| Symptoms |
Commonly Reported By |
- recurrent otitis media or “glue ear” - chronic rhinitis - abdominal protuberance - gibbus deformity - joint restriction - abnormal gait - hand/wrist pain - above normal growth or head size |
Primary Care Providers |
- recurrent upper respiratory tract infections - recurrent otitis media or “glue ear” - developmental delay - hepatosplenomegaly - joint restriction - gibbus deformity - coarse facial features |
Pediatricians |
- recurrent otitis media or “glue ear” requiring tube placement - chronic rhinitis - snoring |
Otolaryngologists |
- inguinal and umbilical hernia - carpal tunnel syndrome |
General/Pediatric Surgeons |
- corneal clouding - retinal degeneration |
Opthalmologists |
Findings in MPS I may overlap with those of other lysosomal storage disorders, particularly other mucopolysaccharide diseases and multiple sulfatase deficiency. Detailed clinical findings and biochemical testing are necessary for their differentiation. There are some early clinical signs and symptoms, which alone are not diagnostic, but may warrant more definitive testing. Although these findings at presentation will vary with the severity of the disorder, MPS I should be suspected in individuals with coarse facial features, hepatosplenomegaly, and characteristic skeletal, joint, or ocular findings.
Confirming a Diagnosis
Analysis of urinary glycosaminoglycans (heparan sulfate and dermatan sulfate) was the first method available for diagnosis of MPS I and may still be used as a preliminary investigative test.
Today, diagnosing relies on demonstrating a deficiency of the lysosomal enzyme alpha-L-iduronidase using enzyme assays specific for alpha-L-iduronidase.[4] [5] [6] This enzyme activity may be measured in most tissues; however, a diagnosis is usually made using peripheral blood leukocytes, plasma, or cultured fibroblasts.
For a list of MPS I diagnostic laboratories, see the Diagnostic Centers section of this website.
Prenatal Diagnosis
Prenatal diagnosis is routinely carried out on cultured cells from amniotic fluid or chorionic villus biopsies using the same enzyme assay that is used for monitoring alpha-L-iduronidase in cultured fibroblasts or leukocytes.
Genotype-Phenotype Correlations
Genotype-phenotype correlations in MPS I are complex and further research is required before they may be clinically useful.
Carrier Testing
Carrier testing is a service often requested by MPS I families. However, to date, the analysis of alpha-L-iduronidase enzyme activity does not provide definitive carrier information. This is related to the fact that there is considerable overlap between the normal and heterozygous ranges[6] and that pseudodeficiency of alpha-L-iduronidase has been reported. Thus, there may be issues associated with interpreting results of enzyme levels in the general population.
Carrier testing is most often performed if the family mutation is known. However, the large number of mutations that underlie MPS I and the technologies available to assess gene mutations do not currently allow for routine carrier detection by molecular methods.[6] The value of carrier testing for the purpose of identifying couples who may be at risk of having an affected child is also limited. This is because, even if one can accurately determine the carrier status of a relative of an MPS I patient, the determination of the carrier status of the unrelated spouse is difficult.
Molecular Genetic Testing and Molecular Diagnosis
When considering DNA-based tests one must take into account the great heterogeneity of mutations underlying MPS I. Mutant alleles need to be identified for the specific family before molecular diagnosis can be undertaken for members at risk. Many patients will likely be compound heterozygotes; thus both mutant alleles must be known for carrier testing to be helpful for the family. Once the mutant allele(s) are identified (either by the mutation itself, or by an intragenic polymorphism), molecular diagnosis may become easier and require less DNA material, which is important for prenatal testing.[6] However, the large number of private mutations may keep mutation analysis impractical for some families. Until mutation analysis becomes more readily available, diagnosis should be established by enzyme assay. DNA-based diagnosis is the only definitive test for determining carrier status but will likely have limited value in individuals who are at low risk of being carriers.
References:
1. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. 8th ed. New York: McGraw-Hill; 2001. p. 3427-36.
2. Cleary MA, Wraith JE. The presenting features of mucopolysaccharidosis type IH (Hurler syndrome). Acta Paediatr. 1995;84:337-339.
3. Scheie HG, Hambrick GW, Barness LA. A newly recognized forme fruste of Hurler’s disease (Gargoylism). American Journal of Ophthalmology 1962;53(5):753-69.
4. Hall CW, Liebaers I, Di Natale P, Neufeld EF. Enzymatic diagnosis of the genetic mucopolysaccharide storage disorders. Methods Enzymol 1978;50:439-456.
5. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 7th ed. New York: McGraw-Hill, Medical Publishing Division; 1995. p. 2465.
6. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler KW, et al, editors. The Metabolic and Molecular Bases of Inherited Disease. Vol. III. 8th ed. New York: McGraw-Hill; 2001. p. 3421-52.
