Clinical Diagnosis

Arylsulfatase 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 leukodystrophy
  • Diffuse 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.

Testing

Arylsulfatase A (EC 3.1.6.8) enzyme activity

• Arylsulfatase 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.

Testing Strategy

To 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 MLD
  • A 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 sulfatides
• Metachromatic lipid deposits in a nerve or brain biopsy

Carrier 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) Disorders

Individuals 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].

Natural History

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].

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].

Genotype-Phenotype Correlations

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.

ARSA enzyme activity

• The 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) pseudodeficiency

• ARSA-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 genotype
  • Homozygosity 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.

Nomenclature

The term metachromatic leukodystrophy (metachromatischen Leukodystrophien) was first used by Peiffer [1959] to describe what had previously been known as “diffuse brain sclerosis.”

The term “metachromatic leukoencephalopathy” has also been used.

MLD has also been referred to as “Greenfield's disease” after the first report of the late-infantile form of MLD.

Prevalence

Arylsulfatase A deficiency. The overall prevalence of arylsulfatase A deficiency has been reported at between 1:40,000 and 1:160,000 in different populations [Von Figura et al 2001].

The disorder seems to occur throughout the world; however, most data come from European and North American populations.

Assuming this prevalence, the overall carrier frequency is between 1:100 and 1:200.

Over a nine-year period, Bonkowsky et al [2010] found that MLD was the most common diagnosis among children in Utah with an inherited leukodystrophy.

Based on their determination of carrier status for the most common ARSA mutations in two large (>~3000-person) samples of the Polish population, Lugowska et al [2011] estimated the birth incidence at 4.1:100,000 live births. Comparing this to the incidence calculated from the number of cases of MLD diagnosed from 1975 to 2004 (0.38:100,000), they suggest that metachromatic leukodystrophy may be substantially underdiagnosed in the Polish population.

In the following consanguineous populations, the disease prevalence can be much higher (figures are approximate):

• 1:75 in Habbanite Jews in Israel
• 1:8000 in Israeli Arabs
• 1:10,000 in Christian Israeli Arabs
• 1:2500 for the western portion of the Navajo Nation in the US

ARSA-PD alleles. 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] (see Molecular Genetic Testing).

The homozygous ARSA-PD genotype occurs in as many as 0.5%-2% of the European/ Euro-American population and may be even more common in Asian and African populations. Thus, an ARSA-PD homozygous genotype is more than 400-fold more common than the ARSA-MLD homozygous genotype, and an [ARSA-PD]+[ARSA-MLD] compound heterozygous genotype is 30- to 50-fold more common than the ARSA-MLD homozygous genotype.

An ARSA-MLD mutation is as likely to be found on an ARSA-PD allele as on a wild type allele, implying that 0.5%-1% of ARSA-PD alleles are associated with a cis ARSA-MLD mutation (so-called [ARSA-PD; ARSA-MLD] alleles).

Evaluations Following Initial Diagnosis

To 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 intervention
• Baseline assessment of development/cognitive abilities and behavior to monitor disease progression or changes with attempted therapy
• Examination of the peripheral nervous system

See Wang et al [2011] for clinical follow up recommendations. Click for full text.

Treatment of Manifestations

Whether 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 Manifestations

Hematopoietic 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 Complications

Prevention 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.

Surveillance

The 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 therapy
• Monitoring 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 independence
• Monitoring for difficulties in swallowing or weight loss, which trigger consideration of gastrostomy
• Special attention following general anesthesia or an infection with a high fever as these may trigger exacerbation of disease progression

Agents/Circumstances to Avoid

While 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Attempts 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 MLD

• Viral 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 studies

• Matzner 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.

Other

Lead 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.

Mode of Inheritance

Arylsulfatase A deficiency (MLD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one mutant allele).
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with arylsulfatase A deficiency are obligate heterozygotes (carriers) for a disease-causing mutation in ARSA.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Biochemical testing. Analysis of arylsulfatase A enzyme activity in leukocytes or cultured fibroblasts for carrier detection is fairly reliable if the range of enzyme activity within a family is known; however, it is much less reliable for testing individuals with no family history of MLD because of the substantial variation in "normal" enzyme activity resulting from the high frequency of pseudodeficiency alleles.

Molecular genetic testing. Molecular genetic methods can be used for carrier testing for at-risk family members if the ARSA mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical testing. Analysis of arylsulfatase A enzyme activity in cultured amniotic fluid cells or chorionic villus cells has been used for the prenatal diagnosis of arylsulfatase A deficiency. Cells for culturing are obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The chief limitation to this approach is the need to grow sufficient cells for testing, which may take two to three weeks after amniocentesis or CVS sampling.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

In instances in which one parent has a very low level of arylsulfatase A enzyme activity caused by a pseudodeficiency allele, prenatal diagnosis using the assay of enzyme activity is unreliable. Either sulfatide loading of the cultured cells or molecular genetic testing can be used in these instances to clarify diagnostic issues.

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis or chorionic villus sampling.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Molecular Genetic Pathogenesis

The 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].

Normal 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].

Published Guidelines/Consensus Statements

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Suggested Reading

1. Aiuti A, Rovelli A, Roncarolo MG, Naldini L. HSC gene therapy trial for metachromatic leukodystrophy: first report on gene marking efficiency. Hum Gene Ther. 2010;21:1363.

Revision History

• 25 August 2011 (me) Comprehensive update posted live
• 23 September 2008 (me) Comprehensive update posted live
• 30 May 2006 (me) Review posted to live Web site
• 15 November 2004 (mf) Original submission