Leucodistrofie/METACHROMATIC LEUKODYSTROPHY

a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)

vi) LEUCODISTROFIA METACROMATICA
(METACHROMATIC LEUKODYSTROPHY)

DEFINITION:

A lysosomal storage disorder characterized by the accummulation of lipid (sulfatide) primarily in the central nervous system (CNS) resulting in 3 clinical variants.

EPIDEMIOLOGY:

incidence: 1/100,000
age of onset:
12-18 months (Type I); 4-12 years (Type II); after puberty (Type III)
risk factors:
familial - autosomal recessive
chrom.#: 22q13.31-qter
gene: arylsulfatase A (ARSA)
M = F

PATHOGENESIS:

Background
arylsulfatase A is a lysosomal enzyme which catalyzes the hydrolysis of the 3-O-sulfate linkages of cerebroside sulfate (sulfatide) to form galactocerebroside deficiency of arylsulfatase A in MLD first reported by in 1963 by Austin a sphingolipid activator protein (SAP-1) is necessary for the in vivo hydrolysis of sulfatide in MLD, galactosyl sulfatide and to a smaller extent lactosyl sulfatide accumulate in the white matter of the CNS, in the peripheral nerves, and to a lesser extent in the kidneys, gallbladder, and other visceral organs accumulation of sulfatides in the myelin sheath results in the progressive breakdown of membranes of the myelin sheath

Genetic Defect
genetic defects -> deficiency of arylsulfatase A activity -> accumulation of sulfatide within lysosomes in the CNS white matter -> neurological manifestations
three clinical variants:
Type I - Late Infantile Form
Type II - Juvenile Form
Type III - Adult Form
deficiency of ARSA activity is most marked in the late infantile form with higher residual ARSA activity found in the other forms

CLINICAL FEATURES:

Type I (Late Infantile Form)
1. CNS Manifestations
2. Ophthalmologic Manifestations
  nystagmus
  greyish discolouration of the macula
  optic atrophy -> blindness
Type II (Juvenile Form)
1. CNS Manifestations
  
  1. Psychomotor Retardation
  normal development up to 4-12 years of age
  loss of developmental milestones by the end of the first decade
  in most cases, the gait disturbances precede the behavioural-cognitive
  deterioration but in other cases, the reverse occurs
  
  1. Gross Motor
  ataxia with progressive gait disturbances -> loss of ambulation progressive hypertonia with tremor, postural abnormalities, and/or leg scissoring diminished deep tendon reflexes
  
  2. Speech/Language
  slurred speech with speech deterioration
  
  3. Cognitive/Behavioural
  abnormal/bizarre behaviour
  daydreaming
  difficulty in following directions
  emotional difficulties
  mental deterioration
  2. Others
  pseudobulbar palsy
  seizures
  urinary incontinence
  
  Ophthalmologic Manifestations
  optic atrophy -> blindness
3. Type III (Adult Form)
1. CNS Manifestations
  1. Psychomotor Retardation
  normal development up to puberty then present with cognitive and behavioural abnormalities
  
  1. Cognitive/Behavioural
  personality changes
  anxious, apathetic, bewildered, emotionally labile, psychosis
  poor school or job performance
  decreased mental alertness, defective visual-spatial discrimination, disorganized thinking, poor memory
  others
  alcoholism, depersonalization, inappropriate affect
  
  2. Gross Motor
  progressive clumsiness and slowing
  increasing muscle tone -> spasticity of limbs
  increased deep tendon reflexes
  dystonic movements and pareses
  
  Others
  generalized seizures
  peripheral neuropathy
  urinary incontinence
  
  Ophthalmologic horizontal nystagmus optic atrophy -> blindness

INVESTIGATIONS:

Diagnostic
deficiency of arylsulfatase A activity in leukocytes and cultured skin fibroblasts
prenatal deficiency of enzyme activity in cultured chorionic villi or amniocytes
2. Imaging Studies

1. CT/MRI
progressive loss of white matter due to demyelination cerebral atrophy with ventricular enlargement
3. Electrophysiologic Studies
decreased nerve conduction velocities
abnormal evoked potentials
4. Pathology

1. Peripheral (Sural) Nerve
spherical granular masses that stain metachromatically (stain strongly positive with periodic acid-Schiff (PAS) and Alcian blue or acetic acid-cresyl violet)
5. Others

1. Urinalysis
metachromatic granules in the urinary sediment excessive amounts of sulfatide excreted in the urine

CSF elevated protein

MANAGEMENT: 1. Supportive

no treatment for the underlying disorder multidisciplinary approach:
Paediatrics, Neurology, Ophthalmology, Orthopedics genetic counselling
bone marrow transplantation is still experimental

2. Prognosis

Type I - death in the 1st decade (2-4 years after diagnosis)
Type II - death in the 2nd decade (4-6 years after diagnosis)
Type III - death in the 3rd decade (5-10 years after diagnosis)

CLINICAL ANALYSES

Arylsulfatase A, Leukocytes; 

Test Collection Information

Lab Name: 
   Special Testing 
Days Test is Set Up: 
   Wednesday, Sunday 
Times of Anaysis: 
   4 - 8 days 
Normal Vol: 
   7.0 ml ACD whole blood 
Pediatric Volume: 
Container: 
   ACD Yellow top tube 
Collection Intructions: 
   Collect blood in 7 ml ACD yellow top tube 
    (Solution A or B). Sample MUST
arrive within 48
   hrs of collection. Refrigerate intact specimen; 
   do not freeze. 

Reference Ranges and Information

Reference Range: 
   Greater than or equal to 2.5 U/10 cells 
Usage: 
   Detection of Metachromatic Leukodystrophy 
Limitations: 
   Results from this assay may not reflect 
    carrier status because of
individual variation of
   arylsulfatase A enqyme levels. 
Methods: 
   Colorimetric 
Additional Information: 
   Test sent to Mayo Medical Laboratories. 
Synonyms: 
   Metachromatic Leukodystrophy; Mucolipidoses, 
    Types II and III;ARS-A;

DESCRIPTION

This condition was first described by Greenfield (1933). 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 protein is usually over 100 mg percent.

