Metachromatic Leukodystrophy

Updated: Jan 22, 2021

Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG

Overview

Background

Metachromatic leukodystrophy (MLD) is part of a larger group of inherited lysosomal storage diseases, some of which are progressive and neurodegenerative disorders (MLD included). Four types of MLD occur with varying ages at onset and courses (ie, late infantile, early juvenile, late juvenile, and adult).[1, 2, 3]

All forms of the disease involve a progressive deterioration of motor and neurocognitive function. The classification is somewhat arbitrary because the types overlap, and some cases do not fall neatly within a single type. Metachromatic leukodystrophy actually describes a continuum of clinical severity. Phenotypic variation between siblings with MLD suggests that a number of biochemical and epigenetic factors contribute to the clinical phenotype.[4] As the term implies, the presence of white matter abnormalities on brain images is characteristic.[5, 6]

Pathophysiology

In patients, inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes metachromatic leukodystrophy (MLD). A deficiency in the lysosomal enzyme sulfatide sulfatase (arylsulfatase A [ARSA]) is present.[7] Some patients with clinical MLD have normal ARSA activity but lack an activator protein that is involved in sulfatide degradation. Both defects result in the accumulation of sulfatide compounds in neural tissue and nonneural tissue, such as the kidneys and gallbladder, as well. These defects result from different gene mutations, mostly in the ARSA gene, and many new causative mutations have been identified.[7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]

Histologic examination of the tissues often reveals metachromatic granules. Central and peripheral myelination is abnormal, with a widespread loss of myelinated oligodendroglia in the central nervous system (CNS) and segmental demyelination of peripheral nerves.[18] Arylsulfatase A deficiency leads to defective glial and neuronal differentiation from neural progenitor cells.[19] The sulfatide accumulations produce extensive damage and result in loss of both cognitive and motor function.[9]

Immunohistochemistry and morphometric analyses have revealed that microglia damage precedes major myelin breakdown in patients with MLD, as well as in those with X-linked adrenoleukodystrophy, which should be considered in the differential diagnosis.[20]

Epidemiology

The incidence of metachromatic leukodystrophy (MLD) is estimated to be 1 case per 40,000 births in the United States.

Morbidity and mortality rates vary with each form of the disease. In general, young patients have the most rapidly progressive disease, whereas patients with adult onset MLD experience a more chronic and insidious progression of disease.

No differences have been identified on the basis of race or sex.

Patients with the late infantile form of MLD are usually 4 years old or younger and typically present initially with gait disturbances, loss of motor developmental milestones, optic atrophy, and diminished deep tendon reflexes. Progressive loss of both motor and cognitive function is fairly rapid. Death of patients with the late infantile form of metachromatic leukodystrophy (MLD) results within approximately 5 years after the clinical observation of symptoms.

Patients with the early juvenile form of MLD (4-6 years) tend to present with loss of motor developmental milestones; the most obvious signs are gait disturbances, ataxia, hyperreflexia followed by hyporeflexia, seizures, and decreased cognitive function. Progression is typically less rapid than in the infantile form. Gradual deterioration in school performance may be the first sign. Rarely, the presenting problem is acute cholecystitis or pancreatitis secondary to gallbladder involvement. Abdominal masses and gastrointestinal tract bleeding have been reported. Patients with the early juvenile form usually die within 10 to 15 years of diagnosis, and most patients die before the age of 20 years.

The late juvenile form of MLD (age range, 6-16 years) and the adult form (>16 years) progress slowly, and patients tend to present with behavioral disturbances or decreased cognitive function. A decline in school or work performance may be recognized first. Seizures may occur in any form of MLD and may be the only initial symptom. Motor dysfunction often follows. Initial behavioral disturbances are commonly mistaken for those of various psychiatric disorders.[21, 22]

Gallbladder polyps and gallbladder cancer with ascites have been reported in children with metachromatic leukodystrophy (MLD).[23, 24] Patients with the late juvenile form often survive into early adulthood. Patients with the adult form of MLD may have an even slower progression than those with the late juvenile form. Rarely, patients with the adult form may present with choreiform movements, dystonia, or both.

Patient Education

Numerous resources are available for families of patients with metachromatic leukodystrophy (MLD).

The MLD Foundation is the world's largest MLD-focused organization and serves hundreds of families across the globe.

The National Organization for Rare Disorders (NORD) website includes a page titled “Metachromatic Leukodystrophy.”

The National Tay-Sachs and Allied Diseases Association may provide useful information.

The National Institute of Neurological Disorders and Stroke website includes a page titled “NINDS Metachromatic Leukodystrophy Information Page.”

The United Leukodystrophy Foundation is a nonprofit voluntary health organization dedicated to providing patients and their families with information about MLD and to identifying resources for families.

