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).  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]
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.
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. [4, 5] 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.
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