after transplant.
It takes time (sometimes as long as a year) for the transplanted cells to make enough healthy cells to correct a patient's metabolism. During this time, the disorder can continue to cause damage.
The results described here are from reports of individual patients; no larger clinical studies are available. It is a good idea to ask your doctor for help interpreting these data and any other survival outcomes data you find. Your doctor can provide context for these data and discuss your specific situation with you. For more things to consider, see Understanding Survival Outcomes Data.
Transplant outcomes for late-infantile MLD
Most transplants that have been done to treat young children with the late-infantile form of MLD have not been successful in preventing severe damage. This is because the late-infantile form gets worse quickly once problems have developed. However, some children with late-infantile MLD have benefited from a transplant. [1] Good results are more likely when a transplant is done early, before symptoms appear. Most children who are diagnosed early are tested for MLD because they have an older sibling affected with the disorder.
Transplants for juvenile and adult MLD
The juvenile and adult forms of MLD get worse at a slower rate. Transplants for these forms have helped some people. The best results have appeared in people who received a transplant before symptoms of disease appeared or at an early stage of the disease.
In published reports of transplants for older children and young adults with MLD, transplant has succeeded in stopping central nervous system damage for some patients. Those patients' mental abilities stayed the same or in some cases improved somewhat. In other patients, transplant did not stop the disease and damage continued after transplant. [2,3,4,5]
Outcomes for unrelated donor transplants
Between 1998 and 2006, 29 children (younger than age 18) with either MLD (6 children) or adrenoleukodystrophy (23 children) received an unrelated donor transplant facilitated by the National Marrow Donor Program (NMDP). The estimated 5-year likelihood of survival for the 29 transplant recipients was 50% (Figure 1).
Figure 1. Inherited Metabolic Disorders: Survival of pediatric (age < 18 years) marrow recipients with myeloablative preparative regimens, unrelated donor transplants facilitated by the NMDP, 1998 - 2006. (NMDP data) View Larger VersionHow to read this figure
Making treatment decisions
If you or your family member has MLD, it is important to see a doctor who is an expert in MLD. If your doctor has not treated other patients with MLD, ask him or her to refer you to an expert for consultation. If transplant is a treatment option, talk with your doctor about the risks, limits and possible benefits of transplant.
Even after a successful transplant, a patient will face physical problems from MLD. However, a transplant may offer a person with MLD a chance to live a longer life as well as to keep his or her ability to think and learn.
More information on metachromatic leukodystrophy
You can get further information about MLD from disease-specific organizations such as:
Krivit W, Shapiro E, Kennedy W, et al. Treatment of late infantile metachromatic leukodystrophy by bone marrow transplantation. N Engl J Med. 1990; 322(1):28-32.
Paul Orchard, M.D., University of Minnesota BMT Program at Fairview University Medical Center, Minneapolis, Minn. Charles Peters, M.D., Children's Mercy Hospital, Kansas City, Mo.
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