As Hunter syndrome is an X-linked, recessive, inherited disease, males are mainly affected, although there are a small number of female case studies.1,2 Affected females generally have low levels of I2S activity and the non-neuropathic type, although the somatic symptoms can be severe.2
Over 330 mutations have been described for the I2S gene (IDS), which include whole and partial deletions, large gene rearrangements, point mutations, and other changes.1,3 The genotype-phenotype relationship has been difficult to establish due to the rarity of Hunter syndrome.1 The complete absence of the functional enzyme from gene deletion or gene/pseudogene rearrangement may result in the severe phenotype.1
This information is valuable to provide to families when available.3 However, in other cases, the amount of I2S or activity does not correlate with phenotypic severity.1 Point mutations that result in the change of single amino acids in the enzyme have been reported to be associated with a wide range of phenotypes, spanning the entire phenotypic spectrum from neuropathic to non-neuropathic.1 Importantly, the same IDS mutation may be associated with different phenotypes, even among family members.1,3
Females carrying a mutation in one IDS allele are usually asymptomatic.1 Enzyme activity cannot be used to reliably identify female carriers as although I2S activity is ~50% of that seen in non-affected individuals, there is considerable overlap between the non-affected and heterozygous ranges.1,2 Instead, genetic testing to determine the IDS mutation, usually previously identified in an affected male relative, is needed to confirm carrier status.1
Identification of the mutation in a potential carrier is very important for genetic counseling and prenatal diagnosis, as many centers do not perform prenatal diagnosis by measuring enzyme activity in fetal samples.1
1. Martin R et al. Pediatrics. 2008;121(2):e377-e386. 2. Wraith JE et al. Eur J Pediatr. 2008;167(3):267-277. 3. Burton BK, Giugliani R. Eur J Pediatr 2012;171(4):631-639.
Hunter syndrome is a
progressive genetic disease
If you suspect Hunter syndrome, refer your patient to a metabolic geneticist for an accurate diagnosis.