Mucopolysaccharidosis II (MPS2), also known as Hunter syndrome, is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase, which catalyzes a step in the catabolism of glycosaminoglycans. In patients with MPS2, glycosaminoglycans accumulate within tissues and organs, contributing to the signs and symptoms of the disease. MPS2 affects multiple organs and physiologic systems and has a variable age of onset and variable rate of progression. MPS2 is chronic and progressive. A newborn infant may appear normal, and yet, within a few years progress into a physically abnormal and mentally impaired individual. (PMID:18245410)
The rarity of Hunter syndrome and the fact that most mutations are private makes evaluation of the genotype-phenotype relationship difficult; however, the complete absence of functional enzyme caused by total or partial gene deletion or by gene/pseudogene rearrangement seems to result in the severe phenotype. 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 spectrum from severe to attenuated. The same IDS mutation may be associated with different phenotypes. (PMID:18245410)
Although complete absence of iduronate 2-sulfatase (IDS) activity is invariably associated with a severe phenotype, the converse is not true. Neither the amount of IDS nor its activity, as determined by routine diagnostic assays, correlates with phenotype severity in patients with Hunter syndrome. (PMID:18245410)
Hunter syndrome is an X-linked, recessive inherited disease that affects males nearly exclusively. Females carrying a mutation in 1 IDS allele are usually asymptomatic. (PMID:18245410)
The traditional classification of patients into ‘mild’ or ‘severe’ subtypes, on the basis of length of survival and the presence or absence of CNS disease, is a gross simplification. The disorder should rather be regarded as a continuum between two extremes (severe and attenuated). (PMID:18038146)
Mucopolysaccharidosis type 2 comprises the following Phenodis entries:
Phenodis:2217 Mucopolysaccharidosis type 2, severe form Orphanet:217085
Phenodis:2218 Mucopolysaccharidosis type 2, attenuated form Orphanet:217093
Mucopolysaccharidosis II is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme iduronate sulfatase, leading to progressive accumulation of glycosaminoglucans in nearly all cell types, tissues, and organs. Patients with MPS II excrete excessive amounts ... Mucopolysaccharidosis II is a rare X-linked recessive disorder caused by deficiency of the lysosomal enzyme iduronate sulfatase, leading to progressive accumulation of glycosaminoglucans in nearly all cell types, tissues, and organs. Patients with MPS II excrete excessive amounts of chondroitin sulfate B (dermatan sulfate) and heparitin sulfate (heparan sulfate) in the urine (McKusick, 1972; Wraith et al., 2008).
Tonnesen et al. (1983) found that cross-correction between the 2 cell populations of the Hunter syndrome heterozygote is inhibited by fructose 1-phosphate or mannose 6-phosphate. Intercellular uptake of lysosomal enzymes in cultured fibroblasts is prevented by addition of ... Tonnesen et al. (1983) found that cross-correction between the 2 cell populations of the Hunter syndrome heterozygote is inhibited by fructose 1-phosphate or mannose 6-phosphate. Intercellular uptake of lysosomal enzymes in cultured fibroblasts is prevented by addition of either mannose-6-phosphate or fructose-1-phosphate to the culture medium. They studied 25 obligatory carriers to determine the usefulness of fructose 1-phosphate as a means of carrier detection. In 23 carriers, (35)S-sulfate incorporation was significantly increased. In 1 carrier, incorporation was already increased before addition of fructose and in 1 carrier it was normal both before and after fructose. Tonnesen (1984) identified Hunter carriers by studying (35)S-sulfate accumulation in the presence and absence of fructose-1-phosphate. Petruschka et al. (1983) tested the Tonnesen technique by studying various mixtures of normal and Hunter cells in culture as well as obligatory carriers. They concluded that the method 'seems to be suitable for carrier detection.' Archer et al. (1983) concluded that carrier detection was best when hair-root analysis and serum enzyme levels were taken together. Daniele and Di Natale (1987) demonstrated crossreacting material in the serum and fibroblasts of Hunter patients. Zlotogora and Bach (1986) proposed that prenatal diagnosis of Hunter syndrome may be possible by measurement of iduronate sulfatase in the mother's serum. The level of IDS consistently rises in the serum of pregnant women. In pregnancies with Hunter-affected male fetuses, serum enzyme levels did not change. The normal increase occurs usually by the sixth to twelfth week. Bakker et al. (1991) found that the IDS cDNA probe was partially deleted in 3 of 12 Dutch patients with Hunter syndrome. In 2 of the 3 patients, Southern blots showed the presence of a deletion junction fragment which could be used for highly reliable direct carrier detection in their families. Schroder et al. (1993) used different carrier detection tests, i.e., IDS activity in serum, sulfate incorporation in cultured skin fibroblasts, and RFLP analysis, in 13 unrelated families with 16 patients and 36 females at risk for MPS II. Twenty-nine females were confirmed as carriers, and in 5 women, the heterozygous state was excluded. The use of the intragenic IDS cDNA probes and flanking probes provided accuracy in carrier detection that was equal to or better than biochemical methods. Structural alterations were found in the DNA of 2 patients: one showed a major deletion including the whole coding sequence of the IDS gene; an aberrant Southern fragment occurred in the HindIII/pc2S15 blot of the other patient, suggesting a new HindIII restriction site by point mutation in an IDS gene intron. Ben Simon-Schiff et al. (1993) confirmed the reliability of the serum assay of IDS activity in the identification of heterozygotes; the serum test correctly detected 11 of 12 of the first-degree relatives tested by the serum assay, 6 of 7 carriers, and 5 of 5 noncarriers. The only case with an apparent false negative result in the serum test was thought to represent an instance of germinal mosaicism. In a family in which there was no surviving affected individual, Timms et al. (1998) described carrier testing using direct dye primer sequencing of PCR products to identify mixed bases in an obligate carrier. Two mixed bases were observed within exon 8 of the IDS gene. These resulted in a missense mutation and a nonsense mutation. Four additional female family members were screened for the same mutations, and none were found in any of these additional subjects, including in 1 who had been identified previously as a carrier by skin biopsy. Timms et al. (1998) concluded that this approach can be used to provide unambiguous information about a subject's carrier status, even in families in which the disorder is mild. As a means of molecular diagnosis, Jonsson et al. (1995) developed a rapid method to sequence the entire iduronate 2-sulfatase coding region: PCR amplicons representing the IDS cDNA were sequenced with an automatic machine, and output was analyzed by computer-assisted interpretation of tracings. Mutations were found in 10 of 11 patients studied. Unique missense mutations were identified in 5 patients.