Galactosphingosulfatides that are strongly metachromatic, doubly refractile inpolarized 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 distension 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 is marked genu recurvatum.
The first manifestations, appearing before the second birthday, include hypotonia, muscle weakness and unsteady gait,thus suggesting a myopathy or neuropathy.
Bayever et al. (1985) observed apparent improvement (i.e., continued developmental progress) in a boy with late infantile MLD given a bone marrow transplant from an HLA-identical sister. Krivit et al. (1990) reported improvement in neurophysiologic function and sulfatide metabolism in an affected 10-year-old girl who had received a bone marrow transplant 5 years previously.
The defect concerns the lysosomal enzyme arylsulfatase A (ARSA; EC 3.1.6.8 ) (Austin et al.,1964).
Austin's test to demonstrate absence of arylsulfatase A activity in the urine is useful in early diagnosis (Greene et al., 1967). Since the metachromatic material is cerebroside sulfate, MLD is a sulfatide lipidosis.
Consider juvenile sulfatidosis for a disorder that combines features of a mucopolysaccharidosis with those of metachromatic leukodystrophy.
Stumpf and Austin (1971) presented evidence to suggest that the abnormality in arylsulfatase A is qualitatively different in the late infantile and juvenile forms of metachromatic leukodystrophy.
Kaback and Howell (1970) demonstrated profound deficiency of arylsulfatase A in cultured skin fibroblasts of patients and an intermediate deficiency incarriers. Normally enzyme levels are low in mid trimester amniotic cells; hence, homozygotes cannot be reliably identified by amniocentesis.
Only one asterisk is assigned to the metachromatic leukodystrophies, adult and late infantile forms, because the enzymatic evidence indicates that these are allelic disorders.
With both artificial and natural substrate, no difference in degree of deficiency of arylsulfatase A was found (Percy et al.,1977).
However, when the degradation of natural substrate by fibroblasts from the 2 forms of the disease was studied, a distinctive difference was found (Porter et al., 1971). 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.
Arylsulfatase A and B are probably quite different in amino acid composition but amino acid assays have not been performed on type B for lack of samples of proven homogeneity (Nicholls and Roy, 1971). Dubois et al. (1977) described an enzymatically a typical family.
Langenbeck et al. (1977) proposed a one locus, multiple allele hypothesis to explain the peculiar findings in that kindred. In screening for metachromatic leukodystrophy, low arylsulfatase A is not necessarily indicative of this disease. 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.
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.
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 ofthe latter cases represent the compound heterozygote for the deficient allele and another allele coding for an in vitro low enzyme activity (pseudodeficiency).
Kihara (1982) recognized 5 allelic forms of MLD (late infantile, juvenile and adult forms, partial cerebroside sulfate deficiency, and pseudo-arylsulfatase A deficiency) and 2 nonallelic forms (cerebroside sulfatase activator deficiency and multiple sulfatase deficiency).
Fusion of cells from the infantile and juvenile forms did not result in complementation of arylsulfatase A activity (Chang et al., 1982). Hence, these are allelic disorders.
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. 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.
Porter et al. (1971) corrected the metabolic defect in cultured fibroblasts byaddition of arylsulfatase A to the medium.
Moser (1972) suggested that juvenile cases of MLD, especially those of late juvenile onset, should be classed with the adult form.
An alternative possibility is that some of these cases with phenotype intermediate between those of the late infantile and adult forms represent genetic compounds.
The same very low levels of arylsulfatase A are found in the infantile, juvenile and adult forms.
The reason for the differences in age of onset is 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. 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 refers to a condition of apparent enzyme deficiency inpersons without neurologic abnormalities.
This paradox is due in part to the nonspecificity of the synthetic substrates used for assays and in part to a high redundancy of arylsulfatase A (Kihara et al., 1986).
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. In Israel, Herz and Bach (1984) estimated the frequency of the pseudodeficiency allele to be about 15%. In a Spanish population, Chabaset al. (1993) estimated the frequency of the pseudodeficiency allele to be 12.7%.
Propping etal. (1986) studied consecutive admissions to a state psychiatric hospital and a group of patients 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-Sachsh eterozygotes showed no consistent deficit in any component of the neurologic or neuropsychologic tests. Hohenschutz et al. (1988) described a possible 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 the adult form of metachromatic leukodystrophy, initial symptoms, which begin after age 16, have usually been psychiatric, leading 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 gall bladder 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. Percy and Kaback (1971) found no difference in enzyme levels between the infantile and adult-onset types.
Some other factor must account for the difference in age of onset. Porter et al.(1971) reported 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.
A variant form was observed in 3 adult sibs of Iranian-Jewish extraction by Yatziv and Russell (1981). Clinical progression was insidious and protracted.
The hallmark was dystonia, mainly induced by intention and manifested by dysarthria and torsion spasm of the neck, spine, and limbs. Choreoathetosis was sometimes observed.
Sural nerve biopsy and marked deficiency of arylsulfatase A (ARSA) in urine,leukocytes and fibroblasts made the diagnosis.
The clinically normal parents both showed reduction in ARSA activity by 50%.
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. 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 thiolproteases, e.g., leupeptin, arylsulfatase A polypeptides were partially protected from degradation with increase in catalytic activity of arylsulfatase A and improved ability ofthe 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.
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 whitematter 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.
Baldinger et al. (1987) discussed the complications of genetic counseling and prenatal diagnosis resulting from the occurrence of the pseudodeficiency phenotype.
The pseudodeficiency allele was found to have 2 A-to-G transitions (Gieselmann et al., 1989): onean asn350-to-ser mutation in exon 6, causing the loss of an N-glycosylation site, and the other occurring in exon 8 at the 3-prime end of the gene, causing the loss of a polyadenylation signal. Gieselmann (1991) found that these 2 mutations could be detected simultaneously with a rapid 3-prime-mismatch polymerase chain reaction.
Shen et al.(1993) found another complication: a pseudodeficiency allele in which only 1 of the 2 A-to-G mutations was present.
Poenaru et al. (1988) described a method of first-trimester prenatal diagnosis of metachromatic leukodystrophy using immunoprecipitation-electrophoresis on chorionic villus material.
By somatic cell hybridization methods, DeLuca et al. (1979) assigned arylsulfatases A and B to chromosomes 22 and 5, respectively.
From study of human-rodent hybrid clones, Geurts van Kessel et al. (1980) concluded that arylsulfatase A is located distal to 22q13. In an infant with deletion of 22q13.31-qter, Narahara et al. (1992) found partial deficiency of ARSA, indicating that the ARSA locus is in the deleted region.
Stein et al. (1989) cloned and sequenced a full-length cDNA for human arylsulfatase A.
The predicted amino acid sequence comprised 507 residues, including a putative signal peptide of 18 residues. The cDNA hybridized to 2.0- and 3.9-kb species in RNA from human fibroblasts and human liver.
RNA species of similar size were detected in metachromatic leukodystrophy fibroblasts of 2 patients.
One was a form in which synthesis of ARSA polypeptides was not detectable and the second was a form in which catalytically active enzyme was synthesized but was unstable in lysosomes. 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.
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, 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 etal. (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 mutationat 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.
Kappler et al. (1994) found that a patient with late-infantile MLD was a genetic compound for 2 alleles, each of which carried 2 deleterious mutations.
One allele carried 2 missense mutations; the other allele bore a splice donor site mutation and amissense mutation, both of which had previously been described but on different alleles.
When ARSA cDNAs carrying these mutations, separately or in combination, were transfected into baby hamster kidney cells, expression of arylsulfatase A activity could not be detected.
Among the lysosomal storage disorders, a single allele with 2 disease-causing mutations had been described for the GLA gene in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease.
Barth et al. (1995) found 7 novel mutations in ARSA associated with MLD that they had detected by chemical mismatch analysis.
Coulter-Mackie et al. (1995) described a child with MLD who had inherited a common splicing mutation, termed the 'I' allele, from the father and had a ring chromosome 22 from which thearylsulfatase A gene was deleted.

