U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Arylsulfatase A Deficiency

Synonyms: ARSA Deficiency, Metachromatic Leukodystrophy

, MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Revision: April 30, 2020.

Estimated reading time: 38 minutes


Clinical characteristics.

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms.

Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings.

Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form.

Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms.


The diagnosis of MLD is established in a proband with progressive neurologic dysfunction, MRI evidence of leukodystrophy, or ARSA enzyme deficiency and identification of biallelic ARSA pathogenic (or likely pathogenic) variants on molecular genetic testing, or identification of elevated urinary excretion of sulfatides, or less commonly, identification of metachromatic lipid deposits in nervous system tissue.


Treatment of manifestations: Physical therapy and an enriched environment to maximize intellect, neuromuscular function, and mobility; family support to enable parents and/or caregivers to anticipate decisions on walking aids, wheelchairs, feeding tubes, and other changing care needs; treatment of seizures using anti-seizure medication in standard protocols; treatment of contractures with muscle relaxants. Standard treatments for gastroesophageal reflux, constipation, drooling, dental care, pulmonary function, and impaired vison.

Prevention of primary manifestations: Hematopoietic stem cell transplantation (HSCT) is the only therapy for primary central nervous system manifestations. Outcomes depend on the clinical stage and the presence of neurologic symptoms. The best results are observed when HSCT is performed in pre- and very early symptomatic individuals with the juvenile or adult form of the disease. HSCT is not recommended for individuals with symptomatic, late-infantile MLD.

Prevention of secondary complications: Therapies designed to prevent decline in mobility, cognitive ability, communication, or food intake; safety measures for movement limitations and seizure precautions.

Surveillance: Regular monitoring by a neurologist or metabolic geneticist including evaluation for changes in motor function, development of seizures, contractions, feeding difficulties, and disease progression following anesthesia or fever; periodic brain MRI examination.

Genetic counseling.

MLD is inherited in an autosomal recessive manner. 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. Carrier testing of at-risk family members and prenatal testing for a pregnancy at increased risk are possible if both ARSA pathogenic variants have been identified in an affected family member.


Suggestive Findings

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) should be 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.
  • MRI evidence of a leukodystrophy. Diffuse symmetric abnormalities of periventricular myelin with hyperintensities on T2-weighted images. Initial parieto-occipital preponderance is observed in most individuals with late-infantile MLD, with subcortical U-fibers and cerebellar white matter spared. The abnormal white matter is often described as having a tigroid pattern or radial stripes. As the disease progresses, MRI abnormalities become more pronounced in a rostral-to-caudal progression and cerebral atrophy develops [Groeschel et al 2011]. Anterior lesions may be more common initially in individuals with later onset. Not all persons with MLD show white matter lesions initially. Isolated cranial nerve enhancement preceding intraparenchymal white matter involvement has been reported [Morana et al 2009, Singh et al 2009].
  • Arylsulfatase A (ARSA) enzyme deficiency. ARSA activity in leukocytes that is less than 10% of normal controls using the usual synthetic-substrate-based assay. Decreased ARSA activity is not sufficient for the diagnosis of MLD, as it may reflect ARSA pseudodeficiency.
    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 (sulfatide loading test). 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) Enzyme activity and sulfatide loading can be performed in cultured amniocytes or CVS cells for prenatal diagnoses; see Genetic Counseling, Prenatal Testing and Preimplantation Genetic Testing.

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: For MLD the term "pseudodeficiency" refers to very low levels of ARSA enzyme activity in an otherwise healthy individual. The term has been applied to other enzyme deficiency disorders, such as hexosaminidase A deficiency, where specific variants are associated with reduced enzymatic activity when measured using synthetic substrate but have normal enzymatic activity when measured using a natural substrate.

Newborn screening for MLD based on enzyme activity has been difficult due to the high occurrence of ARSA enzyme pseudodeficiency and the inability to distinguish MLD from pseudodeficiency. A mass spectrometry-based method to quantify sulfatides in dried blood and urine spots has been developed [Spacil et al 2016] and a large-scale pilot study for newborn screening to evaluate this method for sulfatide analysis in dried blood spots has begun at the University of Washington, Seattle.

Establishing the Diagnosis

The diagnosis of arylsulfatase A deficiency (metachromatic leukodystrophy, MLD) is established in a proband by the presence of suggestive findings (e.g., progressive neurologic dysfunction, MRI evidence of leukodystrophy, or ARSA enzyme deficiency) and ANY of the following:

NOTE: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ARSA variants of uncertain significance (or of one known ARSA pathogenic variant and one ARSA variant of uncertain significance) does not establish or rule out a diagnosis.

Molecular Genetic Testing

Three classes of ARSA alleles resulting in low ARSA enzyme activity need to be distinguished (see Genotype-Phenotype Correlations):

  • ARSA pathogenic variants that cause MLD (ARSA-MLD alleles) in the homozygous or compound heterozygous state
  • ARSA alleles with sequence variants resulting in pseudodeficiency (ARSA-PD)
  • Alleles with two ARSA sequence variants on the same chromosome (cis configuration). For example, individuals can have ARSA-MLD and ARSA-PD alleles in cis.

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing. Parental testing may be necessary to determine the phase of the identified variants in the proband.

  • Single-gene testing. Sequence analysis of ARSA is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • Use of a multigene panel that includes ARSA and other genes of interest (see Differential Diagnosis) can be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Arylsulfatase A Deficiency

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
ARSA Sequence analysis 390%-95% 4, 5, 6
Gene-targeted deletion/duplication analysis 7<1% 8

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Four pathogenic variants (c.465+1G>A, c.1210+1G>A, p.Pro428Leu, and p.Ile181Ser) account for 25%-50% of the ARSA pathogenic variants in individuals of central and western European ancestry (see Table 4).


Using scanning for pathogenic variants, Gort et al [1999] identified all of the ARSA pathogenic variants in 18 unrelated affected persons of Spanish heritage.


This test method also detects the ARSA pseudodeficiency alleles (termed ARSA-PD), common variants that result in lower-than-average ARSA enzyme activity but do not cause MLD either in the homozygous state or in the compound heterozygous state with an ARSA-MLD allele.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Complete deletion of ARSA associated with MLD has been reported [Coulter-Mackie et al 1995, Eng et al 2004, Bisgaard et al 2009]. No instances of whole-gene duplication are known. Dispermic chimeris, in which two copies of ARSA were transmitted by the father, has been reported [Coulter-Mackie et al 2001].

