α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.

Long-Term Sebelipase Alfa Treatment in Children and Adults With Lysosomal Acid Lipase Deficiency.

OBJECTIVES: Sebelipase alfa is approved for treatment of lysosomal acid lipase deficiency (LAL-D). This single-arm, open-label study (NCT02112994) evaluated sebelipase alfa efficacy and safety in patients with LAL-D. METHODS: Patients >8 months of age diagnosed with LAL-D received sebelipase alfa 1.0 mg/kg by intravenous infusion every other week (qow) for up to 144 weeks. Dose escalation to 3.0 mg/kg qow and subsequently to 3.0 mg/kg weekly was permitted, per protocol; dose reductions for tolerability were permitted to 0.35 mg/kg qow. Descriptive statistical analyses were conducted. RESULTS: Thirty-one patients were enrolled and treated. Baseline median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were 63.5 and 65.5 U/L, respectively. Twenty-eight patients completed 96 weeks of treatment, and 25 continued into the extended treatment period; 19 completed 144 weeks. From baseline to week 144, median ALT and AST levels changed by -42.0 and -22.0 U/L, respectively, median liver and spleen volumes changed from 1.4 to 1.3 and from 2.6 to 2.3 multiples of normal, respectively, median low-density lipoprotein cholesterol levels decreased by 52.6 mg/dL, and median high-density lipoprotein cholesterol increased by 9.8 mg/dL. Liver biopsies showed mostly improved or stable histopathology at 48 and 96 weeks versus baseline. Infusion-associated reactions were mild (n = 1) or moderate (n = 2). One patient (a candidate for liver transplant at baseline) discontinued treatment because of liver transplant (unrelated to treatment). Two patients tested positive for nonneutralizing, anti-drug antibodies on 1 occasion each. CONCLUSION: Sebelipase alfa was well tolerated and resulted in sustained improvements in liver and lipid parameters.

Growth Differentiation Factor-15 and Syndecan-1 Are Potential Biomarkers of Cardiac and Renal Involvement in Classical Fabry Disease under Enzyme Replacement Therapy.

BACKGROUND AND AIMS: Inflammation and endothelial damage play a pivotal role in Fabry disease (FD) manifestations. In daily clinical practice, FD is mainly monitored by traditional biomarkers of target organ injury, such as serum creatinine and proteinuria, which provide no information about inflammation and endothelial damage. MATERIALS AND METHODS: We investigated the serum levels of 3-nitrotyrosine (3-NT), an oxidative stress biomarker, and of growth differentiation factor-15 (GDF-15) and syndecan-1 in classical FD patients on enzyme replacement therapy (ERT) for at least 6 months and their relationship with Fabry-related cardiac and renal manifestations. RESULTS: Fifty-two classical FD patients (37 females) on ERT for 62.0 ± 27.5 months were included in the study. The main clinical manifestations included nephropathy (67.3%) and cardiomyopathy (21.1%). Serum levels of 3-NT, syndecan-1, and GDF-15 were 33.3 (4.8-111.1) nmol/mL, 55.7 (38.8-74.9) ng/mL, and 541.8 (392.2-784.4) pg/mL, respectively. There was a direct correlation between interventricular septal thickness and serum GDF-15 (r = 0.59; p < 0.001) and syndecan-1 (r = 0.30, p = 0.04). Among kidney parameters, there was a significant correlation between estimated glomerular filtration rate and GDF-15 (r = -0.61; p < 0.001), as well as between 24 h proteinuria and syndecan-1 (r = 0.28; p = 0.04). Serum GDF-15 levels were significantly higher in patients with cardiomyopathy (p = 0.03) as well in those with both nephropathy and cardiomyopathy (p = 0.02) than in patients without these comorbidities. Serum GDF-15 levels were also significantly higher in patients who started ERT at an older age (≥40 years). In multivariate analysis, syndecan-1, 3-NT, GDF-15, time on ERT, and arterial pressure differentiated Fabry patients with both cardiac and renal involvement from those without these manifestations. CONCLUSIONS: GDF-15 and syndecan-1 were associated with parameters of cardiac and renal involvement in classic FD patients on ERT. Their potential association with residual risk and disease outcomes should be investigated.

Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil.

