What is leukodystrophy?
Leukodystrophy is a term used to describe a group of rare, primarily inherited neurological disorders. Leukodystrophy is not a single disorder. The term refers to genetic diseases that mainly affect the white matter of the central nervous system (CNS). White matter is tissue made up of bundles of nerve fibers (axons) that connect nerve cells. The fibers are covered and protected by an insulating layer of myelin, which provides nutritional support to nerve cells and helps speed up signals between them, allowing them to send and receive messages quickly.
Leukodystrophies result from the abnormal production, processing, or development of myelin and other components of CNS white matter, such as cells called oligodendrocytes and astrocytes. Oligodendrocytes and astrocytes belong to a group of cells called glia, which surround, support, and insulate nerve cells.
Leukodystrophies are usually progressive, meaning they get worse over time. Some forms are present at birth, while others may not show symptoms until a few years after birth. Some leukodystrophies mostly affect adults.
Symptoms of leukodystrophy
Symptoms of leukodystrophy vary according to the specific type and may be difficult to recognize in the early stages of the disorder. Each type of leukodystrophy affects myelin differently and in different locations of the central nervous system, leading to a range of symptoms.
The most common symptom is a gradual decline in functional abilities in an infant or child who previously appeared healthy. Progressive loss may appear in:
- muscle tone
- balance and mobility
- walking ability (gait)
- speech
- feeding ability
- vision
- hearing
- behavior
Other symptoms may include:
- learning disabilities
- bladder issues
- breathing problems
- developmental delay
- muscle control disorders
- seizures
Types of leukodystrophy
Scientists have identified more than 50 different leukodystrophies. Some of the most common leukodystrophies are described below. There are many other leukodystrophies, and some are still unidentified.
Alexander disease
Alexander disease is a disorder characterized by the destruction of white matter and the formation of abnormal clumps of protein called Rosenthal fibers that accumulate in astrocytes in the brain. Alexander disease is caused by mutations in the GFAP gene and can appear at any age, although most cases appear in infancy or early childhood. There is no known cure for the disease, but symptoms may be treated.
Autosomal dominant leukodystrophy with autonomic diseases
Autosomal dominant leukodystrophy with autonomic diseases (ADLD) is a rare, slowly progressive disorder whose symptoms include problems with autonomic dysfunction (issues with automatic functions like heart rate, blood pressure, and sweating), difficulty coordinating movements (ataxia), and mild cognitive impairment. People with ADLD develop symptoms in adulthood, usually in their 40s or 50s. The disorder is caused by mutations in the LMNB1 gene which is responsible for making lamin B1 protein.
Canavan disease
Canavan disease is a neurological disorder in which parts of the brain develop into spongy tissue full of small fluid-filled spaces, causing progressive brain atrophy. There is no cure, nor is there a standard course of treatment. Treatments are available for some symptoms. People with Canavan disease usually die before age 10, although some children may survive into their teens and 20s. It is caused by a mutation in the ASPA gene which makes an enzyme called aspartoacylase.
Cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is a rare, genetic disorder characterized by abnormal storage of lipids in many areas of the body. It affects the body's ability to metabolize fats, causing them to form fatty yellow nodules called xanthomas which accumulate in the body—especially in the brain. CTX is caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene. Symptoms may include seizures, dementia, hallucinations, depression, difficulty with coordination, and difficulty with speech. If diagnosed early, CTX can be effectively treated.
Childhood ataxia with CNS hypomyelination
Childhood ataxia with central nervous system hypomyelination (CACH, also called vanishing white matter disease) is a disorder characterized by ataxia, muscle stiffness, and damage to the optic nerve. It is caused by mutations in any of the five genes that make the protein eukaryotic initiation factor 2B (eIF2B). Mutations in any of these five genes make it difficult for cells to regulate protein synthesis, a process that governs the production of protein (including proteins that help form myelin) in cells.