ALLELIC VARIANTS

.0001 ARYLSULFATASE A PSEUDODEFICIENCY [ARSA, MUTATION IN POLYADENYLATION SIGNAL]

In an individual homozygous for the ARSA pseudodeficiency allele, Gieselmann et al. (1989) found 2 A-to-G transitions: one changed arg350 to serine, leading to loss of an N-glycosylation site.
This loss explained the smaller size of ARSA in ARSA pseudodeficient fibroblasts. Introduction of ser350 into normal ARSA cDNA did not affectthe rate of synthesis, stability, or catalytic properties of ARSA in stably transfected baby hamster kidney cells, however.
The other A-to-G transition changed the first polyadenylylation signal downstream of the stop codon from AATAAC to AGTAAC.
The latter change caused a severe deficiency of a 2.1-kb RNA species.
The deficiency of the 2.1-kb RNA species explained the diminished synthesis of ARSA in pseudodeficiency fibroblasts.
The same change was found in 4 unrelated individuals with pseudodeficiency. In those who are homozygous for the pseudodeficiency allele or carry it in heterozygous state with a normal allele, enough arylsulfatase A is synthesized to prevent clinically apparent disease. In combination with other mutant alleles, it may cause metachromatic leukodystrophy.
Nelson et al. (1991) likewise found the A-to-G change at nucleotide 1620 in the first polyadenylation signal of the ARSA gene resulting in loss of its major mRNA species and a greatly reduced level of enzyme activity.
This change was found to be closely linked to another A-to-G transition at nucleotide 1049 which changed asparagine-350 to serine but did not affect ARSA activity.
The findings of Nelson et al. (1991) supported the conclusion of Gieselmann et al. (1989) that the change in nucleotide 1620 is always associated with that at nucleotide 1049.
Barth et al. (1994) stated that the 2 mutations do not always occur together and that at least the N350S mutation may be found alone.
The carrier frequency of the ARSA pseudodeficiency mutation in Australia was estimated to be about 20%. Li et al. (1992) described a polymerase chain reaction (PCR)-based method for genotypically identifying pseudodeficiency.
Barth et al. (1994) used PCR and restriction endonuclease digestion to determine the frequency of A-to-G transitions at bases 1049 (N350S) and 1620 in healthy persons from England. Mutations were found in 24 of 77 screened persons.
Two were homozygous for both mutations, 16 were heterozygous for both, 5 were heterozygous for the N350S mutation alone, and 1 was homozygous for the N350S mutation.
Study of the 16 persons heterozygous for both mutations showed that in 15 persons both mutations were located on the same chromosome, and in 1 person the mutations were located on different chromosomes.
Persons homozygous for both mutations had the lowest activities of ARSA.

.0002 ARYLSULFATASE A POLYMORPHISM [ARSA, ARG350SER]

In a homozygote for ARSA deficiency, Gieselmann et al. (1989) demonstrated that an A-to-G transition in the polyadenylylation signal downstream of the stop codon, from AATAAC to AGTAAC, was responsible for the severe deficiency of a 2.1-kb RNA species and the diminished synthesis of ARSA.
A second mutation, arg350-to-serine, resulting from an A-to-G transition, appeared to be responsible for the small size of ARSA produced by pseudodeficiency fibroblasts because it led to loss of an N-glycosylation site.
It was not, however, responsible for the defective synthesis of enzyme.
The arg350-to-ser mutation is a polymorphism that does not affect the activity or stability of the enzyme, whereas the other mutation causes the loss of about 90% of ARSA mRNA, which explains the loss of 90% of ARSA crossreacting material and enzyme activity.

.0003 METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE [ARSA, IVS2DS, A-G, +1] ARYLSULFATASE A, ALLELE I

In a patient with juvenile-onset metachromatic leukodystrophy, Polten et al. (1991) found 2 different metachromatic leukodystrophy alleles.
One, designated allele I, differed in 3 positions from the published sequence for the ARSA gene.
Two of the substitutions represented functionally silent changes; only the loss of a splice donor site in allele I was considered to be relevant to metachromatic leukodystrophy.
Specifically, an A-to-G transition destroyed the splice donor site of exon 2 by changing the classic exon-intron boundary consensus sequence from AGgt to AGat. In all 6 instances of homozygosity for allele I, Polten et al. (1991) reported that the clinical picture was that of the late-infantile form of metachromatic leukodystrophy. Heinisch et al. (1995) found this mutation in homozygous state in 3 separate Arab families living in the Jerusalem area.

.0004 ARYLSULFATASE A, ALLELE A [ARSA, PRO426LEU]

In a patient with juvenile onset metachromatic leukodystrophy, Polten et al. (1991) found compound heterozygosity for allele I and for allele A which they showed contained a C-to-T transition (CCG to CTG) causing the change of proline at position 426 to leucine.
To test the functional consequence of this mutation, Polten et al. (1991) introduced it into arylsulfatase A cDNA by site-directed mutagenesis, and the mutated cDNA was transiently expressed in baby-hamster kidney cells after transfection.
Only a small increase in the activity of arylsulfatase A was observed in the transfected cells (3%; range, 2-5).
Polten et al. (1991) determined the frequency of alleles I and A by allele-specific oligonucleotide hybridization.
Of 68 patients studied, 50 carried at least 1 of the 2 alleles. In 23 patients, they found homozygosity for one or the other allele or compound heterozygosity for the 2.
Neither allele was found in 18 of the 68 patients.
In total, 37 I alleles and 36 A alleles were found. In 8 instances of homozygosity for allele A, Polten et al. (1991) found that in 5 it was associated with the adult form and in 3 with the juvenile form of the disease.
Compound heterozygosity for allele A and allele I resulted in the juvenile form of metachromatic leukodystrophy in 7 of 7 instances.
Heterozygosity for allele I (with the other allele unknown) was usually associated with late-infantile disease, and heterozygosity for allele A with later onset of the disease.

