Metachromatic leukodystrophy

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

This topic will review the clinical manifestations, diagnosis, and treatment of metachromatic leukodystrophy. Other lysosomal storage disorders 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 — MLD is caused by deficient activity of the lysosomal enzyme arylsulfatase A (ARSA) as a result of, in almost all cases, pathogenic variants in the arylsulfatase A gene (ARSA). Of note, there is a variant form with different clinical characteristics caused by a deficiency of sphingolipid activator protein SAP-B (saposin B), which normally stimulates the degradation of sulfatides by ARSA [1]. This form is caused by pathogenic variants in the prosaposin gene (PSAP).

ARSA is responsible for the desulfation of cerebroside sulfate, a major glycolipid of myelin. As a result, decreased ARSA activity leads to the accumulation of cerebroside sulfate in the central nervous system, peripheral nerves, kidneys, and other visceral organs. The accumulation of cerebroside 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 [2].

Genetics — Over 60 pathogenic ARSA variants have been described in MLD. Two alleles, A and I, together account for approximately 50 percent of cases [3,4]. These alleles contribute to the different clinical expressions of the disease [3].

●Homozygosity for the I allele is associated with very low or undetectable residual ARSA activity and late infantile onset; compound heterozygotes (with the other allele unknown) also appear to have a late infantile onset.

●Homozygosity for the A allele is associated with low but detectable residual ARSA activity and the juvenile or adult onset forms; compound heterozygotes have later onset of disease.

●The presence of both alleles is associated with juvenile onset.

There is evidence for a correlation between genotype and phenotype in late-onset MLD, a category that includes late juvenile and adult onset [5]. Patients who are homozygous for the ARSA P426L variant generally present with progressive gait disturbance (spastic paraparesis or cerebellar ataxia), while mental involvement becomes evident later. In contrast, compound heterozygotes for ARSA I179S variant present with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits are scarce. (See 'Juvenile and adult onset' below.)

Some normal individuals have low ARSA enzyme activity approximating those 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 [6]. The frequency of the allele is about 10 percent in most populations, resulting in a 1 percent frequency of the pseudodeficiency phenotype [6,7].

EPIDEMIOLOGY — The prevalence of MLD ranges from 1:40,000 to 1:100,000 in northern European and North American populations [8,9]. 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 [10-12].

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) [13].

CLINICAL MANIFESTATIONS — Three major subtypes of MLD are primarily distinguished by the age at disease onset [3]:

●Late infantile onset (age 6 months to 2 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) [14-16]. Gallbladder involvement is common with manifestations that include hyperplastic polyps and a probable increased risk of gallbladder carcinoma [17-21].

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 [22].

Late infantile onset — The late infantile form of MLD typically appears at six months to two years of age, though onset up to age four is considered late infantile by some investigators [23]. Infants and toddlers may present with developmental delay or regression of motor skills due to the peripheral nerve involvement even before any evidence of brain magnetic resonance imaging (MRI) changes. Other early signs can include gait difficulties, seizures, ataxia, hypotonia, extensor plantar responses, and optic atrophy [23,24]. Deep tendon reflexes are sometimes reduced or absent, reflecting the peripheral neuropathy. The prognosis is worse than later onset forms of MLD; progression to death typically occurs within five to six years.

Juvenile and adult 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 [23,25]. Seizures may occur, and progression to death occurs within six years of onset. Another group of children present between 6 and 16 years of age (late juvenile) with behavioral changes and intellectual impairment and, in many cases, seizures. Progression is slower, and these children may survive until early adulthood.

Adult onset MLD (age 17 years or older) is usually heralded by dementia and behavioral difficulties, and a substantial minority present with neuropathy, psychosis, schizophrenia, or seizures [23]. Optic atrophy has also been reported [26]. 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 [27].

Investigations — In late-onset MLD, nerve conduction studies show marked slowing. Sensory potentials are affected earlier and more severely than are motor responses [28,29]. There is segmental demyelination with metachromatic material in Schwann cells and macrophages on peripheral nerve biopsy [30,31].

