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Thread: Metachromatic Leukodystrophy case pictures - NEURORADIOLOGY ATLAS

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    Default Metachromatic Leukodystrophy case pictures - NEURORADIOLOGY ATLAS

    INTRODUCTION
    Metachromatic leukodystrophy (sulfatide lipidosis) (MLD) is a rare autosomal recessive lysosomal storage disease that causes progressive demyelination of the central and peripheral nervous system.

    This topic will review the clinical manifestations, diagnosis, and treatment of metachromatic leukodystrophy. Other lysosomal storage disorders and leukodystrophies are discussed separately. (See "Adrenoleukodystrophy" and "Alexander disease" and "Aspartoacylase deficiency (Canavan disease)" and "Cerebrotendinous xanthomatosis" and "Neurologic manifestations of Fabry disease" and "Krabbe disease" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Overview of Niemann-Pick disease" and "Pelizaeus-Merzbacher disease" and "Sjögren-Larsson syndrome" and "Vanishing white matter disease".)

    ETIOLOGY
    Metachromatic leukodystrophy (MLD) is caused by deficient activity of arylsulfatase A as a result of, in almost all cases, mutations in the arylsulfatase A gene (ARSA gene). In a few patients, MLD is caused by a deficiency of sphingolipid activator protein SAP-B (saposin B), which normally stimulates the degradation of sulfatides by ARSA . This variant form of MLD is caused by mutations in the prosaposin gene (PSAP gene).

    ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin. As a result, decreased ARSA activity leads to the accumulation of cerebroside sulfate in the central nervous system, peripheral nerves, kidneys, and other visceral organs. The accumulation of cerebroside sulfate destroys oligodendroglial and Schwann cells, causing central and peripheral demyelination. Electron microscopy shows thickened lines in the myelin whorls and lamellar inclusions of sulfatides in the Schwann cells .

    Genetics — At least 60 mutations in the ARSA gene have been described in MLD. Two alleles, A and I, together account for approximately 50 percent of cases . These alleles contribute to the different clinical expressions of the disease

    Description
    The metachromatic leukodystrophies comprise several allelic disorders. Kihara (1982) recognized 5 allelic forms of MLD: late infantile, juvenile, and adult forms, partial cerebroside sulfate deficiency, and pseudoarylsulfatase A deficiency; and 2 nonallelic forms: metachromatic leukodystrophy due to saposin B deficiency (249900) and multiple sulfatase deficiency or juvenile sulfatidosis (272200), a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy

    Late Infantile and Juvenile Forms
    This condition was described by Greenfield (1933). In the late infantile form, onset is usually in the second year of life and death occurs before 5 years in most. Clinical features are motor symptoms, rigidity, mental deterioration, and sometimes convulsions. Early development is normal but onset occurs before 30 months of age. The cerebrospinal fluid contains elevated protein. Galactosphingosulfatides that are strongly metachromatic, doubly refractile in polarized light, and pink with PAS are found in excess in the white matter of the central nervous system, in the kidney, and in the urinary sediment (Austin, 1960).
    Metachromatic Leukodystrophy case pictures NEURORADIOLOGY attachment.php?s=3ed90979e5a4bf26c3d0bc40f231503a&attachmentid=1536&d=1440444470

    Masters et al. (1964) described 4 cases in 2 families. Progressive physical and mental deterioration began a few months after birth. Megacolon with attacks of abdominal distention was observed. Sufficient difference from the usual cases existed for the authors to suggest that more than one entity is encompassed by metachromatic leukodystrophy. A curious feature of later bedridden stages of the disease was marked genu recurvatum. The first manifestations, appearing before the second birthday, included hypotonia, muscle weakness and unsteady gait, thus suggesting a myopathy or neuropathy.

    Gustavson and Hagberg (1971) described 13 cases of late infantile MLD from 11 families. Two pairs of families were related to each other and 3 sets of parents were consanguineous, suggesting autosomal recessive inheritance.

