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Metachromatic Leukodystrophy

Metachromatic leukodystrophy


Metachromatic leukodystrophy (MLD) is a rare degenerative neurological disease, and is the most common form of the leukodystrophies, a group of disorders affecting the fatty covering that acts as an insulator around nerve fibers known as the myelin sheath. With destruction of the myelin sheath, progressive deterioration of muscle control and intellectual ability occurs. Metachromatic leukodystrophy is inherited as an autosomal recessive trait, meaning that that the disease is inherited from parents that are both carriers, but do not have the disorder. There are three forms of MLD, distinguished by the age of onset and by the molecular defect in the gene underlying the disease.


The late infantile form of metachromatic leukodystrophy, which is the most common form, usually begins in the second year of life (ranges 13 years). After normal early development, the infant displays irritability and an unstable walk. As the disease progresses, physical and mental deterioration occur. Developmental milestones, such as language development, are not met, and muscle wasting eventually gives way to spastic movements, then profound weakness. Seizures usually occur, followed by paralysis.

The juvenile form of MLD usually begins between the ages of 4 and 10 (ranges 320 years), and presents with disturbances in the ability to walk (gait disturbances), urinary incontinence, mental deterioration, and emotional difficulties. Some scientists distinguish between early and late juvenile MLD. Late juvenile MLD is similar to the adult form of the disease. Adult MLD begins after the age of 20 (ranges 1630 years) and presents mainly with emotional disturbances and psychiatric symptoms, leading to a diagnosis of psychosis. Disorders of movement and posture appear later. Dementia (loss of mental capacity), seizures, and decreased visual function also occur.


The frequency of MLD is estimated to be 1 in 40,000 persons in the United States. No differences have been identified on the basis of race, sex, or ethnic origin.

Causes and symptoms

MLD is caused by a deficiency of the enzyme arylsulfatase A (ARSA). Without properly functioning ARSA, a fatty substance known as sulfatide accumulates in the brain and other areas of the body such as the liver, gall bladder, kidneys, and/or spleen. The buildup of sulfatide in the central nervous system causes demyelination, the destruction of the myelin protective covering on nerve fibers. With progressive demyelination, motor skills and mental function diminish.

MLD is an autosomal recessive inherited disease and can be caused by mutations in two different genes, the ARSA and the prosaposin gene. Mutations in the ARSA gene are far more frequent. So far, about 50 mutations have been identified in ARSA gene.


Diagnosis of MLD is suspected in a person displaying its symptoms. Magnetic resonance imaging may be used to identify lesions and atrophy (wasting) in the white matter of the brain that are characteristic of MLD. Urine tests usually show elevated sulfatide levels. Some psychiatric disorders coupled with difficulty walking or muscle wasting suggest the possibility of MLD. Blood testing can show a reduced activity of the ARSA enzyme.

Deficiency of the ARSA enzyme alone is not proof of MLD, because a substantial ARSA deficiency without any symptoms or clinical consequences is frequent in the general population. During diagnosis and genetic counseling, these harmless ARSA enzyme deficiencies must be distinguished from those causing MLD. The only diagnostic test that solves this problem and is definitive for MLD diagnosis is analysis of the genetic mutation.

Treatment team

The treatment team usually involves a neurologist , a pediatrician, an ophthalmologist, an orthopedist, a genetic counselor, a neurodevelopmental psychologist, a bone marrow transplant physician, a genetic and/or metabolic disease specialist, and also a physical and an occupational therapist.


No effective treatment is available to reverse the course of MLD. Drug therapy is part of supportive care for symptoms such as behavioral disturbances, feeding difficulties, seizures, and constipation. Bone marrow transplantation has been tried and there is evidence that this treatment might slow the progression of the disease. In infants, during a symptom-free phase of the late infantile form, neurocognitive function may be stabilized, but the symptoms of motor function loss progress. Persons with the juvenile and adult forms of MLD and with mild or no symptoms are more likely to be stabilized with bone marrow transplantation. Gene therapy experimentation on animal models as a possible therapy is still under consideration, and there are not yet any gene therapy-related clinical trials for MLD.

Recovery and rehabilitation

MLD patients require follow-up evaluation and treatment. Physical therapists, occupational therapists, orthopedists, ophthalmologists, and neuropsychologists are often involved in helping maintain optimal function for as long as possible.

Clinical trials

As of early 2004, there is one open clinical trial for MLD sponsored by Fairview University and the National Institutes of Health: "Phase II Study of Allogeneic Bone Marrow or Umbilical Cord Blood Transplantation in Patients With Lysosomal or Peroxisomal Inborn Errors of Metabolism." Further information about the trial can be found at the National Institutes of Health clinical trials website <>.


In young children with the late infantile form of MLD, progressive loss of motor and cognitive functions is rapid. Death usually results within five years after the onset of clinical symptoms. In the early juvenile form of MLD, although progression is less rapid, death usually occurs within 1015 years of diagnosis, and most young people with the disease die before the age of 20. Persons with the late juvenile form often survive into early adulthood, and patients with the adult form may have an even slower progression.

Special concerns

Genetic counseling is important to inform the family about the risk of occurrence of MLD in future offspring. Prenatal testing may be available on an experimental basis in some centers.



Icon Health Publications. The Official Parent's Sourcebook on Metachromatic Leukodystrophy: A Revised and Updated Directory for the Internet Age. San Diego: Icon International Publishers, 2002.

von Figura, K., V. Gieselman, and J. Jaeken. "Metachromatic leukodystrophy." In The Metabolic and Molecular Bases of Inherited Disease, 8th ed., C. Scriver, A. Beadet, D. Valle, W. Sly, et al, eds. New York: McGraw-Hill Professional, 2001.


Giesselmann, V. "Metachromatic leukodystrophy: recent research developments." J Child Neurol. 18, no. 9 (September 2003): 591594.


"NINDS Metachromatic Leukodystrophy Information Page." National Institute of Neurological Disorders and Stroke. (March 4, 2004). <>.


National Tay-Sachs and Allied Diseases Association. 2001 Beacon Street, Suite 204, Brighton, MA 02135. (617) 277-4463 or (800) 90-NTSAD (906-8723). [email protected] <>.

United Leukodystrophy Foundation. 2304 Highland Drive, Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483; Fax: (815) 895-2432. [email protected] <>.

Igor Medica, MD, PhD

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