Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive genetic disorder that results in a wide range of clinical symptoms from mild somatic complications and a normal lifespan to severe central nervous system involvement and a significantly shortened lifespan. An extensive review of the literature was performed to pool data from studies that have identified mutations in patients with mucopolysaccharidosis type I (MPS I) and have reported clinical information about disease severity in an attempt to make correlations between a patient's genotype and phenotype. To date, all patients with a nonsense mutation identified on both alleles have developed the severe form of MPS I. The phenotypes of patients with missense, insertion, deletion, or splice site mutations are much more variable. Missense mutations are the most likely to allow for some residual enzyme activity, and in particular, the R89Q mutation has been identified in several mild patients even when in combination with a nonsense mutation. Conversely, most splice site and insertion/deletion mutations result in the severe phenotype unless in combination with a less severe missense mutation. Currently, genotype-phenotype correlations cannot be confidently made unless the patient has 2 nonsense mutations. Although most families have private mutations, some insight into phenotypic expression may be obtained by observing the clinical severity of other patients with the same genotype. This review also confirms that MPS I allele frequencies vary between different ethnic populations, and that W402X and Q70X are the most common mutations and are present in over 50% of Caucasian alleles.