MPS II is a multisystem disorder. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy, and, in most patients, neurologic decline. Death usually occurs in the second decade of life, although some patients with less severe disease have ... MPS II is a multisystem disorder. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy, and, in most patients, neurologic decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade (summary by Wraith et al., 2008). McKusick (1972) recognized 2 clinically distinguishable forms of MPS II: a severe form (called MPS IIA) with progressive mental retardation and physical disability and death before age 15 years in most cases, and a mild form (called MPS IIB) compatible with survival to adulthood in which reproduction is known to have occurred (DiFerrante and Nichols, 1972) and in which intellect is impaired minimally, if at all. McKusick (1972) noted a lack of corneal clouding in the X-linked form of MPS as opposed to the autosomal forms (see MPS I-H, 607014). Wraith et al. (2008) stated that MPS II should be regarded as a continuum between 2 extremes (severe and attenuated). They noted that although the clinical course for the more severely affected patients is relatively predictable, there is considerable variability in the clinical phenotype and progression of the more attenuated form of the disease. Danes and Bearn (1965) found that fibroblasts from patients with this disorder show metachromatic cytoplasmic inclusions and that about half the fibroblasts of heterozygotes show such inclusions. Hobolth and Pedersen (1978) described a kindred with 6 cases of mild Hunter syndrome additionally remarkable for survival to ages 65 and 87 in 2 of the cases and for progeny from 3 affected males. Tsuzaki et al. (1987) described an unusually mild form of Hunter syndrome. At 14 years of age, their patient had normal growth and development. He had mild dysostosis radiologically, coarse facial features, flexion contractures of the elbows and shoulder joints, and moderate hepatosplenomegaly. At age 8 he had the murmur of aortic regurgitation, and at age 12 angiocardiography was said to have shown grade 4 aortic regurgitation. The mother was a healthy carrier. Ballenger et al. (1980) described spastic quadriplegia in a 24-year-old man due to impingement of the thickened meninges on the cervical spinal cord. Tracheal narrowing required tracheostomy. Sapadin and Friedman (1998) noted extensive Mongolian spots in a 4.5-year-old African American boy with Hunter syndrome. These patches were present at birth over the buttocks and lumbar sacral area. Other patches continued to appear over the paraspinal area of the entire back, and smaller lesions occurred on the anterior trunk. 'Pebbly' skin first appeared on the proximal arms, soon after became visible on the scapulas and thighs, and later in the pectoral areas. The other features were typical of Hunter syndrome, which was confirmed by enzyme assay. Ochiai et al. (2003) investigated the occurrence of Mongolian spots in 7 Japanese infants with Hunter syndrome before and after hematopoietic stem cell transplantation (HSCT). Pre-HSCT observation revealed that all the patients had extensive Mongolian spots that were present at birth and showed no signs of resolution during the post-HSCT period. Electron microscopic findings showed that pigment-bearing dermal melanocytes contained many free melanosomes in stage IV. These were surrounded by extracellular sheaths and encircled by elastic fibers. The results of Ochiai et al. (2003) indicated a strong clinical correlation between extensive Mongolian spots and Hunter syndrome, and ultrastructural findings suggested that the hyperpigmentation is a long-lasting symptom. Ochiai et al. (2003) concluded that recognition of extensive Mongolian spots is essential as it may lead to early diagnosis in patients with mild forms of Hunter syndrome. - Clinical Variability Patients with complete deletion of the IDS locus often have atypical phenotypes, including ptosis, obstructive sleep apnea, and seizures (Wraith et al., 1991; Froissart et al., 1993). Steen-Bondeson et al. (1992) and others have suggested that some of these atypical features in Hunter syndrome patients may be caused by deletion of additional genes in the region of IDS; see MOLECULAR GENETICS section.
In a review, Muenzer et al. (2009) noted that a paucity of common and recurrent mutations in the IDS gene makes genotype/phenotype correlations difficult. They stated that complete deletions and complex rearrangements of the IDS gene always result ... In a review, Muenzer et al. (2009) noted that a paucity of common and recurrent mutations in the IDS gene makes genotype/phenotype correlations difficult. They stated that complete deletions and complex rearrangements of the IDS gene always result in a severe phenotype. Although 3 mutations in codon 468 of exon 9 (300823.0012, 300823.0013, 300823.0015) have been associated with a severe phenotype, each has also been reported in patients with attenuated phenotypes. Similarly, the 1122C-T transition (300823.0002), which creates an alternate splice site with the loss of 20 amino acids, is primarily associated with an attenuated phenotype. - Contiguous Gene Deletion on Xq28 Involving the IDS Gene In a patient with classic severe Hunter syndrome who also suffered from epileptic seizures, Steen-Bondeson et al. (1992) identified a deletion with a proximal breakpoint between DXS295 and DXS296. They noted that epileptic seizures were also described in 2 patients reported by Wilson et al. (1991) and Wraith et al. (1991) with a complete deletion of the IDS gene. A comparison of the breakpoints in the 3 patients suggested that a gene or genes located in the vicinity to the IDS gene may be involved in the development of epilepsy. Birot et al. (1996) described a family with a cytogenetically evident deletion in Xq27.2-q28 that removed the IDS and FMR1 genes. This was said to be the largest deletion in this region of the X chromosome identified in a male patient, indicating that absence of any of the genes in this region would not be lethal. Timms et al. (1997) used genomic DNA sequencing to identify several new genes in the IDS region. DNA deletion patients with atypical symptoms were analyzed to determine whether these atypical symptoms could be due to involvement of these other loci. The occurrence of seizures in 2 individuals correlated with a deletion extending proximal to IDS, up to and including part of the FMR2 locus (309548). Other (nonseizure) symptoms were associated with distal deletions. In addition, a group of patients with no variant symptoms, and a characteristic rearrangement involving a recombination between the IDS gene and an adjacent IDS pseudogene, showed normal expression of loci distal to IDS. Timms et al. (1997) concluded that together these results identified FMR2 as a candidate gene for seizures, when mutated along with IDS. Karsten et al. (1997) noted that the region of the IDS gene, in addition to the IDS2 gene that harbors sequences homologous to exons 2 and 3 and introns 2, 3, and 7, contains several novel genes (e.g., genes W, X, and Y). In addition, a neighboring region has undergone a duplication and exists in an inverted version on the telomeric side of IDS. Karsten et al. (1997) identified 2 distinct deletions separated by 30 kb in a patient with Hunter syndrome. One deletion included exons 5 and 6 of the IDS gene; the second deletion included exons 3 and 4 of the W gene, located telomeric of the IDS gene. Both deletions were the result of nonhomologous (illegitimate) recombination events between short direct repeats at the deletion breakpoints. Lagerstedt et al. (2000) analyzed a 43.6-kb deletion in a patient with Hunter syndrome and found a fusion transcript including sequences from the gene W and the IDS gene. Surprisingly, a similar but longer fusion transcript containing exons 2-4 of gene W and exons 4-9 of the IDS gene could be detected in RNA of normal cell lines originating from various tissues.
