Leukemia (Blood Cancer)

Mucopolysaccharidosis type I 

            Mucopolysaccharidosis type I, or MPS I, is a rare genetic metabolic disorder caused by a deficiency of a lysosomal enzyme required to break down mucopolysaccharides. The disorder presents as a spectrum ranging from severe forms, classically known as Hurler syndrome, which is associated with life-threatening complications, to attenuated forms, classically known as Scheie syndrome or Hurler-Scheie syndrome. This disease can cause significant disability but it can also have a near-normal life expectancy.     However, since presentation varies greatly between individuals, these designations are imprecise, so Hurler syndrome is generally used for severely affected individuals, and attenuated Mucopolysaccharidosis type I is used for all others. Mucopolysaccharidosis, also known as glycosaminoglycans, are complex sugars produced by cells and exported to the extracellular space. They include various molecules including heparin sulfate and dermatan sulfate, and they can be found on almost all cell surfaces as well as in the basement membrane, which separates epithelial cells from the connective tissue underneath. Mucopolysaccharides are degraded inside the cell, where they’re engulfed by a lysosome that releases enzymes, which break down Mucopolysaccharides. Each mucopolysaccharide requires multiple enzymes to fully degrade, and some mucopolysaccharides are degraded by the same enzymes. For example, both heparan sulfate and dermatan sulfate need the lysosomal enzymes iduronate sulfatase and alpha-L-iduronidase to be broken down.

MPS I is an autosomal recessive disorder, caused by a variation in the IDUA gene, which results in an alpha-L-iduronidase deficiency. This deficiency prevents heparin sulfate and dermatan sulfate from being degraded, and as a result, they build up in various tissues, leading to many complications as well as distinctive facial features, like a prominent forehead, a flat nose bridge, and enlarged lips, tongue, and gums. MPS I is also classically associated with corneal clouding, where the corneas turn opaque, leading to visual problems and even blindness. Skeletal malformations like short stature, kyphosis, hip dysplasia, and joint disease are also common, as well as other complications like hernias, respiratory problems, cardiomyopathy, thickened heart valves, hydrocephalus, and neurosensorial hearing loss. The severe form also causes severe developmental delays and intellectual disability, which are not seen in the attenuated form.

Screening for MPS I can be done by testing the urine for mucopolysaccharides and measuring alpha-L-iduronidase enzyme activity in leukocytes. In the United States, the disorder was recently added to the Recommended Uniform Screening Panel. The diagnosis can be confirmed through molecular genetic testing for newborns. Treatment depends on the severity of the disease. The earlier the treatment starts, the better the outcome. Many complications can be avoided with prompt diagnosis and early treatment.

    

The severe form requires a bone marrow transplant, and often enzyme replacement therapy with alpha-L-iduronidase. A bone marrow transplant is the only treatment to lead to improved intellectual outcomes in children with Hurler syndrome because the enzyme replacement therapy does not affect the brain. With the attenuated form, enzyme replacement therapy may be enough. These therapies do not correct all the symptoms of MPS I. Symptom-specific treatments like corneal transplant, heart valve replacement, and surgical correction of orthopedic complications and hernias may also be needed. Respiratory support, occupational, physical, speech therapy, and hearing aids can improve the quality of life, and some children benefit from specialized education programs. Finally, genetic counseling for the affected person and their family should be done.

                All right, as a quick recap... Mucopolysaccharidosis type I occurs because of a complete or partial deficit of functional alpha-L-iduronidase. This leads to the buildup of mucopolysaccharides like heparin sulfate and dermatan sulfate in various tissues. Corneal clouding is a specific feature, but the disorder is associated with a wide range of potential symptoms. Screening can be done by testing for urinary mucopolysaccharides, or checking levels of alpha-L-iduronidase in white blood cells. Treatment options include bone marrow transplantation and enzyme replacement therapy.