Metachromatic leukodystrophy

INTRODUCTION — Metachromatic leukodystrophy (sulfatide lipidosis; MLD) is a rare autosomal recessive lysosomal disease that causes progressive demyelination of the central and peripheral nervous system.

This topic will review the clinical manifestations, diagnosis, and treatment of MLD. Other lysosomal diseases and leukodystrophies are discussed separately. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy" and "Alexander disease" and "Aspartoacylase deficiency (Canavan disease)" and "Cerebrotendinous xanthomatosis" and "Fabry disease: Neurologic manifestations" and "Krabbe disease" and "Mucopolysaccharidoses: Clinical features and diagnosis" and "Overview of Niemann-Pick disease" and "Pelizaeus-Merzbacher disease" and "Sjögren-Larsson syndrome" and "Vanishing white matter disease".)

ETIOLOGY

Pathophysiology — MLD is caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA) as a result of, in almost all cases, biallelic pathogenic variants in the ARSA gene.

ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin. Decreased ARSA activity leads to the accumulation of cerebroside sulfate in the central nervous system (CNS), peripheral nerves, kidneys, and other visceral organs. The accumulation of sulfatide (cerebroside-3-sulfate) destroys oligodendroglial and Schwann cells, causing central and peripheral demyelination. Electron microscopy shows thickened lines in the myelin whorls and lamellar inclusions of sulfatides in the Schwann cells [1]. There is segmental demyelination with metachromatic material in Schwann cells and macrophages on peripheral nerve biopsy [2,3].

A rare variant form of MLD with different clinical characteristics is caused by a deficiency of sphingolipid activator protein B (Sap-B or saposin B), which normally stimulates the degradation of sulfatides by ARSA [4]. This form is caused by pathogenic variants in the prosaposin (PSAP) gene. Like ARSA deficiency, Sap-B deficiency leads to the accumulation of sulfatide in the CNS, causing progressive demyelination.

Genetics — Biallelic pathogenic variants in ARSA are the main cause of MLD. In rare cases, pathogenic variants in PSAP are causative.

●Pathogenic ARSA variants – Hundreds of pathogenic ARSA variants have been described in MLD. Two alleles, A and I, together account for approximately 50 percent of cases in individuals of European ancestry [5,6]. However, different populations have different allele distributions [7].

•Homozygosity for the I allele (c.459+1G>A) is associated with very low or undetectable residual ARSA activity and late-infantile onset; compound heterozygotes (with the other allele unknown) also have a late-infantile onset. The I allele is the most common of the null alleles (also called "0" alleles), which are pathogenic variants that completely abolish enzyme activity; other common null alleles are c.1210+1G>A and p.Asp257His [8].

•Homozygosity for the A allele (p.P426L) is associated with low but detectable residual ARSA activity and the juvenile- or adult-onset forms; compound heterozygotes have later onset of disease. The A allele is the most common of hypomorphic alleles (also called "R" [for residual] alleles), which are pathogenic variants that cause reduced but not absent enzyme activity.

•The presence of both I and A alleles is associated with juvenile onset.

●Genotype-phenotype correlations – There is evidence for a correlation between genotype and phenotype in late-onset MLD, a category that includes late juvenile and adult onset [9]. Patients who are homozygous for the ARSA p.P426L variant generally present with progressive gait disturbance (spastic paraparesis or cerebellar ataxia), while mental involvement becomes evident later. By contrast, compound heterozygotes for the ARSA I179S variant present with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits are scarce. (See 'Juvenile onset' below and 'Adult onset' below.)

●ARSA pseudodeficiency allele – Some individuals without MLD have low ARSA enzyme activity approximating that of patients with MLD. This nonpathogenic reduction in ARSA activity is caused by homozygosity for the ARSA pseudodeficiency allele. This allele contains two sequence alterations, a polyadenylation defect, and an amino acid substitution. The combined effect of these changes is to reduce ARSA enzyme activity to approximately 8 percent of normal [10]. The frequency of the allele is approximately 10 percent in most populations, resulting in a 1 percent frequency of the pseudodeficiency phenotype [10,11].

●Pathogenic PSAP variants – Approximately 13 PSAP pathogenic variants have been reported worldwide in patients with MLD as of 2023 [12,13].

EPIDEMIOLOGY — The prevalence of MLD ranges from 1:40,000 to 1:100,000 in northern European and North American populations [14,15]. However, a higher prevalence has been found in certain groups, including Habbanite Jews in Israel, Arabs living in Israel, and Navajo Indians in the United States [16-18].

In a retrospective review of 122 children with an inherited leukodystrophy from a regional center in Utah, MLD was the etiology in 8 percent, making it the most common diagnosis, similar in frequency to Pelizaeus-Merzbacher disease (7 percent) and higher in frequency than mitochondrial diseases (5 percent) or adrenoleukodystrophy (4 percent) [19].

CLINICAL MANIFESTATIONS — Three major subtypes of MLD are primarily distinguished by the age at disease onset [5]:

●Late-infantile onset (age six months to two years)

●Juvenile onset (age 3 to <16 years)

●Adult onset (age ≥16)

Peripheral neuropathy occurs in all forms and may be a presenting feature, particularly in the late-infantile form (table 1) [20-22]. Gallbladder involvement is common with manifestations that include hyperplastic polyps and a probable increased risk of gallbladder carcinoma [23-27].

Earlier age at onset and the presence of motor symptoms at onset regardless of age have been associated with rapid disease progression, while onset with cognitive symptoms only has been associated with milder disease progression [28].

Late-infantile onset — The late-infantile form of MLD is the most common and most severe form and typically appears at six months to two years of age, though onset up to age four is considered late-infantile by some investigators [29,30].

Infants and toddlers may present with developmental delay or regression of motor skills due to peripheral neuropathy even before any evidence of brain magnetic resonance imaging (MRI) changes. In some cases, the first symptoms may be apparent after a febrile illness or anesthesia [8]. Symptoms may then abate for weeks before continuing to progress. Other early signs can include gait difficulties, seizures, ataxia, hypotonia, extensor plantar responses, and optic atrophy [29,31]. Deep tendon reflexes are sometimes reduced or absent, reflecting the peripheral neuropathy.

Sensory potentials are affected earlier and more severely than are motor responses [32].

The prognosis is worse than later-onset forms of MLD; progression to death typically occurs within five to six years, although some patients survive into the second decade of life [8].

Juvenile onset — The juvenile-onset form of MLD is heterogeneous in presentation. Some children present between four and six years of age (early juvenile) with intellectual impairment, behavioral difficulties, gait disturbance, ataxia, upper motor neuron signs, and a peripheral neuropathy; seizures may also occur [29,33].

Another group of children presents between 6 and 16 years of age (late juvenile) with behavioral changes, intellectual impairment, and, in many cases, seizures.

Progression is slower compared with the late infantile form, and these children may survive until early adulthood.

Adult onset — Adult-onset MLD (age 17 years or older), the least common form, is usually heralded by dementia and behavioral difficulties, and a substantial minority present with neuropathy, psychosis, schizophrenia, or seizures [29,30]. Optic atrophy has also been reported [34].

A late-onset or adult-onset phenotype limited to psychiatric disease with minimal or no motor findings is well described but often remains undiagnosed for many years; the course is static or very slowly progressive [35]. Affected patients may survive for 20 to 30 years after onset [30].

NEUROIMAGING — Typical changes of MLD (image 1) may not be evident on brain MRI in early or presymptomatic disease [36]. In the late-infantile form of MLD, initial lesions are seen in the parieto-occipital central white matter and, later, in the frontal and periventricular white matter, corpus callosum, and cerebellar white matter [37]. A tigroid pattern (radially oriented stripes or dots on axial images) of white matter T2-weighted hyperintensities is seen in a majority of symptomatic cases, particularly with juvenile onset [36-39]. Diffuse, symmetric white matter lesions and cortical atrophy are seen with disease progression. In juvenile- and adult-onset MLD, there is frontal predominance of white matter lesions. MRI evaluation is important as extent of involvement can be a component of decision-making about treatment [40-42].

A retrospective study reported that levels of N-acetylaspartate (NAA) measured by magnetic resonance spectroscopy may be useful in therapeutic trials as a biomarker of MLD disease progression [43], but the utility of NAA levels in clinical practice is not established.