.0005 METACHROMATIC LEUKODYSTROPHY, ADULT [ARSA, GLY99ASP]

In a Japanese patient with adult-type metachromatic leukodystrophy, Kondo et al. (1991) identified a G-to-A transition in exon 2, which resulted in amino acid substitution of aspartic acid for glycine-99. In transient expression studies, COS cells transfected with the mutant cDNA carrying gly99-to-asp did not show increase of ARSA activity, thus confirming that the mutation was the cause of MLD.

.0006 METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE [ARSA, SER96PHE]

In a patient with the late infantile form of metachromatic leukodystrophy, Gieselmann et al. (1991) found homozygosity for the mutations characteristic of the arylsulfatase A pseudodeficiency allele but, in addition, a C-to-T transition in exon 2 causing a substitution of phenylalanine for serine-96.
Gieselmann et al. (1991) pointed out the necessity for care in not overlooking a mutation causing severe deficiency associated with the changes of pseudodeficiency.
This can be a serious problem since homozygous pseudodeficiency is present in 1-2% of the population.

.0007 METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE [ARSA, 11BP DEL, EX8]

Bohne et al. (1991) demonstrated an 11-bp deletion in exon 8 of one allele of the ARSA gene in a patient with the late infantile form of MLD.
Although this allele produced normal amounts of mRNA, no arylsulfatase A crossreacting material could be detected in cultured fibroblasts from the patient.
The 11-bp deletion was found between nucleotides 2506 and 2516. It caused a frameshift downstream of the codon for amino acid 467.
The polypeptide encoded by the mutant allele should be 29 amino acids longer than wildtype ASA.
The other allele, which had been inherited from the father, had a splice donor site mutation in exon 7.
This allele is known also to generate no ASA polypeptide.
Thus, this was another example where absence of ASA polypeptide correlated with the severe late infantile form of MLD.

.0008 METACHROMATIC LEUKODYSTROPHY, JUVENILE [ARSA, ILE-TO-SER, EX3]

In a patient with juvenile-onset metachromatic leukodystrophy, Fluharty et al. (1991) identified a T-to-G transversion at nucleotide 799, resulting in a change from isoleucine to serine in exon 3.
They designated this mutation E3P799 according to the following scheme:
location in the gene, e.g., E3 = exon 3 or its immediately adjacent splice-recognition sequence; type of alteration, e.g., P = point mutation leading to amino acid substitution, or S = mutation in splice recognition sequence;
and number of initial nucleotide in the altered sequence, e.g., 799 = 799th nucleotide beyond start of initiation codon.

.0009 METACHROMATIC LEUKODYSTROPHY, JUVENILE [ARSA, IVS7, G-A]

In a patient with juvenile-onset metachromatic leukodystrophy, Fluharty et al. (1991) found compound heterozygosity for a point mutation and for a G-to-A transition that resulted in an altered splice-recognition sequence between exon 7 and the following intron.
The mutation involved nucleotide 2195, the first nucleotide in intron 7.

.0010 METACHROMATIC LEUKODYSTROPHY, LATE-ONSET [ARSA, ARG84GLN]

Kappler et al.(1992) described an arg84-to-gln mutation in 2 sisters with late-onset metachromatic leukodystrophy.
One sister developed abnormal behavior at the age of 14 years and was thought to have 'frontal lobe syndrome.' Later she developed peripheral neuropathy and dementia.
At the age of 30 she was bedridden.
The other sister presented similar biochemical alterations. In spite of cranial CT alterations characteristic of MLD, her clinical status was almost normal when she was 21 years old.
At the age of 29 years, she was still without complaints.
Both sisters showed residual ARSA activity, further validating the concept that different degrees of residual ARSA activity account for phenotypic variation in this disorder.

.0011 METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE [ARSA, GLY309SER]

Kreysing et al. (1993) described compound heterozygosity for 2 mutant ARSA alleles in a male patient who presented with gait disturbances at the age of 18 months.
Subsequently he lost acquired capabilities such as walking and sitting, developed spastic paresis, and finally became bedridden.
He showed episodes of pain attacks occurring several times per hour.
Electromyelography showed signs of denervation and decreased nerve conduction velocity.
Sural nerve biopsy demonstrated metachromatic granules.
The patient had residual ARSA activity of about 10%. Fibroblasts of the patient showed significant sulfatide degradation activity exceeding that of adult MLD patients.
One of the mutant alleles was a G-to-A transition in exon 5 causing a gly309-to-ser substitution.
Transient expression of this allele resulted in only 13% enzyme activity as compared with the normal.
The mutant enzyme was correctly targeted to the lysosomes but was unstable.
The other allele showed a deletion of C447 in exon 2, causing a frameshift and a premature stop codon at amino acid position 105.
The findings in this patient contrasted with previous results showing that the late-infantile type of MLD is always associated with the complete absence of ARSA activity.
In this case, the expression of the mutant ARSA protein may have been influenced by particular features of oligodendrocytes, such that the level of mutant enzyme is lower in these cells than in others.

.0012 METACHROMATIC LEUKODYSTROPHY, LATE-INFANTILE [ARSA, 1BP DEL, FS105TER]

See above.

SEE ALSO :

REFERENCES

1. Austin, J.; Armstrong, D.; Fouch, S.; Mitchell, C.; 
Stumpf, D. A.;
Shearer, L.; Briner, O.: 
   Metachromatic leukodystrophy (MLD). VIII. MLD
in adults: diagnosis and
pathogenesis. Arch.
   Neurol. 18: 225-240, 1968.

2. Austin, J.; McAfee, D.; Armstrong, D.; 
O'Rourke, M.; Shearer, L.;
Bachhawat, B. K. : 
   Abnormal sulphatase activities in two human 
diseases (metachromatic
leukodystrophy and
   gargoylism). Biochem. J. 93: 15C-17C, 1964. 