Urinary Sulfatides

All types of MLD excrete abnormally high sulfatides in urine. These can be quantified by high-performance liquid chromatography (HPLC), mass spectrometry, and thin-layer chromatography (TLC). TLC is a semi-quantitative method. For HPCL and mass spectrometry, reference and pathologic values vary by laboratory. Because urine production is highly variable, sulfatide excretion is measured in a 24-hour urine sample or normalized to the urinary excretion of creatinine. ARSA-PD/ARSA-MLD compound heterozygotes can excrete higher-than-normal amounts of sulfatides but urinary sulfatide excretion is not as elevated as in individuals with MLD (usually >10x normal).

Note: Elevated urine sulfatides and ARSA enzyme deficiency in the presence of dysmorphic features, dysostosis multiplex, or ichthyosis should prompt evaluation for multiple sulfatase deficiency (see Differential Diagnosis).

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).

Clinical Characteristics

Clinical Description

The clinical presentation of arylsulfatase A deficiency (metachromatic leukodystrophy, MLD) is heterogeneous with respect to the age of onset, the rate of progression, and the initial symptoms. Three clinical subtypes of MLD are primarily distinguished by age of onset:

  • Late-infantile MLD, comprising 50%-60% of affected individuals
  • Juvenile MLD, approximately 20%-30%
  • Adult MLD, approximately 15%-20%

The age of onset within a family is usually similar, but exceptions occur [Arbour et al 2000]. Although the presenting symptoms and age of onset vary, all individuals eventually develop complete loss of motor, sensory, and intellectual functions. The disease course may be from several years in the late-infantile-onset form to decades 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. Age of onset is before age 30 months, following a period of apparently normal development. In the initial stage, weakness, hypotonia, and depressed deep tendon reflexes are observed. Clumsiness, frequent falls, toe walking, and dysarthria are other typical presenting signs. Symptoms may first be noted following anesthesia or a febrile illness and may subside for weeks before continuing to progress. Less commonly, seizures are the first neurologic sign. Out of 38 individuals reported with late-infantile MLD, 61% presented with motor or gait abnormalities and 39% of individuals presented with seizures [Mahmood et al 2010]. Seventy-five percent of individuals show first motor symptoms before age 18 months [Kehrer et al 2011a]. Peripheral neuropathy with slow nerve conduction velocities (NCVs) is common. Brain auditory and visual evoked response testing demonstrate impairment in hearing and vision.

As the disease progresses, language, cognitive development, and gross- and fine-motor skills regress. Peripheral neuropathy can lead to pain in the arms and legs. In one study, individuals with the late-infantile form had lost the ability to sit without support and to move by age three years, and all had lost both trunk and head control by age three years four months [Kehrer et al 2011a]. Eventually spasticity becomes prominent and bulbar involvement can result in airway obstruction and feeding difficulties requiring gastrostomy tube placement. Generalized or partial seizures can occur and vision and hearing become progressively compromised. Eventually, the child becomes bedridden with tonic spasms, decerebrate posturing, and general unawareness. Most children die within five years after the onset of symptoms, although survival can extend into the second decade of life with current levels of care.

Juvenile MLD. Age of onset is between ages 30 months and 16 years with a median age of six years two months [Kehrer et al 2011a]. Symptoms start insidiously with a decline in school performance, abnormal behaviors, or psychiatric symptoms. In published reports of individuals with juvenile MLD, 66% presented with inattention and difficulties at school, 26% with gait difficulties, 18% with tremor or ataxia, 13% with neuropathy, and 5% with seizures [Mahmood et al 2010]. Early- and late-juvenile subvariants are sometimes differentiated, neuromuscular difficulties developing first in individuals with earlier-onset MLD and behavioral issues developing first in individuals with later-onset MLD.

Progression is similar to but slower than in the late-infantile form. The rate of motor deterioration can be quite variable [Kehrer et al 2011a]. The majority of individuals die before age 20 years, but survival is quite variable.

Adult MLD. Symptoms are first noted after sexual maturity (age ~16 years) but may not occur until the fourth or fifth decade. As with juvenile MLD, presenting symptoms vary. Initial signs are often emerging problems in school or job performance. Alcohol or drug use, poor money management, emotional lability, inappropriate affect, and frank psychosis often lead to psychiatric evaluation and an initial diagnosis of dementia, schizophrenia, or depression. In others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) predominate initially, leading to diagnosis of multiple sclerosis or other neurodegenerative diseases. Among published cases of adult MLD, 72% presented with dementia and behavioral difficulties, 16% with psychosis and schizophrenia, 28% with neuropathy, and 12% with seizures [Mahmood et al 2010]. Peripheral neuropathy, though a frequent aspect of adult-onset MLD, is not present in all individuals.

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 quadriparesis, or decorticate posturing occurs. Severe contractures and generalized seizures may occur. The duration of the disease ranges from several years to decades.

Other findings in MLD

  • In the past, findings of increased concentration of cerebrospinal fluid 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. Notably, nerve conduction abnormalities, which are almost universal in individuals with MLD, can be present before clinical symptoms appear.
  • Outside the central nervous system, sulfatide accumulation has been found in other organs. In the gallbladder, hyperplastic polyps are common and hemobilia as well as gallbladder carcinoma have been reported as complications [Garavelli et al 2009, van Rappard et al 2016b]. Polypoid masses in stomach and duodenum complicated by intestinal intussusception have also been reported [Yavuz & Yuksekkaya 2011].

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

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 0%-10% of control values in synthetic-substrate-based 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

  • Early-onset (late-infantile) MLD. Affected individuals are usually homozygous or compound heterozygous for ARSA-MLD alleles that make no detectable functional arylsulfatase A enzyme (I-type or null alleles) [Cesani et al 2009]. The most common I-type alleles are c.465+1G>A, c.1210+1G>A, and p.Asp257His.
  • Later-onset MLDs. Affected individuals have one or two ARSA-MLD alleles that encode for an arylsulfatase A enzyme with some residual functional activity (≤1% when assayed with physiologic substrates) known as R-type alleles. The most common R-type ARSA-MLD alleles are p.Ile181Ser and p.Pro428Leu [Fluharty et al 1991]:
    • Juvenile-onset MLD. Often these individuals are compound heterozygous for an I-type and an R-type allele.
    • Adult-onset MLD. Both alleles provide some residual enzyme activity (R-type ARSA-MLD alleles).

Adult MLD subtypes

There are substantial limitations to the use of these genotype-phenotype correlations in predicting the clinical presentation and natural history of an affected individual. The predictive value is best for individuals homozygous for two I-type alleles, but individuals with one or two R-type alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors [Wang et al 2011]. Notably, additional variants in the same allele can further affect enzyme function and disease severity [Regis et al 2002].