In Hunter syndrome (mucopolysaccharidosis II [MPS-II]), systemic accumulation of glycosaminoglycans (GAGs) due to a deficiency of iduronate-2-sulfatase (IDS), caused by mutations in the IDS gene, leads to multiple somatic manifestations and in patients with the severe (neuronopathic) phenotype, also to central nervous system (CNS) involvement. These symptoms cannot be effectively treated with current enzyme-replacement therapies, as they are unable to cross the blood-brain barrier (BBB). Pabinafusp alfa, a novel IDS fused with an anti-human transferrin receptor antibody, was shown to penetrate the BBB and to address neurodegeneration in preclinical studies. Subsequent phase 1/2 and 2/3 clinical studies in Japan have shown marked reduction of GAG accumulation in the cerebrospinal fluid (CSF), along with favorable clinical responses. A 26-week, open-label, randomized, parallel-group phase 2 study was conducted in Brazil to further evaluate the safety and efficacy of intravenously administered pabinafusp alfa at 1.0, 2.0, and 4.0 mg/kg/week in MPS-II patients. The safety profiles in the three dosage groups were similar. Neurodevelopmental evaluation suggested positive neurocognitive signals despite a relatively short study period. The 2.0-mg/kg group, which demonstrated marked reductions in substrate concentrations in the CSF, serum, and urine, was considered to provide the best combination regarding safety and efficacy signals.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Mucopolysaccharidosis type VI: case report with first neonatal presentation with ascites fetalis and rapidly progressive cardiac manifestation.

BACKGROUND: The Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome (OMIM 253200) is an autosomal recessive lysosomal disorder, caused by the deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (also known as arylsulfatase B) due to mutations of the ARSB gene. Cardiologic features are well recognized, and are always present in MPS VI patients. Generally, the onset and the progression of the cardiologic symptoms are insidious, and just a few patients have developed a rapidly progressive disease. Cardiac involvement in MPS VI is a common and progressive feature. For MPS patients, cardiac evaluations are recommended every 1 to 2 years, including blood pressure measurement, electrocardiography and echocardiography. However, congestive heart failure and valvular surgical repair are not frequently seen, and if so, they are performed in adults. Here we report on an atypical MPS VI case with ascites fetalis and a rapidly progressive cardiac disease. CASE PRESENTATION: A 6-month-old Brazilian male, only child of a Brazilian healthy non-consanguineous couple. During pregnancy, second trimester ultrasonography observed fetal ascites and bilateral hydrocele. Physical exam at 6 months-old revealed a typical gibbus deformity and MPS was suspected. Biochemical investigation revealed a diagnosis of MPS type VI, confirmed by molecular test. Baseline echocardiogram revealed discrete tricuspid regurgitation and a thickened mitral valve with posterior leaflet prolapse, causing moderate to severe regurgitation. The patient evolved with mitral insufficiency and congestive heart failure, eventually requiring surgical repair by the first year of age. CONCLUSIONS: We report the first case of MPS VI whose manifestations started in the prenatal period with fetal ascites, with severe cardiac valvular disease that eventually required early surgical repair. Moreover, in MPS with neonatal presentation, including fetal hydrops, besides MPS I, IVA and VII, clinicians should include MPS VI in the differential diagnosis.

Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy.

In the phase 3 Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE), at 1 year, eliglustat was noninferior to imiglucerase enzyme therapy in maintaining stable platelet counts, hemoglobin concentrations, and spleen and liver volumes. After this primary analysis period, patients entered a long-term extension phase in which all received eliglustat. Duration on eliglustat ranged from 2 to 5 years, depending on timing of enrollment (which spanned 2 years), treatment group to which patients were randomized, and whether they lived in the United States when commercial eliglustat became available. Here we report long-term safety and efficacy of eliglustat for 157 patients who received eliglustat in the ENCORE trial; data are available for 46 patients who received eliglustat for 4 years. Mean hemoglobin concentration, platelet count, and spleen and liver volumes remained stable for up to 4 years. Year to year, all 4 measures remained collectively stable (composite end point relative to baseline values) in ≥85% of patients as well as individually in ≥92%. Mean bone mineral density z scores (lumbar spine and femur) remained stable and were maintained in the healthy reference range throughout. Eliglustat was well tolerated over 4 years; 4 (2.5%) patients withdrew because of adverse events that were considered related to the study drug. No new or long-term safety concerns were identified. Clinical stability assessed by composite and individual measures was maintained in adults with Gaucher disease type 1 treated with eliglustat who remained in the ENCORE trial for up to 4 years. This trial was registered at www.clinicaltrials.gov as #NCT00943111.

