Metachromatic Leukodystrophy 

Updated: Dec 10, 2019
Author: Theodore Moore, MD, MS; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 



Metachromatic leukodystrophy (MLD) is part of a larger group of lysosomal storage diseases, some of which are progressive, inherited, and neurodegenerative disorders (metachromatic leukodystrophy included). Four types of metachromatic leukodystrophy occur with varying ages of onset and courses (ie, late infantile, early juvenile, late juvenile, adult).[1] 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. Metachromatic leukodystrophy actually describes a continuum of clinical severity. As the term implies, the presence of white matter abnormalities on brain images is characteristic.


In patients, the inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes metachromatic leukodystrophy. A deficiency in the lysosomal enzyme sulfatide sulfatase (arylsulfatase A) is present in metachromatic leukodystrophy. Some patients with clinical metachromatic leukodystrophy 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.[2, 3, 4, 5, 6]

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.[7] The sulfatide accumulations produce extensive damage and result in loss of both cognitive and motor functions. 



United States

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


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.


No differences have been identified based on race.


No differences have been identified based on sex.


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 metachromatic leukodystrophy and may be the only presenting symptom. Motor dysfunction often follows. Initial behavioral disturbances are commonly mistaken for those of various psychiatric disorders.[8, 9] 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.

Patient Education

Numerous resources are available to families.

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) 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.

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.

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




Features of symptoms found in patients with each of the 4 forms of metachromatic leukodystrophy (MLD) are shown below.

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

The early juvenile form includes the following:

  • Gait disturbances

  • Tremors

  • Clumsiness

  • Loss of previously achieved skills

  • Intellectual decline

  • Behavioral changes

  • Seizures (possible)

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


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

  • 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 metachromatic leukodystrophy:

  • Dementia

  • Memory loss

  • Disinhibition

  • Impulsiveness

  • Decreased motor function

  • Optic atrophy



Diagnostic Considerations

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 metachromatic leukodystrophy [MLD]) distinguishes arylsulfatase A pseudodeficiency from metachromatic leukodystrophy. Arylsulfatase A pseudodeficiency may also be distinguished using gene mutation analysis or an evaluation of radiolabeled sulfatide fibroblast uptake and accumulation.

Other problems to consider include the following:

  • Schizophrenia

  • Antisocial personality disorder

  • X-linked adrenoleukodystrophy

  • Multiple sulfatase deficiency

Differential Diagnoses



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.[10]

Imaging Studies

Brain MRI may be performed to identify white matter lesions and atrophy, which are characteristic of metachromatic leukodystrophy but nonspecific.[11]

Other Tests

The following tests may be indicated:

  • Nerve conduction studies

  • Neurocognitive, neuropsychological testing, or both


The following procedures may be indicated:

  • 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.


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


Age at









Effect of Bone



Late infantile

< 4



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




Less common

Motor milestones lost,

learning and behavior


Death within

10-15 y

May be beneficial in symptomatic and asymptomatic patients

Late juvenile





Personality changes,

behavioral changes,

dementia, psychoses,

decreased school or

work performance


May be beneficial in asymptomatic or mildly symptomatic patients






Personality changes,

behavioral changes,

dementia, psychoses,

decreased school or

work performance


May be beneficial in asymptomatic or mildly symptomatic patients



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;[12, 13] 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.[14, 15, 16, 17] Gene therapy using the patient's own cells has the advantage of not having the risks of graft versus host disease and always having a source. Researchers are developing innovative methods 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.[18] Gene therapy has had success in treating X-linked severe combined immune deficiency (SCID), adenosine deaminase deficiency-SCID, and chronic granulomatous disease. A phase I/II clinical trial is actively recruiting to evaluate gene therapy for metachromatic leukodystrophy.

The study has shown that this strategy 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.[19] Further information can be obtained regarding this clinical trial at the Web site under its identifier: NCT01560182.

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 metachromatic leukodystrophy 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.[20]

In the United States and Europe, clinical trials are evaluating the safety and efficacy of a recombinant human arylsulfatase A (rhARSA) enzyme, metazym. The new drug had obtained Orphan Drug status from the US Food and Drug Administration (FDA) in early 2008. In the United States, the sponsor for rhARSA is Shire Human Genetic Therapies in Cambridge, Massachusetts. 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 due to a lack of efficacy (, identifier NCT00681811).

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

Another therapeutic approach under study in mice is the use of oligodendroglial cell therapy. Givogri et al reported their transplantation of oligodendrocyte progenitors into mouse neonatal MLD brain.[21] 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

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 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.


Appropriate consultations involve the following specialists:

  • Neurologist

  • Ophthalmologist

  • Pediatrician

  • Orthopedist

  • Genetic counselor

  • Neurodevelopmental psychologist

  • Bone marrow transplant physician

  • Genetic, metabolic disease specialist, or both


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. Multiple genetic mutations have been implicated as causes of this disorder. 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.

Long-Term Monitoring

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.


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



Medication Summary

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.