Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering that acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.
Signs and symptoms Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.
In the late infantile form, which is the most common form of MLD (50–60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner. Children with the juvenile form of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia, then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. Some patients can live for several decades after onset. A recent trend is to try to distinguish early-juvenile (ages 3–7) and late-juvenile forms of the disease. 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 the 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 body's 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 excess sulfatides stored in glial cells and neurons may contribute to initial disease progression and symptomatology. However, sulfatides ultimately result in functional impairment of oligodendrocytes and Schwann cells, leading to widespread demyelination, resulting in the neurological impairments hallmark of MLD. 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) cease to function properly, resulting in mobility impairments and intellectual decline. Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. When the arylsulfatase A enzyme level is normal but the sulfatides are still high – meaning that they are not being broken down because the enzyme is not activated – the resulting disease is saposin B deficiency, which presents similar to MLD. Saposin B deficiency is very rare, much more rare than traditional MLD. The enzyme that is present is not "enabled" to a normal level of efficiency and can't break down the sulfatides which results in all of the same MLD symptoms and progression. A 2011 study contended sulfatide is not completely responsible for MLD because it is non-toxic. It has been suggested that lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.
Genetics
MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows:
If both parents are carriers: 25% (1 in 4) of children will have the disease 50% (2 in 4) of 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 carrier In 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. Urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results. Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted.
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