Mucopolysaccharidosis Type Ii

Clinical characteristics.

Mucopolysaccharidosis type II (MPS II; also known as Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation. The vast majority of affected individuals are male; on rare occasion heterozygous females manifest findings. Age of onset, disease severity, and rate of progression vary significantly among affected males. In those with early progressive disease, CNS involvement (manifest primarily by progressive cognitive deterioration), progressive airway disease, and cardiac disease usually result in death in the first or second decade of life. In those with slowly progressive disease, the CNS is not (or is minimally) affected, although the effect of GAG accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in the slowly progressing form of the disease. Additional findings in both forms of MPS II include: short stature; macrocephaly with or without communicating hydrocephalus; macroglossia; hoarse voice; conductive and sensorineural hearing loss; hepatosplenomegaly; dysostosis multiplex; spinal stenosis; and carpal tunnel syndrome.

Diagnosis/testing.

The diagnosis of MPS II is established in a male proband by identification of deficient iduronate 2-sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma in the presence of normal activity of at least one other sulfatase. Detection of a hemizygous pathogenic variant in IDS confirms the diagnosis in a male proband with an unusual phenotype or a phenotype that does not match the results of GAG testing. The diagnosis of MPS II is usually established in a female proband with suggestive clinical features by identification of a heterozygous IDS pathogenic variant on molecular genetic testing.

Management.

Treatment of manifestations: Interventions commonly include: developmental, occupational, and physical therapy; shunting for hydrocephalus; tonsillectomy and adenoidectomy; positive pressure ventilation (CPAP or tracheostomy); carpal tunnel release; cardiac valve replacement; inguinal hernia repair; hip replacement.

Prevention of primary manifestations: Weekly enzyme replacement therapy (ERT) with infusions of idursulfase (Elaprase^®), a recombinant form of human iduronate 2-sulfatase, is approved to treat somatic manifestations and prolong survival. Pretreatment with anti-inflammatory drugs or antihistamines may be needed for mild or moderate infusion reactions. Hematopoietic stem cell transplantation (HSCT) (using umbilical cord blood or bone marrow) could provide sufficient enzyme activity to slow or stop the progression of the disease; however, no controlled clinical studies have been conducted in MPS II.

Prevention of secondary complications: Anesthesia is best administered in centers familiar with the potential complications in persons with MPS II.

Surveillance: Depends on organ system and disease severity and usually includes annual: cardiology evaluation and echocardiogram; pulmonary evaluation including pulmonary function testing; audiogram; ophthalmology examination; developmental assessment; neurologic examination. Additional studies may include: sleep study for obstructive apnea; nerve conduction velocity to assess for carpal tunnel syndrome; head/neck MRI to document ventricular size and cervicomedullary narrowing; opening pressure on lumbar puncture; and orthopedic evaluation to monitor hip disease.

Evaluation of relatives at risk: While clinical experience suggests that early diagnosis of at-risk males allows initiation of ERT before the onset of irreversible changes and often before significant disease progression, it is unclear at present whether the potential benefits of early initiation of ERT justify early diagnosis by either newborn screening or testing of at-risk male relatives.

Genetic counseling.

MPS II is inherited in an X-linked manner. The risk to sibs depends on the genetic status of the mother. If the mother of the proband has the pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers. Germline mosaicism has been observed. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

Suggestive Findings

MPS II should be suspected in a male proband with the following clinical, radiographic, and laboratory findings.

Clinical features common at age 18 months to four years

• Short stature
• Hepatosplenomegaly
• Joint contractures
• Coarse facies
• Frequent ear/sinus infections
• Umbilical hernia

Radiographic findings. Skeletal survey reveals dysostosis multiplex (i.e., generalized thickening of long bones, particularly the ribs; irregular epiphyseal ossification centers in many areas; notching of the vertebral bodies).

Note: These findings may not be present in early life and are not specific to MPS II.

Laboratory findings. Urine glycosaminoglycan (GAG) analysis shows large concentrations of the GAGs dermatan sulfate and heparan sulfate.

Note: These findings are not specific to MPS II; the profile is similar to that seen in MPS I.

Establishing the Diagnosis

Male proband. The diagnosis of MPS II is established in a male proband by identification of absent or reduced iduronate 2-sulfatase (I2S) enzyme activity in white cells, fibroblasts, or plasma. Most affected males have no detectable activity using the artificial substrate. Detailed analytic protocols for measurement of I2S enzyme activity have been published [Johnson et al 2013]. 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 clinical features with MPS II.

Identification of a hemizygous IDS pathogenic variant by molecular genetic testing (see Table 1) confirms the diagnosis of MPS II in a male proband and may be useful in persons with an unusual phenotype or a phenotype that does not match the results of GAG analysis.