Wilson et al. (1991) found a deletion or gene rearrangement in 7 of 23 Hunter patients of Australian and British origin. In 2 of 14 unrelated German MPS II patients, structural alteration of the IDS gene was found ... Wilson et al. (1991) found a deletion or gene rearrangement in 7 of 23 Hunter patients of Australian and British origin. In 2 of 14 unrelated German MPS II patients, structural alteration of the IDS gene was found by Southern analysis using an IDS cDNA clone as a probe. In one of these patients, a severely affected male, no Southern fragments were detected. In 2 unrelated patients with complete deletion of the IDS gene, Wraith et al. (1991) reported that the phenotype was that of very severe Hunter syndrome. In addition, both had features not commonly seen in MPS II, namely, early onset of seizures in one patient and ptosis in the other. In 12 patients, Bunge et al. (1992) used single-strand conformation polymorphism analysis for mutation analysis. Missense or nonsense mutations and deletions or insertions of a small number of basepairs were found in most; probably only about 20% of Hunter patients have complete deletion or gross structural alteration of the IDS gene. The broad clinical variability among Hunter patients is apparently a reflection of extensive molecular heterogeneity. Palmieri et al. (1992) isolated a 1.2-Mb YAC contig spanning the IDS gene. Several putative CpG islands were identified in the region, suggesting the presence of other genes. Southern analysis of DNA from 25 unrelated Italian MPS II patients uncovered 4 with deletions or rearrangements in the IDS gene. DNA from a patient with a translocation breakpoint in the gene permitted orientation of the contig in relation to the centromere. Steen-Bondeson et al. (1992) investigated the occurrence of rearrangements and deletions of the IDS gene in a Southern analysis of 46 unrelated MPS2 patients of different ethnic origins using a cDNA clone containing the entire IDS gene as a probe. Structural alterations were found in DNA from 9 patients, 2 of whom showed large deletions including all coding sequences of the gene. The distal and proximal breakpoints of these deletions were determined by hybridization of markers flanking the IDS gene. Seven of the observed alterations constituted major rearrangements of the gene. Six of these rearrangements showed similar or identical patterns by Southern analysis, suggestive of a region prone to structural alterations within the IDS gene. Steen-Bondeson et al. (1992) also demonstrated the potential use of the IDS probe for carrier detection in families with a rearranged IDS gene. Froissart et al. (1993) described 2 patients who appeared to have complete deletion of the IDS gene. It appeared that these patients had a more severe form of Hunter syndrome. From a study of a total of 26 cases, Bunge et al. (1993) found that about 20% of patients have deletions of the whole IDS gene or other major structural alterations. In about 23% of cases, deletion of 1, 2, or 3 basepairs was found, while the remaining patients, about 57%, carried point mutations predicting amino acid replacement, premature termination of translation, or aberrant splicing. Hopwood et al. (1993) reviewed mutations in the IDS gene in Hunter syndrome. From the group of 319 patients thus far studied by Southern analysis, 14 had full deletion of the gene and 48 had partial deletion or other gross rearrangements. All patients with full deletions or gross rearrangements had severe clinical presentations. In a total of 32 patients, 29 different 'small' mutations had been characterized: 4 nonsense and 13 missense mutations, 7 different small deletions from 1 to 3 bp, with most leading to a frameshift and premature chain termination, and 5 different splice site mutations also leading to small insertions or deletions in the mRNA. A 60-bp deletion that resulted from the creation of a new donor splice site was observed in 5 unrelated patients with relatively mild clinical phenotypes. Sukegawa et al. (1995) described 8 new examples of point mutations in the IDS gene in Japanese Hunter syndrome patients exhibiting various degrees of severity. Bondeson et al. (1995) identified an IDS pseudogene, which they designated IDS2, located within 90 kb telomeric of the IDS gene. They showed that this region is involved in a recombination event with the primary IDS gene in about 13% of patients with the Hunter syndrome. Analysis of the resulting rearrangement at the molecular level showed that these patients had suffered a recombination event that resulted in a disruption of the IDS gene in intron 7 with an inversion of the intervening DNA. All 6 patients with a similar type of rearrangement showed recombination between intron 7 of the IDS gene and sequences close to exon 3 of the IDS2 locus, implying that these regions are hotspots for recombination. Nucleotide sequencing showed that the inversion is caused by recombination between homologous sequences present in the IDS gene and the IDS2 locus. No detectable deletions or insertions were observed as a consequence of the recombination. The IDS2 pseudogene contains sequences that are related to exons 2 and 3 as well as introns 2, 3, and 7 of the IDS gene. An example of a similar inversion caused by homologous recombination is that involving intron 22 of the factor VIII gene (F8; 300841) causing severe hemophilia A (306700). In the case of the F8 gene, the inversions occur almost exclusively in the male germ cells. It has therefore been hypothesized that mispairing leading to inversion is inhibited by pairing of the X chromosomes in the female germ cells. Interestingly, both the F8 gene and the IDS gene are located in Xq28, a distal