METACHROMATIC LEUKODYSTROPHY, LATE INFANTILE, INCLUDED
METACHROMATIC LEUKODYSTROPHY, JUVENILE, INCLUDED
SULFATIDE LIPIDOSIS
METACHROMATIC LEUKODYSTROPHY, ADULT, INCLUDED
CEREBRAL SCLEROSIS, DIFFUSE, METACHROMATIC FORM
ARSA DEFICIENCY
ARYLSULFATASE A DEFICIENCY
CEREBROSIDE SULFATASE DEFICIENCY PSEUDOARYLSULFATASE A DEFICIENCY, INCLUDED
METACHROMATIC LEUKOENCEPHALOPATHY
MLD
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 ... 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.
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 ... - 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). 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. - Adult Form In the adult form of metachromatic leukodystrophy, initial symptoms, which begin after age 16, are usually psychiatric and may lead to a diagnosis of schizophrenia. Disorders of movement and posture appear late. Differences from the late infantile form also include ability to demonstrate metachromatic material in paraffin- or celloidin-embedded sections and probably greater sulfatide excess in the gray than in the white matter in the adult form. The gallbladder is usually nonfunctional. Betts et al. (1968) described a man who was 28 when admitted to a psychiatric hospital for 'acute schizophrenia' and 35 when he died of bronchopneumonia. Muller et al. (1969) and Pilz and Muller (1969) described 2 unrelated women with this disorder. Affected sibs were recorded by Austin et al. (1968), among others. Kihara et al. (1982) found partial cerebroside sulfatase deficiency (10-20% of normal activity in cultured fibroblasts) as the cause of neuropathy and myopathy since infancy in a 37-year-old white female. She had been institutionalized since age 16 for mental retardation. Waltz et al. (1987) described a 38-year-old man who had been diagnosed as schizophrenic and was treated for that condition for many years. The diagnosis of adult MLD was suspected because of white matter abnormalities detected by CT and MRI scanning of the brain; this diagnosis was confirmed by discovery of markedly reduced leukocyte arylsulfatase A activity. The man held a master's degree in physical education and worked full-time as a high school physical education teacher. Personality changes were first noted at about age 31. Propping et al. (1986) studied consecutive admissions to a state psychiatric hospital and a group of inpatients with chronic psychiatric disorders. The data showed a slight preponderance in the lower levels of arylsulfatase A in leukocytes. Kohn et al. (1988) found no neurologic or EEG changes in MLD heterozygotes but found deficits in the neuropsychologic tests involving spatial or constructional components (but not in tests involving language skills). Tay-Sachs heterozygotes (272800) showed no consistent deficit in any component of the neurologic or neuropsychologic tests. Marcao et al. (2005) reported a woman with adult-onset MLD confirmed by genetic analysis. She presented at age 37 years with dysfunctional and bizarre behavior, including progressive apathy, loss of interest in daily living routines and caring for her 3 children, and memory disturbances. She had no clinical signs of neuropathy, although MRI showed subcortical brain atrophy and periventricular white matter changes. Nerve conduction velocities were normal; sural nerve biopsy findings were consistent with a slowly progressive demyelinating neuropathy. Despite the relatively mild clinical phenotype, ARSA activity was less than 1% of control values. - 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). - Pseudoarylsulfatase A deficiency Pseudoarylsulfatase A deficiency refers to a condition of apparent ARSA enzyme deficiency in persons without neurologic abnormalities. Dubois et al. (1977) described very low arylsulfatase A and cerebroside sulfatase activities in leukocytes of healthy members of a metachromatic leukodystrophy family. Langenbeck et al. (1977) proposed a one locus, multiple allele hypothesis to explain the peculiar findings in that kindred. Butterworth et al. (1978) reported a child with very low levels of the enzyme whose mother was, seemingly, heterozygous and whose father carried a variant gene giving a very low in vitro level. They concluded that low arylsulfatase A is not necessarily indicative of this disease, which should be taken into consideration when screening for the disease. A pseudodeficiency allele at the arylsulfatase A locus was delineated by Schaap et al. (1981). Clinically healthy persons with ARSA levels in the range of MLD patients have been found among the relatives of MLD patients. Cultured fibroblasts from persons with pseudodeficiency catabolize cerebroside sulfate; fibroblasts from MLD patients do not. Zlotogora and Bach (1983) pointed out that lysosomal hydrolases deficient in cases of metachromatic leukodystrophy, Tay-Sachs disease, Fabry disease, and Krabbe disease have also been found to be deficient in healthy persons. The authors suggested that most of the latter cases represent the compound heterozygote for the deficient allele and another allele coding for an in vitro low enzyme activity (pseudodeficiency). Chang and Davidson (1983) could demonstrate no restoration of activity of arylsulfatase A in hybrid cells created from cells of individuals with MLD and individuals with pseudo-ARSA deficiency. They concluded, therefore, that the 2 mutations are allelic. They showed that the 2 conditions can be distinguished in the laboratory by a simple electrophoretic analysis of residual ARSA activity. Kihara et al. (1986) noted that the apparent enzyme deficiency in persons without neurologic abnormalities is due in part to the nonspecificity of the synthetic substrates used for assays and in part to a high redundancy of arylsulfatase A. Yatziv and Russell (1981) reported 3 adult sibs of Iranian-Jewish extraction who had a form of primary dystonia with onset in childhood. The clinical hallmark was dystonia, mainly induced by intention and manifested by dysarthria and torsion spasm of the neck, spine, and limbs. There was a marked deficiency of arylsulfatase A in urine, leukocytes, and fibroblasts. The clinically normal parents both showed reduction in ARSA activity by 50%. Yatziv and Russell (1981) reported the disorder in this family as an 'unusual form of metachromatic leukodystrophy,' but Khan et al. (2003) later reported that genetic analysis of the family indicated pseudoarylsulfatase A deficiency: the mother and all 3 sibs were homozygous, and the father was heterozygous, for a pseudodeficiency allele. Khan et al. (2003) diagnosed the family with autosomal recessive primary dystonia (DYT2; 224500), and noted that the presence of 3 of 4 parental chromosomes carrying an arylsulfatase A pseudodeficiency allele supports an isolated genetic pool.