Krabbe disease
Krabbe disease (also called globoid cell leukodystrophy) is a rare, inherited metabolic disorder characterized by globoid cells (abnormal cells that have more than one nucleus) in the white matter. The disease most often affects infants, with onset before age 6 months, but can occur in adolescence or adulthood. Symptoms include severe deterioration of mental and motor skills, muscle weakness, hypertonia, seizures, spasticity, unexplained fever, blindness, trouble swallowing, and deafness. Treatment for Krabbe disease, which is also considered a lipid storage disease, is symptomatic and supportive. Krabbe disease is caused by a defect in the GALC gene, which affects an essential enzyme for myelin metabolism. Problems with this gene can cause buildup of a toxic myelin breakdown product.
Metachromatic leukodystrophy
Metachromatic leukodystrophy (MLD) is a disorder characterized by the toxic buildup of lipids and other storage materials in cells in CNS white matter and the peripheral nerves. Individuals with MLD have mutations in the ARSA or PSAP genes, which cause a deficiency of the enzyme arylsulfatase A and a decreased ability to break down sulfatides, an essential component of the myelin sheath. An excess of sulfatides can be toxic to the nervous system, gradually destroying myelin-producing cells and leading to nervous system impairment. It is also considered a lipid storage disease. A form of gene therapy can prevent or stop progression if it is provided before or very early in the disease course. Learn more about treatments for MLD.
Pelizaeus-Merzbacher disease
Pelizaeus-Merzbacher disease (PMD) is a rare, progressive, degenerative disorder in which coordination, motor abilities, and intellectual function deteriorate. It is caused by a mutation in the gene that controls the production of a myelin protein called proteolipid protein-1 (PLP1). Severity and onset of the disease ranges widely depending on the type of PLP1 mutation. PMD is one in a spectrum of diseases associated with PLP1, which also includes spastic paraplegia type 2 (SPG2). Symptoms of PLP1-related disorders range from severe central nervous system involvement to progressive weakness and stiffness of the legs. Treatment for PMD is symptomatic and supportive and may include medication for movement disorders.
Refsum disease
Adult Refsum disease
Adult Refsum disease (ARD) is a rare disease that causes weakness or numbness of the hands and feet (peripheral neuropathy). People with ARD lack the enzyme in peroxisomes (cell structures required for normal brain, eye, liver, kidney, and bone function) that breaks down phytanic acid, a type of fat found in certain foods. In ARD, phytanic acid accumulates and is toxic to myelin. The disease usually begins in late childhood or early adulthood with increasing night blindness due to degeneration of the retina (retinitis pigmentosa). If the disease progresses, other symptoms may include deafness, loss of the sense of smell (anosmia), ataxia, dry and scaly skin (ichthyosis), and heartbeat abnormalities (cardiac arrhythmias). Some individuals will have shortened bones in their fingers or toes, or a visibly shortened fourth toe. Although the disease usually appears in early childhood, some people will not develop symptoms until their 40s or 50s. ARD is treatable. With treatment, muscle weakness, numbness, and dry and scaly skin generally disappear. However, vision and hearing problems may persist, and the person’s sense of smell may not return.
Infantile Refsum disease
Infantile Refsum disease (IRD) is an inherited disorder that damages the white matter of the brain and affects movement. Symptoms of IRD begin in infancy with retinitis pigmentosa, which often leads to blindness, and hearing problems that usually progress to deafness by early childhood. Other symptoms may include rapid, jerky eye movements (nystagmus); hypotonia and ataxia; enlarged liver; mental and growth disabilities; abnormal facial features; and white matter abnormalities. IRD is a condition within the Zellweger spectrum of peroxisome biogenesis disorders (PBDs) that also includes neonatal adrenoleukodystrophy. PBDs are caused by inherited defects in any one of the 12 PEX genes that are required for the normal formation and function of peroxisomes. IRD has some residual peroxisome function, resulting in less severe disease within the spectrum.
Although ARD and IRD have similar names, they are separate disorders caused by different defects in the PHYH or PEX7 genes which result in disruption of the breakdown of phytanic acid.
Who is more likely to get leukodystrophy?
All leukodystrophies are the result of genetic defects (mutations).
