Mucopolysaccharidosis type III (MPS III) is a lysosomal storage disease belonging to the group of mucopolysaccharidoses and characterised by severe and rapid intellectual deterioration. The disorder is underdiagnosed (due to the generally very mild dysmorphism); it is the most frequent MPS in the Netherlands and Australia with respective prevalences of 1/53 0000 and 1/67 000. The frequency of the different subtypes varies between countries: subtype A is more frequent in England, the Netherlands and Australia and subtype B is more frequent in Greece and Portugal, whereas types IIIC and IIID are much less common. The first symptoms appear between the ages of 2 and 6 years, with behavioural disorders (hyperkinesia, aggressiveness) and intellectual deterioration, sleep disorders and very mild dysmorphism. The neurological involvement becomes more prominent around the age of 10 years with loss of motor milestones and communication problems. Seizures often occur after the age of 10. A few cases of attenuated forms have also been reported. Deficiencies in one of the four enzymes required for HS degradation are responsible for each of the MPS III subtypes: heparan sulfamidase for MPS IIIA, alpha-N-acetylglucosaminidase for MPS IIIB, alpha-glucosaminide N-acetyltransferase for MPS IIIC, and N-acetylglucosamine-6-sulfate sulfatase for MPS IIID. The four genes coding for these enzymes have been located (MPS IIIA on 17q25, MPS IIIB on 17q21, MPS IIIC in the pericentromeric region of chromosome 8, MPS IIID on 12q14), and numerous mutations have been identified. Transmission is autosomal recessive for each type of MPS III. Diagnosis is based on detection of increased levels of heparan sulfate (HS) in urine. Demonstration of one of the four enzyme deficiencies in cultivated leukocytes or fibroblasts allows determination of the type of MPS III. For types IIIA and IIID, the measurement of the activity of another sulfatase is compulsory for exclusion of multiple sulfatase deficiency (Austin disease, see this term). When mutations have been identified in the index patient, heterozygous individuals in the family can be accurately detected. In the absence of any efficient treatment, prenatal diagnosis (by mutation analysis or measurements of enzyme activity in trophoblasts or amniocytes) is the only option available to parents with a risk of transmitting the disease. Allogenic bone marrow grafts are contraindicated as they do not slow the mental deterioration, even in patients engrafted pre-symptomatically. Gene therapy is currently under investigation in animal models for the IIIA and IIIB subtypes. The neurological degradation accompanied by multiple complications requires a multidisciplinary management to allow adapted symptomatic treatment. The prognosis is poor with death occurring in most cases of type IIIA at the end of the second decade. Longer survival times (30/40 years) have been reported for the B and D subtypes.
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