Hohenschutz et al. (1988) described a probable case of the genetic compound between metachromatic leukodystrophy and pseudodeficiency. The patient developed slight spasticity of the left leg at the age of 36 years and left-sided retrobulbar neuritis at the ... Hohenschutz et al. (1988) described a probable case of the genetic compound between metachromatic leukodystrophy and pseudodeficiency. The patient developed slight spasticity of the left leg at the age of 36 years and left-sided retrobulbar neuritis at the age of 62, together with slight spasticity of both legs. The diagnosis of encephalomyelitis disseminata was made. There were psychiatric manifestations as well. Based on the facts that the pseudodeficiency allele at the ARSA locus is common (gene frequency = 13.7 to 17%), that genetic compounds between the pseudodeficiency allele and the true deficiency allele may be as frequent as 0.073%, and that the residual enzyme activity may fall below a critical threshold in such individuals, Hohenschutz et al. (1989) suggested that the compound heterozygote genotype might be associated with neuropsychiatric disorders of late onset. In 34 individuals with low ASA activity, Kappler et al. (1991) identified 3 different classes: homozygosity for the pseudodeficiency allele (ASAp/ASAp) (10 individuals), compound heterozygosity for ASAp and ASA- (6 individuals), and homozygosity of ASA- (16 individuals). The genotypes exhibited different levels of residual ASA activity. ASAp/ASAp was associated with normal sulfatide degrading capacity and a reduced ASA activity that was the highest of the 3 classes (10-50% of normal). ASAp/ASAp subjects showed no evidence of MLD. ASAp/ASA- subjects showed mildly reduced sulfatide degrading capacity and a reduced ASA activity that was in between the other 2 classes (10% of controls). ASAp/ASA- subjects were either healthy or showed mild neurologic abnormalities. ASA-/ASA- subjects showed markedly reduced sulfatide degradation and markedly reduced ASA activity. Only the ASA-/ASA- genotype was associated with the development of both early- and late-onset MLD, including neuropsychiatric symptoms. Berger et al. (1999) described a family with 3 sibs, 1 of whom developed classic late infantile MLD, fatal at age 5 years, with deficient ARSA activity and increased galactosylsulfatide (GS) excretion. The other 2 sibs, apparently healthy at 12.5 and 15 years, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation analysis demonstrated that 3 different ARSA mutations accounted for the intrafamilial phenotypic heterogeneity. One of the mutations, although clearly modifying ARSA and GS levels, apparently had little significance for clinical manifestation of MLD, The results demonstrated that in certain genetic conditions the ARSA and GS values may not be paralleled by clinical disease, a finding with serious diagnostic and prognostic implications. Moreover, further ARSA alleles functionally may exist which, together with 0-type mutations may cause ARSA and GS levels in the pathologic range but no clinical manifestation of the disease. Regis et al. (2002) identified a late infantile MLD patient carrying on one allele a novel E253K mutation (607574.0044) and the known T391S polymorphism, and on the other allele the common P426L mutation (607574.0004), usually associated with the adult or juvenile form of the disease, and the N350S (607574.0002) and *96A-G pseudodeficiency mutations. To analyze the contribution of mutations based on the same allele to enzyme activity reduction, as well as the possible phenotype implications, they performed transient expression experiments using ARSA cDNAs carrying the identified mutations separately or in combination. Their results indicated that mutants carrying multiple mutations cause greater reduction of ARSA activity than do the corresponding single mutants, the total deficiency likely corresponding to the sum of the reductions attributed to each mutation. Consequently, each mutation may contribute to the ARSA activity reduction, and, therefore, to the degree of disease severity. This is particularly important for the alleles containing a disease-causing mutation and the pseudodeficiency mutations: in these alleles pseudodeficiency could play a role in affecting the clinical phenotype. Rauschka et al. (2006) evaluated 42 patients with late-onset MLD, 22 of whom were homozygous for the P426L mutation and 20 of whom were compound heterozygous for I179S (607574.0008) and another pathogenic ARSA mutation. Patients homozygous for the P426L mutation presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at disease onset but became more apparent as the disease evolved. Peripheral nerve conduction velocities were decreased. In contrast, patients who were heterozygous for I179S presented with schizophrenia-like behavior changes, social dysfunction, and mental decline, but motor deficits were scarce. There was less residual ARSA activity in those with P426L mutations compared to those with I179S mutations. Biffi et al. (2008) reported 26 patients with MLD who were classified clinically according to age at onset into late-infantile (17), early juvenile (6), late-juvenile (2), and adult (1). These patients were found to carry 18 mutations in the ARSA gene, including 10 rare and 8 novel mutations, that were classified as null '0' alleles lacking residual activity and 'R' alleles with residual activity. The null/null homozygous patients were the most severely affected with severe clinical manifestations, profound motor and cognitive deficits, and rapid disease progression. Patients who were null/R compound heterozygous showed a similar presentation and disease evolution, although less rapid, to null/null homozygotes. Despite some variability, all R/R homozygous patients showed a milder disease burden and slower progression when compared with null/null and null/R subjects. Biffi et al. (2008) observed early involvement of the peripheral nervous system in all patients with at least 1 null allele, and the authors suggested that evaluation of nerve conduction velocities could be used as a frontline test for all MLD patients,
In patients with MLD, Polten et al. (1991), Gieselmann et al. (1991), Kondo et al. (1991), Bohne et al. (1991), and Fluharty et al. (1991) identified mutations in the ARSA gene (e.g., 607574.0003).
Gieselmann et al. ... In patients with MLD, Polten et al. (1991), Gieselmann et al. (1991), Kondo et al. (1991), Bohne et al. (1991), and Fluharty et al. (1991) identified mutations in the ARSA gene (e.g., 607574.0003). Gieselmann et al. (1994) stated that 31 amino acid substitutions, 1 nonsense mutation, 3 small deletions, 3 splice donor site mutations, and 1 combined missense/splice donor site mutation had been identified in the ARSA gene in metachromatic leukodystrophy. Two of these mutant alleles account for about 25% of MLD alleles each. - Pseudodeficiency Alleles Gieselmann et al. (1989) determined 2 pseudodeficiency alleles of the ARSA gene (607574.0001-607574.0002).
Although MLD occurs panethnically, with an estimated frequency of 1/40,000, Heinisch et al. (1995) found it to be more frequent among Arabs living in 2 restricted areas in Israel. Ten families with affected children were found, 3 in ... Although MLD occurs panethnically, with an estimated frequency of 1/40,000, Heinisch et al. (1995) found it to be more frequent among Arabs living in 2 restricted areas in Israel. Ten families with affected children were found, 3 in the Jerusalem region and 7 in a small area in lower Galilee. Whereas all patients from the Jerusalem region were homozygous for the splice donor site mutation at the border of exon/intron 2 (607574.0003), 5 different mutations were found in the 7 families from lower Galilee, all of them in homozygous state. Two of the families were Muslim Arabs and 2 were Christian Arabs. Four different haplotypes were represented by the 5 mutations. Zlotogora et al. (1994) studied the ARSA haplotypes defined by 3 intragenic polymorphic sites in 3 Muslim Arab families and 1 Christian Arab family from Jerusalem with the splice donor site mutation at the border of exon/intron 2. The parents were first cousins in all 4 families, but no relationship between these families was known. All 4 patients had the same haplotype, i.e., BglI(1), BamHI(1), BsrI(1), which is rare (3.9%) in the general population. Zlotogora et al. (1994) found the same haplotype in 8 non-Arab patients from the US and Europe who were homozygous for this allele. The strong association between this mutation and haplotype suggested a common origin for the mutation, which may have been introduced into Jerusalem at the time of the Crusades. Holve et al. (2001) found that cases of MLD among Navajo Indians were clustered in a portion of the western Navajo Nation to which a small number of Navajo fled after armed conflict with the United States Army in the 1860s. The observed incidence of MLD in that region was 1/2,520 live births, with an estimated carrier frequency of 1/25 to 1/50. No cases were observed in the eastern part of the Navajo Nation over a period of 18 years (60,000 births). Bottleneck and founder effect from the mid-19th century could explain the high incidence of MLD as well as a number of other heritable disorders among the Navajo. In Israel, Herz and Bach (1984) estimated the frequency of the pseudodeficiency allele to be about 15%. In a Spanish population, Chabas et al. (1993) estimated the frequency of the pseudodeficiency allele to be 12.7%. In a retrospective hospital- and clinic-based study involving 122 children with an inherited leukodystrophy, Bonkowsky et al. (2010) found that the most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (312080) (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (300100) (4.1%). No final diagnosis was reported in 51% of patients. The disorder was severe: epilepsy was found in 49%, mortality was 34%, and the average age at death was 8.2 years. The population incidence of leukodystrophy in general was found to be 1 in 7,663 live births.
Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is suspected in individuals with the following:...