A list of current clinical trials for many diseases can be found at ClinicalTrials.gov, which is a website maintained by the National Institutes of Health.

Presentation

History

Features of symptoms found in patients with each of the 4 forms of metachromatic leukodystrophy (MLD) are provided in the following lists.

1. The infantile form includes the following:

Gait disturbances
Memory deficits
Seizures (may be present)
Loss of motor developmental milestones
Decreased attention span
Speech disturbances
Decline in school performance

2. The early juvenile form includes the following:

Gait disturbances
Tremors
Clumsiness
Loss of previously achieved skills
Intellectual decline
Behavioral changes
Seizures (possible)

3. The late juvenile and adult forms include the following:

Decreased work or school performance
Behavioral changes
Memory loss
Seizures (may be present)
Psychoses
Gradual loss of motor skills

A study by Harrington and colleagues[25] confirmed clear overall differences in symptom profiles and overall disease progression related to late infantile and juvenile MLD; however, each subtype was characterized by some variability among individuals.

Physical

Neurodevelopmental tests demonstrate the following findings in patients with infantile or early juvenile metachromatic leukodystrophy (MLD):

Loss of previously achieved developmental milestones
Tremors
Truncal ataxia
Hyperreflexia progressing to hyporeflexia
Hypotonia
Gait abnormalities
Optic atrophy

Neurocognitive tests demonstrate the following abnormalities in patients with late juvenile or adult MLD:

Dementia
Memory loss
Disinhibition
Impulsiveness
Decreased motor function
Optic atrophy

DDx

Diagnostic Considerations

As many as 1 to 2% of people may have low (5-15%) or reference range levels of arylsulfatase A (ARSA) in the serum, but sulfatide is not stored. These individuals are usually healthy and asymptomatic. The presence of normal urinary sulfatide levels (vs elevated levels in patients with metachromatic leukodystrophy [MLD]) distinguishes ARSA pseudodeficiency from MLD. Arylsulfatase A pseudodeficiency may also be distinguished using gene mutation analysis or an evaluation of radiolabeled sulfatide fibroblast uptake and accumulation.

Other diagnoses to consider include the following:

Schizophrenia
Antisocial personality disorder
Multiple sulfatase deficiency ^[26]
Phelan-McDermid syndrome ^{[27, 28]}
Different adult-onset leukodystrophies ^{[2, 20, 29]}

Differential Diagnoses

Workup

Laboratory Studies

Arylsulfatase A (ARSA) enzyme activity may be decreased in leukocytes or cultured skin fibroblasts. Cerebral spinal fluid (CSF) protein levels may be increased (although this finding is nonspecific). The range of values of ARSA activity in the CSF has been established empirically for metachromatic leukodystrophy (MLD) in clinical practice.[30]

Metachromatic leukodystrophy may be distinguished from ARSA pseudodeficiency using one of the following tests:

Urine sulfatide level
Radiolabeled sulfatide fibroblast loading
DNA mutation analysis

Arylsulfatase A activity may be measured to identify carriers and make prenatal diagnoses. This test is available in a few select laboratories. In addition, multiplexed immune-quantification assays have been developed that screen numerous lysosomal proteins. Implementation of this technique in newborn screening (using blood spots) for early identification of lysosomal storage disorders has been shown to be feasible but requires further validation.[31]

Other Tests

Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of metachromatic leukodystrophy but is nonspecific.[32]

The following procedures may be indicated:

Peripheral nerve biopsy (usually not needed)
Lumbar puncture

Metachromatic granules are found in biopsy specimens from peripheral nerves, the kidney, or the gallbladder. Widespread loss of myelin in the CNS and peripheral nerves may be present.

The following tests may be indicated:

Nerve conduction studies
Neurocognitive, neuropsychological testing, or both

Procedures

Staging

Table 1. Characteristics of the 4 Forms of Metachromatic Leukodystrophy (Open Table in a new window)

Form	Age at Onset (y)	Inheritance Pattern	Frequency	Neurocognitive Deficit	Progression	Effect of Bone Marrow Transplantation
Late infantile	< 4	Autosomal recessive	Most common	Motor milestones lost, neurocognitive function lost	Death within 5-6 y	Not helpful in symptomatic patients; may halt cognitive deterioration in asymptomatic patients
Early juvenile	4-6	Autosomal recessive	Less common	Motor milestones lost, learning and behavior impaired	Death within 10-15 y	May be beneficial in symptomatic and asymptomatic patients
Late juvenile	6-16	Autosomal recessive	Rare	Personality changes, behavioral changes, dementia, psychoses, decline in school or work performance	Slow	May be beneficial in asymptomatic or mildly symptomatic patients
Adult	>16	Autosomal recessive	Rare	Personality changes, behavioral changes, dementia, psychoses, decline in school or work performance	Slow	May be beneficial in asymptomatic or mildly symptomatic patients

Treatment

Medical Care

Symptomatic supportive care is indicated for problems including, but not limited to, behavioral disturbances, feeding difficulties, seizures, and constipation. No effective treatment is available to reverse the deterioration and loss of function that metachromatic leukodystrophy causes.