part of the X chromosome that is generally unpaired in males. Bondeson et al. (1995) provided additional information concerning the IDS2 gene. Birot et al. (1996) described a patient with Hunter syndrome in whom an exchange between the IDS gene and pseudogene through interchromosomal recombination had apparently caused internal deletion of exons 4, 5, 6, and 7. In the rearranged gene, the junction intron contained pseudogene intron 3- and intron 7-related sequences. Rathmann et al. (1996) identified IDS mutations in 31 families/patients with MPS II. Twenty mutations were novel and unique and another was novel but was found in 3 unrelated patients. One of the mutations detected was of special interest as it is an A-to-G substitution in an intron far from the coding region that is deleterious because it creates a new 5-prime splice donor site that results in the inclusion of a 78-bp intronic sequence (300823.0014). The authors analyzed a total of 101 point mutations in the coding region and found that they tended to be more frequent in exons 3, 8, and 9. CpG dinucleotides were involved in 47% of the point mutations, of which G:C-to-A:T transitions constituted nearly 80%. Almost all recurrent point mutations involved CpG sites. Analysis of a collection of 50 families studied by this group revealed that mutations occurred more frequently in male meioses; they estimated the male-to-female ratio to be between 3.76 and 6.3. Froissart et al. (1998) studied 70 unrelated Hunter patients and found a mutation in each. There was striking molecular heterogeneity. Large gene rearrangements were identified in 14 patients. In the 56 other patients, 43 different mutations were identified, and 31 had not previously been described. Since only a few mutations were present in several patients, genotype/phenotype correlations were difficult. The mother was not found to be a carrier in 5 among 44 sporadic cases. Haplotype analysis demonstrated a high frequency of mutations in male meiosis. Isogai et al. (1998) characterized 25 different small mutations in the IDS gene in a series of 43 Japanese patients with Hunter disease. As in other series, 3 different mutations in codon 468 of exon 9 were found: arg468 to trp (309900.0012), arg468 to gln (309900.0013), arg468 to leu (309900.0015). All 3 mutations were associated with a severe phenotype. Timms et al. (1998) described a patient with features of moderate to severe Hunter syndrome and a 178-bp deletion upstream of IDS exon 1 spanning a predicted promoter element. Sequencing of all 9 IDS exons failed to show any additional mutations within the coding region or in intron/exon boundaries. The 178-bp deletion was flanked by 2 13-bp direct repeats and potential DNA topoisomerase II recognition sites. These findings suggested to Timms et al. (1998) nonhomologous recombination as a possible mechanism for the deletion. Expression studies detected no IDS transcripts. In a study of 31 Spanish families with Hunter disease, Gort et al. (1998) found 22 novel small mutations (7 reported previously by the same group) and 4 large deletions or rearrangements. This brought the number of separate IDS mutations that had been reported to that time to nearly 150. Li et al. (1999) provided yet more evidence of the molecular heterogeneity of this condition by identifying 17 mutations in 18 unrelated patients with MPS2. The mutations included 7 missense mutations, 5 small deletions, 2 insertions, 2 splice site mutations, and an intragenic deletion of exons 4, 5, 6, and 7. Nine of the small mutations were novel. In 36 Russian patients with Hunter syndrome, Karsten et al. (1998) found 25 different mutations, of which 15 were novel. Most of the missense mutations resulted in intermediate or severe phenotypes.
Schaap and Bach (1980) reported a frequency of approximately 1 in 34,000 males born in Israel between 1967 and 1975.
In a questionnaire study in the United Kingdom, Young and Harper (1982) estimated the frequency of ... Schaap and Bach (1980) reported a frequency of approximately 1 in 34,000 males born in Israel between 1967 and 1975. In a questionnaire study in the United Kingdom, Young and Harper (1982) estimated the frequency of the Hunter syndrome as about 1 in 132,000 male births. The severe form was 3.38 times more frequent than the mild form. No increased incidence in Jews was noted. In British Columbia, 6 cases of the Hunter syndrome were born between 1952 and 1986, giving a frequency of 1 in 110,950 live male births (Lowry et al., 1990). Chakravarti and Bale (1983) concluded that the high frequency of Hunter disease in Israeli Jews (Goodman, 1979) is compatible with genetic drift. Using multiple ascertainment sources, Nelson et al. (2003) estimated the incidence rate for mucopolysaccharidoses in western Australia for the period 1969 to 1996. An incidence of approximately 1 in 320,000 live births (1 in 165,000 male live births) was obtained for Hunter syndrome. Lin et al. (2009) analyzed the incidence of MPS in Taiwan between 1984 and 2004 and found that the combined birth incidence for all MPS cases was 2.04 per 100,000 live births. MPS II (Hunter syndrome) had the highest calculated birth incidence (1.07 per 100,000 live births), comprising 52% of all MPS cases diagnosed. Although the overall incidence of MPS in Taiwan was consistent with reports from Western populations, Lin et al. (2009) noted that in contrast to reports of a higher incidence of MPS I in most Western populations, their study showed a higher incidence of MPS II in Taiwan.
The diagnosis of mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) cannot be made on clinical findings alone. The physical findings vary widely, depending on disease severity. ...
