March 22, 2022
Years published: 1986, 1987, 1988, 1994, 1995, 1997, 2003, 2019
NORD gratefully acknowledges Jocelyn Rosenzweig, NORD Editorial Intern from the University of Connecticut, and Laura Adang MD, PhD, Division of Child Neurology, Children’s Hospital of Philadelphia, for assistance in the preparation of this report.
Metachromatic leukodystrophy (MLD) is a rare hereditary disease characterized by accumulation of fats called sulfatides. This causes the destruction of the protective fatty layer (myelin sheath) surrounding the nerves in both the central nervous system and the peripheral nervous system. There are three types of MLD based on the age symptoms appear: late-infantile MLD, juvenile MLD, and adult MLD. All subtypes ultimately affect both intellectual and motor function. Symptoms vary by type but can include difficulty talking, seizures, difficulty walking, personality changes, and behavior and personality changes. MLD is caused by changes (mutations) in the ARSA gene and, in rare cases, the PSAP gene.
This condition is called metachromatic leukodystrophy because when viewed under a microscope, sulfatide accumulation in cells appears as granules that are colored differently than other cellular material (metachromatic). A leukodystrophy is a genetic disorder that disrupts myelination in the brain.
Each MLD subtype has specific symptoms and rate of progression. Each subtype is based on age of onset.
Over half of the children affected by MLD show symptoms in the first 3 years of life. This form is called late-infantile MLD. Often the first signs of disease are from demyelination of the peripheral nervous system and include difficulty walking.
Juvenile MLD (J-MLD) is less common and occurs in 20-30% of people with MLD. Onset is between 4 years old and sexual maturity, usually between 12 and 14 years of age. Often with J-MLD, the first signs include behavioral problems or new difficulty in school.
All forms of MLD are progressive. In late-infantile MLD, within months of the first symptoms, most children lose the ability to talk and walk. The progression in the juvenile and adult forms can occur over years to decades. Regardless of the subtype, last stage of the disease is often characterized by blindness, inability to move, unresponsiveness, and an inability to speak.
MLD is an autosomal recessive genetic disorder. Recessive genetic disorders occur when both copies of the gene are affected. If a child is affected, most of the time, their parents are carriers, meaning each parent will have one changed (mutated) copy and one normal copy of the ARSA gene, but will not have symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25%. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females. The ARSA gene encodes the protein arylsulfatase A. There is some association with specific mutations and the subtype of MLD (genotype-phenotype correlation). Rarely, children with MLD have working copies of the ARSA gene, but abnormalities in PSAP gene, which encodes several saposin proteins, including saposin B, an activator of arylsulfatase A.
Abnormalities in these proteins result in the inability of the body to breakdown fats (lipids) that contain sulfate (sulfatides). Accumulation of sulfatides then occurs in the nervous system, kidneys, testes, and brain, and interferes with the production of myelin, the substance that insulates and protects the nerves. When the sulfatides build up within the nervous system, the myelin breaks down and nerves connecting the brain and spinal cord do not function properly. This leads to problems with brain function that results in the mental and physical problems present in those who have MLD. The symptoms vary depending on which parts of the brain are affected.
The true prevalence rate of MLD is unknown, but is estimated to be between 1 in 40,000 and 1 in 160,000. The Navajo also have a higher prevalence rate of 1 in every 2,500 people. In certain populations in the Middle East, these numbers may be even higher.
MLD is first suspected by recognizing the characteristic pattern of progressive impairment. In the late-infantile form, the first signs are often difficult walking, which can present as new inability to fully lift the feet while walking (foot drop) or by toe walking. For adult MLD, the first signs are slurred speech and behavioral issues that include difficulty in school, behavior changes, and decreased ability in school. Individuals with juvenile MLD can present with motor or cognitive symptoms.
Clinical Testing and Work-Up
The diagnosis of MLD is made through both genetic and biochemical testing. Genetic testing can identify mutations in the ARSA and PSAP genes. Biochemical testing includes sulfatase enzyme activity and urinary sulfatide excretion.
An MRI can confirm a diagnosis of MLD. An MRI shows imaging of a person’s brain and can show the presence and absence of myelin. There is a classic pattern of myelin loss in the brains of individuals affected by MLD. As the disease progresses, imaging shows accumulating injury to the brain. Of note, in young children, the initial brain imaging can be normal.
In pre- or minimally symptomatic children, stem cell transplantation can be considered. Otherwise, the main treatment is supportive and focused on symptomatic relief.
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Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011 May;13(5):457-84. https://www.ncbi.nlm.nih.gov/pubmed/21502868
Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A. Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. Hum Mutat. 2009 Oct;30(10):E936-45. https://www.ncbi.nlm.nih.gov/pubmed/19606494
Gomez-Ospina N. Arylsulfatase A Deficiency. 2006 May 30 [Updated 2017 Dec 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1130/ Accessed March 4, 2019.
Metachromatic leukodystrophy. Genetics Home Reference. Reviewed February 2013. https://ghr.nlm.nih.gov/condition/metachromatic-leukodystrophy Accessed March 4, 2019.
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