Clinical Characteristics
Ocular Features
Progressive corneal clouding is a major feature and appears early in life. Intracellular accumulations of heparan and dermatan sulfate are responsible for the ground glass appearance. However, congenital glaucoma also occurs in MPS I and must be considered as a concomitant cause of a diffusely cloudy cornea.
Abnormal storage of mucopolysaccharides has been found in all ocular tissues and in the retina leads to a pigmentary retinopathy. The ERG may be abolished by 5 or 6 years of age. Papilledema is often followed by optic atrophy. Photophobia is a common symptom. Shallow orbits give the eyes a prominent appearance.
Systemic Features
This group of lysosomal deficiency diseases is probably the most common. MPS I is clinically heterogeneous encompassing three clinical entities: Hurler, Hurler-Scheie, and Scheie. In terms of clinical severity, Hurler is the most severe and Scheie is the mildest. Infants generally appear normal at birth and develop the typical coarse facial features in the first few months of life. Physical growth often stops at about 2 years of age. Skeletal changes of dysostosis multiplex are often seen and kyphoscoliosis is common as vertebrae become flattened. The head is large with frontal bossing and a depressed nasal bridge. Cranial sutures, especially the metopic and sagittal sutures, often close prematurely. The lips are prominent and an open mouth with an enlarged tongue is characteristic. The neck is often short. Odontoid hypoplasia increases the risk of vertebral subluxation and cord compression. Joints are often stiff and arthropathy eventually affects all joints. Claw deformities of the hands and carpal tunnel syndrome are common. Most patients are short in stature and barrel-chested.
Cardiac valves often are thickened and endocardial fibroelastosis is frequently seen. The coronary arteries are often narrowed. Respiratory obstructions are common and respiratory infections can be serious problems. Hearing loss is common.
Most patients reach a maximum functional age of 2 to 4 years and then regress. Language is limited. Untreated, many patients die before 10 years of age.
Genetics
Inheritance
The Hurler/Scheie phenotypes are all the result of mutations in the IDUA gene (4p16.3). They are inherited in an autosomal recessive pattern. A deficiency in alpha-L-iduronidase causes three phenotypes: Hurler (607014; MPS IH), Hurler-Scheie (607015; MPS IH/S), and Scheie (607016; MPS IS) syndromes.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.