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  1. Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited disorder in which the desulfation of 3-0-sulfogalactosyl-containing glycolipids is defective. Desulfation of the 3-0-sulfogalactosyl residues depends on the combined action of arylsulfatase A (ASA) and saposin B, a nonenzymatic activator protein. MLD is caused by the deficiency either of ASA or, more rarely, of saposin B. Sulfated glycolipids occur in the myelin sheaths of the central and peripheral nervous system and to a lesser extent in visceral organs like kidney, gallbladder, and liver. In MLD the sulfated glycolipids accumulate in lysosomes of these tissues and are responsible for their metachromatic staining. The clinical and histopathologic manifestations ofMLD are dominated by the demyelination observed in the central and peripheral nervous system.

  2. The clinical onset and severity of MLD show great variation. Three major forms of MLD are usually distinguished based on the age of onset. First, a late infantile form with onset of clinical symptoms before 30 months of age and fatal in childhood; second, a juvenile form with onset between 2 1/2 and 16 years; and third, an adult form with onset after 16 years of age. In the late infantile form, which is the most frequent form children develop, symptoms usually appear in the second year of life after an initially normal development. Symptoms involve gait problems due to neuropathy, spasticity, and ataxia accompanied by mental regression. Disease course is highly invariable and stereotypic and leads to a complete loss of motor function usually before the age of 3 ½ years. Deterioration of gross motor function in juvenile MLD is more variable with respect to age range and dynamics. There may be impaired fine motor skills, concentration and behavioral problems as first symptoms. However, once loss of independent walking occurs in juvenile patients, their gross motor function declines as rapidly as in the late infantile form. In the adult forms, psychotic symptoms and behavioral abnormalities often precede or accompany a decline in intellectual capacities and motor function, leading to the misdiagnosis of a psychosis.

  3. Demonstration of reduced nerve conduction velocity and of demyelination by magnetic resonance imaging (MRI) are the major laboratory findings. On MRI central white matter is early affected with typically butterfly-shaped confluent white matter hyperintensities on T2w with a characteristic tigroid pattern. Regardless of the type of disease, corpus callosum is involved early. White matter changes on MRI clearly precede the onset of clinical symptoms in juvenile and adult MLD. As the disease progresses, there is increasing white matter involvement including U-fibers and involvement of cerebellar white matter as well as cerebral atrophy.

  4. More than 160 different mutations have been characterized in the ASA gene. Only a few mutations occur with high frequency. Homozygosity for null alleles is the cause of the late infantile form of MLD. In the juvenile and adult forms of MLD, one or both ASA alleles are associated with at least some residual activity. There is strong evidence that the severity of the disease correlates inversely with the residual activity of ASA.

  5. Biochemically the diagnosis is primarily based on demonstration of the deficiency of ASA. The diagnosis, however, is complicated by the facts that absence of ASA activity does not prove MLD and that its presence does not exclude it. Considerable reduction of ASA activity is observed in individuals homozygous for the benign ASA pseudodeficiency allele, which encodes only 5–15 percent of residual activity. Up to 2 percent of Europeans are homozygous for the pseudodeficiency allele. Based on conventional colorimetric assays for ASA activity determination, it can be difficult to distinguish reliably a deficiency leading to MLD from benign pseudodeficiency. The latter can be identified with DNA-based assays detecting the polymorphisms of the ASA pseudodeficiency allele. A further complication arises from the fact that MLD-causing mutations occur in the pseudodeficiency allele as frequently as in the wild-type ASA allele. Normal ASA activity is observed in MLD patients with a deficiency of saposin B, because the colorimetric diagnostic assay for ASA does not depend on saposin B. Given these difficulties diagnosis can be confirmed by quantification of sulfatide in urine which is abundant in MLD patients. Prenatal diagnosis is possible by determination of ASA activity in cultured amniotic fluid cells or chorionic villi. In particular when mutations are known prenatal diagnosis can also be done by sequencing the ASA gene.

  6. Currently, there is no standardized treatment protocol available for patients with MLD. Several approaches, however, have been studied clinically. All have in common the aim to substitute the deficient enzyme activity either by exogeneous or endogeneous enzyme replacement, the latter via bone marrow transplantation or gene therapy. Only bone marrow transplantation has been reported to have an effect on disease course and brain changes in some cases of juvenile MLD, but inclusion and exclusion criteria are not yet clear.

  7. Prevention of the disease is restricted to the possibility of prenatal diagnosis and carrier identification in families with known risk or in populations with a high incidence of MLD. Different mouse models for MLD have been developed, of which one mimics both the biochemical and the pathological alterations seen in MLD. These mouse models have been used in various preclinical therapeutic studies examining the feasibility of gene therapy, cell transplantation and enzyme replacement therapy in MLD.

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