Several treatment approaches are promising and include bone marrow or blood transplantation, gene therapy, enzyme replacement therapy, and cell therapy.

Marrow or blood transplantation

Allogeneic blood or marrow transplantation is a standard of care for patients with certain inborn errors of metabolism.[33] Early and late outcomes show promise for MLD pediatric patients after cord blood transplantation.[34] Remyelination was observed after hematopoetic stem cell transplantation (HSCT), and importance of immunomodulation in addition to metabolic correction in MLD patients was highlighted for promotion of white matter recovery.[35]

In individuals with asymptomatic late infantile and early juvenile forms of the disease, bone marrow or cord blood transplantation may stabilize neurocognitive function[36, 37] ; however, symptoms of motor function loss frequently progress. Mildly symptomatic and asymptomatic late juvenile and adult-onset forms are more likely to be stabilized with bone marrow or blood transplantation because of slower disease progression.

Patients should be carefully evaluated and counseled prior to bone marrow transplantation. The migration of hematopoietically derived cells in sufficient numbers to treat the affected areas usually requires 6 months to 1 year. During this interval, the patient's condition continues to deteriorate. Although transplantation may be successful, enzyme release to surrounding tissues can widely vary, often with unpredictable benefits.

In addition, the transplantation conditioning regimen and the catabolic state of the patient during transplantation may contribute to a brief period of accelerated deterioration. A study has shown that in children with juvenile metachromatic leukodystrophy, if disease progression does happen after hematopoetic stem cell transplantation (HSCT), it happens early after HSCT and proceeds faster than in children that did not go throught the transplantation.[38]

The bone marrow transplantation procedure can potentially carry significant morbidity and mortality rates. Therefore, patient counseling regarding the risks versus the potential for later stabilization of the disease is necessary.

Evaluation for transplantation includes careful neuropsychological and developmental testing to establish current levels of function and to provide findings for comparison with future results. Organ systems, including cardiac, pulmonary, liver, and kidney functions, require assessment. Brain MRI and a thorough neurologic examination should be included.

If patients are asymptomatic or mildly symptomatic, the evaluations mentioned above should be performed and multidisciplinary treatment needs to be discussed. The treatment may involve a geneticist, a metabolic specialist, a neurologist, a neuropsychologist, a pediatrician, a transplantation specialist, or a combination of several experts.

An appropriately matched and unaffected relative, in whom the cells manufacture adequate levels of arylsulfatase A, should serve as a donor. An appropriately matched unrelated donor may be used in centers with experienced staff, although this transplantation process carries higher morbidity and mortality rates. Bone marrow or placental (cord) blood may serve as the source of stem cells.

Gene therapy

In addition to bone marrow transplantation, gene therapy is under development as a possible solution to correct the underlying genetic abnormality.[39, 40, 41, 42] Hematopoietic stem cell gene therapy shows evidence of safety and clinical benefit for late-infantile[43] and older pediatric patients with MLD.[44]

The study has shown that gene therapy can result in stable ARSA gene replacement with high enzyme expression, including in the cerebrospinal fluid. In the 3 patients who were treated prior to onset of symptoms, the early data suggest that the regimen is a safe method to halt progression of the disease.[45] Further information can be obtained regarding this clinical trial at the ClinicalTrials.gov website under its identifier: NCT01560182.

Researchers are developing innovative methods to overcome the barrier of getting adequate ARSA enzyme activity into the CNS. One such procedure involves transduction of neurospheres with a vector containing arylsulfatase A.[46]

Enzyme replacement

A therapeutic strategy that has been useful for patients with other metabolic storage diseases is direct enzyme replacement. The difficulty with this strategy has always been getting adequate enzyme activity into the CNS. Intravenous injections of a recombinant human arylsulfatase A in a mouse model of MLD initially demonstrated no evidence of impact on CNS stores of sulfatide. However, with a significant increase in the injection frequency, researchers were able to demonstrate a reduction in CNS stores.[47]

A new strategy called evolutionary redesign was used for murinization of 1 or 3 amino acid positions in the human ARSA (hARSA) protein, which increased the hARSA activity 3- and 5-fold, respectively, and no significant impact on the protein stability was observed.[48]

In the United States and Europe, clinical trials are being carried out to evaluate the safety and efficacy of a recombinant human ARSA (rhARSA) enzyme, Metazym (Shire HGT). The drug had obtained orphan drug status from the US Food and Drug Administration in early 2008. The phase I clinical trial for its use in children with late-infantile metachromatic leukodystrophy showed that the drug was safe. Unfortunately, the extension study was terminated because of a lack of efficacy (ClinicalTrials.gov, identifier NCT00681811).

