Clinical characteristics.

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile, juvenile, and adult MLD. The 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. Language, cognitive, and gross and fine motor skills regress as the disease progresses. 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 a decline in school performance and the 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 the age of 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 predominate initially. Peripheral neuropathy is common. The 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.

Diagnosis/testing.

The diagnosis of MLD is established in a proband with the suggestive findings of progressive neurologic dysfunction, brain MRI evidence of leukodystrophy, or arylsulfatase A enzyme deficiency by identification of biallelic ARSA pathogenic variants on molecular genetic testing, elevated urinary excretion of sulfatides, or – less commonly – metachromatic lipid deposits in nervous system tissue.

Management.

Targeted therapy: Allogeneic hematopoietic stem cell transplantation (HSCT) can treat primary central nervous system manifestations in those with pre- and very early symptomatic juvenile- or adult-onset MLD. Autologous HSCT using gene-modified hematopoietic stem cells (also known as ex vivo gene therapy) is approved in the European Union and United Kingdom for individuals who have either asymptomatic late-infantile or early juvenile disease. or early symptomatic early juvenile MLD with maintained ability to walk independently and before the onset of cognitive decline.

Supportive care: Developmental and educational support. Treatment per orthopedist, physical medicine and rehabilitation, and physical and occupational therapists to avoid contractures and falls and maintain neuromuscular function and mobility, muscle relaxants for contractures, and safety measures for gait or movement limitations. Feeding therapy, swallowing aids, suction equipment, and other standard treatments for drooling, swallowing difficulty, and gastroesophageal reflux. Gastrostomy tube as needed for feeding. Treatment of seizures using anti-seizure medications in standard protocols. Standard treatments for impaired vison and/or hearing and respiratory issues. Family support to enable parents and/or caregivers to anticipate decisions on walking aids, wheelchairs, feeding tubes, and other changing care needs.

Surveillance: Brain MRI examination to monitor the status of demyelination using MLD brain MRI severity scoring with frequency per neurologist. Assess motor function and support needs using gross motor function measurement (GMFM). Monitor for disease exacerbations following febrile infections. At each visit, assess physical mobility, self-help skills, development, neurobehavioral and psychiatric issues, growth, nutrition, safety of oral intake, need for feeding support, constipation, respiratory issues, and family needs. Vision and hearing assessment as needed.

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.
• Evidence of a leukodystrophy on brain MRI. 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 enzyme deficiency. Arylsulfatase A enzyme activity in leukocytes that is less than 10% of normal controls using the usual synthetic-substrate-based assay. Decreased arylsulfatase A enzyme activity is not sufficient for the diagnosis of MLD, as it may reflect arylsulfatase A enzyme 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 arylsulfatase A 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 made presymptomatically. (3) Enzyme activity and sulfatide loading can be performed in cultured amniocytes or chorionic villus sampling (CVS) cells for prenatal diagnoses (see Genetic Counseling, Prenatal Testing and Preimplantation Genetic Testing).

Arylsulfatase A enzyme pseudodeficiency. Pseudodeficiency is suggested by arylsulfatase A enzyme activity in leukocytes that is 5% to 20% of normal controls. Pseudodeficiency is difficult to distinguish from true arylsulfatase A enzyme deficiency by biochemical testing alone.

Note: For MLD, the term "pseudodeficiency" refers to very low levels of arylsulfatase A 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 a synthetic substrate but have normal enzymatic activity when measured using a natural substrate.

Newborn screening for MLD. Newborn screening (NBS) for MLD is under consideration due to advancements in therapy. However, the enzyme activity-based approach faces challenges, primarily due to the frequent occurrence of arylsulfatase A enzyme pseudodeficiency and the difficulty distinguishing MLD from pseudodeficiency. To address this, a two-tier algorithm has been developed for screening MLD in dried blood spots (DBS) [Hong et al 2021]. This algorithm utilizes C16:0 sulfatide as the primary test and assesses arylsulfatase A enzyme activity when abnormal C16:0 sulfatide levels are detected. The feasibility of this algorithm was demonstrated through testing on 27,335 newborns [Hong et al 2021].

MLD is among the 14 disorders included in ScreenPlus, a pilot NBS study including 100,000 infants [Kelly et al 2024] designed to evaluate feasibility, efficacy, accuracy of screening assays, and the prevalence of the disease. The data acquired through this pilot program will be instrumental in the federal US Recommended Uniform Screening Panel (RUSP) nomination process, potentially paving the way for introducing MLD NBS in other regions and countries.

Establishing the Diagnosis

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

• Identification of biallelic ARSA pathogenic variants on molecular genetic testing (See Table 1.)
• Identification of increased urinary excretion of sulfatides (See Other Testing.)
• Identification of metachromatic lipid deposits in nervous system tissue following a nerve or brain biopsy (See Other Testing.)

Clinical Description

The clinical presentation of arylsulfatase A deficiency (also known as metachromatic leukodystrophy or 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%-40%
• Adult MLD, approximately 10%-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 cognitive functions. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms [Gieselmann & Ingeborg 2019]. 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. Furthermore, the presenting symptoms appear to correlate with the rate of disease progression. Motor symptoms predict a faster deterioration compared to cognitive symptoms [Kehrer et al 2021].

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. Other presenting signs are coordination difficulties (e.g., clumsiness, frequent falls, delayed or abnormal walking, strabismus, nystagmus, and dysarthria), clonus/tremor, and cognitive changes (e.g., cognitive delays, irritability, extreme fatigue, and nocturnal awakenings) [Eichler et al 2022]. 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. Peripheral neuropathy with slow nerve conduction velocities (NCVs) is common. Brain auditory and visual evoked response testing demonstrate impairment in hearing and vision [Kehrer et al 2011a, Fumagalli et al 2021].

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. Notably, one study found that gastrostomy tube placement did not prolong survival in a cohort with late-infantile MLD [Fumagalli et al 2021]. 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 [Gieselmann & Ingeborg 2019]. Symptoms start insidiously and can include motor symptoms such as difficulty with coordination, tremors, abnormal movements, and a regression of fine motor skills. Cognitive symptoms may also manifest, such as learning difficulties, concentration issues, and behavioral disorders (e.g., personality changes, impulsive behavior, sleep problems, and loss of interest in activities) [Kehrer et al 2014, Eichler et al 2022].

Some medical professionals distinguish between early-onset and late-onset juvenile MLD, and recent studies support measurable differences between these two subgroups [Fumagalli et al 2021, Kehrer et al 2021]. The early-onset juvenile form is typically diagnosed before the age of six years and shares many similarities with the late-infantile form. Some of the initial symptoms may include motor and gait disturbances. In contrast, the late-onset juvenile variant often presents initially with behavioral abnormalities, followed by a decline in school performance, language regression, and gait disturbances. For prognostic purposes, the age at onset and quality of symptoms should be considered, with presence of motor symptoms at onset being a negative prognostic factor [Kehrer et al 2021]. In general, the rate of motor deterioration is variable, but regardless of the age of onset, once motor deterioration begins, the regression tends to be rapid in all individuals with juvenile MLD [Kehrer et al 2011a]. Most individuals die before age 20 years, but survival is 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 late-onset juvenile MLD, presenting symptoms vary. Initial signs are often related to cognitive dysfunction, such as 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 diagnoses 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 is usually mild or not present.

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 are 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

• MRI of the brain is a powerful tool to investigate the involvement of the central nervous system in this disease. MLD primarily affects the white matter, and its changes during the disease can be seen on T₂-weighted MRI as hyperintense areas. Several scoring systems have been developed to evaluate disease severity and progression consistently [Eichler et al 2009, Sessa et al 2016]. The initial pathologic hallmarks of the disease include changes in the signal of periventricular white matter and involvement of the corpus callosum [Groeschel et al 2011, Fumagalli et al 2021, Schoenmakers et al 2022]. Longitudinal assessments show that the cerebellum is initially spared. Advanced MRI techniques and computational tools are being implemented to evaluate demyelination load and volume loss more accurately [Amedick et al 2023, Feldmann et al 2023].
• Several studies have addressed the electrophysiologic findings of peripheral neuropathy in MLD and their progression over time. Studies show that both motor and sensory NCVs show uniform slowing, as is expected for a demyelinating polyneuropathy [Raina et al 2019]. Measurement of NCVs is no longer necessary for diagnosis but can be used to monitor disease progression or responses in therapeutic trials.
• Brain stem auditory evoked responses (BAERs) are frequently found to be abnormal in individuals with late-infantile MLD. When studying the progression of late-infantile MLD, it has been observed that central waves in BAERs tend to disappear early, which is contrary to the expected pattern of progressive shortening of the I-V interpeak latency seen in healthy children during the first years of life, reflecting normal brain stem myelination. However, the use of BAERs is less straightforward in individuals with juvenile and adult MLD. Some individuals may exhibit recordings that are close to normal or maintain stable I-V interpeak latencies despite experiencing psychomotor deterioration [Fumagalli et al 2021].
• Sulfatide accumulation has been found outside the central nervous system in other organs. Accumulation n the gallbladder, hyperplastic polyps, hemobilia, and gallbladder carcinoma has been reported [van Rappard et al 2016b]. Polypoid masses in the stomach and duodenum complicated by intestinal intussusception have also been reported [Yavuz & Yuksekkaya 2011].

Pathogenesis. MLD is a disorder of impaired breakdown of sulfatides (cerebroside sulfate or 3-O-sulfogalactosylceramide), 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 [Gieselmann & Ingeborg 2019].

Genotype-Phenotype Correlations

There are three classes of ARSA alleles resulting in reduced arylsulfatase A enzyme activity:

• 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 (ARSA-PD-MLD).

Arylsulfatase A enzyme activity

• The genotypes ARSA-MLD/ARSA-MLD, ARSA-PD-MLD/ARSA-MLD, and ARSA-PD-MLD/ARSA-PD-MLD result in arylsulfatase A enzyme activity that is 0%-10% of control values in synthetic-substrate-based assays.
• The genotype ARSA-PD/ARSA-MLD usually results in arylsulfatase A enzyme activity that is approximately 10% of control values.
• The genotype ARSA-PD/ARSA-PD results in arylsulfatase A 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 (0-type or null alleles) [Cesani et al 2009]. The most common 0-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.
  • Juvenile-onset MLD. Often these individuals are compound heterozygous for an 0-type and an R-type allele.
  • Adult-onset MLD. Both alleles provide some residual enzyme activity (R-type ARSA-MLD alleles).

Adult MLD subtypes

• Neurologic type. Affected individuals are usually homozygous for the p.Pro428Leu R-type ARSA-MLD allele [Rauschka et al 2006].
• Psychiatric type. Affected individuals are usually compound heterozygous for the p.Ile181Ser allele and any other R-type ARSA-MLD allele [Rauschka et al 2006].

There are substantial limitations to using these genotype-phenotype correlations in predicting an affected individual's clinical presentation and natural history. The predictive value is best for individuals homozygous for two 0-type alleles. Still, individuals with one or two R-type alleles show considerable phenotypic variability, implicating other genetic and/or environmental factors. Additional variants in the same allele can further affect enzyme function and disease severity [Regis et al 2002].

Arylsulfatase A pseudodeficiency

• ARSA-MLD/ARSA-PD genotype. Associated arylsulfatase A enzyme activity is 5% to 10% of normal controls.
  • The polyadenylation site variant c.*96A>G appears to contribute most strongly to the low arylsulfatase A enzyme activity characteristic of clinical pseudodeficiency [Harvey et al 1998].
  • The glycosylation site alteration p.Asn352Ser is associated with increased excretion of the newly synthesized enzyme from cells and a possible decrease in the arylsulfatase A enzyme within the lysosome [Harvey et al 1998].
  • The most common ARSA-PD allele in the European and North American populations has these two sequence variants in cis configuration, designated c.[1055A>G;*96A>G].
• ARSA-PD/ARSA-PD genotype
  • Homozygosity for the c.*96A>G variant (almost always in cis with p.Asn352Ser) is associated with arylsulfatase A enzyme activity that is approximately 10% of normal controls and could result in diagnostic uncertainty.
  • Homozygosity for the p.Asn352Ser variant alone results in 50% or more of the mean control arylsulfatase A 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 (MLD). The overall prevalence of MLD has been reported to be between 1:40,000 and 1:170,000 in different populations [Gieselmann & Ingeborg 2019]. Assuming the prevalence stated, the overall carrier frequency is predicted to be between 1:100 and 1:200. Based on data from the Genome Aggregation Database (gnomAD), it is estimated that the frequency of pathogenic and likely pathogenic variants (allele frequency) in ARSA is approximately 1 in 360. Using the Hardy-Weinberg formula, this frequency suggests an overall incidence of 1:130,000 [Karczewski et al 2020]. This is likely an underestimate, as variants currently classified as of unknown significance may be pathogenic [Trinidad et al 2023]. The disorder is pan ethnic; however, most data come from European and North American populations.

The following populations have an increased prevalence of MLD due to the presence of founder variants (figures are approximate; see Table 6):

• 1:75 in Habbanite Jewsish population in Israel
• 1:8,000 in Israeli Arabs
• 1:2,500 in individuals of Yup'ik ancestry from Alakanuk, Alaska
• 1: 6,400 in individuals of Navajo ancestry from the western portion of the Navajo Nation in the United States

ARSA-PD alleles. The frequency of ARSA-PD variants is significantly higher as compared to ARSA-MLD variants. The p.Asn352Ser ARSA-PD variant is commonly found in all populations examined, including African / African American (33.88%), Admixed American (27.81%), Middle Eastern (19.85%), Amish (18.09%), East Asian (16.40%), South Asian (14.73%), Ashkenazi Jewish (13.91%), European (non-Finnish) (12.68%), European (Finnish) (6.482%), and Other (14.85%) [Karczewski et al 2020] (see also gnomAD). Thus, individuals with biallelic ARSA-PD variants are more common than individuals with biallelic ARSA-MLD variants and individuals compound heterozygous for ARSA-PD/ARSA-MLD variants. ARSA-MLD variants can be found on a wild type allele or in cis on an ARSA-PD allele (ARSA-PD-MLD alleles).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MLD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

While environmental factors are thought to influence the onset and severity of MLD manifestations, 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 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 HSCT and other 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 Targeted Therapy). 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, workup should begin with measurement of urinary excretion of sulfatides.
• Measurement of arylsulfatase A enzyme activity in peripheral blood leukocytes or cultured fibroblasts can support the diagnosis but is not sufficient by itself. See Suggestive Findings, Arylsulfatase A enzyme pseudodeficiency.

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

Therapies Under Investigation

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. A Phase I/II, open-labeled, monocentric study of direct intracranial administration of a replication-deficient adeno-associated virus gene transfer vector serotype rh.10 expressing the human ARSA cDNA to children with MLD is currently active (ClinicalTrials.gov). Other gene therapy vectors using different serotypes and mode of delivery are in earlier stages of development [Miyake et al 2021, Mullagulova et al 2023, St Martin et al 2023].

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 [Í Dali et al 2021]. Intrathecal delivery of the enzyme is being tested in individuals with late-infantile form (ClinicalTrials.gov) and has thus far proven safe [Í Dali et al 2020].

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.

Mode of Inheritance

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ARSA pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ARSA pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an ARSA pathogenic variant, each sib of an affected individual has at conception 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. Unless an affected individual's reproductive partner also has MLD or is a carrier (see Family planning), offspring will be 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.

Biochemical testing. Analysis of arylsulfatase A enzyme activity in leukocytes or cultured fibroblasts for carrier detection is 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 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.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. ARSA founder variants have been identified in the Yup'ik population of Alakanuk, Alaska, the Navajo population, and Habbanite and Yemenite Jewish populations (see Table 6).

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 and preimplantation genetic testing for MLD are possible.

Biochemical testing. Measurement of sulfatides in the amniotic fluid supernatant is feasible and can be useful in the prenatal diagnosis of MLD [Kubaski et al 2022]. Analysis of arylsulfatase A enzyme activity in cultured amniotic fluid cells or chorionic villus cells has also been used for the prenatal diagnosis of MLD.

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.

Molecular Pathogenesis

Arylsulfatase A synthesis and function. 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. During post-translational processing, the p.Cys71 must be converted to formylglycine before the sulfatase becomes active [Lukatela et al 1998, Dierks et al 2005].

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 arylsulfatase A enzyme activity (A-type ARSA-MLD variants). In instances in which the properties of the mutated arylsulfatase A enzyme have been explored, processing and stability have been affected, leading to an altered enzyme or the 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].

Pathophysiology. The molecular pathogenic processes involved in arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) need to be better understood. In MLD, the desulfation of 3-O-sulfogalactosyl-containing lipids is defective. Sulfatides are most abundant in the myelin of both the central and peripheral nervous systems and the kidneys. Additionally, they can be present in various other tissues, particularly those with specialized excretory cells, such as the respiratory epithelium, gastric mucosa, gallbladder, and uterine endometrium [Gieselmann & Ingeborg 2019]. Deficient arylsulfatase A activity results in progressive accumulation of sulfatides, mainly within lysosomes. The observed demyelination appears to be secondary to sulfatide-induced changes within the cells responsible for myelin maintenance, namely, the oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system. Psychosine sulfate (lyso-sulfatide) is also 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].

Mechanism of disease causation. Loss of function

ARSA-specific laboratory technical considerations. Molecular genetic testing also detects ARSA pseudodeficiency alleles (ARSA-PD), common variants that result in lower-than-average arylsulfatase A enzyme activity but do not cause MLD either in the homozygous state or in the compound heterozygous state with an ARSA-MLD allele. Disease-causing ARSA-MLD variants are as likely to be found in cis configuration with an ARSA-PD sequence variant as wild type alleles. One individual with intragenic recombination leading to somatic mosaicism has been reported [Regis et al 2006].

Author Notes

Dr Natalia Gomez-Ospina, MD, PhD, is an Assistant Professor at Stanford University with clinical and basic research interest in Lysosomal Storage Disorders.

Websites:
Natalia Gomez-Ospina | Stanford Medicine
Gomez-Ospina Lab

Email: ude.drofnats@psozemog

Acknowledgments

We would like to express our heartfelt gratitude to the patient support groups, dedicated individuals, and researchers who have tirelessly contributed to our understanding and treatment of MLD.

Author History

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

Revision History

• 8 February 2024 (sw) Comprehensive update posted live
• 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. Available online. 2011. Accessed 1-30-24.

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