Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.