Myelin, which is whitish in color and makes up much of the white matter in the brain, is a complex substance made up of many different proteins and lipids (fatty substances). Production, recycling, and maintenance of each protein and lipid are controlled by a specific group of genes. Each type of leukodystrophy is caused by a defect in one of the genes that control the structure or amount of one of the proteins or lipids in myelin. Mutations in any of these genes can affect how the lipid or protein works and can interrupt the normal formation, processing, and development of myelin and the function of white matter. Damage to or destruction of myelin can slow or delay the speed of brain signals or keep them from reaching their destination.
How is leukodystrophy diagnosed and treated?
Diagnosing leukodystrophy
Doctors usually diagnose leukodystrophy based on information identified through taking a medical and family health history, conducting physical and neurological examinations, ordering imaging scans such as MRI (magnetic resonance imaging) or CT (computed tomography), and other laboratory tests.
However, even with the help of these tools, leukodystrophy can be difficult to diagnose. Doctors can use other specialized tests such as DNA sequencing to check for genetic disorders. Whole-exome and whole-genome sequencing—tests that map out and analyze the genetic information contained in all of a person's genes—often are used to identify and pinpoint specific genetic problems.
Treating leukodystrophy
Treatment for most types of leukodystrophy is symptomatic and supportive, and may include:
- Medications to manage muscle tone, seizures, and spasticity.
- Physical, occupational, and speech therapy to help improve mobility and function, and help people adapt to cognitive challenges.
- Nutritional, educational, and recreational programs
Stem cell or bone marrow transplantation is showing promise for a few types of leukodystrophy. Research in this area is ongoing.
One of the leukodystrophies, CTX, can now be treated. With early, accurate diagnosis, CTX can be effectively treated with chenodeoxycholic acid (CDCA) replacement therapy. CDCA helps the body metabolize or break down fats such as cholesterol and can slow or stop progression of the disease.
What are the latest updates on leukodystrophy?
NINDS, a component of the National Institutes of Health (NIH), supports research on leukodystrophy. Projects include:
- Lysosomal Disease Network (LDN). LDN’s centers are working to help solve major challenges in diagnosis, disease management, and therapy for lysosomal diseases. Solutions to these issues will have direct impact on people with lysosomal diseases, including important implications for medical practice and individual quality-of-life. LDN is a part of the NIH Rare Diseases Clinical Research Network (RDCRN), and is supported through collaboration between NINDS, the National Center for Advancing Translational Science (NCATS), and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
- The Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) is a consortium of scientists, industry stakeholders, and patient advocacy leaders that promotes advances in the diagnosis and treatment of leukodystrophies. GLIA-CTN supports the collection, analysis, and sharing of clinical data and biological specimens; the education of clinicians; and training for new researchers to pave the way for transformative therapeutic trials across the leukodystrophies. GLIA-CTN is also part of RDCRN.
- The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from people with leukodystrophy to support ongoing and future research projects. MDBP is one of the world’s largest biorepositories. MDBP researchers hope to use the data and samples to uncover new genetic causes for various leukodystrophies, develop biomarkers for use in clinical trials, and learn more about the natural history of these disorders. Knowledge gained from these efforts may help improve diagnostic tools and treatment options. MDBP is supported by NINDS and NCATS.
More information about leukodystrophy research supported by NINDS and other NIH Institutes and Centers may be found using NIH RePORTER, a searchable database of current and past research projects supported by NIH and other Federal agencies. RePORTER also includes links to publications and resources from these projects.
How can I or my loved one help improve care for people with leukodystrophy?
Consider participating in a clinical trial so clinicians and scientists can learn more about leukodystrophy. Clinical research with human study participants helps researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.
All types of study participants are needed—those who are healthy or may have an illness or disease—of all different ages, sexes, races, and ethnicities to ensure that study results apply to as many people as possible, and that treatments will be safe and effective for everyone who will use them.
For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with leukodystrophy at Clinicaltrials.gov, a searchable database of federal and private clinical studies.
Where can I find more information about leukodystrophy?
Information may be available from the following organizations and resources: