Version May 2024
INTRODUCTION — This monograph discusses implications of genetic test results for the ARSA gene. ARSA encodes arylsulfatase A, deficiency of which causes metachromatic leukodystrophy (MLD), a lysosomal disease characterized by progressive and ultimately fatal neurodegeneration.
Indications for ARSA genetic testing and care of the tested individual are discussed separately [1]. (See 'Resources' below.)
BACKGROUND
How to read the report — The table summarizes considerations for reviewing the genetic test report, including the importance of obtaining a hard copy, verifying the correct individual was tested, and reviewing which gene(s) and which variant(s) in those genes were analyzed (table 1). Coding DNA variants are designated with a "c"; variants in protein sequence are designated with a "p" followed by the specific change.
Testing for clinical care should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory. If initial testing was not done in a clinically certified laboratory and results will impact clinical decision-making, testing should be repeated in a certified laboratory. This includes positive results (expected or unexpected) or negative results in an individual at risk due to family history or clinical suspicion for carrying a pathogenic variant in a leukodystrophy gene.
The glossary summarizes terms that may be used in the report (table 2). Additional terms are defined separately. (See "Genetics: Glossary of terms".)
ARSA gene — ARSA encodes arylsulfatase A, an enzyme that removes sulfate molecules from cerebroside sulfate, a myelin glycolipid. When enzyme activity is severely reduced, cerebroside sulfate accumulates, initially in lysosomes and eventually in other cellular compartments [2]. This accumulation causes lysosomal dysfunction and cell death, affecting oligodendroglial cells, some neurons, macrophages, and Schwann cells. The result is demyelination and neurodegeneration, with progressive functional decline. Other cell types such as gallbladder cells can also be affected.
Common variants — MLD is rare, although some populations have higher disease frequencies [2]. (See 'Metachromatic leukodystrophy' below.)
Hundreds of ARSA pathogenic variants have been described; they may be null or hypomorphic alleles.
●Null alleles – Null alleles (also called "0" alleles) are pathogenic variants that completely abolish enzyme activity.
●Hypomorphic alleles – Hypomorphic alleles (also called "R" [for residual] alleles) are pathogenic variants that cause reduced but not absent enzyme activity.
The remainder of MLD cases are due to variants in the PSAP gene (>60 described) [3]. PSAP encodes prosaposin (pSap), a precursor protein that can be cleaved to generate four saposins: SapA, SapB, SapC, and SapD [2]. Pathogenic variants in PSAP can cause either a single saposin deficiency or a deficiency of the entire pSap protein. Deficiency of SapB, which activates sphingolipids, results in an MLD phenotype [2]. Additional leukodystrophies have other genetic causes. (See "Neuropathies associated with hereditary disorders", section on 'Lysosomal diseases' and "Differential diagnosis of acute central nervous system demyelination in children", section on 'Leukodystrophies'.)
Pseudodeficiency alleles — Pseudodeficiency alleles are variants in the ARSA gene (also called ARSA-PD) that cause reduced enzyme activity but do not cause clinical disease, even when co-inherited with a pathogenic variant on the other ARSA allele [4]. Screening for pseudodeficiency alleles is important when low but not absent arylsulfatase A levels are detected.
Examples of pseudodeficiency alleles include [5]:
●c.*96A>G (an abnormality of polyadenylation)
●c.1055A>G, p.(Asn352Ser), also referred to as c.1049A>G or p.(Asn350Ser)
●c.1524+95A>G
●Two variants together in cis on the same allele
Pseudodeficiency alleles are common in the general population (frequency 1 to 2 percent or more in some populations) [6]. They can complicate interpretation of genetic test results. Biochemical confirmation with enzyme testing and urine sulfatides is essential to determine whether individuals with these alleles have arylsulfatase A deficiency and are at risk for clinical disease. Typically, pseudodeficiency is suggested by leukocyte arylsulfatase A activity of 5 to 20 percent of control, although urine sulfatides or genetic testing is necessary to differentiate pseudodeficiency from disease [7].
Consultation with a genetics expert or disease expert is essential.
Genotype-phenotype correlation — The type of pathogenic variant determines the amount of residual arylsulfatase A activity, which in turn determines the age of onset and rate of disease progression [2,8].
