The inheritance probabilities per birth are as follows:
If both parents are carriers:
25% (1 in 4) children will have the disease
50% (2 in 4) children will be carriers, but unaffected
25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier
If one parent is affected and one is free of MLD:
0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene
100% (4 in 4) children will be carriers (but unaffected)
If one parent is a carrier and the other is free of MLD:
50% (2 in 4) children will be carriers (but unaffected)
50% (2 in 4) children will be free of MLD – unaffected child that is not a carrierIn addition to these frequencies there is a pseudo-deficiency that affects 7–15% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist. This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed. Diagnosis
Clinical examination and MRI are often the first steps in an MLD diagnosis. MRI can be indicative of MLD but is not adequate as a confirming test. An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD. The confirming urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results.
Generally early-juveniles have motor skill declines as their first symptoms while late-juveniles show cognitive declines first. The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.Palliative care can help with many of the symptoms and usually improves quality of life and longevity.Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the bodys sulfatide. Causes
MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD. Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system – CNS) and the peripheral nerves (peripheral nervous system – PNS) which control, among other things the muscles related to mobility, cease to function properly.Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor.