Analysis of urinary glycosaminoglycans (inclusive of heparan sulfate and dermatan sulfate) was the earliest method available for diagnosis of MPS I and remains a useful preliminary investigative test. However, definitive diagnosis is now established by enzyme assays using cultured fibroblasts, leukocytes or dried blood tests. Additionally, genetic testing may be used to support the diagnosis.,,
Genotype-phenotype correlations in MPS I are complex and further research is required before they can be clinically useful. To date, research has indicated that nonsense mutations (including the two most common mutations, W402X and Q70X) when present in a homozygous or compound heterozygous state confer a phenotype with severe disease and CNS involvement.  The clinical consequences of other types of mutations (missense, deletion, insertion and splice-site mutations) are not as straightforward and have been identified in patients with severe, intermediate, and mild disease in the homozygous and heterozygous form, even when in association with a known severe nonsense allele. Thus, prediction of phenotype in patients shown to have at least one missense, deletion, insertion, or splice-site mutation can only be made by looking at the phenotype of patients who have previously presented with the mutations.
The 2 most common mutations identified in patients with a less severe phenotype without CNS involvement are the missense and splice-site mutations R89Q and 678-7g>a, respectively. Together they account for 30%-40% of mutations in such individuals.
Established mutations represent only a fraction of known cases, and as these studies progress, it is expected that more mutations will be discovered that are null (mutations resulting in complete absence of α-L-iduronidase activity) and lead to severe MPS I disease with CNS involvement. Mutations that cause less severe forms of MPS I disease without CNS involvement are expected to be limited and mostly of the missense type. Although some genotype-phenotype correlations have been established, some striking variations in disease manifestation have also been reported in affected siblings with the same mutations. In general, patients with slight residual enzyme activity will have a less severe phenotype.
The MPS I Registry program, sponsored and administered by Sanofi Genzyme, is a worldwide database that tracks health-related information for people with MPS I, allowing doctors and health care professionals to understand the disorder.