Metachromatic Leukodystrophy

Updated: Jan 22, 2021
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Metachromatic leukodystrophy (MLD) is part of a larger group of inherited lysosomal storage diseases, some of which are progressive and neurodegenerative disorders (MLD included). Four types of MLD occur with varying ages at onset and courses (ie, late infantile, early juvenile, late juvenile, and adult). [1, 2, 3]

All forms of the disease involve a progressive deterioration of motor and neurocognitive function. The classification 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. Phenotypic variation between siblings with MLD suggests that a number of biochemical and epigenetic factors contribute to the clinical phenotype. [4]  As the term implies, the presence of white matter abnormalities on brain images is characteristic. [5, 6]



In patients, inability to degrade sulfated glycolipids, especially the galactosyl-3-sulfate ceramides, characterizes metachromatic leukodystrophy (MLD). A deficiency in the lysosomal enzyme sulfatide sulfatase (arylsulfatase A [ARSA]) is present. [7]  Some patients with clinical MLD have normal ARSA activity but lack an activator protein that is involved in sulfatide degradation. Both defects result in the accumulation of sulfatide compounds in neural tissue and nonneural tissue, such as the kidneys and gallbladder, as well. These defects result from different gene mutations, mostly in the ARSA gene, and many new causative mutations have been identified. [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]

Histologic examination of the tissues often reveals metachromatic granules. Central and peripheral myelination is abnormal, with a widespread loss of myelinated oligodendroglia in the central nervous system (CNS) and segmental demyelination of peripheral nerves. [18]  Arylsulfatase A deficiency leads to defective glial and neuronal differentiation from neural progenitor cells. [19]  The sulfatide accumulations produce extensive damage and result in loss of both cognitive and motor function. [9]  

Immunohistochemistry and morphometric analyses have revealed that microglia damage precedes major myelin breakdown in patients with MLD, as well as in those with X-linked adrenoleukodystrophy, which should be considered in the differential diagnosis. [20]




The incidence of metachromatic leukodystrophy (MLD) is estimated to be 1 case per 40,000 births in the United States.

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 MLD experience a more chronic and insidious progression of disease.

No differences have been identified on the basis of race or sex.

Patients with the late infantile form of MLD are usually 4 years old or younger and typically present initially with gait disturbances, loss of motor developmental milestones, optic atrophy, and diminished deep tendon reflexes. Progressive loss of both motor and cognitive function is fairly rapid. Death of patients with the late infantile form of metachromatic leukodystrophy (MLD) results within approximately 5 years after the clinical observation of symptoms.

Patients with the early juvenile form of MLD (4-6 years) 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. Progression is typically less rapid than in the infantile form. 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 gastrointestinal tract bleeding have been reported. Patients with the early juvenile form usually die within 10 to 15 years of diagnosis, and most patients die before the age of 20 years.

The late juvenile form of MLD (age range, 6-16 years) and the adult form (>16 years) progress slowly, and patients tend to present with behavioral disturbances or decreased cognitive function. A decline in school or work performance may be recognized first. Seizures may occur in any form of MLD and may be the only initial symptom. Motor dysfunction often follows. Initial behavioral disturbances are commonly mistaken for those of various psychiatric disorders. [21, 22]  

Gallbladder polyps and gallbladder cancer with ascites have been reported in children with metachromatic leukodystrophy (MLD). [23, 24] Patients with the late juvenile form often survive into early adulthood. Patients with the adult form of MLD 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 for families of patients with metachromatic leukodystrophy (MLD).

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) website includes a page titled “Metachromatic Leukodystrophy.” 

The National Tay-Sachs and Allied Diseases Association may provide useful information.

The National Institute of Neurological Disorders and Stroke website includes a page titled “NINDS Metachromatic Leukodystrophy Information Page.

The United Leukodystrophy Foundation is a nonprofit voluntary health organization dedicated to providing patients and their families with information about MLD and to identifying resources for families.

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