eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Metachromatic Leukodystrophy

Alan K Ikeda, MD, Assistant Professor, Department of Pediatrics, Division of Hematology and Oncology, David Geffen School of Medicine at UCLA; Assistant Director of Pediatric Blood and Marrow Transplantation, Mattel Children's Hospital
Theodore Moore, MD, MS, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine; Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute

Updated: Sep 15, 2008

Introduction

Background

Metachromatic leukodystrophy (MLD) is part of a larger group of lysosomal storage diseases, some of which are progressive, inherited, and neurodegenerative disorders (MLD included). Four types of MLD occur with varying ages of onset and courses (ie, late infantile, early juvenile, late juvenile, adult). All forms of the disease involve a progressive deterioration of motor and neurocognitive function. The typing is somewhat arbitrary because the types overlap and some cases do not fall neatly within a single type. MLD actually describes a continuum of clinical severity. As the term implies, the presence of white matter abnormalities on brain images is characteristic.

Pathophysiology

In patients, the inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes MLD. A deficiency in the lysosomal enzyme sulfatide sulfatase (arylsulfatase A) is present in MLD. Some patients with clinical MLD have normal arylsulfatase A activity but lack an activator protein that is involved in sulfatide degradation. Both defects result in the accumulation of sulfatide compounds in neural and in nonneural tissue, such as the kidneys and gallbladder. These defects may result from a number of different mutations, and many new causative mutations have been identified.^1,2

Histologic examination of the tissues often reveals metachromatic granules. Central and peripheral myelination are abnormal, with a widespread loss of myelinated oligodendroglia in the CNS and segmental demyelination of peripheral nerves. The sulfatide accumulations produce extensive damage and result in loss of both cognitive and motor functions.

Frequency

United States

Incidence is estimated to be 1 case per 40,000 births.

Mortality/Morbidity

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 experience a more chronic and insidious progression of disease.

Race

No differences have been identified based on race.

Sex

No differences have been identified based on sex.

Age

For a summary of distinguishing characteristics of each form, see the Table.

Patients with the late infantile form are usually aged 4 years or younger and typically present initially with gait disturbances, loss of motor developmental milestones, optic atrophy, and diminished deep tendon reflexes. In addition, progressive loss of both motor and cognitive functions is fairly rapid, and death results within approximately 5 years after the onset of clinical symptoms.
Patients with the early juvenile form (4-6 y) 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. Although progression is typically less rapid than in the infantile form, death usually occurs within 10-15 years of diagnosis, and most patients die before age 20 years. 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 GI tract bleeding have been reported.
The late juvenile (6-16 y) and adult (>16 y) forms progress slowly, and patients tend to present with behavioral disturbances or decreased cognitive function. Decreased school or work performance may be recognized first. Seizures may occur in any form of MLD and may be the only presenting symptom. Motor dysfunction often follows. Initial behavioral disturbances are commonly mistaken for those of various psychiatric disorders.^3,4 Patients with the late juvenile form often survive into early adulthood. Patients with the adult form 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.

Clinical

History

Features of symptoms found in patients with each of the 4 forms of metachromatic leukodystrophy (MLD) include the following:

Infantile form
- Gait disturbances
- Memory deficits
- Seizures (may be present)
- Loss of motor developmental milestones
- Decreased attention span
- Speech disturbances
- Decline in school performance
Early juvenile form
- Gait disturbances
- Tremors
- Clumsiness
- Loss of previously achieved skills
- Intellectual decline
- Behavioral changes
- Seizures (possible)
Late juvenile and adult forms
- Decreased work or school performance
- Behavioral changes
- Memory loss
- Seizures (may be present)
- Psychoses
- Gradual loss of motor skills

Physical

Neurodevelopmental tests demonstrate the following findings in patients with infantile or early juvenile 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

Differential Diagnoses

Attention Deficit Hyperactivity Disorder
Krabbe Disease
Schizophrenia and Other Psychoses

Workup

Laboratory Studies

Arylsulfatase A enzyme activity may be decreased in leukocytes or in cultured skin fibroblasts.
CSF protein levels may be increased (although this finding is nonspecific).
Metachromatic leukodystrophy (MLD) may be distinguished from arylsulfatase A pseudodeficiency using one of the following tests:
- Urine sulfatide levels
- 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.⁵

Imaging Studies

Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of MLD but nonspecific.⁶

Other Tests

Nerve conduction studies
Neurocognitive, neuropsychological testing, or both

Procedures

Peripheral nerve biopsy (usually not needed)
Lumbar puncture

Histologic Findings

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.

