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Metachromatic leukodystrophy (MLD)

Metabolic diseases

by Alexander Kurz

General outline

Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder of myelin metabolism. Due to the deficiency of the enzyme arylsulfatase A sulfatides (cerebroside sulfate) accumulate in the white matter of the central and peripheral nervous system as well as in other body organs including kidney, liver, pancreas, testes, and retina.

The sulfatides show a peculiar staining which is called „metachromatic“. There are late infantile, juvenile, and adult variants of the disease.

Symptoms and course

In the adult variant of MLD onset may occur from the mid-teens to the seventh decade. The most common signs are personality or behavioural change and signs of intellectual deterioration. Patients show impairment of memory and concentration, and their behaviour becomes childish. Atypical psychotic features are common and often lead to a misdiagnosis of schizophrenia. Progressive dementia is usually accompanied by spasticity, unvoluntary movements, emotional lability and involuntary movements. Evidence of peripheral neuropathy is variable, but occasionally this is the presenting feature. The disease may progress slowly over several decades; the mean survival time is 14 years. In the final stages patients are mute, blind, quadriparetic, and unresponsive.

Causes and risk factors

The defect in MLD involves the lysosomal enzyme arylsulfatase. A number of mutations were identified in the arylsulfatase A (ARSA) gene (22q13.31). Inheritance is autosomal recessive. The arylsulfatase A deficit generates an abnormal storage of sulfatides. Microscopically there is diffuse demyelinisation in the white matter of the central nervous system, ventricular enlargement and atrophy of the corpus callosum with loss of oligodendroglia and accumulation of sulfatide-containing metachromatic granules in neurons and glial cells. Similar changes are seen in the peripheral nerves.


The prevalence is estimated at 1 : 40.000 (Ben-Yoseph and Mittchell, 1995).

Diagnostic procedures

The diagnosis of MLD can be established during life by the demonstration of reduced activity of arylsulfatase A in peripheral blood leukocytes or by the finding of metachromatic lipid material in centrifuged urine or peripheral nervous tissue.

The cerebrospinal fluid may show an elevated protein content. Nerve conduction studies may reveal evidence of a peripheral neuropathy with slowed motor nerve conduction and absent sensory action potentials.

The CT shows symmetrical hypodensities of the white matter whereas brain atrophy is only mild. Abnormal signal in the periventricular white matter on T2-weighted MRI scanning appears to be more specific. Proton MRS shows reduced N-acetylaspartate and increased myoinositol in affected areas. Genetic test can be used to identify mutations in the arylsulfatase A gene on chromosome 22 or mutations in the sufatid activator gene on chromosoms 10 (rare).

Care and treatment

Bone marrow transplantation is used in MLD to replace the deficient enzyme. After successful transplantation, enzyme activity increases to normal or heterozygote levels, and the correction is permament without the need for further treatment.

The new enzyme levels prevent the accumulation of sulfatades and contribute to the removal of abnormal tissue deposits. In patients with MLD bone marrow transplantation slows down or even halts the progression of the disease and stabilises clinical, neurophysiologic, and neuroradiologic features. These favourable result occur when transplantation is performed early in the disease. At more advanced stages results have been disappointing.

Results in significant improvements in the clinical course of MLD. Outcomes based on neuropsychological tests indicate continued maintenance and in some cases increase in cognitive function.

Available services

United Leukodystrophy Foundation 2304 Highland Drive Sycamore, Illinois USA 60178

You can also contact the Department of Neurology.


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Last Updated: Friday 09 October 2009


  • Acknowledgements

    This information was gathered in the framework of the European Commission financed project "Rare forms of dementia". Neither the European Commission nor any person acting on its behalf is responsible for any use that might be made of the following information.
  • European Union