Female proband. Although the disease is almost exclusively reported in males, rare sporadic cases in females do occur. The diagnosis of MPS II is usually established in a female proband presenting with suggestive clinical features by identification of a heterozygous IDS pathogenic variant on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MPS II is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MPS II has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

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.

CNS involvement, the most significant feature in the group of children often labeled with "early progressive" 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 slowly progressive form of the disease, the CNS is minimally affected, if at all, yet the effect of glycosaminoglycan (GAG) accumulation on other organ systems may be early progressive to the same degree as in those who have progressive cognitive decline. Survival into the early adult years with normal intelligence is common in this group.

The early progressive CNS phenotype may be more than twice as prevalent as the slowly progressive form of the disease; however, accurate prevalence rates are not available. Some form of neurologic involvement is seen in 84% of affected males. Cardiovascular involvement was reported in 82% of affected individuals [Wraith et al 2008].

In individuals with MPS II, GAG accumulation occurs in virtually all organs; however, specific body systems are more affected than others.

Following are the clinical presentations of the organ systems that are earliest and most progressively affected in individuals with MPS II.

Genotype-Phenotype Correlations

Limited information is available regarding genotype-phenotype correlations:

• The pathogenic variant 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 slowly progressive phenotype [Muenzer et al 2009].
• Males with complete absence of functional enzyme as a result of gene deletion or complex gene rearrangements (~17% of affected individuals) invariably manifest the early progressive CNS presentation of the disease [Wraith et al 2008].
• Recent data from a cohort study of Dutch individuals with MPS II suggest that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. While the molecular effects of IDS pathogenic variants do not discriminate between MPS II phenotypes, the IDS genotype is indicated as a strong predictor [Vollebregt et al 2017].

Penetrance

Penetrance of MPS II in males is complete; however, it is anticipated that if newborn screening becomes available for MPS II, much milder presentations would be documented.

Nomenclature

The modifier terms "mild/attenuated" and "severe" were often used in the past to describe the phenotypic variability of the condition, but it is clear (as for all MPS disorders) that the range of severity is wide. It is now considered inappropriate to use these terms since the disease significantly alters the quality of life. Thus, the terms "slowly progressive" (to describe the former "attenuated" form of the disease) and "early progressive" (to describe the form of the disease previously designated "severe") are currently being considered to better reflect the continuum of disease severity.

Prevalence

Several surveys suggest an incidence between 1:100,000 and 1:170,000 male births [Nelson et al 2003, Baehner et al 2005].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mucopolysaccharidosis type II (MPS II), the following evaluations are recommended if they have not already been completed:

• Echocardiogram
• Pulmonary function testing preferably in individuals age six years and older. Pulmonary function testing (e.g., spirometry) can be quite challenging in younger individuals and may be impossible for individuals with significant CNS involvement since it requires their full cooperation and is effort dependent [Kamin 2008].
• Sleep study if sleep apnea is a potential concern or in case of sleep disturbances not related to upper airway obstruction or impairment of ventilatory control (e.g., difficulty initiating or maintaining sleep, awakening several times per night, decreased REM sleep, atypical sleep stage distribution, and restless legs), which might start to manifest at a median age of four to five years [Rapoport & Mitchell 2017]
• Audiologic evaluation
• Nerve conduction velocity (NCV) and nerve ultrasound examination 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 early progressive form, there is an increased risk of compromising the upper airway. See Prevention of Secondary Complications.
• Ophthalmologic evaluation
• Developmental assessment
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Management guidelines for individuals with MPS II have been published [Scarpa et al 2011].

At 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 Clinical Description). Commonly required interventions include the following:

• Developmental, occupational, and physical therapy
• Shunting for hydrocephalus
• Tonsillectomy and adenoidectomy
• Positive pressure ventilation (CPAP or tracheostomy)
• Carpal tunnel release
• Cardiac valve replacement
• Inguinal hernia repair
• Hip replacement

Enzyme replacement therapy (ERT) (see Prevention of Primary Manifestations) has shown encouraging results in possibly modifying/correcting the non-CNS manifestations, as confirmed in a long-term study [Lampe et al 2014b].

Prevention of Primary Manifestations

Enzyme replacement therapy (ERT). It is now a decade since ERT with intravenous idursulfase (Elaprase^®), a recombinant form of human iduronate 2-sulfatase, has been approved in the United States and the European Union at a weekly dose of 0.5 mg/kg for the treatment of MPS II. The approval was mainly based on the results from a first trial on individuals with the slowly progressive form of the disease [Muenzer et al 2006]. In the following year several other studies were undertaken to investigate clinical safety and efficacy of ERT; these clearly showed that idursulfase has positive effects on functional capacity (distance walked in 6 minutes and forced vital capacity), liver and spleen volumes, and urine GAGs excretion [da Silva et al 2016]. Recently, a 3.5-year independent study determined that long-term use of ERT is similarly effective in young (age 1.6 to 12 years at the start of ERT) and older individuals (age 12 to 27 years at the start of ERT) [Tomanin et al 2014, Muenzer et al 2017]. In addition, two recent studies have confirmed ERT efficacy in improving somatic signs and symptoms of the disease in all individuals, including infants younger than age one year and individuals with the early progressive MPS II phenotype [Lampe et al 2014a, Lampe et al 2014b].