    Lyon et al. (1961) described affected brothers with onset at 7 and 4 years of age and with marked elevation of protein in the cerebrospinal fluid. Schutta et al. (1966) recognized a juvenile form of metachromatic leukodystrophy with onset between ages 4 and 10 years, as compared with the more frequent late infantile form with onset between ages 12 and 24 months.

    Moser (1972) suggested that juvenile cases of MLD, especially those of late juvenile onset, should be classed with the adult form. An alternative possibility was that some of these cases with phenotype intermediate between those of the late infantile and adult forms represented genetic compounds. The same very low levels of arylsulfatase A were found in the infantile, juvenile, and adult forms, and the reason for the differences in age of onset was unknown.

    Von Figura et al. (1986) pointed out that the late-onset form of MLD is a heterogeneous group in which symptoms may develop at any age beyond 3 years. The age of demarcation of juvenile forms from adult forms is somewhat arbitrarily set at age 16 by some and age 21 by others. In the late-onset forms the disease progresses more slowly, and in mild cases the diagnosis may even go unsuspected during life.

    Biochemical Features
    Austin et al. (1964) determined that the defect in MLD involves the lysosomal enzyme arylsulfatase A. Since the metachromatic material is cerebroside sulfate, MLD is a sulfatide lipidosis. Stumpf and Austin (1971) presented evidence suggesting that the abnormality in arylsulfatase A is quantitatively and qualitatively different in the late infantile and juvenile forms of metachromatic leukodystrophy. Percy and Kaback (1971) found no difference in enzyme levels between the infantile and adult-onset types, and concluded that some other factor must account for the difference in age of onset.

    Porter et al. (1971) corrected the metabolic defect in cultured fibroblasts by addition of arylsulfatase A to the medium. They found that cultured fibroblasts from late-onset metachromatic leukodystrophy hydrolyzed appreciable amounts of exogenous cerebroside sulfate, whereas fibroblasts from patients with the early-onset form hydrolyzed none. Studies of cell-free preparations showed no cerebroside sulfatase activity. Percy et al. (1977) found that cultured skin fibroblasts from the adult-onset patients, although clearly abnormal, were able to catabolize sulfatide significantly more effectively than cultured skin fibroblasts from late infantile patients.

    By the technique of isoelectric focusing on cellulose acetate membranes, Farrell et al. (1979) found differences in arylsulfatase A isozymes that correlated with the clinical type of metachromatic leukodystrophy, i.e., juvenile or late infantile. Chang et al. (1982) showed that fusion of cells from the infantile and juvenile forms of MLD did not result in complementation of arylsulfatase A activity, and concluded that they are allelic disorders.

    In the cells from patients with juvenile and adult forms of MLD, von Figura et al. (1983) found severe deficiency in the arylsulfatase polypeptide but a rate of synthesis that was 20 to 50% of control. In the absence of NH4Cl, the mutant enzyme was rapidly degraded upon transport into lysosomes. In the presence of inhibitors of thiol proteases, e.g., leupeptin, arylsulfatase A polypeptides were partially protected from degradation with increase in catalytic activity of arylsulfatase A and improved ability of the cells to degrade cerebroside sulfates. Therapeutic use of this approach was suggested. The approach might be useful in other lysosomal storage diseases in which an unstable mutant enzyme is produced, e.g., the late form of glycogen storage disease II (232300). In a study of 8 patients with the juvenile form of MLD, von Figura et al. (1986) found that the mutation leads to the synthesis of arylsulfatase A polypeptides with increased susceptibility to cysteine proteinases. Multiple allelic mutations within this group were suggested by clinical heterogeneity, variability in residual activity, and response to inhibitors (cysteine proteinases).

    References:
    http://www.omim.org/entry/250100
    Metachromatic leukodystrophy











    Last edited by Medical Photos; 08-24-2015 at 07:27 PM.

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