3. Austin, J.; McAfee, D.; Shearer, L. : 
   Metachromatic form of diffuse cerebral 
sclerosis. IV. Low sulfatase
activity in the urine
   of nine living patients with metachromatic 
leukodystrophy (MLD). Arch.
Neurol. 12:
   447-455, 1965.

4. Austin, J. H. : 
   Metachromatic form of diffuse cerebral sclerosis.
 III. Significance of
sulfatide and other
   lipid abnormalities in white matter and kidney.
 Neurology 10: 470-483, 1960.

5. Austin, J. H. : 
   Some recent findings in leukodystrophies and in 
gargoylism.In: Aronson,
S. M.; Volk, B. W.: 
   Inborn Disorders of Sphingolipid Metabolism. 
Oxford: Pergamon Press
(pub.) 1967. Pp.
   359-387.

6. Baldinger, S.; Pierpont, M. E.; Wenger, D. A. : 
   Pseudodeficiency of arylsulfatase A: 
a counseling dilemma. Clin. Genet.
31: 70-76, 1987. 

7. Barth, M. L.; Fensom, A.; Harris, A. : 
   Identification of seven novel mutations 
associated with metachromatic
leukodystrophy. Hum.
   Mutat. 6: 170-176, 1995. 

8. Barth, M. L.; Ward, C.; Harris, A.; 
Saad, A.; Fensom, A. : 
   Frequency of arylsulphatase A pseudodeficiency 
associated mutations in a
healthy
   population. J. Med. Genet. 31: 667-671, 1994. 

9. Bayever, E.; Ladisch, S.; Philippart, M.; Brill, N.; 
Nuwer, M.; Sparkes,
R. S.; Feig, S.
   A. : 
   Bone-marrow transplantation for metachromatic
 leucodystrophy. Lancet II:
471-473, 1985.

10. Beratis, N. G.; Danesino, C.; Hirschhorn, K. : 
   Detection of homozygotes and heterozygotes 
for metachromatic
leukodystrophy in lymphoid
   cell lines and peripheral leukocytes. Ann. Hum. 
Genet. 38: 485-493, 1975. 

11. Betts, T. A.; Smith, W. T.; Kelly, R. E. : 
   Adult metachromatic leukodystrophy 
(sulphatide lipidosis) simulating
acute schizophrenia:
   report of a case. Neurology 18: 1140-1142, 1968.

12. Black, J. W.; Cumings, J. N. : 
   Infantile metachromatic leukodystrophy. J. Neurol. 
Neurosurg. Psychiat.
24: 233-239, 1961.

13. Bohne, W.; von Figura, K.; Gieselmann, V. : 
   An 11-bp deletion in the arylsulfatase A gene 
of a patient with late infantile
   metachromatic leukodystrophy. Hum. 
Genet. 87: 155-158, 1991. 

14. Bosch, E. P.; Hart, M. N. : 
   Late adult-onset metachromatic 
leukodystrophy: dementia and
polyneuropathy in a
   63-year-old man. Arch. Neurol. 
35: 475-477, 1978.

15. Bruns, G. A. P.; Mintz, B. J.; Leary, A. C.; 
Regina, V. M.; Gerald, P. S. : 
   Expression of human arylsulfatase A in 
man-hamster somatic cell hybrids.
Cytogenet. Cell
   Genet. 22: 182-185, 1978.

16. Butterworth, J.; Broadhead, D. M.; 
Keay, A. J. : 
   Low arylsulphatase A activity in a family 
without metachromatic
leukodystrophy. Clin.
   Genet. 14: 213-218, 1978.

17. Chabas, A.; Castellvi, S.; Bayes, M.; 
Balcells, S.; Grinberg, D.;
Vilageliu, L.; Marfany,
    G.; Lissens, W.; Gonzalez-Duarte, R. : 
   Frequency of the arylsulphatase A 
pseudodeficiency allele in the Spanish
population. Clin.
   Genet. 44: 320-323, 1993. 

18. Chang, P. L.; Davidson, R. G. : 
   Pseudo arylsulfatase-A deficiency in healthy
 individuals: genetic and
biochemical
   relationship to metachromatic leukodystrophy.
 Proc. Nat. Acad. Sci. 80:
7323-7327, 1983. 

19. Chang, P. L.; Davidson, R. G. : 
   Complementation of arylsulfatase A in somatic
 hybrids of metachromatic
leukodystrophy and
   multiple sulfatase deficiency disorder fibroblasts.
 Proc. Nat. Acad. Sci.
77: 6166-6170,
   1980. 

20. Chang, P. L.; Rosa, N. E.; Davidson, R. G. : 
   Somatic cell hybridization studies on the 
genetic regulation and allelic
mutations in
   metachromatic leukodystrophy. Hum. 
Genet. 61: 231-235, 1982. 
  
21. Coulter-Mackie, M. B.; Rip, J.; Ludman, 
M. D.; Beis, J.; Cole, D. E. C. : 
   Metachromatic leucodystrophy (MLD) in a 
patient with a constitutional
ring chromosome 22. 
   J. Med. Genet. 32: 787-791, 1995. 
  
22. Cravioto, H.; O'Brien, J.; Lockwood, R.; 
Kasten, F. H.; Booker, J. : 
   Metachromatic leukodystrophy 
(sulfatide lipidoses) cultured in vitro.
Science 156:
   243-245, 1967. 
    
23. DeLuca, C.; Brown, J. A.; Shows, T. B. : 
   Lysosomal arylsulfatase deficiencies 
in humans: chromosome assignment of
arylsulfatase A
   and B. Proc. Nat. Acad. Sci. 76: 
1957-1961, 1979. 
    
24. DeLuca, C.; Champion, M. J.; Shows, T. B. : 
   Arylsulfatase-A (ARSA) synteny with 
beta-glucuronidase (BGUS) indicates
assignment to
   human chromosome 7 in man-Chinese 
hamster hybrids. (Abstract) Winnipeg
Gene Mapping Conf.
   , 1977.

25. Dubois, G.; Harzer, K.; Baumann, N. : 
   Very low arylsulfatase A and cerebroside 
sulfatase activities in
leukocytes of healthy
   members of metachromatic leukodystrophy 
family. Am. J. Hum. Genet. 29:
191-194, 1977. 
   
26. Eto, Y.; Tahara, T.; Koda, N.; 
Yamaguchi, S.; Ito, F.; Okuno, A. : 
   Prenatal diagnosis of metachromatic 
leukodystrophy: a diagnosis by
amniotic fluid and its
   confirmation. Arch. Neurol. 39: 29-32, 1982.

