Clinical investigator perspectives on patient outcomes in children with neuronopathic mucopolysaccharidosis II during intrathecal idursulfase-IT treatment.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. RESULTS: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. CONCLUSIONS: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

Advancing clinical development for neuronopathic Hunter syndrome through a quantitatively-driven reverse translation framework.

A quantitatively-driven evaluation of existing clinical data and associated knowledge to accelerate drug discovery and development is a highly valuable approach across therapeutic areas, but remains underutilized. This is especially the case for rare diseases for which development is particularly challenging. The current work outlines an organizational framework to support a quantitatively-based reverse translation approach to clinical development. This approach was applied to characterize predictors of the trajectory of cognition in Hunter syndrome (Mucopolysaccharidosis Type II; MPS-II), a rare X-linked lysosomal storage disorder, highly heterogeneous in its course. Specifically, we considered ways to refine target populations based on age, cognitive status, and biomarkers, that is, cerebrospinal fluid glycosaminoglycans (GAG), at trial entry. Data from a total of 138 subjects (age range 2.5 to 10.1 years) from Takeda-sponsored internal studies and external natural history studies in MPS-II were included. Quantitative analyses using mixed-effects models were performed to characterize the relationships between neurocognitive outcomes and potential indicators of disease progression. Results revealed a specific trajectory in cognitive development across age with an initial progressive phase, followed by a plateau between 4 and 8 years and then a variable declining phase. Additionally, results suggest a faster decline in cognition among subjects with lower cognitive scores or with higher cerebrospinal fluid GAG at enrollment. These results support differences in the neurocognitive course of MPS-II between distinct groups of patients based on age, cognitive function, and biomarker status at enrollment. These differences should be considered when designing future clinical trials.

The effect of intrathecal recombinant arylsulfatase A therapy on structural brain magnetic resonance imaging in children with metachromatic leukodystrophy.

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow-up (median duration, 104 weeks) in IV rhASA-treated versus IT rhASA-treated children. GM volume decline over time was steeper in children receiving low-dose (10 or 30 mg) versus high-dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA-treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA-treated children showed a strong positive correlation with 88-item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high-dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit.

Effects of sulfatide on peripheral nerves in metachromatic leukodystrophy.

OBJECTIVE: To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover. METHODS: A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed. RESULTS: CSF sulfatide levels correlated with neither Z-scores for GMFM-88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z-scores of nerve conduction parameters, number of large (≥7 µm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g-ratios and cortical latencies of somatosensory-evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high-dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g-ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non-myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves. INTERPRETATION: Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.

Cognitive and adaptive behaviors associated with disease severity and genotype in patients with mucopolysaccharidosis II.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare, X-linked lysosomal storage disease caused by pathogenic variants of the iduronate-2-sulfatase gene (IDS) and is characterized by a highly variable disease spectrum. MPS II severity is difficult to predict based on IDS variants alone; while some genotypes are associated with specific phenotypes, the disease course of most genotypes remains unknown. This study aims to refine the genotype-phenotype categorization by combining information from the scientific literature with data from two clinical studies in MPS II. METHODS: Genotype, cognitive, and behavioral data from 88 patients in two clinical studies (NCT01822184, NCT02055118) in MPS II were analyzed post hoc in combination with published information on IDS variants from the biomedical literature through a semi-automated multi-stage review process. The Differential Ability Scales, second edition (DAS-II) and the Vineland Adaptive Behavior Scales™, second edition (VABS-II) were used to measure cognitive function and adaptive behavior. RESULTS: The most common category of IDS variant was missense (47/88, 53.4% of total variants). The mean (standard deviation [SD]) baseline DAS-II General Conceptual Ability (GCA) and VABS-II Adaptive Behavior Composite (ABC) scores were 74.0 (16.4) and 82.6 (14.7), respectively. All identified IDS complete deletions/large rearrangements (n = 7) and large deletions (n = 1) were associated with a published 'severe' or 'predicted severe' progressive neuronopathic phenotype, characterized by central nervous system involvement. In categories comprising more than one participant, mean baseline DAS-II GCA scores (SD) were lowest among individuals with complete deletions/large rearrangements 64.0 (9.1, n = 4) and highest among those with splice site variants 83.8 (14.2, n = 4). Mean baseline VABS-II ABC scores (SD) were lowest among patients with unclassifiable variants 79.3 (4.9, n = 3) and highest among those with a splice site variant 87.2 (16.1, n = 5), in variant categories with more than one participant. CONCLUSIONS: Most patients in the studies had an MPS II phenotype categorized as 'severe' or 'predicted severe' according to classifications, as reported in the literature. Patients with IDS complete deletion/large rearrangement variants had lower mean DAS-II GCA scores than those with other variants, as well as low VABS-II ABC, confirming an association with the early progressive 'severe' (neuronopathic) disease. These data provide a starting point to improve the classification of MPS II phenotypes and the characterization of the genotype-phenotype relationship.

Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Long-term open-label extension study of the safety and efficacy of intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II.

Enzyme replacement therapy with weekly infused intravenous (IV) idursulfase is effective in treating somatic symptoms of mucopolysaccharidosis II (MPS II; Hunter syndrome). A formulation of idursulfase for intrathecal administration (idursulfase-IT) is under investigation for the treatment of neuronopathic MPS II. Here, we report 36-month data from the open-label extension (NCT02412787) of a phase 2/3, randomized, controlled study (HGT-HIT-094; NCT02055118) that assessed the safety and efficacy of monthly idursulfase-IT 10 mg in addition to weekly IV idursulfase on cognitive function in children older than 3 years with MPS II and mild-to-moderate cognitive impairment. Participants were also enrolled in this extension from a linked non-randomized sub-study of children younger than 3 years at the start of idursulfase-IT therapy. The extension safety population comprised 56 patients who received idursulfase-IT 10 mg once a month (or age-adjusted dose for sub-study patients) plus IV idursulfase (0.5 mg/kg) once a week. Idursulfase-IT was generally well tolerated over the cumulative treatment period of up to 36 months. Overall, 25.0% of patients had at least one adverse event (AE) related to idursulfase-IT; most treatment-emergent AEs were mild in severity. Of serious AEs (reported by 76.8% patients), none were considered related to idursulfase-IT treatment. There were no deaths or discontinuations owing to AEs. Secondary efficacy analyses (in patients younger than 6 years at phase 2/3 study baseline; n = 40) indicated a trend for improved Differential Ability Scale-II (DAS-II) General Conceptual Ability (GCA) scores in the early idursulfase-IT versus delayed idursulfase-IT group (treatment difference over 36 months from phase 2/3 study baseline: least-squares mean, 6.8 [90% confidence interval: -2.1, 15.8; p = 0.2064]). Post hoc analyses of DAS-II GCA scores by genotype revealed a clinically meaningful treatment effect in patients younger than 6 years with missense variants of the iduronate-2-sulfatase gene (IDS) (least-squares mean [standard error] treatment difference over 36 months, 12.3 [7.24]). These long-term data further suggest the benefits of idursulfase-IT in the treatment of neurocognitive dysfunction in some patients with MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Ten years of the Hunter Outcome Survey (HOS): insights, achievements, and lessons learned from a global patient registry.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.

Immunogenicity of idursulfase and clinical outcomes in very young patients (16 months to 7.5 years) with mucopolysaccharidosis II (Hunter syndrome).