DiagnosisClinical DiagnosisArylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is suspected in individuals with the following:Progressive neurologic dysfunction. Presenting signs may be behavioral or motor. Symptoms can occur at any age beyond one year and follow a period of normal development [Von Figura et al 2001, Gieselmann 2008, Gieselmann & Krägeloh-Mann 2010, Kehrer et al 2011a].MRI evidence of a leukodystrophyDiffuse symmetric abnormalities of periventricular myelin with hyperintensities on T2-weighted images. Initial posterior involvement is observed in most late- infantile cases with subcortical U-fibers and cerebellar white matter spared. As the disease progresses, MRI abnormalities become more pronounced in a rostral-to-caudal progression; cerebral atrophy develops [Groeschel et al 2011].Anterior lesions may be more common initially in individuals with later onset.TestingArylsulfatase A (EC 3.1.6.8) enzyme activityArylsulfatase A (ARSA) enzyme deficiency. The diagnosis of MLD is suggested by ARSA enzyme activity in leukocytes that is less than 10% of normal controls using the usual Baum type assay in which other arylsulfatases are incompletely blocked [Baum et al 1959]. Note: (1) The use of low temperature assays can minimize interference by other arylsulfatases and lower the baseline level [Rip & Gordon 1998]. (2) Cultured skin fibroblasts have often been used to confirm deficiency of ARSA enzyme activity and to evaluate the capacity of intact cells for sulfatide breakdown. Such testing is usually not necessary for establishing the diagnosis but can be useful when the diagnosis is ambiguous (pseudodeficiency vs. late-onset MLD) or is being made presymptomatically. (3) Sulfatide loading of cultured amniocytes or CVS cells can be critical in prenatal diagnoses – see Genetic Counseling.ARSA enzyme pseudodeficiency. Pseudodeficiency is suggested by ARSA enzyme activity in leukocytes that is 5% to 20% of normal controls. Pseudodeficiency is difficult to distinguish from true ARSA enzyme deficiency by biochemical testing alone. Note: (1) As used here, the term "pseudodeficiency" only refers to very low levels of ARSA enzyme activity in an otherwise healthy individual. Pseudodeficiency was first noted in parents and relatives of individuals with MLD. (2) Although the term “pseudodeficiency” has subsequently been applied to other enzyme deficiency disorders, it does not always have the same meaning. For example, in hexosaminidase A deficiency, the term "pseudodeficiency allele" refers to mutations that are associated with reduced enzymatic activity when measured using synthetic substrate but are associated with normal enzymatic activity when measured using natural substrate.Because assay of ARSA enzymatic activity cannot distinguish between MLD and ARSA pseudodeficiency, the diagnosis of MLD is confirmed by one or more of the following additional tests:Molecular genetic testing of ARSA (see Molecular Genetic Testing)Urinary excretion of specialized compounds. Sulfatides accumulate in kidney epithelial cells in MLD and eventually slough into the urine in amounts from ten- to 100-fold higher than controls as measured by thin layer chromatography, high-pressure liquid chromatography (HPLC), and/or mass spectrometric techniques. Because urine production is highly variable, urinary sulfatide excretion is referenced on the basis of urinary excretion in 24 hours or to another urinary component such as creatinine (which is a function of muscle mass).Metachromatic lipid deposits in a nerve or brain biopsy. Sulfatides interact strongly with certain positively charged dyes used to stain tissues, resulting in a shift in the color of the stained tissue termed metachromasia. When frozen tissue sections are treated with acidified cresyl violet (Hirsch-Peiffer stain), sulfatide-rich storage deposits stain a golden brown. The finding of metachromatic lipid deposits in nervous system tissue is pathognomonic for MLD. Note: (1) Fixing the tissue with alcohol before staining extracts the sulfatides such that the metachromasia is no longer observed. (2) Although still considered by some to be the diagnostic "gold standard" for MLD, this highly invasive approach is now used only in exceptional circumstances (e.g., confirmation of a prenatal diagnosis of MLD following pregnancy termination).Newborn screening for MLD has been difficult to provide because of the high occurrence of ARSA enzyme pseudodeficiency and the inability to distinguish MLD from pseudodeficiency. Tan et al [2010] described an immune-based assay which can differentiate MLD and pseudodeficiency. The adaptation of this method by Fuller et al [2011] for the analysis of blood spot samples suggests the possibility of an effective newborn screening test for MLD. Molecular Genetic TestingGene. ARSA is the only gene in which mutations are known to cause arylsulfatase A deficiency (metachromatic leukodystrophy, MLD).Three classes of ARSA alleles resulting in low ARSA enzyme activity need to be distinguished:1. Disease-causing ARSA-MLD alleles in the homozygous or compound heterozygous state result in ARSA enzyme activity that is insufficient to prevent sulfatide accumulation and thus cause MLD:Alleles that result in no functional enzyme activity are termed "I" (or "O") alleles. Presence of two "I" alleles typically results in late-infantile-onset MLD.Alleles that result in some residual enzyme activity are designated "A" (or "R") alleles and are associated with later-onset (i.e., juvenile or adult) MLD. Presence of two "A" alleles typically results in adult-onset MLD.Compound heterozygosity of one "I" allele and one "A" allele is usually associated with juvenile-onset MLD. Note: Exceptions to this oversimplification of the class of alleles determining age of onset of MLD occur; however, the classification provides a first-order explanation for genotype/phenotype relationships.2. Pseudodeficiency (ARSA-PD) alleles are common polymorphisms that result in lower than average ARSA enzyme activity; however, ARSA-PD alleles still produce sufficient functional enzyme to avoid sulfatide accumulation and thus do not cause MLD in either of the following:The homozygous state (i.e., [ARSA-PD]+[ARSA-PD])The compound heterozygous state with an ARSA-MLD allele (i.e., [ARSA-PD]+[ARSA-MLD])The most common ARSA-PD allele in the European and American populations has two sequence variants in a cis configuration (i.e., on the same chromosome), designated as c.[1049A>G; *96A>G] denoting two changes in one allele. The two changes:c.1049A>G (p.Asn350Ser), a glycosylation site variant that alters one of the N-glycosylation positions and results in poor targeting of the ARSA protein to the lysosomec.*96A>G, a polyadenylation site variant occurring in the 3' untranslated region that alters the site signaling of the polyadenylation of the mRNA and greatly reduces the amount of ARSA protein producedThe c.1049A>G (p.Asn350Ser) ARSA-PD variant occurs in isolation (without the cis c.*96A>G variant) in up to 5% of the European populations studied, in 20%-30% of the Asian populations studied, and in up to 40% of some African-derived populations. Even in the homozygous state, this PD variant typically results in a level of ARSA enzyme activity higher than that associated with MLD.The c.*96A>G variant occurs in isolation (without the cis c.1049A>G variant) only rarely [Gort et al 1999].3. [ARSA-MLD; ARSA-PD] alleles in which a disease-causing ARSA-MLD mutation occurs in cis configuration (i.e., on the same chromosome) with an ARSA-PD allele have been reported. These are sometimes referred to ARSA-MLD-PD alleles. Unless an ARSA-MLD mutation is on the other allele, these individuals are carriers but do not have MLD.Clinical testingTargeted mutation analysisARSA-MLD alleles. The disease-causing mutations included in targeted mutation analysis vary by laboratory. The four most common mutations occurring in the central and western European populations and their derivative North American populations (which have been most studied) include c.459+1G>A and c.1204+1G>A (the most common I-type mutations) and p.Pro426Leu and p.Ile179Ser (the most common A-type mutations). In general, these four alleles typically account for between 25% and 50% of the ARSA alleles in these populations (see Table 4). Note: The higher incidence of specific mutations in particular ethnic groups would modify the targeted mutations for such groups (e.g., Navajos or Alaskan Eskimos).ARSA-PD alleles. Assays distinguish between the isolated occurrence or cis configuration of the c.1049A>G mutation and the polyadenylation site mutation c.