27. Farrell, D. F. : 
   Heterozygote detection in MLD: allelic 
mutations at the ARA locus. Hum.
Genet. 59:
   129-134, 1981. 
    
28. Farrell, D. F.; MacMartin, M. P.;
Clark, A. F. : 
   Multiple molecular forms of arylsulfatase 
A in different forms of
metachromatic
   leukodystrophy (MLD). Neurology 29: 16-20, 1979.

29. Fluharty, A. L.; Fluharty, C. B.; 
Bohne, W.; von Figura, K.; Gieselmann,
V. : 
   Two new arylsulfatase A (ARSA) mutations 
in a juvenile metachromatic
leukodystrophy (MLD)
   patient. Am. J. Hum. Genet. 49: 
1340-1350, 1991. 
  
30. Francke, U.; Tetri, P.; Taggart, R. T.; 
Oliver, N. : 
   Conserved autosomal syntenic group on 
mouse (MMU) chromosome 15 and human
(HSA) chromosome
   22: assignment of a gene for arylsulfatase 
A to MMU 15 and regional
mapping of DIA1, ARSA,
   and ACO2 on HSA22. Cytogenet. Cell 
Genet. 31: 58-69, 1981. 
 
31. Geurts van Kessel, A. H. M.; 
Westerveld, A.; de Groot, P. G.; Meera
Khan, P.; Hagemeijer,
    A. : 
   Regional localization of the genes 
coding for human ACO2, ARSA, and NAGA
on chromosome 22.
Cytogenet. Cell Genet. 28: 169-172, 1980.

32. Gieselmann, V. : 
   An assay for the rapid detection of the 
arylsulfatase A pseudodeficiency
allele
   facilitates diagnosis and genetic 
counseling for metachromatic
leukodystrophy. Hum. Genet.
   86: 251-255, 1991. 
    
33. Gieselmann, V.; Fluharty, A. L.; 
Tonnesen, T.; Von Figura, K. : 
   Mutations in the arylsulfatase A 
pseudodeficiency allele causing
metachromatic
   leukodystrophy. Am. J. Hum. 
Genet. 49: 407-413, 1991. 
    
34. Gieselmann, V.; Polten, A.; Kreysing, J.; 
von Figura, K. : 
   Arylsulfatase A pseudodeficiency: loss
 of a polyadenylylation signal and
N-glycosylation
site. Proc. Nat. Acad. Sci. 86: 9436-9440, 1989. 
    
35. Gieselmann, V.; Zlotogora, J.; Harris, A.; 
Wenger, D. A.; Morris, C. P. : 
   Molecular genetics of metachromatic
 leukodystrophy. Hum. Mutat. 4:
233-242, 1994. 
    
36. Goebel, H. H.; Pilz, H.; Argyrakis, A. : 
   Adult metachromatic leukodystrophy. II. 
Ultrastructural findings in
peripheral nerve and
   skeletal muscle. Europ. Neurol. 
15: 308-317, 1977.

37. Greene, H.; Hug, G.; Schubert, W. K. : 
   Arylsulfatase A in the urine and 
metachromatic leukodystrophy. J. Pediat.
71: 709-711,
   1967.

38. Greenfield, J. G. : 
   Form of progressive cerebral sclerosis
 in infants associated with primary
degeneration of
   interfascicular glia. Proc. Roy. Soc. 
Med. 26: 690-697, 1933.

39. Gustavson, K.-H.; Hagberg, B. : 
   The incidence and genetics of 
metachromatic leukodystrophy in northern
Sweden. Acta
   Paediat. Scand. 60: 585-590, 1971. 
     
40. Hagberg, B.; Sourander, P.; 
Svennerholm, L. : 
   Sulfatide lipidosis in childhood. Am. J. 
Dis. Child. 104: 644-656, 1962.

41. Haltia, T.; Palo, J.; Haltia, M.; Icen, A. : 
   Juvenile metachromatic leukodystrophy: 
clinical, biochemical, and
neuropathologic studies
   in nine new cases. Arch. Neurol. 
37: 42-46, 1980. 
   
42. Heinisch, U.; Zlotogora, J.; Kafert, 
S.; Gieselmann, V. : 
   Multiple mutations are responsible 
for the high frequency of
metachromatic leukodystrophy
   in a small geographic area. Am. J. 
Hum. Genet. 56: 51-57, 1995. 
    
43. Herz, B.; Bach, G. : 
   Arylsulfatase A in pseudodeficiency. 
Hum. Genet. 66: 147-150, 1984. 
    
44. Hohenschutz, C.; Eich, P.; Friedl, W.; 
Waheed, A.; Conzelmann, E.;
Propping, P. : 
   Pseudodeficiency of arylsulfatase A: a 
common genetic polymorphism with
possible disease
   implications. 
Hum. Genet. 82: 45-48, 1989. 
  
45. Hohenschutz, C.; Friedl, W.; Schlor, 
K.-H.; Waheed, A.; Conzelmann, E.;
Sandhoff, K.;
    Propping, P. : 
   Probable metachromatic 
leukodystrophy/pseudodeficiency compound
heterozygote at the
   arylsulfatase A locus with neurological 
and psychiatric symptomatology.
Am. J. Med. Genet.
   31: 169-175, 1988.

46. Hors-Cayla, M. C.; Heuertz, S.; 
Van Cong, N.; Weil, D.; Frezal, J. : 
   Confirmation of the assignment of 
the gene for arylsulfatase A to
chromosome 22 using
   somatic cell hybrids. 
Hum. Genet. 49: 33-39, 1979. 

47. Jervis, G. A. : 
   Infantile metachromatic 
leukodystrophy (Greenfield's disease). J.
Neuropath. Exp. Neurol.
   19: 323-341, 1960.

48. Kaback, M. M.; Howell, R. R. : 
   Infantile metachromatic leukodystrophy:
 heterozygote detection in skin
fibroblasts and
   possible applications to intrauterine 
diagnosis. New Eng. J. Med. 282:
1336-1340, 1970. 
    
49. Kappler, J.; Sommerlade, H. J.; 
von Figura, K.; Gieselmann, V. : 
   Complex arylsulfatase A alleles 
causing metachromatic leukodystrophy.
Hum. Mutat. 4:
   119-127, 1994. 
    