BACKGROUND: Twenty-eight treatment-naïve mucopolysaccharidosis II patients (16 months-7.5 years) received 0.5 mg/kg idursulfase weekly for one year in NCT00607386. Serum anti-idursulfase immunoglobulin G antibodies (Abs) were seen in 68% of patients. METHODS: This post hoc analysis examined the relationship between Ab status, genotype, adverse events (AEs), and efficacy. Event rate analyses, time-varying proportional hazards (Cox) modeling, and landmark analyses were performed to evaluate the relationship between Ab status and safety. We calculated the cumulative probability of AEs by genotype to evaluate the relationship between genotype and safety. Urinary glycosaminoglycan (uGAG) concentration, index of liver size, and spleen volume were compared by Ab status and genotype. SAFETY RESULTS: The overall infusion-related AE (IRAE) rate was higher in Ab+ patients than in Ab- ones. However, the rate was highest before Abs developed, then decreased over time, suggesting that Abs did not confer the risk. A landmark analysis of patients who were IRAE-naïve at the landmark point found that Ab+ patients were no more likely to experience post-landmark IRAEs than were Ab- patients. In the genotype analysis, all patients in the complete deletion/large rearrangement (CD/LR) and frame shift/splice site mutation (FS/SSM) groups seroconverted, compared with only one-third of patients in the missense mutation (MS) group (p < 0.001). The cumulative probability of having ≥1 IRAE was 87.5% in the CD/LR group and 46.2% in the MS group, with a shorter time to first IRAE in the CD/LR group (p = 0.004). EFFICACY RESULTS: Ab+ patients had a reduced response to idursulfase for liver size and uGAG concentration, but not for spleen size. However, when percent change from baseline in liver size and in uGAG level at Week 53 were adjusted for genotype, the difference was significant only for neutralizing Ab+ groups. In the genotype analysis, the CD/LR and FS/SSM groups had a reduced response in liver size and uGAG concentration compared with the MS group. CONCLUSIONS: Safety outcomes and spleen size response on idursulfase treatment appeared to be associated with genotype, not Ab status. Liver size and uGAG response on idursulfase treatment at Week 53 appeared to be associated with both neutralizing Ab status and genotype.

A multicenter, open-label study evaluating safety and clinical outcomes in children (1.4-7.5 years) with Hunter syndrome receiving idursulfase enzyme replacement therapy.

PURPOSE: The primary objective of this study was to determine the safety of idursulfase in Hunter syndrome patients aged 5 years or younger. METHODS: Idursulfase (0.5 mg/kg) was administered intravenously on a weekly basis (52 infusions per patient) in an open-label study. Safety monitoring included adverse events, anti-idursulfase antibodies, vital signs, physical examination, 12-lead electrocardiogram, concomitant medications or procedures, and laboratory testing (clinical chemistry, hematology, and urinalysis). The following exploratory efficacy outcomes were assessed at baseline and at weeks 18 or 36 or 53: urinary glycosaminoglycan levels, liver or spleen size, developmental milestones, and growth indices. Pharmacokinetic parameters were assessed at week 27. RESULTS: Twenty-eight boys aged 1.4-7.5 years were enrolled (one discontinued for noncompliance) in the study. All the patients reported adverse events (16 patients (57%) reported possibly or probably treatment-related adverse events). The only severe adverse event was sleep apnea (two patients); others were mild or moderate. Sixteen patients had infusion-related adverse events, a similar proportion as previously reported. Thirteen patients (46%) experienced at least one serious adverse event: pyrexia and bronchopneumonia were the most common (three patients each). No clinically important drug-related changes in laboratory parameters or vital signs or electrocardiograms were reported. Nineteen patients (68%) developed anti-idursulfase immunoglobulin G antibodies. Growth rates remained within normal age-related ranges. Developmental quotients were lower than normal but remained stable. By week 18, organ size and urinary glycosaminoglycan levels decreased as compared with baseline and remained stable throughout the study. CONCLUSION: Idursulfase safety, tolerability, and efficacy were similar to that previously reported in males ≥5 years.

The impact of Hunter syndrome (mucopolysaccharidosis type II) on health-related quality of life.

BACKGROUND: Hunter syndrome (mucopolysaccharidosis type II (MPS II)) is a rare metabolic disease that can severely compromise health, well-being and life expectancy. Little evidence has been published on the impact of MPS II on health-related quality of life (HRQL). The objective of this study was to describe this impact using the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) questionnaire and a range of standard validated questionnaires previously used in paediatric populations. METHODS: Clinical and demographic characteristics collected in a clinical trial and responses to four HRQL questionnaires completed both by patients and parents prior to enzyme replacement treatment were used. The association between questionnaire scores and clinical function parameters were tested using Spearman rank-order correlations. Results were compared to scores in other paediatric populations with chronic conditions obtained through a targeted literature search of published studies. RESULTS: Overall, 96 male patients with MPS II and their parents were enrolled in the trial. All parents completed the questionnaires and 53 patients above 12 years old also completed the self-reported versions. Parents' and patients' responses were analysed separately and results were very similar. Dysfunction according to the HS-FOCUS and the CHAQ was most pronounced in the physical function domains. Very low scores were reported in the Self Esteem and Family Cohesion domains in the CHQ and HUI3 disutility values indicated a moderate impact. Scores reported by patients and their parents were consistently lower than scores in the other paediatric populations identified (except the parent-reported Behaviour score); and considerably lower than normative values. CONCLUSIONS: This study describes the impact on HRQL in patients with MPS II and provides a broader context by comparing it with that of other chronic paediatric diseases. Physical function and the ability to perform day-to-day activities were the most affected areas and a considerable impact on the psychological aspects of patients' HRQL was also found, with a higher level of impairment across most dimensions (particularly Pain and Self Esteem) than that of other paediatric populations. Such humanistic data provide increasingly important support for establishing priorities for health care spending, and as a component of health economic analysis.