EVALUATION AND DIAGNOSIS

When to suspect the diagnosis — The diagnosis of MLD should be suspected in patients with progressive neurologic decline and MRI evidence of a leukodystrophy. However, the diagnosis can be challenging for the late-infantile form, as the brain MRI may be normal initially and the early presenting symptoms of hyporeflexia and developmental delay are relatively nonspecific.

Investigations — Important studies to obtain for patients with suspected MLD are:

●ARSA enzyme activity in leukocytes or cultured fibroblasts (often available as a composite test "white cell enzymes [lysosomal enzymes]")

●Measurement of urinary sulfatides quantified by high-performance liquid chromatography, mass spectrometry, or thin-layer chromatography

●Molecular genetic testing for ARSA and PSAP pathogenic variants

Both enzyme assay and substrate (sulfatide) measurement are essential parts of the biochemical diagnosis, to complement gene sequencing (at least in a proband; gene sequencing is adequate in a sibling of an index case). Measuring both enzyme activity and sulfatides is also helpful in distinguishing ARSA pseudodeficiency from MLD. (See 'Differential diagnosis' below.)

Confirming the diagnosis — In a patient with progressive neurologic dysfunction and/or leukodystrophy, the diagnosis of MLD due to ARSA deficiency is established when all of the following are present:

●The identification of biallelic ARSA pathogenic variants.

●Deficient ARSA enzyme activity in leukocytes. In patients with MLD, ARSA activity levels typically range from undetectable to less than 10 percent of normal values.

●Elevated urinary excretion of sulfatides. Elevated urinary sulfatides are present in all types of MLD, including MLD due to sphingolipid activator protein B (Sap-B) deficiency [8,44,45].

The finding of normal ARSA activity associated with elevated urinary sulfatides suggests the possibility of Sap-B deficiency (a variant of MLD) and should prompt molecular analysis of the PSAP gene [13].

Historically, the diagnosis of MLD was made by demonstrating metachromatic lipid deposits on nerve biopsy and, less commonly, on rectal biopsy [46]. However, this approach is essentially never used in modern clinical practice.

Availability of newborn screening for MLD is limited and is not yet recommended in the United States by the federal Recommended Uniform Screening Panel [47]. MLD newborn screening, based on detection of elevated blood sulfatide levels, is occurring in Germany and in New York [48].

DIFFERENTIAL DIAGNOSIS

ARSA pseudodeficiency — Individuals with non-disease-causing pseudodeficiency alleles in the ARSA gene have low ARSA enzyme activity levels approximating those of patients with MLD. Thus, the diagnosis of MLD cannot be based only on the activity of ARSA; screening for pseudodeficiency alleles is important when low but not absent levels of ARSA are detected [11]. ARSA pseudodeficiency is present in approximately 1 percent of the general population.

Multiple sulfatase deficiency — Multiple sulfatase deficiency (MSD) is a rare autosomal disorder caused by deficiency of all lysosomal and microsomal sulfatase enzymes [49]. Onset occurs from infancy through early childhood. The initial symptoms and progression are widely variable with ichthyosis and features of mucopolysaccharidosis [50]. All the features of MLD may be present in MSD, but the disorders can be distinguished clinically by the occurrence of systemic features of MSD (eg, ichthyosis, organomegaly, short stature, skeletal involvement, dental anomalies, macrocephaly with or without hydrocephalus, and cardiac manifestations) that are not found in MLD [50]. ARSA enzyme activity is very low in MSD, and there is elevated urinary excretion of sulfatides and mucopolysaccharides. The diagnosis of MSD is based on the findings of low activity levels in two or more sulfatase enzymes and biallelic pathogenic variants in SUMF1 [50].

Other leukodystrophies — Generalized leukodystrophy is a nonspecific finding that occurs in other conditions. These disorders can generally be distinguished from MLD based upon clinical features and genetic testing:

●Adrenoleukodystrophy (ALD) – ALD is a peroxisomal disorder of beta-oxidation that results in accumulation of very long-chain fatty acids (VLCFAs) in all tissues. It is an X-linked genetic disorder caused by pathogenic variants in the ABCD1 gene. ALD consists of a spectrum of clinical syndromes (including leukodystrophy, myeloneuropathy, and adrenal insufficiency) that vary in the age and severity of clinical presentation. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

●Alexander disease – This is a rare genetic disorder that predominantly affects infants and children and is associated with cerebral white matter disease. Contrast enhancement of gray and white matter brain structures on MRI is a feature of Alexander disease but is not associated with MLD. The presence of a demyelinating peripheral neuropathy, which is usually present in the late-infantile or juvenile forms of MLD, also distinguishes MLD from Alexander disease. The diagnosis of Alexander disease can be established based upon clinical and radiographic features and is usually confirmed by demonstrating a pathogenic variant in the GFAP gene. (See "Alexander disease".)