A real breakthrough in understanding the effect of ERT has been provided by the recent analysis of data from the Hunter Outcome Survey (HOS), which showed that survival in idursulfase-treated individuals was higher than in those who were untreated [Burton et al 2017]. An additional report from the analysis of the HOS data, investigating clinical outcomes after up to three years of idursulfase treatment in a broad population of individuals with MPS II, suggests that the treatment improves GAG storage (as evidenced by decreases in urinary GAG levels and hepatosplenomegaly) as well as results on the six-minute walk test, left ventricular mass index, absolute forced vital capacity, and absolute forced expiratory volume in 1 second [Muenzer et al 2017].

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. The young age does not add safety concerns, and individuals have significant amelioration of somatic symptoms [Lampe et al 2014a].

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 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.

Current data are insufficient to indicate whether the incidence or severity of infusion-related reactions is different for individuals younger than age five years with severe respiratory compromise or with severe CNS disease. Further studies and longer follow up are needed to better understand the effects of ERT. A recent attempt to assess the impact of anti-idursulfase antibodies during long-term idursulfase enzyme replacement therapy did not establish a clear association between infusion-related adverse events and antibody levels [Giugliani et al 2017].

In order to overcome the limitations in the treatment of the CNS, intrathecal ERT and gene therapy are currently under investigation as future therapies [Motas et al 2016, Stapleton et al 2017]. Shire recently sponsored a Phase I/II clinical trial examining the use of intrathecal iduronate-2-sulfatase in young individuals with MPS II with CNS involvement (see Clinical Trials).

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 [Guffon et al 2009, Annibali et al 2013]; 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], and anecdotal case reports published to date have been disappointing, quite unlike the reports of bone marrow transplantation (BMT) in Hurler syndrome (MPS I). Overall, 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 [Tanaka et al 2012]. A recent single report of seven-year follow up of a prenatally diagnosed boy with MPS II who received HSCT with umbilical cord blood cells at age 70 days suggest that cognitive skills were preserved [Barth et al 2017]. It has been shown that HSCT and ERT have equal efficacy in restoring growth in children with MPS II; both treatments are limited by age of the affected individual and disease progression (e.g., neurologic and heart impairment) at the start of treatment [Patel et al 2014]. Nevertheless, the use of HSCT has been controversial because of limited information regarding the long-term outcomes and the associated high risk of morbidity and mortality. Until two decades ago, HSCT had high mortality rates because of (1) the preconditioning regimen prior to HSCT, which caused severe side effects including increased susceptibility to infection and (2) poor donor selection, which resulted in a high risk of graft-versus-host disease [Stapleton et al 2017]. With the development of new conditioning protocols and the creation of bone marrow donor registries and umbilical cord banks, HSCT has become more accessible [Barth et al 2017]. Although further studies are required, HSCT should continue to be considered as a treatment option particularly because of its lower cost (compared to lifelong ERT treatment) and potential for improving quality of life for affected individuals and their families [Barth et al 2017].

Prevention of Secondary Complications

Given the risks associated with sedation with/without 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 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 that 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, which has been 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 [McGarvey & Pollack 2008].

Surveillance

Guidelines for surveillance have been developed [Scarpa et al 2011].

Modes 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
• Ophthalmology 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 Risk

Although clinical experience suggests that early diagnosis of at-risk males allows initiation of ERT before the onset of irreversible changes and often before significant disease progression [Muenzer 2014], a recent study showed that while early diagnosis and use of ERT improved outcomes, mortality and morbidity remained high [Franco et al 2017]. It is still unclear whether early diagnosis (either by newborn screening or testing of at-risk male relatives) is beneficial as 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 Investigation

A 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 Trials). Preliminary results showed no toxicity of the protein injected intrathecally at the dosage used (10 mg and 30 mg). The GAG concentration in the CSF was significantly reduced but clinical efficacy needed further evaluation [Muenzer et al 2014].

Another ongoing multicenter study is evaluating the effect of a one-year course of monthly intrathecal administration of 10 mg of idursulfase on neurodevelopmental status in children with MPS II and cognitive impairment who have previously received and tolerated a minimum of four months of Elaprase^® therapy.

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]. Tissue uptake (including the brain and spinal cord) via the transferrin receptor of a fusion protein between iduronate 2-sulfatase (I2S) and a monoclonal antibody against the mouse transferrin receptor is being studied [Zhou et al 2012].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.