Arylsulfatase A (ARSA) pseudodeficiency

  • ARSA-MLD/ARSA-PD genotype. Associated ARSA enzyme activity is 5% to 10% of normal controls:
    • The polyadenylation site variant, c.*96A>G, appears to contribute most strongly to the low ARSA enzyme activity characteristic of clinical pseudodeficiency [Harvey et al 1998].
    • p.Asn352Ser, 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].
    • The most common ARSA-PD allele in the European and American populations has these two sequence variants in cis configuration (i.e., on the same chromosome), designated as c.[1055A>G; *96A>G].
  • ARSA-PD/ARSA-PD genotype
    • Homozygosity for the c.*96A>G pathogenic variant (almost always in conjunction with p.Asn352Ser) is associated with ARSA enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
    • Homozygosity for the p.Asn352Ser pathogenic variant alone results in 50% or more of the mean control ARSA enzyme activity in leukocytes.


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.


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]. Assuming the prevalence stated, the overall carrier frequency is between 1:100 and 1:200. The disorder is pan ethnic; however, most data come from European and North American populations. Males and females are affected equally and there is no difference in survival.

Based on their determination of carrier status for the most common ARSA pathogenic variants in two large (>~3000-person) samples of the Polish population, Ługowska et al [2011] estimated the birth incidence at 4.1:100,000 live births. Comparing this to the incidence calculated from the number of individuals with 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
  • 1:8,000 in Israeli Arabs
  • 1:2,500 in Eskimos
  • 1: 6,400 for the western portion of the Navajo Nation in the US

ARSA-PD alleles. 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 variant 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 variant (so-called ARSA-MLD-PD alleles).

Differential Diagnosis

Arylsulfatase A deficiency. The two phenotypes that show notable overlap with arylsulfatase A deficiency are multiple sulfatase deficiency and saposin B deficiency (Table 2).

Table 2.

Disorders to Consider in the Differential Diagnosis of Arylsulfatase A Deficiency

DisorderAge at OnsetMain Clinical ManifestationsUrinary ExcretionEnzyme Activity
Multiple sulfatase deficiency 1-4 yrs, probably variableMLD-like clinical picture w/↑ CSF protein & slowed NCVs; MPS-like features, & ichthyosis↑ sulfatide & mucopolysaccharidesVery low ARSA enzyme activity; deficiency of most sulfatases in leukocytes or cultured cells 1
Saposin B deficiency (OMIM 249900)VariableMLD-like clinical picture↑ sulfatide & other glycolipidsARSA enzyme activity in normal range

CSF = cerebrospinal fluid; MPS = mucopolysaccharidosis; NCV = nerve conduction velocity


Including arylsulfatase B, arylsulfatase C, galactose-6 sulfatase, glucuronate-2 sulfatase, iduronate sulfatase, heparan-N-sulfamidase, and N-acetylglucosamine-6 sulfatase.

Other ARSA deficiency conditions. ARSA enzyme activity is also deficient in many tissues in defects of the phosphomannosyl lysosomal recognition pathway, such as I-cell disease (mucolipidosis II). The phenotype in I-cell disease is severe in infancy and is not likely to be confused with arylsulfatase A deficiency.

Other leukodystrophies and lysosomal storage diseases. MLD is difficult to differentiate from other progressive degenerative disorders that manifest after a period of normal development. Delayed development in late infancy, coupled with loss of acquired abilities, should prompt MRI evaluation. If a generalized leukodystrophy is evident, other conditions to consider include: Krabbe disease, X-linked adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Alexander disease, fucosidosis (OMIM 230000), Canavan disease, and gangliosidoses such as hexosaminidase A deficiency (including Tay-Sachs disease).

Although some mucopolysaccharidoses can have a similar presentation to arylsulfatase A deficiency, the characteristic physical features seen in most mucopolysaccharidoses (i.e., short stature, dysostosis multiplex, coarse facial appearance, corneal clouding, hepatosplenomegaly, pulmonary congestion, and heart problems) are not found in individuals with MLD. The evaluation of appropriate lysosomal enzymes can distinguish the disorders.

Arylsulfatase A pseudodeficiency. Because of the high prevalence of the ARSA-PD alleles, low ARSA enzyme activity caused by arylsulfatase pseudodeficiency can be found in association with many disorders and can be erroneously implicated in individuals diagnosed with common psychiatric or neurologic disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with arylsulfatase A deficiency (metachromatic leukodystrophy, 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
  • For those identified presymptomatically or predicted to have late-onset MLD, referral for HSCT evaluation, preferably at an institution with expertise in allogenic HSCT in individuals with metabolic disorders
  • Baseline assessment of development/cognitive abilities and behavior to monitor disease progression or changes with attempted therapy
  • Peripheral nervous system evaluation
  • Hearing assessment
  • Visual assessment
  • Consultation with a clinical or biochemical geneticist and/or genetic counselor

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

Treatment of Manifestations

Whether the intent is to prolong life or to let the disease run its 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 to anticipate decisions concerning walking aids, car seats, wheelchairs, suction equipment, swallowing aids, feeding tubes, and other supportive measures.

Seizures and contractures should be treated with anti-seizure medication and muscle relaxants, respectively. Gastroesophageal reflux, constipation, and drooling are common problems that may be helped by specific medical or surgical interventions.

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 – including the usual regime of age-appropriate vaccinations, flu shots, nutritional support, and other typical medical care. 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) is an available therapy that attempts to treat the primary central nervous system (CNS) manifestations of MLD. Despite significant improvement in allogeneic transplantation, this therapy remains controversial because:

  • Systematic outcome data are limited and difficult to generalize due the use of different eligibility criteria and transplantation protocols;
  • Outcome data from older cohorts do not predict current outcomes given constantly improving transplant-related morbidity and mortality due to advances in donor-recipient HLA typing and matching, conditioning, infectious disease detection and management, and the use of non-carrier donors; and
  • Different types of MLD have shown different responses.

However, in the absence of alternative approaches, HSCT needs to be discussed with families, particularly with those with slower progressing, late-onset forms of MLD. At-risk relatives can be diagnosed by biochemical or molecular genetic testing before symptoms occur and could benefit most from this intervention. Despite mounting evidence of utility, HSCT is not expected to fully abrogate the manifestations of the disease.

Late-infantile MLD. Allogenic HSCT even at a presymptomatic stage has been shown to be ineffective and is not recommended [Bredius et al 2007, van Rappard et al 2016a]. Disease progression in late-infantile MLD is faster than the pace of engraftment and subsequent CNS migration of bone marrow-derived monocyte/macrophages, even in clinically asymptomatic individuals.

