Contributor: Gordon K. Klintworth
Located within the gene encoding for a-L-iduronidase on the short arm of human chromosome 4 (4p16.3) are mutations that account for two entities that manifest a deficiency of this enzyme (mucopolysaccharidosis type I-H and mucopolysaccharidosis type I-S. These conditions vary in severity with mucopolysaccharidosis type I -H being the most serious, and mucopolysaccharidosis type I -S the least severe. A separate genetic mutation seems to be responsible for these two disorders as only one clinical phenotype develops in affected families.

In mucopolysaccharidosis type I the tears can be used to evaluate the efficiency of bone marrow transplantation.


Striking physical abnormalities characterize the phenotype of Mucopolysaccharidosis type I-H. These include a grotesque facies with a prominent brow, an oversized tongue, a large saddle-shaped nose with broad nostrils, and a short neck associated with dwarfism, limitations in the mobility of joints, a protuberant abdomen with hepato- splenomegaly, umbilical and/or inguinal hernias, cardiac abnormalities, deafness and mental retardation. Skeletal abnormalities of the vertebrae are accompanied by a large shallow sella turcica, and broad stubby fingers due to hyperplastic terminal pharyngeal bones.
Infants with mucopolysaccharidosis type I -H may appear normal at birth, but have inguinal or umbilical hernias. Corneal clouding and the other characteristic physical findings of mucopolysaccharidosis type I -H are seldom recognized until 6 to 24 months after birth. Yet an abnormal accumulation of GAGs within the tissue has been confirmed in fetuses with mucopolysaccharidosis type I-H aborted at 20 weeks gestation. Excessive dermatan sulfate and heparan sulfate are excreted in the urine and, interestingly, the disease affects cartilage, bone and the cornea, tissues not normally containing these GAGs. In mucopolysaccharidosis type I -H, death usually ensues before the reproductive age is reached.

In theory the mutations responsible for mucopolysaccharidosis type I 1-H and mucopolysaccharidosis type I -S could be allelic, i.e. at the same locus on a particular chromosome. If this is so, one would expect a rare individual to inherit one gene for each of these diseases and to manifest a phenotype intermediate between mucopolysaccharidosis type I -H and mucopolysaccharidosis type I-S. Indeed, some individuals with a deficiency of a-L-iduronidase and clouded corneas have a clinical phenotype intermediate beween mucopolysaccharidosis type I I-H and mucopolysaccharidosis type I-S and have been designated mucopolysaccharidosis type I -H/S. More than two decades ago McKusick and colleagues hypothesized that the genetic mutations responsible for mucopolysaccharidosis type I-H and Mucopolysaccharidosis type I-S involved allelic mutations at the a-L-iduronidase locus and that individuals with the "Hurler-Scheie compound" inherited a Hurler gene fron one parent and the Scheie gene fron the other. Others, however, have suggested that a single different mutation might be reponsible, and strong support for this view is the inbred family reported by Jensen and colleagues that is more likely to be homozygous at one locus than heterozygous at two loci.

A diffuse cloudy luster occurs, particularly in the central cornea in mucopolysaccharidosis type I-H. This opacification reflects an abnormal accumulation of glycosaminoglycans in the cornea demonstrable with histochemical methods. By light microscopy the epithelium, fibroblasts (keratocytes)(especially beneath the epithelium) and endothelium of the cornea contain stored material. When examined by TEM the affected corneal cells contain fibrillogranular or amorphous material and occasional myelin figures, within numerous small, round or oval membrane-bound vacuoles. Long-spacing collagen is sometimes evident in the stroma. The lesions in canine mucopolysaccharidosis type I are virtually identical to those in humans, but in contrast to humans with mucopolysaccharidosis type I-H the corneal epithelium of affected dogs has been unremarkable. Corneal clouding has cleared in humans and dogs with mucopolysaccharidosis type I-H following bone marrow transplantation. A pigmentary retinopathy and optic atrophy are common; rarely, papilledema follows increased intracranial pressure.

The ocular manifestations of mucopolysaccharidosis type I-S include corneal clouding, a pigmentary retinopathy, bilateral narrow or closed angle glaucoma, and chronic papilledema with optic atrophy. By light microscopy the keratocytes as well as the basal epithelial cells in the cornea are vacuolated and stain with reagents that demonstrate glycosaminoglycans.

Cornea clouding invariably occurs in mucopolysaccharidosis type I-H/S and several patients have had corneal grafts. Following penetrating keratoplasty the grafts have remained clear for 2, 4 and 8 years. Corneal specimens obtained from two patients with mucopolysaccharidosis type I I-H/S have disclosed numerous vacuoles containing a predominance of fibrillogranular and multimembranous materials within corneal epithelial cells, histiocytes, keratocytes and endothelial cells.
Aside from corneal opacification visual impairment may be due retinal degeneration. The ERG is sometimes extinguished and a pigmentary retinopathy with "bone spicule" shaped areas of pigmentation resembling retinitis pigmentosa may be present. Papilledema has also been reported.
In mucopolysaccharidosis type I the tears can be used to evaluate the efficiency of bone marrow transplantation.

Mucopolysaccharidosis type I-H is the most severe phenotype found in persons with mutations in the CCC gene. Striking physical abnormalities characterize the phenotype of Mucopolysaccharidosis type I-H. These include a grotesque facies with a prominent brow, an oversized tongue, a large saddle-shaped nose with broad nostrils, and a short neck associated with dwarfism, limitations in the mobility of joints, a protuberant abdomen with hepatomegaly, splenomegaly, umbilical and/or inguinal hernias, cardiac abnormalities, deafness and mental retardation. Skeletal abnormalities of the vertebrae are accompanied by a large shallow sella turcica, and broad stubby fingers due to hyperplastic terminal pharyngeal bones.
Infants with mucopolysaccharidosis type I-H may appear normal at birth, but have inguinal or umbilical hernias. Corneal clouding and the other characteristic physical findings of mucopolysaccharidosis type I-H are seldom recognized until 6-24 months after birth. Yet an abnormal accumulation of glycosaminoglycans  within the tissue has been confirmed in fetuses with mucopolysaccharidosis type I-H aborted at 20 weeks gestation. Excessive dermatan sulfate and heparan sulfate are excreted in the urine and, interestingly, the disease affects cartilage, bone and the cornea, tissues not normally containing these glycosaminoglycans.