●Aspartoacylase deficiency (Canavan disease) – This is an autosomal recessive spongiform leukodystrophy that is prevalent in the Ashkenazi Jewish population. The disease typically begins in infancy and is marked by relentless progression; rare cases present with juvenile onset and milder features. In symptomatic infants with compatible clinical features (eg, hypotonia, poor head control, macrocephaly) and neuroimaging findings, the diagnosis of Canavan disease is supported by elevated levels of urine N-acetylaspartate (NAA) and/or identification of biallelic pathogenic variants in the ASPA gene. (See "Aspartoacylase deficiency (Canavan disease)".)

●Gangliosidoses such as hexosaminidase A deficiency (Tay-Sachs disease [TSD]) – TSD is a neurodegenerative lysosomal disease with autosomal recessive inheritance caused by biallelic (homozygous or compound heterozygous) pathogenic variants in the HEXA gene. The prevalence of TSD is higher in Ashkenazi Jewish, French Canadian, Louisiana Cajun, and Pennsylvania Dutch populations. In the classic infantile presentation, the onset occurs at approximately five to six months of age. Symptoms include incoordination, exaggerated startle response, loss of muscle tone, progressive neurologic deterioration, functional decline, and loss of previously attained developmental milestones. The retinal cherry red spot typically develops between 3 and 12 months of age. The median survival is approximately four years. The diagnosis is made by serum testing for hexosaminidase A enzyme activity and/or genetic testing for pathogenic variants in the HEXA gene. (See "Gene test interpretation: HEXA (Tay-Sachs disease gene)", section on 'Tay-Sachs disease'.)

●Krabbe disease – Krabbe disease (globoid cell leukodystrophy) is a rare autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC), which leads to accumulation of psychosine (galactosylsphingosine), globoid cell formation, and decreased myelin. Most patients present within the first 12 months of life. A peripheral motor-sensory neuropathy occurs in most patients and may be the initial presenting symptom in later-onset patients. Infantile-onset disease is associated with irritability, developmental delay or regression, limb spasticity, axial hypotonia, and optic atrophy. The diagnosis in symptomatic patients is made by measurement of GALC activity in leukocytes isolated from whole blood or cultured skin fibroblasts. (See "Krabbe disease".)

●Pelizaeus-Merzbacher disease (PMD) – PMD is a dysmyelinating disorder in which normal myelination never occurs. Pathogenic variants of the PLP1 gene result in a range of phenotypes that form a clinical spectrum, from the more severe PMD at one end to the relatively mild X-linked spastic paraplegia type 2 (SPG2) at the other. The major clinical features of PMD are nystagmus, spasticity, athetosis, tremor, and ataxia. The symptoms vary in onset and severity. Brain MRI of patients with the PMD phenotype reveals patchy or diffuse leukodystrophy. The diagnosis is confirmed by demonstrating a pathogenic variant in the PLP1 gene. Unlike PMD, MLD does not present with nystagmus. Furthermore, brain MRI abnormalities are typically diffuse in PMD but usually have periventricular and/or frontal predominance in MLD. (See "Pelizaeus-Merzbacher disease".)

TREATMENT — There are no fully curative therapies for MLD, but progression of early juvenile- or adult-onset MLD can be mitigated to some extent. Allogeneic hematopoietic cell transplantation (HCT) is the first-line treatment option offered for eligible patients. Ex vivo HCT gene therapy has also been associated with benefit and is approved for treatment in the European Union.

Hematopoietic cell transplantation — Allogeneic HCT may be considered the standard of care for eligible patients with no or early MLD disease involvement. We use shared decision-making to determine if patients are amenable to HCT. While allogeneic HCT may halt or prevent central nervous system (CNS) manifestations of MLD for some patients with asymptomatic or mild disease, it is associated with significant risks of severe or fatal complications. Nevertheless, some patients, families, or guardians of patients may reasonably choose HCT based upon the potential benefit and despite the known risks of treatment. Shared decision-making must include discussions of what is known and what is uncertain regarding benefits, risks, and burdens of this therapy.