Development of a mnemonic screening tool for identifying subjects with Hunter syndrome.

UNLABELLED: The Hunter Outcome Survey (HOS), an international, long-term observational registry of patients with Hunter syndrome, was used to develop a simple mnemonic screening tool (HUNTER) to aid in the diagnosis of Hunter syndrome. Data regarding the prediagnosis prevalence of ten specific signs and symptoms present in individual patients enrolled in the HOS were used to develop the HUNTER mnemonic screening tool. A total score of 6 or greater using a weighting scheme in which certain manifestations were assigned a weight of 2 (facial dysmorphism, nasal obstruction or rhinorrhea, enlarged tongue, enlarged liver, enlarged spleen, joint stiffness) and others assigned a weight of 1 (hernia, hearing impairment, enlarged tonsils, airway obstruction or sleep apnea) correctly identified 95 % of patients who had no family history of Hunter syndrome or who were not diagnosed prenatally. No association between age at diagnosis and HUNTER score was found. CONCLUSION: The HUNTER mnemonic appears to be a useful screening tool. Further validation in the clinical setting will be necessary to confirm its utility.

The Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS) questionnaire: evaluation of measurement properties.

PURPOSE: This study was to conduct the psychometric validation of the patient and parent versions of the Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS). METHODS: Data collected in a 53-week placebo-controlled multinational trial were used to evaluate item performance and reliability, validity, and ability to detect change of the six HS-FOCUS function domains. RESULTS: HS-FOCUS was completed by 49 patients above 12 years old and 84 parents. Floor effects and high average inter-item correlations suggested that some items were less informative or redundant. For both patients and parents, the internal consistency and test-retest reliability met the >0.70 criteria for all domains except for the breathing, sleeping, and schooling/work in patients. Construct validity showed moderate to high correlations with CHAQ, CHQ, and HUI3 in activity-related concepts. Significant differences in domain scores were found in most domains among severity in disability measured by CHAQ DIS. Significant differences in HS-FOCUS change scores were found in patients whose CHAQ DIS score also changed. CONCLUSIONS: Psychometric validation of the HS-FOCUS demonstrates it is a reliable, valid, and responsive instrument that can be applied in clinical trials or disease registries. Findings on the individual item performance suggest some items could be removed without compromising its validity.

Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS).

OBJECTIVE: To evaluate the occurrence of infusion-related reactions (IRRs) in patients with mucopolysaccharidosis type II (MPS II) receiving idursulfase enrolled in the observational database HOS - the Hunter Outcome Survey. STUDY DESIGN: Information in HOS regarding the frequency, timing and severity of reported IRRs during the first year of treatment with idursulfase was analyzed, and formation of antibodies to idursulfase was characterized. The analysis was restricted to patients who started treatment with idursulfase at or after enrolment in HOS and for whom at least 1 year of follow-up data was available (n=104; data collected on or before 16 October 2009). RESULTS: A total of 65 IRRs were reported in 33 (31.7%) patients in the first year of enzyme replacement therapy (ERT). Six of these patients experienced more than three events. Nearly all of the initial IRRs occurred during the first 3months of ERT; five patients (4.8% of the total patient population) experienced their first IRR after 3months of treatment. Only two patients (1.9% of the total patient population) experienced their first IRR after more than 6 months of ERT. Most of the IRRs were of mild-to-moderate severity. After initially stopping the infusion, IRRs were generally readily managed by slowing the infusion and/or use of antihistamines or antipyretics. No patient in this analysis discontinued ERT because of an IRR event. IgG antibodies to idursulfase were detected in 32/63 patients (50.8%) for whom samples were taken; no patient developed IgE to idursulfase. Serum antibody levels were measured within 24h of an IRR for 10 IRRs in 7 patients; 7/9 samples contained IgG to idursulfase, 2 of which had neutralizing activity. CONCLUSIONS: IRRs in patients receiving idursulfase can typically be readily managed without interruption of treatment. Initial IRRs usually occur in the first 3 months of treatment, but in rare instances may occur after more than 6 months of therapy. Physicians using ERT to treat patients with MPS II, either in the clinic or at home, should therefore be familiar with the timing, nature and recommended management of IRRs.