*96A>G. Note: The Gieselmann procedure [Gieselmann 1991, Gieselmann et al 1991] can only detect the c.1049A>G mutation and the polyadenylation site mutation c.*96A>G when they are in cis configuration.Sequence analysis. The small size of ARSA makes sequencing of the entire coding region and the majority of intronic regions feasible. Sequencing is expected to detect 97% of ARSA mutations [Gort et al 1999]. Small deletions, insertions, and inversions within exons can be easily seen on genomic sequencing.Deletion/duplication analysisComplete deletion of ARSA associated with MLD has been reported [Eng et al 2004, Bisgaard et al 2009]. No instances of whole-gene duplication are known. A case of dispermic chimerism was reported in which two copies of ARSA were transmitted by the father, one with an MLD-causing mutation and the other normal.Table 1. Summary of Molecular Genetic Testing Used in Arylsulfatase A DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method and Phenotype 1Test AvailabilityLate-infantile MLDJuvenile MLDAdult MLDARSATargeted mutation analysisARSA-MLD alleles 236%-50% 3, 440%-50% 3, 473%-90% 3, 4ClinicalSequence analysisARSA-MLD sequence variants 590%-95% 6, 7Deletion / duplication analysis 8Exonic and whole-gene deletions<1%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. The disease-causing mutations included in targeted mutation analysis vary by laboratory.3. Testing for the eight most common mutations (p.Arg84Gln, p.Ser96Phe, c.459+1G>A, p.Ile179Ser, p.Ala212Val, c.1204+1G>A, p.Pro426Leu, and c.1401_1411del), Berger et al [1997] determined that the mutation detection frequency in affected individuals in Austria was 36% for infantile-onset MLD, 50% for juvenile-onset MLD, and 90% for adult-onset MLD.4. Testing for the same eight mutations as Berger et al [1997], Lugowska et al [2005b] determined that the mutation detection rate in affected individuals in Poland was about 50% for late-infantile onset, 45% for juvenile onset, and 73% for adult onset.5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.6. Using mutation scanning, Gort et al [1999] identified all of the disease-causing ARSA mutations in 18 unrelated affected persons of Spanish heritage.7. This test method also detects the ARSA pseudodeficiency alleles (termed ARSA-PD), common polymorphisms that result in lower than average ARSA enzyme activity but do not cause MLD even in the homozygous state or in the compound heterozygous state with an ARSA-MLD allele.8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Because both ARSA-MLD and ARSA-PD mutations can occur in cis configuration, molecular analysis of at least one parent is useful to determine if mutant alleles are in cis configuration or in trans configuration.In instances in which one copy of ARSA has been deleted, a single ARSA-MLD mutation on the remaining allele results in MLD [Eng et al 2004]. Therefore, in instances of apparent homozygosity for an ARSA-MLD mutation in a proband, it is appropriate to establish the presence of the disease-causing ARSA mutation in both parents when possible to assure accurate use of molecular genetic testing in clarifying the genetic status of at-risk relatives.Testing StrategyTo confirm/establish the diagnosis in a proband. Because the most commonly used assay of ARSA enzymatic activity cannot distinguish between MLD and ARSA pseudodeficiency, the diagnosis of MLD is confirmed by one or more of the following additional tests:Molecular genetic testing of ARSA. Molecular genetic testing is used for confirmatory diagnostic testing to determine if low ARSA enzyme activity results from either of the following:A combination of known disease-causing alleles such as homozygosity for an ARSA-MLD mutation or compound heterozygosity for [ARSA-MLD]+[ARSA-MLD] mutations, which confirms the diagnosis of MLDA combination of known non-disease-causing alleles such as ARSA-PD homozygosity or [ARSA-PD]+[ARSA-MLD] compound heterozygosity, which suggest the carrier state for MLD (and thus, a different explanation for the neurologic problem in a symptomatic individual)Urinary excretion of sulfatidesMetachromatic lipid deposits in a nerve or brain biopsyCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersIndividuals with the 22q13.3 deletion syndrome (Phelan-McDermid syndrome) often have a deletion of ARSA. Presence of an ARSA-PD allele on the homologous chromosome resulting in arylsulfatase A pseudodeficiency has been reported in 22q13.3 deletion syndrome [Phelan et al 2001].Ring 22. Coulter-Mackie et al [1995] reported an individual with a ring chromosome 22 (including deletion of ARSA) who had MLD resulting from an ARSA-MLD mutation on the homologous chromosome [Koc et al 2008].
The three clinical subtypes of arylsulfatase A deficiency (MLD) are primarily distinguished by age of onset. Late-infantile MLD comprises 50%-60% of cases, juvenile MLD approximately 20%-30%, and adult MLD approximately 15%-20%. The age of onset within a family is usually similar, but exceptions occur [Arbour et al 2000]....
Natural HistoryThe three clinical subtypes of arylsulfatase A deficiency (MLD) are primarily distinguished by age of onset. Late-infantile MLD comprises 50%-60% of cases, juvenile MLD approximately 20%-30%, and adult MLD approximately 15%-20%. The age of onset within a family is usually similar, but exceptions occur [Arbour et al 2000].The presenting problems and rate of progression vary among individuals; however, all eventually have complete loss of motor and intellectual functions. The disease course may be from three to ten or more years in the late-infantile-onset form and up to 20 years or more in the juvenile- and adult-onset forms [Von Figura et al 2001]. Death most commonly results from pneumonia or other infection. Life span correlates roughly with the age of onset but can be quite variable, particularly in the later-onset forms.Late-infantile MLD. Onset is between ages one and two years, following a period of apparently normal early development. Acquired skills such as walking and speaking deteriorate. Clumsiness, frequent falls, toe walking, and slurred speech are typical presenting signs. Symptoms may first be noted following anesthesia or an infection with fever and may even subside for several weeks before continuing on a downhill course.In the initial stage, weakness and hypotonia are observed. Later, the child is no longer able to stand; speech becomes difficult; and mental function deteriorates. Muscle tone is increased, and pain may occur in the arms and legs. Generalized or partial seizures may occur [Wang et al 2001]. Vision and hearing are compromised with slowed sensory evoked potentials and optic atrophy. Peripheral neuropathy with slow nerve conduction velocities (NCVs) is common [Cameron et al 2004].Eventually, the child becomes bedridden with tonic spasms and decerebrate posturing with rigidly extended extremities. Feeding usually requires the use of a gastrostomy tube. In the final stages, which may last for several years, the children are blind, have no speech or volitional movements, and appear to be generally unaware of their surroundings. Often, parents or caregivers feel that the children respond to familiar voices and touch.The expected life span is often quoted as 3.5 years after the onset of symptoms based on earlier published cases. However, survival can be quite variable and often extends well into the second decade of life with current levels of care.Juvenile MLD. Age of onset is between four years and sexual maturity (age 12-14 years). Although earlier descriptions of juvenile MLD included individuals with onset up to age 18 years, currently, individuals with onset between ages 14 and 18 years