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eMedicine Journal
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Pediatrics
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Genetics And Metabolic Disease
Metachromatic Leukodystrophy Synonyms, Key Words, and Related Terms: metachromatic leukodystrophy, arylsulfatase A deficiency, MLD, neurodegenerative disorders, cerebroside sulfatide, galactosyl sulfatide, bone marrow transplantation, sulfatide sulfatase deficiency, sulfatide accumulation |
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 | AUTHOR INFORMATION | Section 1 of 11    |
Authored by Theodore Moore, MD, Director, UCLA Pediatric Bone Marrow Transplant Program, Clinical Director, Pediatric Hematology/Oncology, Associate Professor, Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California at Los Angeles Medical Center
Coauthored by Robert D Steiner, MD, Professor, Departments of Pediatrics and Molecular and Medical Genetics, Vice Chair for Research, Head of Division of Metabolism, Department of Pediatrics, Oregon Health & Science University; Director, Consulting Staff, Metabolic Bone Disease Clinic, Shriner's Hospital
Theodore Moore, MD, is a member of the following medical societies: American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, and American Society of Hematology
Edited by Karl S Roth, MD, Chair, Professor, Department of Pediatrics, Creighton University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; David Flannery, MD, FAAP, FACMG, Vice Chair of Education, Chief, Section of Medical Genetics, Professor, Department of Pediatrics, Medical College of Georgia; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
| Author's Email: | Theodore Moore, MD |  |
|---|---|---|
| Editor's Email: | Karl S Roth, MD |
eMedicine Journal, October 19 2006, VOLUME 7,
Number 10
| INTRODUCTION | Section 2 of 11  |
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, as 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 recently (Anlar, 2006; von Figura, 2001).
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:
Mortality/Morbidity: Morbidity and mortality rates vary with each form of the disease. In general, young patients have the most rapidly progressive disease, while 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.
| CLINICAL | Section 3 of 11 |
History: Features of symptoms found in patients with each of the 4 forms of MLD include the following:
Physical:
| DIFFERENTIALS | Section 4 of 11 |
Attention Deficit Hyperactivity Disorder
Krabbe Disease
Schizophrenia and Other Psychoses
Other Problems to be Considered:
Arylsulfatase A pseudodeficiency: As many as 1-2% of people may have low (5-15%) or reference range levels of arylsulfatase A in the serum, but sulfatide is not stored. These individuals are usually healthy and asymptomatic. The presence of normal urinary sulfatide levels (elevated in patients with MLD) distinguishes arylsulfatase A pseudodeficiency from MLD. Arylsulfatase A pseudodeficiency may also be distinguished using gene mutation analysis or an evaluation of radiolabeled sulfatide fibroblast uptake and accumulation.
Schizophrenia
Antisocial personality disorder
X-linked adrenoleukodystrophy
Multiple sulfatase deficiency
| WORKUP | Section 5 of 11 |
Lab Studies:
Imaging Studies:
Other Tests:
Procedures:
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 | Section 6 of 11 |
Medical Care: Currently, no effective treatment is available to reverse the deterioration and loss of function 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 (Krivit, 2004; Martin, 2006); 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 (Consiglio, 2001; Matzner, 2000). 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 (Kawabata, 2006). 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 (Matzner, 2005). This has yet to be assessed in humans.
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. 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:
Consultations: Appropriate consultations involve the following specialists:
| MEDICATION | Section 7 of 11 |
Drug therapy is currently not a component of the standard of care for this disease. Provide supportive care for complications.
| FOLLOW-UP | Section 8 of 11 |
Further Outpatient Care:
In/Out Patient Meds:
Transfer:
Deterrence/Prevention:
Prognosis:
Patient Education:
| MISCELLANEOUS | Section 9 of 11 |
Medical/Legal Pitfalls:
Special Concerns:
| TEST QUESTIONS | Section 10 of 11 |
CME Question 1: Which of the following forms of metachromatic leukodystrophy (MLD) is expected to show the most rapid deterioration of neurocognitive function in patients?
A: Infantile form
B: Early juvenile form
C: Late juvenile form
D: Adult form
E:
None of the above
The correct answer is A: The rapid progression of disease and the accompanying high levels of deterioration make the infantile form of MLD extremely difficult to stabilize, even with rapid intervention involving bone marrow transplantation.
CME Question 2: Although seizures are not common in patients with metachromatic leukodystrophy (MLD), seizures may be the presenting symptom in individuals with which of the following forms of MLD?
A:
Infantile form
B: Early juvenile form
C:
Late juvenile form
D:
Adult form
E: All of the above
The correct answer is E: Seizures may be the only presenting symptom in all forms of MLD. Brain MRI demonstrates characteristic changes of MLD.
Pearl Question 1 (T/F): Bone marrow transplantation is the only therapy that is completely effective in reversing the neurologic deficits that metachromatic leukodystrophy causes.
The correct answer is False: At best, bone marrow transplantation may stabilize the disease at the patient’s current level of function. Neurocognitive function rarely improves. In fact, most patients experience a period of deterioration after transplantation until sufficient enzyme activity is produced in the tissues to prevent further damage.
Pearl Question 2 (T/F): Low serum levels of arylsulfatase A are always diagnostic for metachromatic leukodystrophy (MLD).
The correct answer is False: Approximately 1-2% of the population has an arylsulfatase A pseudodeficiency, which may be misdiagnosed as MLD. Additional tests (eg, urinary sulfatide level determination, gene mutation analysis, radionucleotide uptake studies) may be warranted, especially in atypical cases of MLD.
Pearl Question 3 (T/F): Presenting symptoms of metachromatic leukodystrophy (MLD) are often subtle and may include findings such as decreased work or school performance.
The correct answer is True: Diagnosis of MLD may be significantly delayed because of the often vague and nonspecific findings. Consider MLD and other progressive inherited neurodegenerative disorders early on in patients with decreased work or school performance.
Pearl Question 4 (T/F): The most common form of metachromatic leukodystrophy is the infantile form.
The correct answer is True: The most common form of metachromatic leukodystrophy is the infantile form. Unfortunately, this is the most rapidly progressive form and the one least responsive to bone marrow transplantation.
| BIBLIOGRAPHY | Section 11 of 11 |
| NOTE: |
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