50. Kappler, J.; von Figura, K.; 
Gieselmann, V. : 
   Late-onset metachromatic 
leukodystrophy: molecular pathology in two
siblings. Ann. Neurol.
   31: 256-261, 1992. 
   
51. Kihara, H. : 
   Genetic heterogeneity in metachromatic 
leukodystrophy. Am. J. Hum. Genet.
34: 171-181,
   1982. 
    
52. Kihara, H.; Fluharty, A. L.; 
O'Brien, J. S.; Fish, C. H. : 
   Metachromatic leukodystrophy 
caused by a partial cerebroside sulfatase
defect. Clin.
   Genet. 21: 253-261, 1982.

53. Kihara, H.; Meek, W. E.; 
Fluharty, A. L. : 
   Attenuated activities and structural 
alterations of arylsulfatase A in
tissues from
   subjects with pseudo arylsulfatase 
A deficiency. Hum. Genet. 74: 59-62,
1986. 
    
54. Kohn, H.; Manowitz, P.; Miller, 
M.; Kling, A. : 
   Neuropsychological deficits in 
obligatory heterozygotes for metachromatic
leukodystrophy. 
   Hum. Genet. 79: 8-12, 1988. 
   
55. Kondo, R.; Wakamatsu, N.; Yoshino, 
H.; Fukuhara, N.; Miyatake, T.;
Tsuji, S. : 
   Identification of a mutation in the 
arylsulfatase A gene of a patient
with adult-type
   metachromatic leukodystrophy. 
Am. J. Hum. Genet. 48: 971-978, 1991. 
   
56. Kreysing, J.; Bohne, W.; Bosenberg, C.; 
Marchesini, S.; Turpin, J. C.;
Baumann, N.; von
    Figura, K.; Gieselmann, V. : 
   High residual arylsulfatase A (ARSA) 
activity in a patient with
late-infantile
   metachromatic leukodystrophy.
 Am. J. Hum. Genet. 53: 339-346, 1993. 
    
57. Krivit, W.; Shapiro, E.; Kennedy, W.;
 Lipton, M.; Lockman, L.; Smith,
S.; Summers, C. G.;
    Wenger, D. A.; Tsai, M. Y.; Ramsay,
 N. K. C.; Kersey, J. H.; Yao, J. K.; 
    Kaye, E. : 
    Treatment of late infantile metachromatic
 leukodystrophy by bone marrow 
    transplantation. 
    New Eng. J. Med. 322: 28-32, 1990.

58. Langenbeck, U.; Dunker, P.; 
Heipertz, R.; Pilz, H. : 
   Inheritance of metachromatic 
leukodystrophy. (Letter) Am. J. Hum. Genet.
29: 639-640,
   1977. 
   
59. Li, Z. G.; Waye, J. S.; Chang, P. L. : 
    Diagnosis of arylsulfatase A deficiency. 
    Am. J. Med. Genet. 43: 976-982, 1992. 
 
60. Lyon, G.; Arthiu, M.; Thieffry, S. : 
   Leucodystrophie metachromatique 
infantile familiale: etude de deux
observations, dont une
   avec examen anatomique et chimique. 
   Rev. Neurol. 104: 508-533, 1961.

61. Masters, P. L.; MacDonald, W. B.; 
Ryan, M. M. P.; Cumings, J. N. : 
   Familial leucodystrophy. Arch. 
Dis. Child. 39: 345-355, 1964.

62. Moser, H. W. : 
   Sulfatide lipidosis: metachromatic 
leukodystrophy.In: Stanbury, J. B.;
Wyngaarden, J. B.;
   Fredrickson, D. S. : 
   The Metabolic Basis of Inherited 
Disease. New York: McGraw-Hill (pub.)
(3rd ed.) 1972. Pp.
   688-729.

63. Muller, D.; Pilz, H.; Ter Meulen, V. : 
   Studies on adult metachromatic 
leukodystrophy. I. Clinical, morphological 
and histochemical observations in two cases.
 J. Neurol. Sci. 9: 567-584, 1969.

64. Narahara, K.; Takahashi, Y.; Murakami,
 M.; Tsuji, K.; Yokoyama, Y.;
Murakami, R.;
    Ninomiya, S.; Seino, Y. : 
   Terminal 22q deletion associated 
with a partial deficiency of
arylsulphatase A. J. Med.
   Genet. 29: 432-433, 1992. 
  
65. Nelson, P. V.; Carey, W. F.; 
Morris, C. P. : 
   Population frequency of the arylsulphatase 
A pseudo-deficiency allele.
Hum. Genet. 87:
   87-88, 1991. 
     
66. Nicholls, R. G.; Roy, A. G. : 
   Arylsulfatases. In: Boyer, P. D. : 
   The Enzymes. New York: Academic 
Press (pub.) 5 1971. Pp. 21-41.

67. Percy, A. K.; Brady, R. O. : 
   Metachromatic leukodystrophy: 
diagnosis with samples of venous blood. 
   Science 161: 594-595, 1968. 
    
68. Percy, A. K.; Kaback, M. M. : 
   Infantile and adult-onset metachromatic 
leukodystrophy: biochemical
comparisons and
   predictive diagnosis. New Eng. 
J. Med. 285: 785-787, 1971.

69. Percy, A. K.; Kaback, M. M.; 
Herndon, R. M. : 
   Metachromatic leukodystrophy: 
comparison of early- and late-onset forms.
Neurology 27:
   933-941, 1977.

70. Pilz, H.; Duensing, I.; Heipertz, R.; 
Seidel, D.; Lowitsch, K.; Hopf, H.
C.; Goebel, H.
    H. : 
   Adult metachromatic leukodystrophy.
 I. Clinical manifestation in a female
aged 44 years,
   previously diagnosed in the preclinical 
state. Europ. Neurol. 15:
301-307, 1977.

71. Pilz, H.; Muller, D. : 
   Studies on adult metachromatic 
leukodystrophy. II. Biochemical aspects 
of adult cases of
metachromatic leukodystrophy. J. 
Neurol. Sci. 9: 585-595, 1969.

72. Poenaru, L.; Castelnau, L.; Besancon, 
A.-M.; Nicolesco, H.; Akli, S.;
Theophil, D. : 
   First trimester prenatal diagnosis of 
metachromatic leukodystrophy on
chorionic villi by
   'immunoprecipitation-electrophoresis.'. 
J. Inherit. Metab. Dis. 11:
123-130, 1988.