are considered to have adult MLD.The initial manifestations are usually noted during the early years of schooling with a decline in school performance and the emergence of behavior problems. Early- and late-juvenile subvariants are sometimes differentiated, neuromuscular difficulties developing first in the earlier-onset cases and behavioral issues developing first in the later-onset cases.Clumsiness, gait problems, slurred speech, incontinence, and bizarre behaviors eventually prompt diagnostic evaluation. Seizures may occur at any stage of the disease. Balslev et al [1997] suggest that they are more commonly partial seizures.Progression is similar to, but slower than, the late-infantile form. Survival for ten to 20 or more years after the initial diagnosis is common.Adult MLD. Symptoms are first noted after sexual maturity (age ~14 years) but may not occur until the fourth or fifth decade. As with juvenile MLD, presenting symptoms vary. Köhler [2010] has recently reviewed late-onset leukodystrophies.Initial signs are often emerging problems in school or job performance associated with personality changes. Alcohol abuse, drug use, poor money management, and emotional lability often lead to psychiatric evaluation and an initial diagnosis of schizophrenia or depression. Bewilderment, inappropriate affect, and even auditory hallucinations have been reported.In others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) predominate initially, leading to diagnoses of multiple sclerosis or other neurodegenerative diseases. Seizures have also been reported as a presenting feature.Peripheral neuropathy is a frequent aspect of adult-onset MLD, and isolated peripheral neuropathy can be the presenting symptom [Felice et al 2000]. However, it has been completely absent in some cases [Marcao et al 2005].The course is variable. Periods of relative stability may be interspersed with periods of decline. Inappropriate behaviors and poor decision making become problems for the family or other caregivers. Dressing and other self-help skills deteriorate. Eventually, bowel and bladder control is lost. As the disease advances, dystonic movements, spastic quadraparesis, or decorticate posturing occur. Severe contractures and generalized seizures may occur and then resolve later. Eventually, the ability to carry on a conversation and communicate effectively is lost.The individual usually does not lose contact with his/her surroundings until late in the disease, which may extend for two or three decades. In the end stage, the individual is blind, bedridden, and unresponsive. Pneumonia or another infection is usually the cause of death.Other findings in MLD. In the past, findings of increased concentration of cerebrospinal fluid (CSF) protein, decreased NCVs, and abnormal auditory and visual evoked potential studies were used in diagnosis. While such tests are no longer necessary for diagnosis, they may be used in protocols for monitoring disease progression or therapeutic trials.Involvement of the gallbladder occurs: Garavelli et al [2009] reported life-threatening hemobilia and papillomatosis in a person with MLD.Pathogenesis. Arylsulfatase A deficiency is a disorder of impaired breakdown of sulfatides (cerebroside sulfate or 3-0-sulfo-galactosylceramide), sulfate-containing lipids that occur throughout the body and are found in greatest abundance in nervous tissue, kidneys, and testes. Sulfatides are critical constituents in the nervous system where they comprise approximately 5% of the myelin lipids. Sulfatide accumulation in the nervous system eventually leads to myelin breakdown (leukodystrophy) and a progressive neurologic disorder [Von Figura et al 2001].
The simple genotype-phenotype correlations proposed by Polten et al [1991] have been proven useful but are imperfect, and several discrepancies have been noted. The age of onset for a particular genotype is influenced by a variety of environmental and other genetic factors....
Genotype-Phenotype CorrelationsThe simple genotype-phenotype correlations proposed by Polten et al [1991] have been proven useful but are imperfect, and several discrepancies have been noted. The age of onset for a particular genotype is influenced by a variety of environmental and other genetic factors.ARSA enzyme activityThe genotypes ARSA-MLD/ARSA-MLD, ARSA-PD-MLD/ARSA-MLD, and ARSA-PD-MLD/ARSA-PD-MLD result in ARSA enzyme activity that is 5%-10% of control values in Baum-type assays.The genotype ARSA-PD/ARSA-MLD usually results in ARSA enzyme activity that is approximately 10% of control values, while the genotype ARSA-PD/ARSA-PD results in ARSA enzyme activity that is approximately 10%-20% of control values.Age of onset of MLD is not related to the amount of apparent enzyme activity as usually measured. It does, however, correlate reasonably well with the ability of cultured fibroblasts to degrade sulfatide added to the culture medium:Early-onset (late-infantile) MLD. Affected individuals are usually homozygous or compound heterozygous for I-type ARSA-MLD alleles and make no detectable functional arylsulfatase A enzyme. The most common I-type alleles are c.459+1G>A, c.1204+1G>A, and p.Asp255His.Later-onset MLDs. Affected individuals have one or two A-type ARSA-MLD alleles that encode for an arylsulfatase A enzyme with some functional activity (≤1% when assayed with physiologic substrates). The most common A-type ARSA-MLD alleles are p.Ile179Ser and p.Pro426Leu [Fluharty et al 1991]:Juvenile-onset MLD. Often, one allele provides no functional enzyme activity (I-type ARSA-MLD allele), while the other allele provides some residual enzyme activity (A-type ARSA-MLD allele).Adult-onset MLD. Both alleles provide some residual enzyme activity (A-type ARSA-MLD alleles). Regis et al [2002] suggest that an A-type ARSA-MLD allele occurring in cis configuration with an ARSA-PD sequence variant may have a more severe consequence and behave as an I-type ARSA-MLD allele. The p.[Ile179Ser]+[Ile179Ser] genotype, which could be expected in late-onset cases, has not been reported to date. Information on specific mutations does correlate with initial clinical manifestations and can have prognostic implications [Baumann et al 2002, Rauschka et al 2006].Note: In the study of Lugowska et al [2005a], these generalizations regarding genotype/phenotype correlations held up fairly well; however, in a few instances, an A-type ARSA-MLD mutation occurred in late-infantile onset MLD and an I-type ARSA-MLD mutation in adult-onset MLD.Arylsulfatase A (ARSA) pseudodeficiencyARSA-MLD/ARSA-PD genotype. Associated ARSA enzyme activity is 5% to 10% of normal controls:The polyadenylation site mutation, c.*96A>G, appears to contribute most strongly to the low ARSA enzyme activity characteristic of clinical pseudodeficiency [Harvey et al 1998].p.Asn350Ser, the glycosylation site alteration, is associated with an increased excretion of the newly synthesized enzyme from cells and a possible decrease in the ARSA enzyme within the lysosome [Harvey et al 1998].ARSA-PD/ARSA-PD genotypeHomozygosity for the c.*96A>G mutation (almost always in conjunction with p.Asn350Ser mutation) is associated with ARSA enzyme activity that is approximately 10% of normal controls and could provide diagnostic uncertainty.Homozygosity for the p.Asn350Ser mutation alone results in 50% or more of the mean control ARSA enzyme activity in leukocytes.
Arylsulfatase A pseudodeficiency. Because of the high prevalence of the ARSA-PD alleles, low ARSA enzyme activity caused by arylsulfatase pseudodeficiency can be found in association with many disorders. When a low level of arylsulfatase A enzyme activity is identified in an individual initially diagnosed with a psychiatric or neurodegenerative disorder, arylsulfatase A deficiency is often considered a causative or contributing factor. However, schizophrenia, depression, substance abuse, multiple sclerosis, and various forms of dementia occur relatively frequently in the general population and may not be a manifestation of the low level of arylsulfatase A enzyme activity. See Testing Strategy re distinguishing between MLD and arylsulfatase A pseudodeficiency....