●Mechanism – HCT introduces healthy donor cells that migrate into the brain of recipients, engraft, and express ARSA, the enzyme that is deficient in MLD.

●Benefit – HCT appears to treat CNS manifestations of MLD but not peripheral neuropathy [51-54]. Long-term follow-up suggests continued progression of the peripheral neuropathy [54]. In a 2023 systematic review, disease progression at 10 years involving decreased motor function or loss of language occurred in 8 of 20 patients (40 percent) with juvenile onset who received HCT compared with 28 of 41 patients (68 percent) with juvenile onset who did not receive HCT [55]. In a single-center cohort report with 16 evaluable long-term (10-year) MLD survivors who received HCT, the investigators concluded that the aggregate motor and language function was favorable compared with the natural history of MLD [53]. The type of symptoms at presentation may correlate with response to therapy [28].

●Risks and complications – Transplantation-related mortality is high. In a 2023 systematic review, five-year survival after HCT ranged from 57 to 74 percent [55]. At ten-year follow-up in the long-term study cited above, 53 percent were alive; most deaths were related to treatment, while a minority was related to disease progression [53].

HCT is also associated with numerous complications that can affect multiple organ systems, including graft-versus-host disease (GVHD). These are reviewed in detail separately. (See "Early complications of hematopoietic cell transplantation" and "Overview of infections following hematopoietic cell transplantation" and "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and "Survival, quality of life, and late complications after hematopoietic cell transplantation in adults" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)

●Donor selection – Although not available for many patients with MLD, the preferred HCT donor is a noncarrier, human leukocyte antigen-matched sibling [56]. The next best option is umbilical cord blood, which offers many practical advantages over unrelated donor bone marrow or peripheral blood stem cell donors, including an expanded donor pool, ease of procurement, and decreased rates of GVHD. If the preferred options are not available, unrelated bone marrow donors are preferred to peripheral blood stem cell donors, since the latter have been associated with a higher incidence of GVHD in pediatric patients [57,58]. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)

●Patient selection – Data suggest that early transplantation (best presymptomatically) is necessary for positive outcomes [54,59]. Patients with juvenile- or adult-onset MLD who have mild, early symptoms are appropriate candidates for HCT [58]. Older patients with advanced disease are unlikely to benefit. (See 'Juvenile onset' above and 'Adult onset' above.)

Patients with late-infantile onset who are symptomatic are also unlikely to benefit from HCT since they have inexorable progression of symptoms leading to death within a few years. (See 'Late-infantile onset' above.)

●Procedure – HCT for MLD generally is performed with myeloablative conditioning regimens (eg, busulfan and cyclophosphamide, with or without antithymocyte globulin) to provide adequate immunosuppression and prevent graft rejection; this results in pancytopenia, which is reversed by infusion of the hematopoietic stem cells (HSCs). Seizure prophylaxis, typically with levetiracetam, is necessary during busulfan treatment. (See "Preparative regimens for hematopoietic cell transplantation".)

Prophylaxis of GVHD is important. Approaches vary; one common regimen involves treatment with a calcineurin inhibitor plus mycophenolate mofetil. (See "Prevention of graft-versus-host disease".)

Ex vivo gene therapy — Ex vivo gene therapy with HCT is a promising treatment option for MLD [60-62] and has been approved for clinical use in the European Union and the United States [63,64]. Use of ex vivo gene therapy may be considered based upon availability, individual patient factors, and shared decision-making with patients, families, and caregivers. However, ex vivo gene therapy has not been compared with standard HCT, short- and long-term complications remain a concern, cost is greater, and consensus recommendations for treatment with HCT or ex vivo HCT gene therapy have not been established.

●Mechanism – A lentiviral vector is used to transfer a functional ARSA gene into autologous HSCs [65]. The gene-corrected HSCs (atidarsagene autotemcel [arsa-cel]) are then transfused back into patients. This leads to stable engraftment of the transduced HSCs and high levels of ARSA enzyme activity.