Juvenile and adult MLD. Taken together the data support that HSCT is a relatively safe procedure for individuals with pre- and early symptomatic MLD with the juvenile or adult form of the disease [Görg et al 2007, Pierson et al 2008, Cable et al 2011, Krägeloh-Mann et al 2013, Martin et al 2013, Solders et al 2014, Boucher et al 2015, Chen et al 2016, Groeschel et al 2016, van Rappard et al 2016a]. In these clinical types, HSCT can result in disease stabilization and high disease-burden-free survival. Compared with nontransplanted individuals, the transplanted individuals are less likely to lose their gross motor or language function and demonstrate significantly lower MRI severity scores. Motor and cognitive function at the time of HSCT evaluation are good predictors of outcome: Van Rappard et al [2016a] propose that patients with affected motor (inability to walk without support) and cognitive (IQ <75) function receive no benefit from HSCT. Brain stem auditory evoked responses, visual evoked potentials, electroencephalogram, and/or peripheral nerve conduction velocities have been shown to stabilize or improve in individuals with juvenile MLD [Martin et al 2013]. Long-term neuroimaging after HSCT suggest that remyelination occurs [Ding et al 2012].

Regardless of clinical type, HSCT should not be offered to individuals with significant neurologic involvement at the time of evaluation. Engraftment has been shown to require myeloablative conditioning most commonly utilizing full-dose busulfan, which crosses the blood-brain barrier [Boelens & van Hasselt 2016]. This can result in further neurologic decline.

Prevention of Secondary Complications

Therapies designed to prevent decline in mobility, cognitive ability, communication, or food intake are considered to be most beneficial by caregivers and physicians [Eichler et al 2016].

Implement safety measures for gait or movement limitations as well as seizure precautions.

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.

For further information on the specific nursing care requirements for those with MLD who undergo HCST or in late stages of the disease, see Barrell [2007].

Anesthesia (if required) should be administered by an experienced anesthesiologist: exacerbation of symptoms has been noted following anesthesia, as affected individuals may have altered responses to sedatives and anesthetics [Mattioli et al 2007, Birkholz et al 2009, Cappuccio et al 2013].


Individuals with MLD should be followed at regular intervals by a neurologist and a metabolic geneticist.

Periodic brain MRI examination to monitor the status of CNS demyelination should be performed. The MLD MR severity scoring method can be used to provide a measure of brain involvement in these individuals [Eichler et al 2009] to allow for monitoring disease evolution and response to therapy.

Monitor for changes in motor function that 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 (GMFC-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 useful in evaluating and comparing therapeutic trials.

Monitor for onset of seizures and/or contractures, which could indicate a need to change medical management and physical therapy.

Monitor for difficulties with feeding or swallowing. Monitor nutritional needs and need for gastrostomy tube placement.

Special attention is indicated 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].

Evaluation of Relatives at Risk

It is appropriate to consider evaluation of apparently asymptomatic sibs of a proband to identify those who could potentially benefit from hematopoietic stem cell transplantation (HSCT) and other experimental treatment options. Although substantial risk is involved and long-term effects are unclear, the best clinical outcomes are obtained when HSCT occurs before clinical symptoms have appeared; see Prevention of Primary Manifestations.

Evaluations can include the following:

  • Perform molecular genetic testing if the pathogenic variants in the family are known.
  • If the pathogenic variants in the family are not known, work up should begin with measurement of urinary excretion of sulfatides.
  • Measurement of ARSA in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See Suggestive Findings, ARSA enzyme pseudodeficiency.
  • Presymptomatically identified individuals should be followed regularly by a neurologist and a metabolic geneticist.
  • Those predicted to have juvenile and late-onset MLD based on family history or genotype should be referred for HSCT evaluation.
  • Periodic brain MRI examination to monitor the status of CNS demyelination to allow for scoring and monitoring of response to therapy.

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 HSCT include genetic modification of autologous hematopoietic stem and progenitor cells using gene therapy, combination with intrathecal enzyme replacement, or intrathecal cell transplantation.

Ex vivo gene therapy. Gene therapy is the delivery of genetic material using viral vectors to an individual’s cells or tissue for therapeutic purposes; it can be accomplished using ex vivo or in vivo approaches. Ex vivo modification of autologous hematopoietic stem and progenitor cells using a lentivirus expressing functional ARSA enzyme is currently being tested in Phase I/II clinical trials with promising results. An ad hoc analysis of the "TIGET-MLD" trial (ClinicalTrials.gov) was published [Sessa et al 2016]. It describes nine children with a diagnosis of early-onset disease (6 had late-infantile disease, 2 had early-juvenile disease, and 1 had early-onset disease that could not be definitively classified). At the time of analysis, all children had survived, with a median follow up of 36 months (range 18-54 months). The studies showed reconstitution of ARSA activity in hematopoietic cells and in the cerebrospinal fluid. Compared to historical untreated controls, eight individuals, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression. The Gross Motor Function Measurement (GMFM) scores for six individuals was like that of normally developing children. Electroneurographic studies of peripheral nerves documented improvement in three individuals.

In vivo gene therapy. Allogeneic HSCT and autologous HSCT with gene-corrected cells is showing great benefit, primarily in presymptomatic individuals. These are promising therapies for individuals identified at presymptomatic stages with a family history of MLD or perhaps individuals identified on future newborn screening. Unfortunately, most individuals diagnosed with MLD have no family history of MLD. Hence, most children with severe forms of MLD would not be diagnosed at the presymptomatic phase of the disease, making it unlikely for this therapeutic option to be offered or effective for many individuals with MLD. Accordingly, there is a need for therapies that can get to the brain quickly. One way to achieve this is with in vivo gene therapy via intrathecal or intracerebral delivery of viral vectors. TG-MLD (ClinicalTrials.gov) is testing the delivery of an adeno-associated virus serotype rh.10 (AAVrh.10) vector to transfer the cDNA coding for ARSA enzyme in children affected with early onset forms of MLD.

Enzyme replacement therapy (ERT). An alternative to in vivo gene therapy is ERT. For the most part ERT has been 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. However, different forms of human ARSA enzyme are now available, and animal studies suggest that it may be a useful supplement for HSCT [Martino et al 2005, Matzner et al 2005]. Intrathecal delivery of the enzyme is being tested in individuals with late-infantile form (ClinicalTrials.gov). The efficacy and safety of intravenous ERT is being tested in an individual with late-infantile MLD who had received HSCT at a presymptomatic stage of the disease (ClinicalTrials.gov).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other: therapies under preclinical investigation

  • Intracerebral delivery of AAV5 vector encoding human ARSA in non-human primates [Colle et al 2010]
  • Enzyme replacement using a single intracerebroventricular injection of self-complementary AAV1 vector in the CSF in a mouse model of MLD [Hironaka et al 2015]
  • Neonatal systemic injection of an AAV serotype 9 vector in an MLD mouse model [Miyake et al 2014]

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

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 ARSA pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with arylsulfatase A deficiency are obligate heterozygotes (carriers) for a pathogenic variant in ARSA.

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

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the ARSA pathogenic variants in the family. In instances of apparent homozygosity for an MLD-causing ARSA pathogenic variant in a proband, it is appropriate either to establish the presence of the ARSA pathogenic variant in both parents or to confirm the presence of two alleles in the proband by performing deletion/duplication analysis to rule out deletion of one ARSA allele. This is important in clarifying the genetic status of at-risk relatives.