Staging

Characteristics of the 4 Forms of Metachromatic Leukodystrophy

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 functions 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, decreased 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, decreased school or work performance	Slow	May be beneficial in asymptomatic or mildly symptomatic patients

Treatment

Medical Care

Currently, no effective treatment is available to reverse the deterioration and loss of function that metachromatic leukodystrophy (MLD) causes. In individuals with asymptomatic late infantile and early juvenile forms of the disease, bone marrow or cord blood transplantation may stabilize neurocognitive function;^7,8 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 transplantation because of slower progression.

In addition to bone marrow transplantation, gene therapy is under development as a possible solution to correct the underlying genetic abnormality.^9,10 Researchers are developing innovate ways to overcome the barrier of getting adequate enzyme activity into the CNS. One such procedure involves transduction of neurospheres with a vector containing arylsulfatase A.¹¹ As of this writing, gene therapy remains under investigation and is not yet ready for clinical trials.

A therapeutic strategy useful in 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.¹² In Europe, ongoing clinical trials are evaluating the safety and efficacy of a recombinant human arylsulfatase A (rhARSA) enzyme, metazym. The new drug has obtained Orphan Drug status from the US Food and Drug Administration (FDA) in early 2008 and a Phase II (efficacy) clinical trial is currently in development for patients with late-infantile MLD. In the United States, the orphan sponsor for rhARSA is Shire Human Genetic Therapies in Cambridge, Massachusetts.

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri et al (2006) reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain.¹³ 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.

Symptomatic supportive care is indicated for problems including, but not limited to, behavioral disturbances, feeding difficulties, seizures, and constipation.

Bone marrow transplantation may proceed as follows:

Carefully evaluate and counsel patients 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.
The transplantation procedure carries significant morbidity and mortality rates (see Bone Marrow Transplantation). Therefore, counsel patients regarding the risks versus the potential for later stabilization of the disease.
Evaluation for transplantation includes careful neuropsychological and developmental testing to establish current levels of function and to provide findings for comparison with future results. Assess the organ systems, including cardiac, pulmonary, liver, and kidney functions. Perform brain MRI and a thorough neurologic examination.
If patients are asymptomatic or mildly symptomatic, perform the evaluations mentioned above, and discuss multidisciplinary treatment, which may involve a geneticist, metabolic specialist, neurologist, neuropsychologist, pediatrician, transplantation specialist, or a combination.
An 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.

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

Medication

Drug therapy is currently not a component of the standard of care for this disease. Provide supportive care for complications. Recombinant human arylsulfatase A (rhARSA) enzyme is available in Europe and has been designated orphan status in the United States.

Follow-up

Further Outpatient Care

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

Inpatient & Outpatient Medications

Medications are used to provide supportive care or symptomatic relief rather than to treat the underlying cause.

Transfer

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

Deterrence/Prevention

Genetic counseling is important to inform the family regarding the risk of occurrence in future pregnancies.
Metachromatic leukodystrophy (MLD) is transmitted as an autosomal recessive trait.
Available methods of prenatal testing should be discussed. Tests for a deficiency in enzyme activity in amniocytes or amniotic chorionic villi and gene deletion analysis may be available.

Prognosis

See Treatment and Age.

Patient Education

Numerous resources are available to families, including the following:

The MLD Foundation is the world's largest MLD-focused organization and serves hundreds of families across the globe.
The United Leukodystrophy Foundation is a nonprofit voluntary health organization dedicated to providing patients and their families with information regarding MLD and to identifying resources for families.
The National Organization for Rare Disorders (NORD) Web site includes a page titled Leukodystrophy, Metachromatic, and the National Tay-Sachs and Allied Diseases Association may provide useful information.
The National Institute of Neurological Disorders and Stroke Web site includes a page titled the NINDS Metachromatic Leukodystrophy Information Page.
A limited list of current clinical trials for many diseases can be found at ClinicalTrials.gov, which is a Web site maintained by the National Institutes of Health.

Miscellaneous

Medicolegal Pitfalls

Initial presenting signs and symptoms may be subtle and easily confused with those of other, similar diseases.
A high index of suspicion should be maintained when evaluating patients with neurodegenerative disorders.
Failure to recognize metachromatic leukodystrophy (MLD) and other neurodegenerative disorders may leave physicians open to criticism.
Early diagnosis and referral optimize the time for procuring an acceptable bone marrow donor.
Assay of urine arylsulfatase A activity may be unreliable as a diagnostic test.
Beware of arylsulfatase A pseudodeficiency.

Special Concerns

See Deterrence/Prevention.

References

Anlar B, Waye JS, Eng B. Atypical clinical course in juvenile metachromatic leukodystrophy involving novel arylsulfatase A gene mutations. Dev Med Child Neurol. May 2006;48(5):383-7. [Medline].
von Figura K, Gieselman V, Jaeken J. Metachromatic leukodystrophy. In: Scriver C, Beadet A, Valle D, Sly W, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8^th ed. McGraw-Hill Professional; 2001.
Estrov Y, Scaglia F, Bodamer OA. Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis. Feb 2000;23(1):2-6. [Medline].
Fukutani Y, Noriki Y, Sasaki K, et al. Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia. Psychiatry Clin Neurosci. Jun 1999;53(3):425-8. [Medline].
Meikle PJ, Grasby DJ, Dean CJ. Newborn screening for lysosomal storage disorders. Mol Genet Metab. Aug 2006;88(4):307-14. [Medline].
Faerber EN, Melvin J, Smergel EM. MRI appearances of metachromatic leukodystrophy. Pediatr Radiol. Sep 1999;29(9):669-72. [Medline].
Krivit W. Allogeneic stem cell transplantation for the treatment of lysosomal and peroxisomal metabolic diseases. Springer Semin Immun. 2004;26:119-132. [Medline].
Martin PL, Carter SL, Kernan NA. Results of the cord blood transplantation study (COBLT): outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with lysosomal and peroxisomal storage diseases. Biol Blood Marrow Transplant. Feb 2006;12(2):184-94. [Medline].
Consiglio A, Quattrini A, Martino S, et al. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nat Med. Mar 2001;7(3):310-6. [Medline].
Matzner U, Habetha M, Gieselmann V. Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells. Gene Ther. May 2000;7(9):805-12. [Medline].
Kawabata K, Migita M, Mochizuki H. Ex vivo cell-mediated gene therapy for metachromatic leukodystrophy using neurospheres. Brain Res. Jun 13 2006;1094(1):13-23. [Medline].
Matzner U, Herbst E, Hedayati K, et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum Mol Genet. May 2005;14(9):1139-1152. [Medline].
Givogri MI, Galbiati F, Fasano S. Oligodendroglial progenitor cell therapy limits central neurological deficits in mice with metachromatic leukodystrophy. J Neurosci. Mar 22 2006;26(12):3109-19. [Medline].
Alessandri MG, De Vito G, Fornai F. Increased prevalence of pervasive developmental disorders in children with slight arylsulfatase A deficiency. Brain Dev. Oct 2002;24(7):688-92. [Medline].
Hernandez-Palazon J. Anaesthetic management in children with metachromatic leukodystrophy. Paediatr Anaesth. Oct 2003;13(8):733-4. [Medline].
Sevin C, Aubourg P, Cartier N. Enzyme, cell and gene-based therapies for metachromatic leukodystrophy. J Inherit Metab Dis. Apr 2007;30(2):175-83. [Medline].

Keywords

metachromatic leukodystrophy, arylsulfatase A deficiency, MLD, neurodegenerative disorders, cerebroside sulfatide, galactosyl sulfatide, bone marrow transplantation, sulfatide sulfatase deficiency, sulfatide accumulation, cholecystitis, pancreatitis

Contributor Information and Disclosures

Author

Coauthor(s)

Theodore Moore, MD, MS, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, Clinical Director of Pediatric Hematology/Oncology, Director of Pediatric Blood and Marrow Transplant Program, University of California at Los Angeles School of Medicine
Theodore Moore, MD, MS is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Department of Pediatrics, Oregon Health & Science University; Director and Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital and Doernbecher Children's Hospital; Deputy Director, Oregon Clinical and Translational Research Institute
Robert D Steiner, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics, American Society of Human Genetics, Oregon Medical Association, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism, and Western Society for Pediatric Research
Disclosure: Genzyme Honoraria Speaking and teaching; Genzyme Grant/research funds Other; Shire Honoraria Speaking and teaching; Actelion Honoraria Speaking and teaching; Biomarin Honoraria Speaking and teaching; Biomarin Consulting fee Consulting

Medical Editor

Karl S Roth, MD, 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 Clinical Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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 and American College of Medical Genetics
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

Further Reading