DiagnosisClinical DiagnosisThe diagnosis of mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) cannot be made on clinical findings alone. The physical findings vary widely, depending on disease severity. The diagnosis is often suspected in males age 18 months to four years with short stature, hepatosplenomegaly, joint contractures, and coarse facies; subtle early signs and symptoms such as frequent ear/sinus infections and umbilical hernia are often present. A skeletal survey may show skeletal anomalies known collectively as dysostosis multiplex; however, these findings may not be present in early life and are not specific to MPS II. TestingUrine glycosaminoglycans (GAGs). GAG quantitative and qualitative analysis is useful as a preliminary test to help establish that the person has an MPS condition. In MPS II, GAG analysis shows large concentrations of the GAGs dermatan sulfate and heparan sulfate. The profile is similar to that seen in MPS I. Recently, a method based on the use of electrospray ionization–tandem mass spectrometry, has been proposed for the diagnosis of MPSII [Nielsen et al 2010]. Iduronate 2-sulfatase (I2S) enzyme activity. Confirmation of the diagnosis of MPS II is made by demonstrating deficient I2S enzyme activity in leukocytes, fibroblasts, or plasma. Most affected males have no detectable activity using the artificial substrate. Absence or reduced levels of I2S enzyme activity decreases the amount of the sulfate moiety released from the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate during their degradation. Note: Documentation of normal enzymatic activity of at least one other sulfatase is critical, as low levels of I2S enzyme activity are present in multiple sulfatase deficiency, which can share some common clinical features with MPS II.Carrier testing. Measurement of I2S enzyme activity is not reliable for detection of carrier females as a carrier may have normal I2S enzyme activity resulting from X-chromosome inactivation that may be non-random. Molecular Genetic TestingGene. IDS is the only gene in which mutations are known to cause MPS II. A pseudogene (IDS2) is located 90 kb telomeric to IDS. Clinical testing. Three general types of IDS mutations are observed in persons with MPS II: mutations within the gene, exonic and whole-gene deletions, and gross alterations resulting from recombination with the nearby IDS pseudogene, IDS2. Sequence analysis of the entire IDS coding region detects 82% of mutations in both males and females [Froissart et al 2007]. Single nucleotide changes and splicing mutations account for 65% of all mutations. Small (i.e., intra-exonic) deletions and insertions account for 17% of all mutations Note: (1) Sequence analysis may be reported as normal in individuals (males or females) who have the most common pseudogene recombination. Therefore, Southern blot analysis should also be performed; however, this analysis could be preceded by a PCR-based method developed by Lualdi et al [2005] that can verify the presence of the most common types of recombination by analyzing the genomic exchange regions involved in the rearrangements. (2) Lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion in males (but not females); confirmation may require additional testing of a male by deletion/duplication analysis. (3) Sequence analysis of cDNA allows the study of the effect of promoter mutations and intronic mutations affecting splicing that would be missed by other methods. This analysis is accurate in males, but may not be accurate in females.Deletion/duplication analysis. A variety of methods may be used to detect the large (exonic or whole-gene) deletions in males and females that account for 9% of mutations [Froissart et al 2007] (Table 1). Southern blot analysis is used to detect complex rearrangements resulting from recombination with the pseudogene or from other types of processes and accounting for 9% of all mutations [Froissart et al 2007]. These rearrangements could also be detected by deletion/duplication analysis if they are associated with a partial deletion or duplication of IDS. Different single nucleotide polymorphism (SNP) patterns of IDS and its pseudogene, IDS2 could help in the rearrangement characterization. Prior to performing Southern blot analysis, preliminary analysis with the PCR-based method of Lualdi et al [2005] could be performed to exclude the most common types of recombination Table 1. Summary of Molecular Genetic Testing Used in MPS II (Hunter Syndrome) View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesHeterozygous FemalesIDSSequence analysisSequence variants 291% 3, 482% 5ClinicalDeletion/ duplication analysis 6Deletion/duplication of one or more exons or the whole gene 9%9%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 4. Includes the mutation detection frequency using deletion/duplication analysis5. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandUrine GAGs and skeletal survey are useful in establishing the presence ofan MPS condition, but are not specific to MPS II. The gold standard for diagnosis of MPS II in a male proband is assay of iduronate sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma. Molecular genetic testing of IDS to confirm the diagnosis in a male proband may be useful in persons with an unusual phenotype or a phenotype that does not match the results of GAG testing. Carrier testing of at-risk relatives requires prior identification of the disease-causing mutation in the family.Identification of female carriers requires one of the following: Testing for the family-specific mutation that has been identified in an affected male relative ORIf an affected male is not available for testing, molecular genetic testing First by sequence analysis If no mutation is identified, use of deletion/duplication analysis methods to detect intragenic and exonic gene deletions If no mutation is identified, use of Southern blot analysis to detect gene rearrangements between IDS and the pseudogene, IDS2 Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersDeletions extending beyond the IDS locus result in symptoms atypical of MPS II. These deletions cause a more severe central nervous system (CNS) phenotype and may be associated with other atypical features such as ptosis and seizures [Probst et al 2007].
Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) has multisystem involvement with significant variability in both age of onset and rate of progression. ...