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.

PURPOSE: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. METHODS: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. RESULTS: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. CONCLUSIONS: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

Molecular bases of hearing loss in multi-systemic mitochondrial cytopathy.

PURPOSE: Hearing loss is a common clinical feature in classic mitochondrial syndromes. The purpose of this study was to evaluate the diverse molecular etiologies and natural history of hearing loss in multi-systemic mitochondrial cytopathies and the possible correlation between degree of hearing loss and neurological phenotype. METHODS: In this retrospective study we evaluated the clinical features and molecular bases of hearing loss associated with multi-systemic mitochondrial cytopathy. Forty-five patients with sensorineural hearing loss and definite diagnosis of mitochondrial cytopathy according to the published diagnostic criteria were studied. RESULTS: The sensorineural hearing loss was progressive and for the most part symmetrical with involvement of the higher frequencies. Both cochlear and retrocochlear involvement were found in this cohort. No correlation was found between the degree of hearing loss and the number and severity of neurological manifestations. Deleterious mtDNA point mutations of undisputed pathogenicity were identified in 18 patients. The A3243G mutation was the most frequently encountered among this group. MtDNA depletion, over-replication, and multiple deletions were found in further 11 cases. CONCLUSION: This study reveals an expanding spectrum of mtDNA abnormalities associated with hearing loss. No correlation was found between the degrees of hearing loss and the severity of neurological manifestations.

Primer on medical genomics. Part VIII: Essentials of medical genetics for the practicing physician.

After the mapping and sequencing of the human genome, medical professionals from essentially all specialties turned their attention to investigating the role genes play in health and disease. Until recently, medical genetics was considered a specialty of minor practical relevance. This view has changed with the development of new diagnostic and therapeutic possibilities. It is now realized that genetic disease represents an important part of medical practice. Achievements in cancer genetics, in the field of prenatal diagnostics (including carrier testing for common recessive disorders), and in newborn screening for treatable metabolic disorders reinforce the rapidly expanding role of genetics in medicine. Diagnosing a genetic disorder not only allows for disease-specific management options but also has implications for the affected individual's entire family. A working understanding of the underlying concepts of genetic disease with regard to chromosome, single gene, mitochondrial, and multifactorial disorders is necessary for today's practicing physician. Routine clinical practice in virtually all medical specialties will soon require integration of these fundamental concepts for use in accurate diagnosis and ensuring appropriate referrals for patients with genetic disease and their families.

Diagnosis and management of defects of mitochondrial beta-oxidation.

PURPOSE OF REVIEW: At least 22 different inborn errors of metabolism affecting beta-oxidation in skeletal muscle and other tissues have been identified in the past 30 years. Early diagnosis and therapeutic diets offer the best chance for normal growth and development in most patients. RECENT FINDINGS: Clinical heterogeneity has become the hallmark of defects in beta-oxidation. In many cases a correct diagnosis will only be made if these disorders are specifically considered and appropriate studies are obtained, since screening tests which detect other inborn errors of metabolism are often normal in patients with beta-oxidation defects. Dietary management provides the only opportunity for therapy in many cases, including carbohydrate supplements intended to provide more extended delivery of glucose to the bloodstream. Use of a novel odd chain fat supplement as an alternative fuel source in long chain fat metabolism defects offers promise of alleviating muscular symptoms not well controlled by diet. The introduction of expanded newborn screening will lead to the recognition of an increasing number of individuals with these disorders, placing greater demand for services on practitioners knowledgeable in their therapy. Study of the clinical outcome in these patients will provide a better understanding of defects of beta-oxidation. SUMMARY: Clinical symptoms, diagnostic testing, and issues of newborn screening for this important group of disorders are discussed.