Brain MRI reveals symmetric white matter lesions with a periventricular and/or frontal predominance. The subcortical U-fibers are usually spared. A tigroid (striped) pattern of white matter T2-weighted hyperintensities is seen in 70 percent of cases; cortical atrophy is seen with disease progression (algorithm 1) [32,33]. 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 [34], but the utility of NAA levels in clinical practice is not established.

DIAGNOSIS — The clinical picture combined with a typical brain MRI should suggest the diagnosis of MLD. However, the diagnosis can be challenging, particularly for the late infantile form, as the normal MRI, together with hyporeflexia and developmental delay, is relatively nonspecific. Reduced nerve conduction velocity and elevated cerebrospinal fluid protein concentrations may also be helpful to arrive at the diagnosis.

The diagnosis of MLD is established by identification of pathogenic ARSA variant, together with deficient arylsulfatase A (ARSA) enzyme activity in leukocytes. In patients with MLD, ARSA activity levels typically range from undetectable to less than 10 percent of normal values. However, diagnosis based only on the activity of ARSA is complicated by the existence of ARSA pseudodeficiency, which is present in approximately one percent of the general population. As a result, screening for the presence of the pseudodeficiency alleles is important when low but not absent levels are detected in prenatal testing or screening of asymptomatic relatives [7].

Availability of newborn screening for MLD is limited and is not yet recommended in the United States by the federal Recommended Uniform Screening Panel [35]. MLD newborn screening, based on detection of elevated blood sulfatide levels, is occurring in Germany and in New York [36].

TREATMENT — There are no fully curative therapies for MLD, but early MLD is a treatable disease. Allogeneic hematopoietic cell transplantation (HSCT) is the first-line treatment option offered for eligible patients. Ex vivo HSCT gene therapy has also been associated with benefit and is approved for treatment in the European Union.

Hematopoietic stem cell transplantation — Allogeneic HSCT is the standard of care for eligible patients with no or early MLD disease involvement.

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

●Benefit – HSCT appears to treat central nervous system (CNS) manifestations of MLD but not peripheral neuropathy [37-40]. Long-term follow-up suggests continued progression of the peripheral neuropathy [40]. The type of symptoms at presentation correlate with response to therapy [22].

●Donor selection – Although not available for many patients with MLD, the preferred HSCT donor is a noncarrier, human leukocyte antigen-matched sibling [41]. 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 graft-versus-host disease (GVHD). If the preferred options are not available, unrelated bone marrow donors are preferred to peripheral blood stem cell donors, since the latter has been associated with a higher incidence of GVHD in pediatric patients [42,43]. (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 [44]. Patients with juvenile or adult onset MLD who have mild, early symptoms are appropriate candidates for HSCT [43]. Older patients with advanced disease are unlikely to benefit. (See 'Juvenile and adult onset' above.)

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

●Procedure – HSCT 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".)

●Complications – Transplantation-related mortality is high, ranging from 17 to 43 percent in two reports of HSCT for juvenile MLD [39,40]. HSCT is also associated with numerous complications that can affect multiple organ systems. 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".)

Ex vivo gene therapy — Ex vivo gene therapy with HSCT is a promising treatment option for MLD [45-47] and has been approved for clinical use in the European Union [48]. 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 HSCT, short- and long-term complications remain a concern, cost is greater, and consensus recommendations for treatment with HSCT or ex vivo HSCT gene therapy have not been established.

●Mechanism – A lentiviral vector is used to transfer a functional ARSA gene into autologous HSCs [49]. 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 [46,50]. 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 [50]. 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 HSCT 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 HSCT, most commonly febrile neutropenia and stomatitis; and less commonly veno-occlusive disease and thrombotic microangiopathy [46,50]. 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 [51,52] and enzyme replacement therapy [53,54].

SUMMARY

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

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

●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.

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

●The diagnosis of MLD is established by demonstrating genetic pathogenic variants in ARSA, together with deficient arylsulfatase A (ARSA) enzyme activity in leukocytes. Diagnosis based only on the level of ARSA enzyme activity is complicated by the existence of ARSA pseudodeficiency. (See 'Diagnosis' above.)

●There is no fully curative treatment for MLD, but allogeneic hematopoietic cell transplantation (HSCT) appears to halt or prevent disease progression in pre- or early symptomatic patients. HSCT 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.