Differential DiagnosisArylsulfatase A pseudodeficiency. Because of the high prevalence of the ARSA-PD alleles, low ARSA enzyme activity caused by arylsulfatase pseudodeficiency can be found in association with many disorders. When a low level of arylsulfatase A enzyme activity is identified in an individual initially diagnosed with a psychiatric or neurodegenerative disorder, arylsulfatase A deficiency is often considered a causative or contributing factor. However, schizophrenia, depression, substance abuse, multiple sclerosis, and various forms of dementia occur relatively frequently in the general population and may not be a manifestation of the low level of arylsulfatase A enzyme activity. See Testing Strategy re distinguishing between MLD and arylsulfatase A pseudodeficiency.A strong association of the c.1049A>G polymorphism with alcoholism has been reported [Chung et al 2002].Arylsulfatase A deficency. The two phenotypes that show notable overlap with arylsulfatase A deficiency are multiple sulfatase deficiency and saposin B deficiency (Table 2).Table 2. Disorders Considered in the Differential Diagnosis of Arylsulfatase A DeficiencyView in own windowDisorderAge at OnsetMain Clinical ManifestationsUrinary ExcretionEnzyme ActivityMultiple sulfatase deficiency1-4 years, probably variableMLD-like clinical picture, with elevated CSF protein and slowed nerve conduction velocity; MPS-like features, and ichthyosisElevated sulfatide and mucopolysaccharidesVery low ARSA enzyme activity; deficiency of most sulfatases in leukocytes or cultured cells 1Saposin B deficiencyVariableMLD-like clinical pictureElevated sulfatide and other glycolipidsARSA enzyme activity within normal range1. Including arylsulfatase B, arylsulfatase C, iduronate sulfatase (deficient in Hunter syndrome, and heparan-N-sulfamidaseMultiple sulfatase deficiency (Austin variant of MLD) is caused by a defect in processing of an active site cysteine to formylglycine (alanine-semialdehyde), a proenzyme activation step common to most sulfatases [Dierks et al 2005, Zafeiriou et al 2008].Findings that suggest a diagnosis of multiple sulfatase deficiency include: (1) reduced activity of other sulfatases including arylsulfatase B, arylsulfatase C, iduronate sulfatase (the enzyme that is deficient in Hunter syndrome [mucopolysaccharidosis type 2]), and heparan-N-sulfamidase in leukocytes or cultured cells; and (2) the presence of mucopolysaccharides (glycosoaminoglycans) as well as sulfatides in the urine.Although clinical variability of multiple sulfatase deficiency is great, features of both MLD and a mucopolysaccharidosis (MPS) may be present [Macaulay et al 1998]. More severe forms of multiple sulfatase deficiency resemble late-infantile MLD. In other cases, MPS-like features such as coarse facial features and skeletal abnormalities may be evident in infancy and early childhood, with MLD-like symptoms becoming evident in later childhood. Eventually, the disease course resembles MLD with demyelination dominating the clinical picture [Von Figura et al 2001]. Ichthyosis, common to arylsulfatase C deficiency, is also often present.A defect in the formylglycine-generating enzyme (FGE) is causative [Dierks et al 2005]. FGE is responsible for the activation of most sulfatases, and a variable degree of arylsulfatase A deficiency occurs in many tissues in its absence.Other ARSA deficiency conditions. ARSA enzyme activity is also deficient in many tissues in defects of the phosphomannosyl lysosomal recognition pathway, such as I-cell disease (mucolipidosis II) [Kornfeld & Sly 2001]. The phenotype in I-cell disease is severe in infancy and is not likely to be confused with arylsulfatase A deficiency.Saposin B deficiency (cerebroside-sulfate or sphingolipid activator deficiency). A defect in the glycolipid-binding protein saposin B, which is needed to solubilize sulfatides before they can be hydrolyzed by arylsulfatase A, causes an MLD-like disorder. While a number of other glycolipid degradative processes are disrupted in saposin B deficiency, it is the failure in sulfatide catabolism that dominates the clinical picture. Age of onset is variable, with too few cases having been reported to delineate a typical clinical picture. An MLD-like clinical presentation, leukodystrophy on MRI, normal arylsulfatase A enzyme activity, and evidence of excess urinary sulfatide excretion and/or sulfatide storage suggest activator deficiency. Diagnosis depends on depressed sulfatide degradation by cultured cells, immunochemical assessment of saposin B levels, or sequence analysis of the gene encoding prosaposin [Sandhoff et al 2001].The reported severe phenotype resulting from complete deficiency of prosaposin, which also disrupts sulfatide catabolism, is not likely to be confused with MLD.Other leukodystrophies and lysosomal storage diseases. MLD is difficult to differentiate from other progressive degenerative disorders that manifest after a period of normal development. Delayed development in late infancy, coupled with loss of acquired abilities, should prompt MRI evaluation. If a generalized leukodystrophy is evident, other conditions to consider include: Krabbe disease, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Alexander disease, fucosidosis, Canavan disease, and gangliosidoses such as hexosaminidase A deficiency (including Tay-Sachs disease).Although some mucopolysaccharidoses can have a similar presentation to arylsulfatase A deficiency, the characteristic physical features seen in most mucopolysaccharidoses (i.e., short stature, dysostosis multiplex, coarse facial appearance, corneal clouding, hepatosplenomegaly, pulmonary congestion, and heart problems) are not found in individuals with MLD. The evaluation of appropriate lysosomal enzymes can distinguish the disorders.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).Late-infantile MLDJuvenile MLDAdult MLD
To establish the extent of disease in an individual diagnosed with arylsulfatase A deficiency (MLD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with arylsulfatase A deficiency (MLD), the following evaluations are recommended:If the diagnosis is made presymptomatically, baseline measures of ARSA enzyme activity, urinary sulfatide excretion, and myelin integrity by MRI to monitor disease progression and evaluate the need for possible interventionBaseline assessment of development/cognitive abilities and behavior to monitor disease progression or changes with attempted therapyExamination of the peripheral nervous systemSee Wang et al [2011] for clinical follow up recommendations. Click for full text.Treatment of ManifestationsWhether the intent is to prolong life or to let the disease run it natural course, an extended period of nursing care with changing needs can be anticipated. Supportive therapies to maximize the retention of physical and neuromuscular functions help avoid many end-stage care problems.Every effort should be made to maintain intellectual abilities, neuromuscular function, and mobility as long as possible. Provision of an enriched environment and an aggressive physical therapy program provides an optimized quality of life at all stages of the disease. The parents and/or caregivers should be aware of the likely progression of the disorder in order to anticipate decisions concerning walking aids, car seats, wheelchairs, suction equipment, swallowing aids, feeding tubes, and other supportive measures. Specific findings such as seizures and contractures should be treated with antiepileptic drugs and muscle relaxants, respectively. Gastroesophageal reflux, constipation, and drooling are common problems which may be helped by specific medications. The Evanosky Foundation has a very helpful document Suggestions for Caring for a Child with MLD (pdf) based on their family’s experience.Because MLD affects the whole family, management should include a team of professionals to provide genetic counseling and family support through what is often a long disease process. Even children with late-infantile MLD may survive for five to ten years with progressive loss of function and continually changing care needs. Affected individuals remain susceptible to the full range of childhood and adult diseases. A pediatrician or family physician should be involved in developing comprehensive care plans. The usual regime of age-appropriate vaccinations, flu shots, nutritional support, and other typical medical care need be provided. Dental care is important and is often difficult to obtain. Pulmonary function and vision may also need attention.It is important