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.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the ARSA pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MLD are possible.

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 [Besley et al 1991].

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

If 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.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Arylsulfatase A Deficiency: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ARSA 22q13​.33 Arylsulfatase A ARSA database ARSA ARSA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Arylsulfatase A Deficiency (View All in OMIM)


Molecular Pathogenesis

The molecular pathogenic 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. Neuroinflammation has also been proposed based on experiments in murine models of MLD [Stein et al 2015].

Gene structure. 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 has not been investigated. For a detailed summary of gene and protein information, see Table A, Gene.

Benign and pseudodeficiency variants. Several variants of ARSA have been identified (see Table 3). Other synonymous variants have also been reported (see Table A, ClinVar).

Pathogenic variants. At least 200 ARSA pathogenic variants associated with arylsulfatase A deficiency have been reported [Cesani et al 2016]. Disease-causing ARSA-MLD variants 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 a few individuals with MLD [Coulter-Mackie et al 1995, Eng et al 2004, Bisgaard et al 2009]. One case of intragenic recombination leading to somatic mosaicism has been reported [Regis et al 2006].

Table 3.

Selected ARSA Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
Benign & pseudodeficiency
c.1055A>G 2, 3
c.1178C>G 4
c.*96A>G 3
-- NM_000487​.5
-- NM_000487​.5
-- NM_000487​.5
(c.1401_1411del, 1401del11bp)

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


c.1055A>G (ARSA-PD glycosylation site alteration) is a common benign variant occurring in 15%-40% of individuals, depending on the population studied.


The most common ARSA-PD allele in the European and American populations has two sequence variants in cis configuration (i.e., on the same chromosome), designated as c.[1055A>G; *96A>G].


Found in approximately half of the Euro/American population initially studied

Table 4.

Distribution of the Most Common ARSA Pathogenic Variants in Various Populations

Pathogenic Variant% Late-Infantile% Juvenile% Adult% All MLD AllelesReference – Ethnicity 1 (# of affected individuals)
European c.465+1G>A---15Draghia et al [1997] (21)
3911519Ługowska et al [2005b] – P (43)
4016925Ługowska et al [2005a] – Eu (384)
298216Berger et al [1997] (25)
4516228Polten et al [1991] (66)
19.7Cesani et al [2009] (432)
p.Pro428Leu---15 Draghia et al [1997]
0144517Ługowska et al [2005b] – P
03042.518.6Ługowska et al [2005a] – Eu
7156026Berger et al [1997] (25)
0345927Polten et al [1991] (66)
12.2Cesani et al [2009] (432)
c.1210+1G>A11305Ługowska et al [2005b] – P
---2Fluharty et al [1991] (~100)
p.Ile181Ser0172313Ługowska et al [2005b] – P
0153012Berger et al [1997] (25)
2Fluharty et al [1991] (~100)
5Cesani et al [2009] (432)
Japanese p.Gly101Asp40---Eto et al [1993] (10)
---45.5Kurosawa et al [1998] (11)
c.465+1G>A10Eto et al [1993] (10)
p.Gly247Arg55--Eto et al [1993] (10)
---9Kurosawa et al [1998] (11)
p.Thr411Ile9Kurosawa et al [1998] (11)

P = Polish population; Eu = western European population

For additional information on pathogenic variants commonly found in specific populations, see:

Normal gene product. Arylsulfatase A has a precursor polypeptide of approximately 62 kd that is 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 p.Cys71 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, alleles with pathogenic splice site variants, insertions, or deletions do not produce any active enzyme (I-type ARSA-MLD variants). Approximately half of the variants 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 variants). In those cases in which the properties of the mutated 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 mutated protein [von Bülow et al 2002, Poeppel et al 2005].

Chapter Notes

Author History

Arvan L Fluharty, PhD; University of California, Los Angeles (2006-2017)
Natalia Gomez-Ospina, MD, PhD (2017-present)

Revision History

  • 30 April 2020 (lb) Revision: current variant nomenclature added
  • 14 December 2017 (sw) Comprehensive update posted live
  • 6 February 2014 (me) Comprehensive update posted live
  • 25 August 2011 (me) Comprehensive update posted live
  • 23 September 2008 (me) Comprehensive update posted live
  • 30 May 2006 (me) Review posted live
  • 15 November 2004 (mf) Original submission


Published Guidelines / Consensus Statements

  • Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Genet Med. 2011;13:457-84.