●Benefit – Limited data suggest prevention of symptom onset or a halt in disease progression [61,66]. In a nonrandomized, open-label study of 29 children with presymptomatic or early symptomatic late-infantile or early-juvenile MLD who were treated with arsa-cel, two patients died due to MLD progression and one died due to an ischemic stroke [66]. The 26 surviving patients showed sustained engraftment of genetically modified HSCs. At two years after treatment, ARSA enzyme activity was increased above baseline, scores for gross motor function were increased compared with an untreated natural history control group, and most treated children had either normal development or stabilization of motor skills, including maintaining the ability to walk. In addition, most treated children had normal cognitive development and absence or delay of brain white matter involvement and brain atrophy; patients with late-infantile onset showed improvement of peripheral nerve conduction velocity. The benefits of arsa-cel treatment were most apparent in patients who were presymptomatic when treatment started.

●Complications – Ex vivo gene therapy with HCT appears to avert the risk of GVHD; however, patients still require the transplant process, and long-term safety and risk for lentiviral insertional mutagenesis continue to be studied. Although generally well tolerated, adverse events associated with arsa-cel therapy in reported studies were mainly related to myeloablative conditioning with busulfan used for HCT, most commonly febrile neutropenia and stomatitis and less commonly veno-occlusive disease and thrombotic microangiopathy [61,66]. A minority of patients developed anti-ARSA antibodies, which resolved either spontaneously or after B cell depletion therapy using rituximab.

Other therapies — Other experimental options for MLD are being explored, including direct (in vivo) viral gene therapy [67,68] and enzyme replacement therapy [69,70].

SUMMARY AND RECOMMENDATIONS

●Definition – Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disease caused by pathogenic variants in the ARSA gene. In a few patients, a variant form of MLD is caused by pathogenic variants in the PSAP gene. (See 'Etiology' above.)

●Epidemiology – The prevalence of MLD ranges from 1:40,000 to 1:100,000 in northern European and North American populations. (See 'Epidemiology' above.)

●Clinical manifestations – Three major subtypes of MLD are primarily distinguished by the age at disease onset and include late-infantile, juvenile, and adult forms. (See 'Clinical manifestations' above.)

•The late-infantile form of MLD presents from age six months to two years; early signs include regression of motor skills, gait difficulty, ataxia, hypotonia, extensor plantar responses, optic atrophy, and peripheral neuropathy. (See 'Late-infantile onset' above.)

•The juvenile form of MLD presents between 3 and 16 years of age with gait disturbance, intellectual impairment, ataxia, upper motor neuron signs, and a peripheral neuropathy. Seizures may occur. (See 'Juvenile onset' above.)

•Adult-onset MLD (age 17 or older) is usually heralded by dementia and behavioral difficulties. (See 'Adult onset' above.)

●Diagnosis – In a patient with progressive neurologic dysfunction and/or leukodystrophy, the diagnosis of MLD is established by the identification of biallelic pathogenic variants in ARSA, together with deficient ARSA enzyme activity in leukocytes and elevated urinary excretion of sulfatides. The finding of normal ARSA activity associated with elevated urinary sulfatides suggests the possibility of sphingolipid activator protein B (Sap-B) deficiency and should prompt molecular analysis of the PSAP gene [13]. Diagnosis based only on the level of ARSA enzyme activity is complicated by the existence of ARSA pseudodeficiency. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis – The differential diagnosis of MLD includes ARSA pseudodeficiency, multiple sulfatase deficiency (MSD), and other leukodystrophies including X-linked adrenoleukodystrophy, Alexander disease, Canavan disease, gangliosidoses such as hexosaminidase A deficiency, Krabbe disease, and Pelizaeus-Merzbacher disease; these are generally distinguished by their clinical and neuroimaging features in combination with genetic testing. (See 'Differential diagnosis' above.)

●Treatment – There is no fully curative treatment for MLD, but allogeneic hematopoietic cell transplantation (HCT) may halt or prevent disease progression of central nervous system (CNS) manifestations in pre- or early symptomatic patients. However, it is associated with significant risks of severe or fatal complications. We use shared decision-making to determine if patients are amenable to HCT. HCT combined with gene therapy is approved in Europe. Other investigational therapies include viral gene therapy or enzyme therapy. (See 'Treatment' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert Cruse, DO, and Raphael Schiffmann, MD, MHSc, FAAN, who contributed to an earlier version of this topic review.