With the theory that the route of administration may allow for better drug concentrations in the CNS[49] , a multicenter phase I/II clinical trial has been developed to evaluate the safety and efficacy of rhARSA administered intrathecally (ClinicalTrials.gov, identifier NCT01510028). This study is ongoing but closed to accrual. The open-label extension arm of this study is now open by invitation (ClinicalTrials.gov, identifier NCT01887938).

Results of the safety evaluation of intrathecal rhARSA administration showed that it was generally well tolerated by patients, and preliminary data suggest promise in further development of rhARSA therapy for patients with MLD.[50] A population pharmacokinetic model was developed on the basis of the above-described trial (NCT01510028) to further evaluate and predict the potential efficacy of intrathecal enzyme replacement therapy.[51]

Cell therapy

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri and colleagues[52] reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain. These cells engrafted and integrated without disruption or tumor formation. Compared with untreated control mice, the treated mice had reduced sulfatide accumulation in the CNS with increased enzyme activity and prevention of motor deficits. This therapeutic approach is not available for humans at this time.

Consultations

Appropriate consultations involve the following specialists:

Neurologist
Ophthalmologist
Pediatrician
Orthopedist
Genetic counselor
Neurodevelopmental psychologist
Bone marrow transplant physician
Genetic, metabolic disease specialist, or both

Referral or transfer to a major medical center with experience in treating inherited neurodegenerative and metabolic disorders in a multidisciplinary setting is highly recommended.

Follow-up evaluation and treatment are often needed. A physical therapist, occupational therapist, orthopedist, ophthalmologist, neuropsychologist, and other specialists may be involved.

Prevention

Genetic counseling is important to inform the family regarding the risk of occurrence in future pregnancies. Metachromatic leukodystrophy is transmitted as an autosomal-recessive trait. Multiple genetic mutations have been implicated as causes of this disorder.[7] Available methods of prenatal testing should be discussed. Tests for a deficiency in enzyme activity in amniocytes or amniotic chorionic villi and gene mutation analysis may be available.

Medication

Medication Summary

Drug therapy is not a component of the standard of care for metachromatic leukodystrophy|. Supportive care is provided for complications or symptomatic relief. Recombinant human arylsulfatase A (rhARSA) enzyme is available in Europe and has been designated as an orphan drug in the United States.

Author

Anna V Blenda, PhD Clinical Associate Professor, Department of Biomedical Sciences, University of South Carolina School of Medicine, Greenville

Anna V Blenda, PhD is a member of the following medical societies: American Association for Cancer Research, American College of Medical Genetics and Genomics, American Society for Microbiology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Luis O Rohena, MD, PhD, FAAP, FACMG Deputy Chief, Department of Pediatrics, Chief, Medical Genetics, San Antonio Military Medical Center; Associate Professor of Pediatrics, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Professor of Pediatrics, University of Texas Health Science Center at San Antonio

Luis O Rohena, MD, PhD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American College of Medical Genetics and Genomics, American Society of Human Genetics

Disclosure: Nothing to disclose.

Additional Contributors

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, The Scientific Research Honor Society, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Robert D Steiner, MD, FAAP, FACMG Professor (Clinical), Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Editor-in-Chief, Genetics in Medicine; Chief Medical Officer, PreventionGenetics

Robert D Steiner, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: PreventionGenetics, ACMG, Acer Therapeutics, Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, CTX Alliance, Aeglea, Eton, Leadiant<br/>Serve(d) as a speaker or a member of a speakers bureau for: France Foundation, Medscape<br/>Received research grant from: Alexion<br/>Received income in an amount equal to or greater than $250 from: Marshfield Clinic, France Foundation, Medscape, PreventionGenetics, ACMG, Acer Therapeutics; Raptor, Retrophin/Travere, Censa; Biomarin; Best Doctors, Health Advances, Precision for Health, PTC Therapeutics, Aeglea, Leadiant<br/>Travel Support for: CTX Alliance.

Theodore Moore, MD, MS Professor and Chief, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California, Los Angeles, David Geffen School of Medicine

Theodore Moore, MD, MS is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, Society for Pediatric Research, American Society for Blood and Marrow Transplantation, Western Society for Pediatric Research, American Society of Hematology

Disclosure: Nothing to disclose.

David Flannery, MD, FAAP, FACMG Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia

David Flannery, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Alan K Ikeda, MD Interim Medical Director, Director of Oncology, Children's Specialty Center of Las Vegas

Alan K Ikeda, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Blood and Marrow Transplantation, American Society of Pediatric Hematology/Oncology

Disclosure: I own stocks in various pharmaceutical companies. This varies on a given week for: multiple and varies.

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