There are three main presentations:
●Late infantile
•Most common
•Biallelic null variants
•Onset before age three years
•Progressive weakness, hypotonia, loss of milestones, language and cognitive decline
•Final stages of disease characterized by seizures, spasticity, and loss of cognition
●Juvenile
•One null variant and one hypomorphic variant
•Onset from age 3 to 16 years
•Behavioral changes, declining school performance, and gait disturbance
•Progression similar to late infantile form but slower
●Adult
•Least common
•Biallelic hypomorphic variants
•Onset after 16 years
•Neuropsychiatric findings (mood disorders, psychotic symptoms, dementia, seizures)
•May be misdiagnosed as other disorders or as primary dementia, schizophrenia, or seizure disorder
•Life expectancy 20 to 30 years after diagnosis
The full extent of genotype-phenotype relationships is incompletely understood. Some individuals from the same kindred who carry the same pathogenic variants have differing clinical features [2].
Epidemiology and inheritance — MLD is a rare disease but one of the more common leukodystrophies. The prevalence is estimated at approximately 1 in 40,000 to 1 in 160,000 [2]. Certain populations have much higher disease prevalence:
●Arab groups in Israel – 1 in 8000
●Navajo peoples – 1 in 2500
●Habbani Jewish people – 1 in 75
Inheritance is autosomal recessive. As little as 10 to 15 percent of normal arylsulfatase A activity is sufficient for normal neurologic functioning. Generally, MLD occurs with biallelic ARSA disease variants; heterozygosity for an ARSA pathogenic variant is an unaffected carrier state.
Metachromatic leukodystrophy — Metachromatic leukodystrophy (MLD, also called sulfatide lipidosis) is a lysosomal disease with accumulation of sulfatides, a common component of myelin. MLD causes demyelination in the central and peripheral nervous system. Progressive neurodegeneration impairs motor and cognitive function and is ultimately fatal [9].
There are three types of presentations (late infantile, juvenile, adult) that correlate with the severity of arylsulfatase A deficiency. (See 'Genotype-phenotype correlation' above.)
Early diagnosis may increase access to investigational therapies or gene therapy. (See 'Treatment' below.)
Addition of ARSA gene testing to newborn screening panels has been discussed and is being used in limited regions. (See "Overview of newborn screening" and "Metachromatic leukodystrophy", section on 'Diagnosis'.)
IMPLICATIONS FOR DIAGNOSIS AND MANAGEMENT
Pathogenic variant(s) in ARSA — MLD is an autosomal recessive disorder. (See 'Epidemiology and inheritance' above.)
●Biallelic variants – Individuals with biallelic (homozygous or compound heterozygous) pathogenic variants in ARSA have, or will develop, MLD (algorithm 1). Their evaluation and management should be performed by, or in consultation with, an expert in hereditary lysosomal diseases, neurodegenerative conditions, or MLD. (See 'Evaluations and monitoring' below and 'Treatment' below and 'Resources' below.)
●Monoallelic variants – Individuals who are heterozygous for a pathogenic variant are unaffected carriers who may benefit from genetic counseling. (See 'Considerations for relatives' below.)
Evaluations and monitoring — The diagnosis of MLD uses a combination of:
●Clinical findings
●Brain imaging (usually magnetic resonance imaging [MRI])
●Measurement of arylsulfatase A enzyme activity for biochemical confirmation
●Analysis of urine sulfatides for biochemical confirmation
●Genetic testing
Biochemical tests of enzyme activity can be performed on skin fibroblasts, white blood cells (WBCs), or urine (algorithm 1).
Prenatal diagnosis can be performed by genetic testing. (See 'Reproductive counseling' below.)
Regular follow-up and monitoring of clinical status are important to identify needs for supportive care. This includes multidisciplinary monitoring of neurologic function (including development and cognitive function, motor function, gait, swallowing, and presence of seizures), feeding and nutritional status, and general physical health related to mobility, with monitoring for contractures. Hearing and vision may also be assessed and serial MRI scans may be performed [7].
Individuals who undergo hematopoietic stem cell transplant, with or without gene therapy, require specialized monitoring. (See "Metachromatic leukodystrophy", section on 'Treatment'.)
Treatment — Without treatment, progressive neurologic deterioration is eventually fatal.
