Metachromatic leukodystrophy
Metachromatic leukodystrophy (MLD) is a severe, progressive genetic disorder that affects brain and nerve function due to the accumulation of fatty substances known as sulfatides in the cells. This condition is linked to a deficiency of the arylsulfatase A enzyme, which impairs the development of the myelin sheath that insulates nerve fibers, leading to a range of debilitating neurological symptoms. MLD is inherited in an autosomal recessive pattern, meaning a child must receive two copies of the mutated ARSA gene from both parents to manifest the disease. While MLD can occur in any population, it has been observed more frequently in certain ethnic groups, including the Jewish Habbanite community and Navajo Indians.
The onset and severity of symptoms vary widely among individuals, with four main types based on age of onset. Symptoms may include loss of physical and mental milestones, seizures, and progressive neurological decline, often leading to early death in severely affected children. Diagnosis typically relies on clinical symptoms and molecular genetic testing, as routine screening for MLD is not standard. Currently, there is no cure, and treatment primarily focuses on managing symptoms, with options like bone marrow transplants available for some patients in early stages of the disease. Genetic counseling and carrier testing are recommended for individuals concerned about MLD.
Metachromatic leukodystrophy
ALSO KNOWN AS: Arylsulfatase A deficiency; ARSA deficiency; metachromatic leukoencephalopathy; sulfatide lipidosis; cerebroside sulfatase deficiency; MLD
DEFINITION Metachromatic leukodystrophy is a severe, progressive inherited disorder that affects brain and nerve functioning. The symptoms of the disease are caused by the harmful buildup of fatty substances in the body’s cells.
Risk Factors
Metachromatic leukodystrophy is a genetic disease caused by the inheritance of a nonworking ARSA gene from both parents. The condition is estimated to occur in between 1 in 40,000 and 1 in 100,000 people in North America and northern Europe, according to 2023 data from the US National Library of Medicine. Although metachromatic leukodystrophy is panethnic and found all over the world, it has been seen with increased frequency in particular ethnic groups such as the Jewish Habbanite community, Navajo Indians, and some Arab populations in Israel. This condition is not caused by infections and cannot be transmitted by an affected individual.
Etiology and Genetics
Metachromatic leukodystrophy is caused by the lack of a lysosomal enzyme sulfatide sulfatase (arylsulfatase A). When a lysosomal enzyme is missing, substances called sulfatides build up in the cells of the body. The accumulation in the nerve fibers impairs the growth or development of the myelin sheath, the fatty covering that acts as an insulator around nerve fibers. Accordingly, the nerves in the body and brain are gradually demyelinated and stop working correctly.
Metachromatic leukodystrophy is an autosomal recessive genetic condition. This autosomal recessive condition occurs when a child receives two copies of the nonworking ARSA gene that causes metachromatic leukodystrophy. Individuals with only one copy of a nonworking ARSA gene for a recessive condition are known as carriers and have no problems related to the condition. In fact, each person carries between five and ten nonworking genes for harmful, recessive conditions. When two people with the same nonworking recessive ARSA gene mate, however, there is a chance, with each pregnancy, for the child to inherit two copies, one from each parent. That child then has no working copies of the ARSA gene and therefore has the signs and symptoms associated with metachromatic leukodystrophy.
Symptoms
All forms of the disease involve a progressive deterioration of motor and neurocognitive function, including loss of physical milestones, paralysis, blindness, seizures, rigidity, mental deterioration, stumbling gait, and eventual death. However, metachromatic leukodystrophy symptoms vary significantly in severity and time of onset from person to person. Affected individuals are grouped into at least four different types of metachromatic leukodystrophy based on age of onset and symptoms. The symptoms of the late infantile form include a stumbling gait, progressive loss of physical and mental developmental milestones, and progressive blindness that appear in the second year of life. Death most often occurs before five years of age. The early juvenile is characterized by symptoms such as progressive loss of physical and mental developmental milestones, seizures, stumbling walk, and exaggerated reflexes beginning around four to six years of age. Death usually occurs within ten to fifteen years of diagnosis. The late juvenile form usually begins at six to sixteen years of age with seizures, behavioral issues, and decreased cognitive function. These individuals often survive into their twenties and thirties. The adult form of metachromatic leukodystrophy presents after age sixteen with signs such as decreased school or work performance, seizures, stumbling gait, memory loss, and psychiatric and behavioral issues.
Screening and Diagnosis
As of 2014, screening for metachromatic leukodystrophy was not part of routine testing in the prenatal or newborn periods of life. Diagnosis is most often made on the basis of disease signs and symptoms, such as evidence of white matter disease on brain imaging and/or seizures. Biochemical testing is available to confirm the diagnosis through identification of the low or missing enzymes; however, molecular genetic testing is the only definitive test available.
Treatment and Therapy
At this time, there is no cure or disease-specific treatment for metachromatic leukodystrophy. Bone marrow transplants and stem cell transplants may be used to slow disease progress in individuals who are not showing significant signs of disease yet; however, they cannot reverse disease damage that has already been done. Accordingly, therapy for metachromatic leukodystrophy focuses on the treatment of each symptom individually.
Prevention and Outcomes
Carrier testing is available for individuals who are interested in learning if they carry an altered ARSA gene. Genetic counseling is available for parents who have an affected child or are concerned about being a carrier for the ARSA gene. As the severity and symptoms of metachromatic leukodystrophy vary from individual to individual, life expectancy depends on the type and speed of progression of the disease. Severely affected infants often die within a year of symptom onset, while symptoms in adults can progress in a much slower manner.
Bibliography
Chang, Shun-Chiao. "A Systemic Review on Birth Prevalence of Metachromatic Leukodystrophy." Orphanet Journal of Rare Diseases, vol. 19, no. 80, 21 Feb. 2024, doi.org/10.1186/s13023-024-03044-w. Accessed 9 Sept. 2024.
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Gonick, Larry, and Mark Wheelis. The Cartoon Guide to Genetics. New York: Collins, 1991. Print.
Mehta, Atul, and Bryan Winchester, eds. Lysosomal Storage Disorders. Hoboken: Wiley, 2012. Print.
"Metachromatic Leukodystrophy." Genetics Home Reference. National Library of Medicine, 28 July 2014. Web. 4 Aug. 2014.
Parker, James. and Philip Parker, eds. The Official Parent’s Sourcebook on Metachromatic Leukodystrophy: A Revised and Updated Directory for the Internet Age. San Diego: ICON Health, 2002. Print.
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