AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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, 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.

• 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 (Estrov, 2000; Fukutani, 1999). 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Features of symptoms found in patients with each of the 4 forms of MLD include the following:

• Infantile
• • Gait disturbances
  • Memory deficits
  • Seizures (may be present)
  • Loss of motor developmental milestones
  • Decreased attention span
  • Speech disturbances
  • Decline in school performance
• Early juvenile
• • Gait disturbances
  • Tremors
  • Clumsiness
  • Loss of previously achieved skills
  • Intellectual decline
  • Behavioral changes
  • Seizures (possible)
• Late juvenile and adult
• • Decreased work or school performance
  • Behavioral changes
  • Memory loss
  • Seizures (may be present; Bostantjopoulou, 2000)
  • 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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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).
• 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 a number of different lysosomal proteins. In the future, these may be used to screen newborns (using blood spots) for early identification of lysosomal storage disorders (Meikle, 2006).

Imaging Studies

• Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of MLD but nonspecific (Faerber, 1999).

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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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:

• 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 be highly variable, 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

In/Out Patient Meds

• 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.
• 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

• A number of resources are available to families, including the following:
• • 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

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal 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 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• 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].
• 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].
• 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].
• Estrov Y, Scaglia F, Bodamer OA. Psychiatric symptoms of inherited metabolic disease. J Inherit Metab Dis. Feb 2000;23(1):2-6. [Medline].
• Faerber EN, Melvin J, Smergel EM. MRI appearances of metachromatic leukodystrophy. Pediatr Radiol. Sep 1999;29(9):669-72. [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].
• 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].
• Hernandez-Palazon J. Anaesthetic management in children with metachromatic leukodystrophy. Paediatr Anaesth. Oct 2003;13(8):733-4. [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].
• 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].
• 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].
• 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].
• Meikle PJ, Grasby DJ, Dean CJ. Newborn screening for lysosomal storage disorders. Mol Genet Metab. Aug 2006;88(4):307-14. [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. 8th ed. McGraw-Hill Professional;2001.

Article Last Updated: Oct 19, 2006