Natural HistoryMucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) has multisystem involvement with significant variability in both age of onset and rate of progression. CNS involvement, the most significant feature in the group of children often labeled with "severe" disease, manifests primarily by progressive cognitive deterioration. Such cognitive decline, combined with the progressive airway and cardiac disease, usually results in death in the first or second decade of life. In individuals with the attenuated form of the disease, the CNS is minimally affected, if at all, yet the effect of GAG accumulation on other organ systems may be just as severe as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in this group. The severe CNS phenotype may be more than twice as prevalent as the attenuated form of the disease; however, accurate prevalence rates are not available. Eighty-four percent of affected males have some form of neurologic involvement. Cardiovascular involvement was reported in 82% of affected individuals [Wraith et al 2008].GAG accumulation in virtually all organs occurs in MPS II, but specific body systems are more affected than others.The clinical presentations of the organ systems most severely affected in are the following: General. The appearance of newborns with MPS II is normal. Coarsening of facial features — the result of macroglossia, prominent supraorbital ridges, a broad nose, a broad nasal bridge, and deposition of GAG in the soft tissues of the face resulting in large rounded cheeks and thick lips — generally manifests between ages 18 months and four years in the severe form and about two years later for those with the attenuated form. Growth in the first five years of life is above average for most boys with MPS II; after that growth lags and short stature is the norm. Macrocephaly is universal. Eye. In contrast to MPS I, corneal clouding occurs occasionally and not a typical feature of MPS II. However, discrete corneal lesions that do not affect vision may be discovered by slit-lamp examination. Optic nerve head swelling is present in about 20% of affected individuals and optic atrophy was found in approximately 11% of affected individuals [Collins et al 1990, Ashworth et al 2006]. Retinopathy has been reported; electroretinography (ERG) may reveal retinal dysfunction, and visual field loss can occur. Initially, rod-mediated responses are more severely affected than cone-mediated responses [Caruso et al 1986]. Progressive reduction in ERG amplitude suggests a deterioration in retinal function [Leung et al 1971].However, signs and symptoms do not necessarily correlate with ERG change, as often only minimal changes are observed in the RPE despite significant ERG changes [Ashworth et al 2006].Ear, nose, throat. Common oral findings in boys with MPS II include macroglossia, hypertrophic adenoids and tonsils, and ankylosis of the temporomandibular joint, which limits opening of the mouth. These changes may be responsible for progressive swallowing impairment. GAG deposition in the larynx typically results in a characteristic hoarse voice. Teeth are often irregularly shaped and gingival tissue is overgrown. Dentigerous cysts can occur, often causing pain and discomfort. They can be difficult to diagnose particularly in males with CNS involvement. Conductive and sensorineural hearing loss, complicated by recurrent ear infections, occur in most affected individuals. Otosclerosis can contribute to the conductive hearing loss. Neurosensory hearing loss can be attributed to compression of the cochlear nerve resulting from arachnoid hyperplasia, reduction in the number of spiral ganglion cells, and degeneration of hair cells. Joints/skeletal. Joint contractures, particularly of the phalangeal joints, are universal. The contractures cause significant loss of joint mobility and are one of the earliest noteworthy diagnostic clues. The skeletal abnormalities in MPS II are comparable regardless of the severity of the cognitive phenotype but are not specific to MPS II. Termed dysostosis multiplex, these radiographic findings are found in all MPS disorders and manifest as a generalized thickening of most long bones, particularly the ribs, with irregular epiphyseal ossification centers in many areas. Notching of the vertebral bodies is common. Hip dysplasia is the most common long-term orthopedic problem and can become a significant disability with early-onset arthritis if not treated.Respiratory. Frequent upper respiratory infections are one of the earliest findings in MPS II. The airway progressively narrows as GAGs accumulate in the tongue, soft tissue of the oropharynx, and the trachea, eventually leading to airway obstruction. Complicating this obstruction are thickening of respiratory secretions, stiffness of the chest wall, and hepatosplenomegaly, which can reduce thoracic volume. The progression of airway obstruction is relentless and usually results in sleep apnea, the need for positive pressure assistance, and eventually tracheostomy. Cardiovascular. The heart is abnormal in the majority of boys with MPS II and is a major cause of morbidity and mortality (see Table 2); 82% of individuals have cardiovascular signs/symptoms, 62% have a murmur which can be related to valvular disease, including in order of frequency the mitral, aortic, tricuspid, and pulmonary valves. Table 2. Cardiovascular Involvement in MPSIIView in own windowCardiovascular Involvement PrevalenceCardiac valve involvement57%Cardiomyopathy8%Tachycardia7%Hypertension6%Arrhythmia and congestive heart failure 4%Peripheral vascular disease2%Wraith et al [2008]Reported "baseline" organ involvement in 202 individuals enrolled in the Hunter Outcome Survey (HOS) as of May 15, 2007. Note: "Baseline" is defined as a finding present at the time data were initially entered into the HOS database.Gastrointestinal. Hepatomegaly and/or splenomegaly occur in most affected individuals. Umbilical/inguinal hernia is also a frequent finding. In persons with severe MPS II, chronic diarrhea is a common complaint. Nervous system. Infants with MPS II appear normal at birth; early developmental milestones may also be within the normal range. Delay in global developmental milestones is typically the first clue of brain involvement in children with the CNS form of MPS II. As is the case for the other organ systems, progression of the CNS manifestations is inexorable, usually resulting in developmental regression between ages six and eight years.The most common neurologic signs are behavioral and cognitive problems, which Wraith et al [2008] found in 36% and 37% of affected individuals, respectively. Behavior problems occur in both the severe and attenuated forms of the disease [Young & Harper 1981, Wraith et al 2008] but are more common in the severe form. Chronic communicating hydrocephalus may complicate the clinical picture, especially on the background of deteriorating cognitive ability. Seizures may also occur. The decline of cognitive function, combined with progression of severe pulmonary and cardiac disease, generally heralds the terminal phase of the disease, with death in the first or second decade of life. Males who do not have the progressive CNS form of the disease have normal or nearly normal intelligence. However, while deteriorating cognitive abilities and seizures are not common in males with the attenuated form of MPS II, chronic communicating hydrocephalus may still occur. Carpal tunnel syndrome (CTS) is often an overlooked complication of MPS II. Unlike adults with CTS, most children with MPS II do not complain of the typical symptoms. Nonetheless, nerve conduction studies are abnormal; hand function improves after surgical correction.Another nervous system complication that must be monitored is narrowing of the spinal canal (spinal stenosis), particularly in the cervical region, with spinal cord compression. Endocrine. Infants with MPS II appear normal at birth; in the first years of life the height of most children with MPS II is above the 50th percentile and in some it is over the 97th percentile. However, growth velocity decreases with age: by age eight years height is below the third percentile, and nearly all children exhibit growth retardation before puberty [Schulze-Frenking et al 2011]. The cause of short stature is unknown; it may be related to osseous growth-plate disturbances.
Outside of the following two groups neither the amount of I2S protein nor its enzyme activity can be correlated with phenotypic severity. ...
