Mucopolysaccharidosis type I, or MPS I, is a rare genetic metabolic disorder caused by
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 are 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.
Mucopolysaccharides, also known as glycosaminoglycans, are complex sugars produced by cells and exported
to the extracellular space. They include various molecules including heparan 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 breakdown 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 alpha-L-iduronidase deficiency. This deficiency prevents heparan 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 turns 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 with 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 heparan 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.