Several therapies are under development that have the potential to alter disease course. Participation in a clinical trial for disease-modifying therapy is encouraged. The following types of therapies are at various stages of study and availability:
●Allogeneic hematopoietic stem cell transplant – Allogeneic transplantation can be performed using bone marrow, peripheral blood stem cells, or umbilical cord blood from a human leukocyte antigen (HLA)-matched donor. This can slow progression of central nervous system (CNS) disease but not peripheral nervous system abnormalities. It cannot reverse demyelination and is ineffective in some individuals. It is most appropriate for individuals who have not yet developed major disease manifestations. (See "Metachromatic leukodystrophy", section on 'Hematopoietic stem cell transplantation'.)
●Gene therapy – Gene therapy has been approved in Europe using transduction of the ARSA gene into autologous hematopoietic stem cells and autologous hematopoietic stem cell transplantation. (See "Metachromatic leukodystrophy", section on 'Ex vivo gene therapy'.)
●Enzyme replacement – Enzyme replacement therapy and substrate reduction therapy have been investigated but have not been demonstrated to appreciably slow disease progression. This may be due to difficulty in the enzyme reaching the correct cells in the CNS.
●Other investigational approaches – Therapies under study include cellular therapy, modified enzyme products with greater CNS penetration, injection of gene therapy constructs directly into the CNS, and antiinflammatory medications [2].
Variant of uncertain significance (VUS) — If an individual has a pathogenic variant affecting one allele and a VUS affecting the other allele (or a VUS at both alleles), together with a clinical picture suggestive of MLD, biochemical testing becomes especially important (algorithm 1). Biochemical testing including enzyme activity and urine sulfatides analysis can clarify whether the individual has MLD or whether testing is indicated for a different disorder.
Negative testing — Relatives of an individual with known pathogenic variants in ARSA who test negative for the specific variant(s) can generally be reassured they do not carry the pathogenic variants and will not develop the disease, with caveats as described above. (See 'How to read the report' above.)
Individuals in whom MLD is clinically suspected and for whom a familial ARSA variant is not known may require evaluation by a neurologist and/or a genetics expert to ensure that they undergo appropriate evaluations for their symptoms. Any of the following explanations may apply:
●They may have a variant in ARSA that is not evaluated by their genetic test.
●They may have a variant in the other MLD gene, PSAP.
●They may have a variant in another gene involved in another hereditary syndrome.
●They may have an acquired condition.
CONSIDERATIONS FOR RELATIVES
First-degree relatives — Parents of an individual who has MLD due to biallelic pathogenic variants in ARSA are both obligate carriers.
Full siblings of an individual with biallelic pathogenic variants in ARSA have a 25 percent chance of being unaffected noncarriers, a 50 percent chance of being unaffected carriers, and a 25 percent chance of being affected with MLD.
Relatives can be tested for the familial variant(s) if they have been identified. Otherwise, it is prudent to identify the variant in the affected individual first, if possible, followed by testing of first-degree relatives.
Reproductive counseling — Individuals who have had a child with MLD should be offered reproductive counseling to review their options. They may elect to use options for family planning that include adoption, in vitro fertilization (IVF) with donor gametes (donor egg or donor sperm), or IVF with preimplantation genetic testing (PGT). (See "Donor insemination" and "In vitro fertilization: Overview of clinical issues and questions", section on 'Oocyte donation' and "Preimplantation genetic testing".)
If they elect to have another biological child, there is a 50 percent chance the child will inherit a single pathogenic variant in ARSA (from one or the other parent) and a 25 percent chance they will inherit biallelic pathogenic variants (from both parents) and be affected with MLD. Prenatal diagnosis may be useful for decision-making regarding whether to continue the pregnancy if the fetus is affected. (See "Overview of pregnancy termination".)
RESOURCES
●UpToDate topics
•MLD diagnosis and treatment – (See "Metachromatic leukodystrophy".)
•Other hereditary neuropathies – (See "Overview of hereditary neuropathies" and "Neuropathies associated with hereditary disorders".)
●Locating an expert
•MLD specialists – MLD Foundation (https://mldfoundation.org/doctors.php)
•Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
•Genetic counselors – National Society of Genetic Counselors (NSGC)
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