Literature Cited

  • Alvarez-Leal M, Contreras-Hernandez D, Chavez A, Diaz-Contreras JA, Careaga-Olivares J, Zuniga-Charles MA, Reynoso MC, Hernandez-Tellez A. Leukocyte arylsulfatase A activity in patients with alcohol-related cirrhosis. Am J Hum Biol. 2001;13:297–300. [PubMed: 11460894]
  • Arbour LT, Silver K, Hechtman P, Treacy EP, Coulter-Mackie MB. Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol. 2000;23:173–6. [PubMed: 11020646]
  • Artigalás O, Lagranha VL, Saraiva-Pereira ML, Burin MG, Lourenço CM, van der Linden H Jr, Santos ML, Rosemberg S, Steiner CE, Kok F, de Souza CF, Jardim LB, Giugliani R, Schwartz IV. Clinical and biochemical study of 29 Brazilian patients with metachromatic leukodystrophy. J Inherit Metab Dis. 2010;33 Suppl 3:S257–62. [PubMed: 20596894]
  • Barrell C. Juvenile metachromatic leukodystrophy: understanding the disease and implications for nursing care. J Pediatr Oncol Nurs. 2007;24:64–9. [PubMed: 17332420]
  • Barth ML, Fensom A, Harris A. Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum Genet. 1993;91:73–7. [PubMed: 8095918]
  • Berger J, Loschl B, Bernheimer H, Lugowska A, Tylki-Szymanska A, Gieselmann V, Molzer B. Occurrence, distribution, and phenotype of arylsulfatase A mutations in patients with metachromatic leukodystrophy. Am J Med Genet. 1997;69:335–40. [PubMed: 9096767]
  • Bertelli M, Gallo S, Buda A, Cecchin S, Fabbri A, Lapucci C, Andrighetto G, Sidoti V, Lorusso L, Pandolfo M. Novel mutations in the arylsulfatase A gene in eight Italian families with metachromatic leukodystrophy. J Clin Neurosci. 2006;13:443–8. [PubMed: 16678723]
  • Besley GT, Young EP, Fensom AH, Cooper A. First trimester diagnosis of inherited metabolic disease: Experience in the UK. J Inherit Metab Dis. 1991;14:128–33. [PubMed: 1886402]
  • Biffi A, Cesani M, Fumagalli F, Del Carro U, Baldoli C, Canale S, Gerevini S, Amadio S, Falautano M, Rovelli A, Comi G, Roncarolo MG, Sessa M. Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet. 2008;74:349–57. [PubMed: 18786133]
  • Birkholz T, Irouschek A, Knorr C, Schmidt J. Alternative anesthetic management of a child with spastic quadriplegia due to metachromatic leukodystrophy using total intravenous anesthesia. Paediatr Anaesth. 2009;19:551–2. [PubMed: 19453595]
  • Bisgaard AM, Kirchhoff M, Nielsen JE, Kibaek M, Lund A, Schwartz M, Christensen E. Chromosomal deletion unmasking a recessive disease: 22q13 deletion syndrome and metachromatic leukodystrophy. Clin Genet. 2009;75:175–9. [PubMed: 19054018]
  • Boelens JJ, van Hasselt PM. Neurodevelopmental outcome after hematopoietic cell transplantation in inborn errors of metabolism: current considerations and future perspectives. Neuropediatrics. 2016;47:285–92. [PubMed: 27308871]
  • Boucher AA, Miller W, Shanley R, Ziegler R, Lund T, Raymond G, Orchard PJ. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: The largest single-institution cohort report. Orphanet J Rare Dis. 2015;10:94. [PMC free article: PMC4545855] [PubMed: 26245762]
  • Bredius RG, Laan LA, Lankester AC, Poorthuis BJ, van Tol MJ, Egeler RM, Arts WF. Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression. Bone Marrow Transplant. 2007;39:309–10. [PubMed: 17237829]
  • Cable C, Finkel RS, Lehky TJ, Biassou NM, Wiggs EA, Bunin N, Pierson TM. Unrelated umbilical cord blood transplant for juvenile metachromatic leukodystrophy: a 5-year follow-up in three affected siblings. Mol Genet Metab. 2011;102:207–9. [PMC free article: PMC3053057] [PubMed: 21035368]
  • Cappuccio G, Brunetti-Pierri N, Terrone G, Romano A, Andria G, Del Giudice E. Low-dose amitriptyline-induced acute dystonia in a patient with metachromatic leukodystrophy. JIMD Rep. 2013;9:113–6. [PMC free article: PMC3565674] [PubMed: 23430556]
  • Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Biffi A. Characterization of new arylsulfatase a gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. Hum Mutat. 2009;30:E936–45. [PubMed: 19606494]
  • Cesani M, Lorioli L, Grossi S, Amico G, Fumagalli F, Spiga I, Biffi A. Mutation update of arsa and psap genes causing metachromatic leukodystrophy. Hum Mutat. 2016;37:16–27. [PubMed: 26462614]
  • Chen X, Gill D, Shaw P, Ouvrier R, Troedson C. Outcome of early juvenile onset metachromatic leukodystrophy after unrelated cord blood transplantation: A case series and review of the literature. J Child Neurol. 2016;31:338–44. [PubMed: 26187619]
  • Colle MA, Piguet F, Bertrand L, Raoul S, Bieche I, Dubreil L, Sloothaak D, Bouquet C, Moullier P, Aubourg P, Cherel Y, Cartier N, Sevin C. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet. 2010;19:147–58. [PubMed: 19837699]
  • Coulter-Mackie MB, Gagnier L. Spectrum of mutations in the arylsulfatase A gene in a Canadian DNA collection including two novel frameshift mutations, a new missence mutation (C488R) and an MLD mutation (R84) in cis with a pseudodeficiency allele. Mol Genet Metab. 2003;79:91–8. [PubMed: 12809638]
  • Coulter-Mackie MB, Rip J, Beis MJ, Ferreira P, Ludman MD. Multiple metachromatic leucodystrophy alleles in an unaffected subject: a case of dispermic chimaerism. J Med Genet. 2001;38:E15. [PMC free article: PMC1734879] [PubMed: 11333871]
  • Coulter-Mackie MB, Rip J, Ludman MD, Beis J, Cole DE. Metachromatic leucodystrophy (MLD) in a patient with a constitutional ring chromosome 22. J Med Genet. 1995;32:787–91. [PMC free article: PMC1051701] [PubMed: 8558556]
  • Dierks T, Dickmanns A, Preusser-Kunze A, Schmidt B, Mariappan M, von Figura K, Ficner R, Rudolph MG. Molecular basis for multiple sulfatase deficiency and mechanism for formylglycine generation of the human formylglycine-generating enzyme. Cell. 2005;121:541–52. [PubMed: 15907468]
  • Ding XQ, Bley A, Kohlschutter A, Fiehler J, Lanfermann H. Long-term neuroimaging follow-up on an asymptomatic juvenile metachromatic leukodystrophy patient after hematopoietic stem cell transplantation: Evidence of myelin recovery and ongoing brain maturation. Am J Med Genet A. 2012;158A:257–60. [PubMed: 22140054]
  • Draghia R, Letourneur F, Drugan C, Manicom J, Blanchot C, Kahn A, Poenaru L, Caillaud C. Metachromatic leukodystrophy: identification of the first deletion in exon 1 and of nine novel point mutations in the arylsulfatase A gene. Hum Mutat. 1997;9:234–42. [PubMed: 9090526]