73. Polten, A.; Fluharty, A. L.; Fluharty, C. B.; 
Kappler, J.; von Figura, K.; 
    Gieselmann, V.: 
    Molecular basis of different forms of 
metachromatic leukodystrophy. 
    New Eng. J. Med. 324: 18-22, 1991. 

74. Porter, M. T.; Fluharty, A. L.; 
Kihara, H. : 
   Correction of abnormal cerebroside 
sulfate metabolism in cultured
metachromatic
   leukodystrophy fibroblasts. 
   Science 172: 1263-1265, 1971. 

75. Porter, M. T.; Fluharty, A. L.; Trammell, 
J.; Kihara, H. : 
   A correlation of intracellular cerebroside
 sulfatase activity in
fibroblasts with latency
   in metachromatic leukodystrophy. 
   Biochem. Biophys. Res. Commun. 44: 660-666, 1971. 
    
76. Propping, P.; Friedl, W.; Huschka,
 M.; Schlor, K.-H.; Reimer, F.;
Lee-Vaupel, M.;
    Conzelmann, E.; Sandhoff, K. : 
    The influence of low arylsulfatase 
A activity on neuropsychiatric
morbidity: a large-scale
    screening in patients. 
    Hum. Genet. 74: 244-248, 1986. 

77. Quigley, H. A.; Green, W. R. : 
   Clinical and ultrastructural ocular 
histopathologic studies of
adult-onset metachromatic
   leukodystrophy. Am. 
J. Ophthal. 82: 472-479, 1976.

78. Sanguinetti, N.; Marsh, J.; Jackson, M.;
 Fensom, A. H.; Warren, R. C.;
Rodeck, C. H. : 
   The arylsulphatases of chorionic villi:
 potential problems in the
first-trimester
   diagnosis of metachromatic
leucodystrophy and Maroteaux-Lamy 
disease.
Clin. Genet. 30:
   302-308, 1986.

79. Schaap, T.; Zlotogora, J.; Elian, E.; 
Barak, Y.; Bach, G. : 
   The genetics of the aryl sulfatase 
A locus. Am. J. Hum. Genet. 33:
531-539, 1981. 
   
80. Schutta, H. S.; Pratt, R. T. C.; 
Metz, H.; Evans, K. A.; Carter, C. O. : 
   A family study of the late infantile 
and juvenile forms of metachromatic
leukodystrophy. 
   J. Med. Genet. 3: 86-91, 1966.

81. Shen, N.; Li, Z.-G.; Waye, J. S.; 
Francis, G.; Chang, P. L. : 
   Complications in the genotypic 
molecular diagnosis of pseudo
arylsulfatase A deficiency. 
   Am. J. Med. Genet. 45: 631-637, 1993. 
 
82. Sourander, P.; Svennerholm, L. : 
   Sulphatide lipidosis in the adult 
with the clinical picture of
progressive organic
   dementia with epileptic seizures. 
Acta Neuropath. 1: 384-396, 1962.

83. Stein, C.; Gieselmann, V.; Kreysing, J.;
 Schmidt, B.; Pohlmann, R.;
Waheed, A.; 
Meyer, H.E.; O'Brien, J. S.; von Figura, K. : 
   Cloning and expression of human 
arylsulfatase A. J. Biol. Chem. 264:
1252-1259, 1989. 

84. Stumpf, D. A.; Austin, J. : 
   Metachromatic leukodystrophy (MLD).
 IX. Qualitative and quantitative
differences in
   urinary arylsulfatase A in different 
forms of MLD. Arch. Neurol. 24:
117-124, 1971.

85. Tonnesen, T.; Bro, P. V.; Nielsen, 
K. B.; Lykkelund, C. : 
   Metachromatic leukodystrophy and 
pseudoarylsulfatase A deficiency in a
Danish family. 
   Acta Paediat. Scand. 
72: 175-178, 1983.

86. Tonnesen, T.; Vrang, C.; Wiesmann, 
U. N.; Christomanou, H.; Lou, H. O. : 
    A typical metachromatic leukodystrophy? 
Problems with the biochemical
diagnosis. Hum.
    Genet. 67: 170-173, 1984. 
   
87. Van Bogaert, L. V.; Dewulf, A. : 
   Diffuse progressive leukodystrophy
 in the adult with production of
metachromatic
degenerative products (Alzheimer-Baroncini). 
Arch. Neurol. Psychiat. 42: 1083-1097, 1939.

88. von Figura, K.; Steckel, F.; Conary, J.;
 Hasilik, A.; Shaw, E. : 
   Heterogeneity in late-onset metachromatic
 leukodystrophy: effect of
inhibitors of cysteine
   proteinases. Am. J. Hum. Genet. 
39: 371-382, 1986. 
   
89. von Figura, K.; Steckel, F.; Hasilik, A. : 
   Juvenile and adult metachromatic 
leukodystrophy: partial restoration 
   of arylsulfatase A (cerebroside sulfatase) 
activity by inhibitors of thiol 
   proteinases. 
   Proc. Nat. Acad. Sci.80: 
6066-6070, 1983. 
 
90. Waheed, A.; Steckel, F.; Hasilik, A.; 
von Figura, K. : 
   Two allelic forms of human arylsulfatase 
A with different numbers of
asparagine-linked
   oligosaccharides. 
Am. J. Hum. Genet. 35: 228-233, 1983. 
 
91. Waltz, G.; Harik, S. I.; Kaufman, B. : 
   Adult metachromatic leukodystrophy:
 value of computed tomographic
scanning and magnetic
   resonance imaging of the brain. 
   Arch. Neurol. 44: 225-227, 1987.

92. Yatziv, S.; Russell, A. : 
    An unusual form of metachromatic 
leukodystrophy in three siblings. 
    Clin. Genet. 19: 222-227, 1981. 

93. Zlotogora, J.; Bach, G. : 
    Deficiency of lysosomal hydrolases in 
apparently healthy individuals. 
    Am. J. Med. Genet. 14: 73-80, 1983. 

94. Zlotogora, J.; Bach, G.; Barak, Y.; Elian, E. : 
   Metachromatic leukodystrophy in the 
Habbanite Jews: high frequency in a
genetic isolate
   and screening for heterozygotes. 
   Am. J. Hum. Genet. 32: 663-669, 1980. 
    
95. Zlotogora, J.; Furman-Shaharabani, Y.; 
Harris, A.; Barth, M. L.; 
    von Figura, K.;Gieselmann, V. : 
    A single origin for the most frequent 
mutation causing late infantile 
    metachromatic leucodystrophy.
    J. Med. Genet. 31: 672-674, 1994.