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.
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 ASA 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 ASA 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 ASA gene, but abnormalities in PSAP gene, which encodes several saposin proteins, including saposin B, an activator of ASA.
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 ASA 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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