  • Eichler F, Grodd W, Grant E, Sessa M, Biffi A, Bley A, Kohlschuetter A, Loes DJ, Kraegeloh-Mann I. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations. AJNR Am J Neuroradiol. 2009;30:1893–7. [PMC free article: PMC7051299] [PubMed: 19797797]
  • Eichler FS, Cox TM, Crombez E, Dali CI, Kohlschutter A. Metachromatic leukodystrophy: An assessment of disease burden. J Child Neurol. 2016;31:1457–63. [PubMed: 27389394]
  • Eng B, Heshka T, Tarnopolsky MA, Nakamura LM, Nowaczyk MJ, Waye JS. Infantile metachromatic leukodystrophy (MLD) in a compound heterozygote for the c.459 + 1G > A mutation and a complete deletion of the ARSA gene. Am J Med Genet A. 2004;128A:95–7. [PubMed: 15211666]
  • Eto Y, Kawame H, Hasegawa Y, Ohashi T, Ida H, Tokoro T. Molecular characteristics in Japanese patients with lipidosis: novel mutations in metachromatic leukodystrophy and Gaucher disease. Mol Cell Biochem. 1993;119:179–84. [PubMed: 8455580]
  • Fluharty AL, Fluharty CB, Bohne W, von Figura K, Gieselmann V. Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient. Am J Hum Genet. 1991;49:1340–50. [PMC free article: PMC1686463] [PubMed: 1684088]
  • Garavelli L, Rosato S, Mele A, Wischmeijer A, Rivieri F, Gelmini C, Sandonà F, Sassatelli R, Carlinfante G, Giovanardi F, Gemmi M, Della Giustina E, Amarri S, Banchini G, Bedogni G. Massive hemobilia and papillomatosis of the gallbladder in metachromatic leukodystrophy: a life-threatening condition. Neuropediatrics. 2009;40:284–6. [PubMed: 20446223]
  • Görg M, Wilck W, Granitzny B, Suerken A, Lukacs Z, Ding X, Schulte-Markwort M, Kohlschütter A. Stabilization of juvenile metachromatic leukodystrophy after bone marrow transplantation: a 13-year follow-up. J Child Neurol. 2007;22:1139–42. [PubMed: 17890417]
  • Gort L, Coll MJ, Chabas A. Identification of 12 novel mutations and two new polymorphisms in the arylsulfatase A gene: haplotype and genotype-phenotype correlation studies in Spanish metachromatic leukodystrophy patients. Hum Mutat. 1999;14:240–8. [PubMed: 10477432]
  • Groeschel S, Kehrer C, Engel C. I Dali C, Bley A, Steinfeld R, Grodd W, Krägeloh-Mann I. Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course. J Inherit Metab Dis. 2011;34:1095–102. [PubMed: 21698385]
  • Groeschel S, Kuhl JS, Bley AE, Kehrer C, Weschke B, Doring M, Muller I. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016;73:1133–40. [PubMed: 27400410]
  • Grossi S, Regis S, Rosano C, Corsolini F, Uziel G, Sessa M, Di Rocco M, Parenti G, Deodato F, Leuzzi V, Biancheri R, Filocamo M. Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles. Human Mutation. 2008;29:E220–30. [PubMed: 18693274]
  • Harvey JS, Carey WF, Morris CP. Importance of the glycosylation and polyadenylation variants in metachromatic leukodystrophy pseudodeficiency phenotype. Hum Mol Genet. 1998;7:1215–9. [PubMed: 9668161]
  • Hironaka K, Yamazaki Y, Hirai Y, Yamamoto M, Miyake N, Miyake K, Shimada T. Enzyme replacement in the csf to treat metachromatic leukodystrophy in mouse model using single intracerebroventricular injection of self-complementary aav1 vector. Sci Rep. 2015;5:13104. [PMC free article: PMC4539541] [PubMed: 26283284]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • Kehrer C, Blumenstock G, Gieselmann V, Krägeloh-Mann I, et al. The natural course of gross motor deterioration in metachromatic leukodystrophy. Dev Med Child Neurol. 2011a;53:850–5. [PubMed: 21707604]
  • Kehrer C, Blumenstock G, Raabe C, Krägeloh-Mann I. Development and reliability of a classification system for gross motor function in children with metachromatic leucodystrophy. Dev Med Child Neurol. 2011b;53:156–60. [PubMed: 21087233]
  • Krägeloh-Mann I, Groeschel S, Kehrer C, Opherk K, Nägele T, Handgretinger R, Müller I. Juvenile metachromatic leukodystrophy 10 years post transplant compared with a non-transplanted cohort. Bone Marrow Transplant. 2013;48:369–75. [PubMed: 22941383]
  • Kurosawa K, Ida H, Eto Y. Prevalence of arylsulphatase A mutations in 11 Japanese patients with metachromatic leukodystrophy: identification of two novel mutations. J Inherit Metab Dis. 1998;21:781–2. [PubMed: 9819708]
  • Lugowska A, Płoski R, Włodarski P, Tylki-Szymańska A. Molecular bases of metachromatic leukodystrophy in polish patients. J Hum Genet. 2010;55:394–6. [PubMed: 20339381]
  • Ługowska A, Amaral O, Berger J, Berna L, Bosshard NU, Chabas A, Fensom A, Gieselmann V, Gorovenko NG, Lissens W, Mansson JE, Marcao A, Michelakakis H, Bernheimer H, Ol'khovych NV, Regis S, Sinke R, Tylki-Szymanska A, Czartoryska B. Mutations c.459+1G>A and p.P426L in the ARSA gene: prevalence in metachromatic leukodystrophy patients from European countries. Mol Genet Metab. 2005a;86:353–9. [PubMed: 16140556]
  • Ługowska A, Berger J, Tylki-Szymańska A, Löschl B, Molzer B, Zobel M, Czartoryska B. Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland. Clin Genet. 2005b;68:48–54. [PubMed: 15952986]
  • Ługowska A, Ponińska J, Krajewski P, Broda G, Płoski R. Population carrier rates of pathogenic ARSA gene mutations: is metachromatic leukodystrophy underdiagnosed? PLoS One. 2011;6:e20218. [PMC free article: PMC3112151] [PubMed: 21695197]
  • Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W. Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry. 1998;37:3654–64. [PubMed: 9521684]
  • Mahmood A, Berry J, Wenger DA, Escolar M, Sobeih M, Raymond G, Eichler FS. Metachromatic leukodystrophy: A case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol. 2010;25:572–80. [PMC free article: PMC4301611] [PubMed: 20038527]
  • Marcão A, Amaral O, Pinto E, Pinto R, Sá Miranda MC. Metachromatic leucodystrophy in Portugal-finding of four new molecular lesions: C300F, P425T, g.1190-1191insC, and g.2408delC. Mutations in brief no. 232. Online. Hum Mutat. 1999;13:337–8. [PubMed: 10220151]
  • Martin HR, Poe MD, Provenzale JM, Kurtzberg J, Mendizabal A, Escolar ML. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol Blood Marrow Transplant. 2013;19:616–24. [PubMed: 23348427]
  • Martino S, Consiglio A, Cavalieri C, Tiribuzi R, Costanzi E, Severini GM, Emiliani C, Bordignon C, Orlacchio A. Expression and purification of a human, soluble arylsulfatase A for metachromatic leukodystrophy enzyme replacement therapy. J Biotechnol. 2005;117:243–51. [PubMed: 15862354]
  • Mattioli C, Gemma M, Baldoli C, Sessa M, Albertin A, Beretta L. Sedation for children with metachromatic leukodystrophy undergoing MRI. Paediatr Anaesth. 2007;17:64–9. [PubMed: 17184435]