Genotype-Phenotype CorrelationsOutside of the following two groups neither the amount of I2S protein nor its enzyme activity can be correlated with phenotypic severity. The mutation c.1122C>T, which creates a new donor splice site at exon 8 with the loss of 20 amino acids) is primarily associated with the attenuated phenotype [Muenzer et al 2009]. Boys with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the severe CNS presentation of the disease [Wraith et al 2008]. Genotype-phenotype correlations for point mutations, most of which are unique to a particular family, are not reliable for MPS II [Vafiadaki et al 1998, Li et al 1999, Moreira da Silva et al 2001]. At least two sibships have been reported in which one brother has the severe phenotype while another brother has an attenuated phenotype [Yatziv et al 1977]. Several missense mutations have been associated with the severe phenotype (p.Arg468Gln, p.Arg468Trp, and p.Ser333Leu), as well as in individuals with an intermediate or attenuated phenotype.
The differential diagnosis for mucopolysaccharidosis type II (MPS II, or Hunter syndrome) essentially includes all of the other MPS disorders, given the significant overlap of clinical presentation and radiologic findings (see MPS I)....
Differential DiagnosisThe differential diagnosis for mucopolysaccharidosis type II (MPS II, or Hunter syndrome) essentially includes all of the other MPS disorders, given the significant overlap of clinical presentation and radiologic findings (see MPS I).Multiple sulfatase deficiency and mucolipidosis types II and III) may also present with findings similar to MPS II. See: Mucolipidosis II, Mucolipidosis III Alpha/Beta, and Mucolipidosis III Gamma.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).MPS II, severe formMPS II, attenuated form
To establish the extent of disease in an individual diagnosed with mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome), the following evaluations are recommended:Echocardiogram Pulmonary function testing Sleep study if sleep apnea is a potential concern Hearing test Nerve conduction velocity (NCV) study to assess for carpal tunnel syndrome Head-cervical MRI and/or opening pressure on lumbar puncture to assess for hydrocephalus and spinal cord compression. Because MRI needs to be performed under sedation and/or intubation in individuals with the severe form, there is an increased risk of compromising the upper airway. See Prevention of Secondary Complications. Eye examination Developmental assessment Note: Many of these assessments are age dependent. For example, pulmonary function and sleep studies would not be appropriate in a two year old. Treatment of ManifestationsAt this time, treatment of complications in MPS II is symptomatic. The involvement of specialists for each affected organ system is required to monitor and treat specific problems (see Natural History). Commonly required interventions include the following: Shunting for hydrocephalus Tonsillectomy and adenoidectomy Positive pressure ventilation (CPAP or tracheostomy) Carpal tunnel release Cardiac valve replacement Inguinal hernia repair Hip replacement Developmental, occupational, and physical therapy are often necessary. Enzyme replacement therapy (ERT) (see Prevention of Primary Manifestations) is now available for MPS II. ERT has shown encouraging results in possibly modifying/correcting the non-CNS manifestations; however, no data are yet available as to any long-term benefits of such treatment. Prevention of Primary ManifestationsEnzyme replacement therapy (ERT). Idursulfase (Elaprase®) is a recombinant form of human iduronate 2-sulfatase that has been approved in the United States and the European Union for the treatment of MPS II [US Food and Drug Administration 2006a, US Food and Drug Administration 2006b]. Clinical efficacy of ERT was shown in a double-blind placebo-controlled study of 96 patients [Muenzer et al 2006]. After one year of treatment, persons in the weekly idursulfase group compared to the placebo group demonstrated statistically significant improvement of the primary endpoint, a composite consisting of distance walked in six minutes and the percentage of predicted forced vital capacity based on the sum of ranks of change from baseline. Based on the larger clinical response in the weekly compared to the every other week group, idursulfase was approved for the treatment of MPS II in both the US and European Union at a dose of 0.5 mg/kg weekly. Patients with relatively attenuated forms of Hunter syndrome were studied in the clinical trial leading to FDA approval of Elaprase®; thus, it is not known at this time whether the incidence or severity of infusion-related reactions is different for patients younger than age five years with severe respiratory compromise or with severe CNS disease. Because of the trial design, the study only included individuals with the attenuated form of the disease. Despite Elaprase ® being approved for treatment of MPS II, no information is yet available on the outcome of using the drug for individuals who are younger than age five years or have severe CNS disease. Since Elaprase® does not cross the blood-brain barrier, no effect on CNS disease is anticipated. However, there is reason to believe that somatic manifestations of those with severe CNS involvement would benefit from ERT. Infusion-related reactions that may occur with use of Elaprase® ERT are comparable to similar reactions seen with other ERT products used in treatment of lysosomal storage disease and with other infused proteins such as monoclonal antibodies (e.g., infliximab). The etiology of the more severe forms of these non-allergic reactions, referred to as anaphylactoid, is unknown. Current evidence suggests that anaphylactoid (as opposed to anaphylactic) reactions are not immune mediated [Mayer & Young 2006]. Infusion reactions are generally mild and include brief, insignificant decreases or increases in heart rate, blood pressure, or respiratory rate; itching; rash; flushing; and headache. Mild reactions can usually be managed by slowing the infusion rate for several treatments and then slowly returning to the prior rate. Pretreatment with anti-inflammatory drugs or antihistamines, as is often done for ERT in other conditions, is not suggested on the label for Elaprase®; however, if mild or moderate infusion reactions (e.g., dyspnea, urticaria, or systolic blood pressure changes of ≤20 mm Hg) cannot be ameliorated by slowing the infusion rate, the addition of treatment one hour before infusion with diphenhydramine and acetaminophen (or ibuprofen) to the regimen usually resolves the problem. Pretreatment can typically be discontinued after six to ten weeks. Severe non-allergic anaphylactoid reactions such as major changes in blood pressure, wheezing, stridor, rigors, or drop in oxygen saturations should be immediately addressed by stopping the infusion and giving appropriate doses of subcutaneous (SQ) epinephrine, intravenous (IV) diphenhydramine, and hydrocortisone or methylpredinsolone. Subsequent infusions should then be given at a