for most families to develop a network of support services and establish contact with other families who have faced similar situations.Prevention of Primary ManifestationsHematopoietic stem cell transplantation (HSCT) or bone marrow transplantation (BMT) is the only presently available therapy that attempts to treat the primary central nervous system manifestations of MLD [Krivit et al 1999, Peters & Steward 2003, Krivit 2004]. Not all individuals with MLD are suitable candidates for these procedures and not all families are willing to undertake the risks involved. Although identification of adequately matched donors and treatments for complications of HSCT are constantly improving, it remains controversial. Substantial risk is involved and long-term effects are unclear. However, in the absence of alternative approaches, HSCT needs to be discussed with families. This is particularly important for families with more slowly progressing late-onset forms of MLD because family members may be diagnosed with MLD by biochemical or molecular genetic testing before symptoms occur. A number of reports on the experience of individual centers using HSCT have appeared over the past ten years: each involves a limited number of patients and few with MLD. They reflect evolving pretreatment conditioning and improved donor matching. HSCT failures continue; nevertheless, some improvement has been seen. Even when HSCT is successful, however, MLD progresses for a substantial period before implanted cells populate the central nervous system. The best clinical outcomes are obtained when transplantation occurs before clinical symptoms have appeared.Meuleman et al [2008] reported minimal complications in an adult who underwent reduced intensity conditioning accompanied by mesenchymal stromal cell infusion.Although the availability of hematopoietic stem cells from cord blood enhances the chances of obtaining a suitable source of donor cells, the results reported to date indicate that considerable problems remain [Martin et al 2006]. Cartier & Aubourg [2008] concluded that “…banked umbilical cord blood is still associated significant risks of graft failure or GVHD.” In earlier studies, HSCT for MLD appeared to slow disease progression, but not alleviate peripheral nervous system manifestations [Koc et al 2002]. More recently, however, a 13-year follow up of an individual with juvenile MLD treated with HSCT reported slow disease progression in the two years following transplantation, but subsequent stabilization [Görg et al 2007]. Pierson et al [2008] reported three siblings with MLD who were transplanted with umbilical cord blood at different stages of disease: the oldest experienced disease progression; the two younger children had stable or improved neuropsychologic, neuroimaging, and nerve conduction evaluations over a two-year period of follow up.Tokimasa et al [2008] evaluated the feasibility of transplants from unrelated donors using a modified preparative procedure. Two persons with MLD showed complete donor chimerism and survived more than a year after transplantation. Smith et al [2010] followed an adult with psycho-cognitive MLD for 11 years after HSCT. “Cognitive decline, indistinguishable from the natural course of the disease…” was observed. de Hosson et al [2011] reported treatment of five patients and reviewed the literature. They conclude that in most published cases, HSCT has not been effective for MLD.Cable et al [2011] report five-year follow up of three siblings with juvenile MLD who were transplanted with unrelated umbilical cord blood. The disease progressed over the first two years post-transplant followed by stabilization of symptoms. The overall outcome depended on the disease status at the age of transplantation with the oldest showing typical disease progression.In a review of outcomes of persons with MLD undergoing HCST, Orchard & Tolar [2010] concluded that persons with later-onset disease may benefit and presymptomatic children with mutations typical for late-infantile onset (see Genotype-Phenotype Correlations) appear to have significant cognitive benefits; however, it is unclear if progressive motor problems will improve.Lanfranchi et al [2009] reviewed the therapeutic use of stem cells of various origins in a variety of conditions including MLD.HSCT in a presymptomatic neonate has been reported, but complications were encountered and disease progression was not halted [Bredius et al 2007].Prevention of Secondary ComplicationsPrevention of joint contractures by maintaining joint mobility facilitates nursing care in the later stages of the disorder.Affected individuals remain susceptible to the full range of childhood and adult diseases. The pediatrician or general care physician should be involved in developing comprehensive care plans.SurveillanceThe following are appropriate:A program of periodic MRI monitoring developed by the neurologist and primary care physician: Wang et al [2011] propose guidelines for confirmatory testing and subsequent clinical management of presymptomatic individuals suspected to have MLD and other lysosomal storage diseases (click for full text).Eichler et al [2009] propose a scoring system for brain MR images in individuals with MLD.Dali et al [2010] report that N-acetylaspartate (NAA) levels in the brains of patients with MLD as assessed by proton magnetic resonance spectroscopy (MRS) correlate with motor and cognitive function. This finding could be used to monitor disease progression and the effects of treatments. Not all persons with MLD show white matter lesions as the initial MRI finding. Cranial nerve enhancement by MRI in a 25-month-old child with apparent MLD and without intraparenchymal white matter involvement was seen by Singh et al [2009]. Likewise, Morana et al [2009] report that cranial nerve and cauda equina nerve root enhancement by MRI may precede typical white matter abnormalities and could facilitate earlier diagnosis. Haberlandt et al [2009] present three individuals with peripheral neuropathy in whom initial MRI showed no white matter changes, but who later developed MLD.Monitoring of changes in locomotion, communication, and behavior which could indicate a need to alter care and support systems (e.g., introduction of walking aids and/or a wheelchair). A classification system for gross motor function for children with MLD has been developed and tested by Kehrer et al [2011b]; it can be used to monitor the course of the disease and should prove extremely useful in evaluating therapeutic trials.Monitoring for onset of seizures and/or contractures, which could indicate a need to change medical management and physical therapyMonitoring for behavioral changes, inappropriate emotions or actions, problems in following directions, memory loss, and/or incontinence, which indicate a need for increasing physical restriction and curtailing of independenceMonitoring for difficulties in swallowing or weight loss, which trigger consideration of gastrostomySpecial attention following general anesthesia or an infection with a high fever as these may trigger exacerbation of disease progressionAgents/Circumstances to AvoidWhile environmental factors are thought to influence the onset and severity of MLD symptoms, no specific exacerbating agents are known. Initial symptoms are often noted following a febrile illness or other stress, but it is unclear if a high fever actually accelerates progression.Excessive alcohol and drug use are often associated with later-onset MLD, but it is unclear if this is caused by the disease or is simply an attempt at self-medication in the face of increasing cognitive difficulties [Alvarez-Leal et al 2001].Exacerbation of symptoms has been noted following anesthesia because affected individuals may have altered responses to sedatives and anesthetics.