  • Matzner U, Herbst E, Hedayati KK, Lullmann-Rauch R, Wessig C, Schroder S, Eistrup C, Moller C, Fogh J, Gieselmann V. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. 2005;14:1139–52. [PubMed: 15772092]
  • Miyake N, Miyake K, Asakawa N, Yamamoto M, Shimada T. Long-term correction of biochemical and neurological abnormalities in mld mice model by neonatal systemic injection of an aav serotype 9 vector. Gene Ther. 2014;21:427–33. [PubMed: 24572788]
  • Morana G, Biancheri R, Dirocco M, Filocamo M, Marazzi MG, Pessagno A, Rossi A. Enhancing cranial nerves and cauda equina: an emerging magnetic resonance imaging pattern in metachromatic leukodystrophy and krabbe disease. Neuropediatrics. 2009;40:291–4. [PubMed: 20446225]
  • Niida Y, Kuroda M, Mitani Y, Yokoi A, Ozaki M. Paternal uniparental isodisomy of chromosome 22 in a patient with metachromatic leukodystrophy. J Hum Genet. 2012;57:687–90. [PubMed: 22854541]
  • Olkhovich NV, Takamura N, Pichkur NA, Gorovenko NG, Aoyagi K, Yamashita S. Novel mutations in arylsulfatase A gene in three Ukranian families with metachromatic leukodystrophy. Mol Genet Metab. 2003;80:360–3. [PubMed: 14680985]
  • Peiffer J. [On metachromatic leukodystrophy (Scholz type)]. Arch Psychiatr Nervenkr. Z Gesamte Neurol Psychiatr. 1959;199:386–416. [PubMed: 14431398]
  • Pierson TM, Bonnemann CG, Finkel RS, Bunin N, Tennekoon GI. Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy. Ann Neurol. 2008;64:583–7. [PMC free article: PMC2605197] [PubMed: 19067349]
  • Poeppel P, Habetha M, Marcao A, Bussow H, Berna L, Gieselmann V. Missense mutations as a cause of metachromatic leukodystrophy. Degradation of arylsulfatase A in the endoplasmic reticulum. FEBS J. 2005;272:1179–88. [PubMed: 15720392]
  • Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy. N Engl J Med. 1991;324:18–22. [PubMed: 1670590]
  • Rauschka H, Colsch B, Baumann N, Wevers R, Schmidbauer M, Krammer M, Turpin JC, Lefevre M, Olivier C, Tardieu S, Krivit W, Moser H, Moser A, Gieselmann V, Zalc B, Cox T, Reuner U, Tylki-Szymanska A, Aboul-Enein F, LeGuern E, Bernheimer H, Berger J. Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology. 2006;67:859–63. [PubMed: 16966551]
  • Regis S, Corsolini F, Stroppiano M, Cusano R, Filocamo M. Contribution of arylsulfatase A mutations located on the same allele to enzyme activity reduction and metachromatic leukodystrophy severity. Hum Genet. 2002;110:351–5. [PubMed: 11941485]
  • Regis S, Lualdi S, Biffi A, Sessa M, Corsolini F, Parenti G, Filocamo M. Somatic intragenic recombination of the arylsulfatase a gene in a metachromatic leukodystrophy patient. Mol Genet Metab. 2006;89:150–5. [PubMed: 16782379]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Rip JW, Gordon BA. A simple spectrophotometric enzyme assay with absolute specificity for arylsulfatase A. Clin Biochem. 1998;31:29–31. [PubMed: 9559221]
  • Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Biffi A. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: An ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388:476–87. [PubMed: 27289174]
  • Shukla P, Vasisht S, Srivastava R, Gupta N, Ghosh M, Kumar M, Sharma R, Gupta AK, Kaur P, Kamate M, Gulati S, Kalra V, Phadke S, Singhi P, Dherai AJ, Kabra M. Molecular and structural analysis of metachromatic leukodystrophy patients in Indian population. J Neurol Sci. 2011;301:38–45. [PubMed: 21167507]
  • Singh RK, Leshner RT, Kadom N, Vanderver AL. Isolated cranial nerve enhancement in metachromatic leukodystrophy. Pediatr Neurol. 2009;40:380–2. [PMC free article: PMC2705062] [PubMed: 19380076]
  • Solders M, Martin DA, Andersson C, Remberger M, Andersson T, Ringden O, Solders G. Hematopoietic sct: A useful treatment for late metachromatic leukodystrophy. Bone Marrow Transplant. 2014;49:1046–51. [PubMed: 24797185]
  • Spacil Z, Babu Kumar A, Liao HC, Auray-Blais C, Stark S, Suhr TR, Gelb MH. Sulfatide analysis by mass spectrometry for screening of metachromatic leukodystrophy in dried blood and urine samples. Clin Chem. 2016;62:279–86. [PMC free article: PMC4737087] [PubMed: 26585924]
  • Stein A, Stroobants S, Gieselmann V, D'Hooge R, Matzner U. Anti-inflammatory therapy with simvastatin improves neuroinflammation and cns function in a mouse model of metachromatic leukodystrophy. Mol Ther. 2015;23:1160–8. [PMC free article: PMC4817791] [PubMed: 25896249]
  • Tsuda T, Hasegawa Y, Eto Y. Two novel mutations in a japanese patient with the late-infantile form of metachromatic leukodystrophy. Brain Dev. 1996;18:400–3. [PubMed: 8891236]
  • Vagedes P, Saenger W, Knapp EW. Driving forces of protein association: the dimer-octamer equilibrium in arylsulfatase A. Biophys J. 2002;83:3066–78. [PMC free article: PMC1302386] [PubMed: 12496078]
  • van Rappard DF, Boelens JJ, van Egmond ME, Kuball J, van Hasselt PM, Oostrom KJ, Wolf NI. Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood. 2016a;127:3098–101. [PubMed: 27118454]
  • van Rappard DF, Bugiani M, Boelens JJ, van der Steeg AF, Daams F, de Meij TG, Wolf NI. Gallbladder and the risk of polyps and carcinoma in metachromatic leukodystrophy. Neurology. 2016b;87:103–11. [PubMed: 27261095]
  • von Bülow R, Schmidt B, Dierks T, Schwabauer N, Schilling K, Weber E, Usón I, von Figura K. Defective oligomerization of arylsulfatase a as a cause of its instability in lysosomes and metachromatic leukodystrophy. J Biol Chem. 2002;277:9455–61. [PubMed: 11777924]
  • Von Figura K, Gieselmann V, Jacken J. Metachromatic leukodystrophy. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3695-724.
  • Wang J, Zhang W, Pan H, Bao X, Wu Y, Wu X, Jiang Y. ARSA gene mutations in five Chinese metachromatic leukodystrophy patients. Pediatr Neurol. 2007;36:397–401. [PubMed: 17560502]
  • Wang RY, Bodamer OA, Watson MS, Wilcox WR, et al. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13:457–84. [PubMed: 21502868]
  • Yavuz H, Yuksekkaya HA. Intestinal involvement in metachromatic leukodystrophy. J Child Neurol. 2011;26:117–20. [PubMed: 21212458]
  • Zlotogora J, Bach G, Bosenberg C, Barak Y, von Figura K, Gieselmann V. Molecular basis of late infantile metachromatic leukodystrophy in the Habbanite Jews. Hum Mutat. 1995;5:137–43. [PubMed: 7749412]
Copyright © 1993-2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2023 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1130PMID: 20301309


Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...