significantly reduced rate with pretreatment with prednisone 24 hours and eight hours before the infusion, diphenhydramine and acetaminophen or ibuprofen orally one hour before the infusion, and IV methylpredinsolone just before beginning the infusion. Hematopoietic stem cell transplantation (HSCT) using umbilical cord blood or bone marrow is a potential way of providing sufficient enzyme activity to slow or stop the progression of the disease; however, the use of HSCT is controversial because of the associated high risk of morbidity and mortality. Furthermore, it remains unclear if treatment early in life significantly reduces the progression of neurologic disease [Mullen et al 2000]. Anecdotal case reports published to date have been disappointing, quite unlike the reports of bone marrow transplantation (BMT) in Hurler syndrome (MPS I), in which early treatment (age ≤2 years) has met with good success [Tolar et al 2011]. For example, a six-year-old boy who underwent cord blood stem cell transplantation (CBSCT) from an unrelated donor had reduction of hepatomegaly and normal growth; however, he died ten months post-therapy due to a laryngeal post-transplantation lymphoproliferative disorder. Autopsy showed that donor-derived IDS-positive cells were predominantly localized in perivascular brain spaces with some present in the brain parenchyma. However,his hyperactivity, estimated mental age, and brain MR findings had not improved. The efficacy of CBSCT was judged to be insufficient ten months post-therapy [Araya et al 2009].The efficacy of BMT for MPS II cannot be determined until a number of children with MPS II younger than age two years with known or probable severe CNS disease undergo transplantation, along with documentation of long-term follow-up.Prevention of Secondary ComplicationsBecause of risks associated with sedation with/out intubation, anesthesia is best administered in centers familiar with the potential complications in persons with MPS II. Risks associated with general anesthesia include the following: Ankylosis of the temporomandibular (TM) joint can restrict oral access to the airway. Visualization of the vocal cords is compromised by the large tongue, GAG-infiltrated soft tissues, and large tonsils and adenoids. Care must be taken to avoid hyperextension of the neck secondary to atlantoaxial instability and cervicomedullary compression which may be present. Nasopharyngeal intubation is often necessary. When endotracheal intubation is difficult or when sedation is required for brief procedures, laryngeal mask airway may be indicated.The risk of airway complications may continue following successful surgery. Extubation may be difficult because laryngeal edema, reported up to 27 hours post surgery, may prevent maintenance of a proper airway [Hopkins et al 1973]. Breathing a helium-oxygen mixture during extubation has been reported to relieve obstruction and improve outcome [Grosz et al 2001].SurveillanceModes of surveillance for complications over time depend, like treatment, on organ system and disease severity. Because all persons with MPS II face the same organ failure issues, with the time of failure being dependent on severity, when and how often to monitor for change cannot be generalized. However, the following studies/evaluations are likely indicated on at least a yearly basis beginning in early to mid-childhood: Cardiology visit with echocardiogram Pulmonary clinic visit with pulmonary function testing Audiogram Eye examination, including examination through a dilated pupil to view the optic disc Developmental assessment Neurologic examination The following are appropriate at baseline and/or when symptoms/age dictates:Sleep study for obstructive sleep apnea NCV study for evidence of carpal tunnel syndrome Head/neck MRI to document ventricular size and cervicomedullary narrowing Opening pressure on lumbar puncture Orthopedic evaluation to monitor hip disease Evaluation of Relatives at RiskClinical experience suggests that early diagnosis of at-risk relatives allows initiation of ERT before the onset of irreversible changes and often before significant disease progression. It is unclear at present whether early diagnosis, either by newborn screening or testing of at-risk male relatives, is beneficial from the standpoint of early initiation of ERT. No data are available on whether early ERT improves the outcome of the somatic disease in MPS II. ERT is not expected to benefit children with the CNS form of the disease. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationA number of interventions are being evaluated for potential use in MPS II. Recently, a phase I intrathecal delivery of iduronate-2-sulfatase was initiated. See Clinical Trial). Other therapies under preclinical investigation include more direct delivery of enzyme into the CNS, higher peripheral dosing regimens, small molecule therapies such as chaperone and substrate reduction, and gene therapy [Beck 2010]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Mucopolysaccharidosis Type II: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDIDSXq28Iduronate 2-sulfataseIDS @ LOVDIDSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Mucopolysaccharidosis Type II (View All in OMIM) View in own window 309900MUCOPOLYSACCHARIDOSIS TYPE IIMolecular Genetic PathogenesisMutations in IDS result in minimal to absent lysosomal I2S (iduronate 2-sulfatase) enzyme activity, depending on the mutation. Lack of enzyme activity causes heparan and dermatan sulfate (two forms of glysosaminoglycans, or GAGs) to accumulate in the lysosomes of the cell, disrupting their function and causing disease.Normal allelic variants. IDS spans 24 kb with nine exons. An IDS pseudogene, IDS2, is approximately 20 kb away in the telomeric direction. Pathologic allelic variants. Over 300 mutations have been described, the majority being point mutations or small deletions [Froissart et al 2007]. However, up to 10% of MPS II is the result of large intragenic deletions and/or chromosomal rearrangements, typically associated with the severe phenotype. The presence of homologous regions in the nearby IDS2 pseudogene predisposes to unequal recombination events, leading to complex rearrangements and sometimes to large deletions. Table 3. Selected IDS Pathologic Allelic VariantsView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.998C>Tp.Ser333LeuNM_000202.5 NP_000193.1c.1403G>Ap.Arg468Glnc.1402C>Tp.Arg468Trypc.1122C>TSplice variantSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. Iduronate 2-sulfatase (I2S), a 550-amino acid protein, catalyzes the release of sulfate from the iduronate sulfate residues of heparan sulfate and dermatan sulfate [Neufeld & Muenzer 2002]. Abnormal gene product. Missense mutations make up the majority of gene mutations in IDS, resulting in reduced expression of I2S enzyme activity and variable disease severity. Genotype-phenotype predictions are not reliable in these cases. In males with large deletions and intragenic rearrangements, no enzyme is produced and these individuals typically have the severe phenotype.