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAttempts at improving the effectiveness of bone marrow transplantation (BMT) include combined therapy with either genetically engineered ARSA enzyme [Martino et al 2005] or mesenchymal stem cells [Koc et al 2002, Meuleman et al 2008]. Enzyme replacement therapy (ERT) is, at present, considered impractical because of the difficulty of bypassing the blood-brain barrier. Clinical testing of intravenous recombinant human enzyme was discontinued in 2010 after a Phase I/II study failed to show substantial improvement [Shire 2010]. However, different forms of human ARSA enzyme are now available, and animal studies suggest that it may be a useful supplement in other therapies [Martino et al 2005, Matzner et al 2005]. Schröder et al [2010] examined N-linked glycans on recombinant ASAs produced under differing culture conditions and concluded that the enzymes used in various clinical trials may have had different uptake properties.Gene therapy. A large number of papers have been published over the past ten years on experimental gene therapies for arylsulfatase A. These are reviewed by Biffi & Naldini [2007], Sevin et al [2007], Biffi et al [2008], Gieselmann [2008]. Sevin et al [2009], Faust et al [2010], Gieselmann & Krägeloh-Mann [2010], Sevin et al [2010], and Biffi et al [2011].Piguet et al [2009] investigate intracerebral AAVrh.10 as a possible gene therapy vector for MLD. Piguet et al [2010] considered brain-directed gene therapies for MLD. Colle et al [2010] injected an adeno-associated virus vector containing human ARSA into the brains of non-human primates and found that the enzyme was expressed without adverse effects, suggesting that a similar approach could be possible in persons with MLD.Human gene replacement trials can be anticipated in the near future, but the prospects for clinical effectiveness are uncertain and substantial regulatory concerns remain. Participants are presently being recruited for a gene therapy HSCT Phase I/II clinical trial for MLD (see Press Release 10-14-10). Mouse model of MLDViral vectors for introducing ARSA into the enzyme-deficient mouse model have been investigated [Matzner & Gieselmann 2005]. Miyake et al [2010] examined the effectiveness of bone marrow cells expressing the homeobox B4 (HoxB4) gene in curing mice with MLD. These findings support the idea that hematopoietic stem cells (HSCs) transduced with a HoxB4 expression vector could be used to transport therapeutic proteins into the brain. Iwamoto et al [2009] examined the feasibility of intrathecal (IT) injection of an adeno-associated viral vector expressing arylsulfatase A in MLD mice. They achieved widespread distribution of the enzyme in the brain and the reduction of sulfatides.Kurai et al [2007] observed that coexpression of the gene encoding the formylglycine-generating enzyme (deficient in multiple sulfatase deficiency) is necessary for efficient gene replacement and correction in the mouse model.Other studiesMatzner et al [2008] evaluated parameters affecting enzyme replacement that could be an adjunct to therapy. Capotondo et al [2007] evaluated overexpression of ARSA. Hou & Potter [2009] discuss microencapsulated brain-targeted therapy for MLD. Lagranha et al [2008] demonstrated the ability of encapsulated BHK cells overexpressing ARSA to correct the enzyme defect in fibroblasts from persons with MLD. Biffi et al [2008] indicated that autologous hematopoietic stem cells can be genetically modified to constitutively express supra-physiologic levels of arylsulfatase A. Similarly modified stem cells obtained from an individual with MLD could become an effective source of enzyme when transplanted back into the individual. Moreover, transformed autologous cells should result in reduced transplant-related problems.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherLead has been reported to enhance secretion of ARSA enzyme by cells in culture and to lower cellular enzyme levels [Poretz et al 2000]. Minimizing lead exposure is already an important public health goal, and it is uncertain if additional steps would be useful in individuals with MLD.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Arylsulfatase A Deficiency: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDARSA22q13.33Arylsulfatase AARSA homepage - Mendelian genesARSAData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Arylsulfatase A Deficiency (View All in OMIM) View in own window 250100METACHROMATIC LEUKODYSTROPHY 607574ARYLSULFATASE A; ARSAMolecular Genetic PathogenesisThe molecular pathologic processes involved in MLD are poorly understood. While the accumulation of sulfatides in oligodendrocytes and Schwann cells is thought to somehow be responsible for the loss of these cells and the resultant demyelination, these lipids have not proven to be toxic in cell cultures. Psychosine sulfate (lyso-sulfatide) is elevated in tissues from individuals with MLD, and a cytotoxic role parallel to that of psychosine in Krabbe disease has been suggested.Normal allelic variants. ARSA contains eight exons in a relatively short coding region of 3.2 kilobases (kb) and is translated to a 2.1-kb mRNA. The 5' untranslated region is typical of a housekeeping gene but lacks a TATA or CAAT box typical of lysosomal enzymes. The gene extends for nearly 3 kb beyond the stop codon. Additional mRNA products of 3.7 and 4.8 kb are detected in cells; their significance remains uninvestigated.Several normal allelic variants of ARSA have been identified. The most common is p.Thr391Ser, which was found in approximately half of the Euro/American population initially studied. The c.1049A>G (p.Asn350Ser) site (ARSA-PD glycosylation site alteration) is a common normal variant occurring in 15%-40% of individuals, depending on the population studied. A number of other relatively rare polymorphisms and neutral base changes have also been reported.Pathologic allelic variants. More than 150 mutations of ARSA associated with arylsulfatase A deficiency have been reported. Disease-causing ARSA-MLD mutations are as likely to be found in cis configuration with an ARSA-PD sequence variant as in wild-type alleles. Complete deletion of one copy of ARSA has been reported in one individual with MLD [Eng et al 2004].Table 3. Selected ARSA Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference SequencesPseudodeficiency(ARSA-PD)c.1049A>Gp.Asn350SerNM_000487.4 NP_000478.2c.1172C>Gp.Thr391Serc.*96A>G (c.1524+96A>G)--Pathologic(ARSA-MLD)c.251G>Ap.Arg84Glnc.287C>Tp.Ser96Phec.296G>Ap.Gly99Aspc.459+1G>A--c.536T>Gp.Ile179Serc.635C>Tp.Ala212Valc.733G>Ap.Gly245Argc.763G>Cp.Asp255Hisc.1204+1G>A--c.1226C>Tp.Thr409Ilec.1277C>Tp.Pro426Leuc.1401_1411del (1401del11bp)p.Ala468Leufs*84See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsTable 4. Distribution of the Most Common ARSA Mutations in Various PopulationsView in own windowMutation% Late-Infantile% Juvenile% Adult% All MLD AllelesReference - Ethnicity 1 (# of affected individuals)Europeanc.459+1G>A- --15 Draghia et al [1997] (21) 3911519Lugowska et al [2005b] - P (43)4016925Lugowska et al [2005a] - Eu (384)298216Berger et al [1997] (25)4516228Polten et al [1991] (66)p.Pro426Leu---15Draghia et al [1997]0144517Lugowska et al [2005b] - P03042.518.6Lugowska et al [2005a] - Eu7156026Berger et al [1997] (25)0345927Polten et al [1991] (66)c.1204+1G>A11305 Lugowska et al [2005b] - P---2Fluharty et al [1991] (~100)p.Ile179Ser0 17 2313 Lugowska et al [2005b] - P0153012Berger et al [1997] (25)2Fluharty et al [1991] (~100)Japanesep.Gly99Asp40---Eto et al [1993] (10)---45.5Kurosawa et al [1998] (11)c.459+1G>A10Eto et al [1993] (10)p.Gly245Arg55--Eto et al [1993] (10)---9Kurosawa et al [1998] (11)p.Thr409Ile9Kurosawa et al [1998] (11)1. P = Polish population; Eu = Western European populationNormal gene product. Arylsulfatase A has a precursor polypeptide of approximately 62 kd that is then processed by N-linked glycosylation, phosphorylation, sulfation, and proteolytic cleavage to a complex mixture of isoforms that differs from tissue to tissue. A magnesium or calcium ion also becomes tightly bound near the active site. During postsynthetic processing, the Cys69 must be converted to formylglycine before the sulfatase becomes active [Lukatela et al 1998, Dierks et al 2005].As isolated at neutral pH, the arylsulfatase A enzyme is dimeric (~100-120 kd) with two subunits, which may not be identical. At acid pH such as that occurring in the lysosome, the enzyme aggregates further to an octamer, the form present in the crystalline enzyme [Vagedes et al 2002].Abnormal gene product. In general, the splice-site mutations and insertions or deletions do not lead to any active enzyme (I-type ARSA-MLD mutations). Approximately half of the mutations involving an amino acid substitution also fall into this class but are more likely to express an immuno-cross-reactive material.Between 20% and 25% of the single amino acid changes are associated with a low level (≤1%) of ARSA enzyme activity (A-type ARSA-MLD mutations). In those cases in which the properties of the mutant ARSA enzyme have been explored, processing and stability have been affected, leading to altered enzyme or altered ability of the protein to self-associate and an enhanced turnover of the mutant protein [von Bulow et al 2002, Poeppel et al 2005].