Oxidative stress assessment by glutathione peroxidase activity and glutathione levels in response to selenium supplementation in patients with Mucopolysaccharidosis I, II and VI.

We assessed levels of plasma selenium (Se), selenoproteins and their change after Se supplementation in patients with mucopolysaccharidosis (MPS) types I, II and VI. This was done in a retrospective study of the medical records of 30 patients with MPS I (n=13), MPS II (n=9) and MPS VI (n=8) who were being treated with enzyme replacement therapy. As part of routine nutritional monitoring, Se levels were measured, revealing that 28 patients (93.3%) had values below the normal range. Therefore, they received supplementation for 12 months, and Se was measured after 6 and 12 months. Glutathione peroxidase (GPx) activity, total glutathione (GSHt), oxidized glutathione (GSSG) and reduced glutathione (GSH) were measured at baseline and 6 months after Se supplementation. The mean GSHt at baseline was 7.90 ± 2.36 µmol/g Hb, and after Se supplementation it was 5.76 ± 1.13 µmol/g Hb; GSH/GSSG was 2.3 ± 1.16 at baseline and 0.58 ± 0.38 after supplementation. GPx activity was 16.46 ± 3.31 U/g Hb at baseline and 4.53 ± 4.92 U/g Hb after Se supplementation. The difference was shown to be statistically significant by paired t-test. In conclusion, our study demonstrated that oxidative stress parameters were altered by Se supplementation in patients with MPS I, II and VI who were previously deficient in Se.

Short stature as a presenting symptom of attenuated Mucopolysaccharidosis type I: case report and clinical insights.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) results in significant disease burden and early treatment is important for optimal outcomes. Recognition of short stature and growth failure as symptoms of MPS I among pediatric endocrinologists may lead to earlier diagnosis and treatment. CASE PRESENTATION: A male patient first began experiencing hip pain at 5 years of age and was referred to an endocrinologist for short stature at age 7. Clinical history included recurrent respiratory infections, sleep apnea, moderate joint contractures, mild facial dysmorphic features, scoliosis, and umbilical hernia. Height was more than - 2 SD below the median at all time points. Growth velocity was below the 3rd percentile. Treatment for short stature included leuprolide acetate and recombinant human growth hormone. The patient was diagnosed with MPS I and began enzyme replacement therapy with laronidase at age 18. CONCLUSIONS: The case study patient had many symptoms of MPS I yet remained undiagnosed for 11 years after presenting with short stature. The appropriate path to MPS I diagnosis when patients present with short stature and/or growth failure plus one or more of the common signs of attenuated disease is described. Improved awareness regarding association of short stature and growth failure with attenuated MPS I is needed since early identification and treatment significantly decreases disease burden.

Impaired Hematopoiesis and Disrupted Monocyte/Macrophage Homeostasis in Mucopolysaccharidosis Type I Mice.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disease caused by alpha-L-iduronidase deficiency in which heparan and dermatan sulfate degradation is compromised. Besides primary lysosomal glycosaminoglycan accumulation, further changes in cellular functions have also been described in several murine MPS models. Herein, we evaluated alterations in hematopoiesis and its implications on the production of mature progeny in a MPS I murine model. Despite the significant increase in hematopoietic stem cells, a reduction in common myeloid progenitors and granulocyte-macrophage progenitor cells was observed in Idua -/- mice bone marrow. Furthermore, no alterations in number, viability nor activation of cell death mechanisms were observed in Idua -/- mice mature macrophages but they presented higher sensitivity to apoptotic induction after staurosporine treatment. In addition, changes in Ca(2+) signaling and a reduction in phagocytosis ability were also found. In summary, our results revealed significant intracellular changes in mature Idua -/- macrophages related to alterations in Idua -/- mice hematopoiesis, revealing a disruption in cell homeostasis. These results provide new insights into physiopathology of MPS I.

Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial.

BACKGROUND: The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase. METHODS: In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged ≥18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28. FINDINGS: Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8·8%; 95% CI -17·6 to 4·2). The lower bound of the 95% CI of -17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity). INTERPRETATION: Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option. FUNDING: Genzyme, a Sanofi company.

Risk factors for severe clinical events in male and female patients with Fabry disease treated with agalsidase beta enzyme replacement therapy: Data from the Fabry Registry.

BACKGROUND: Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death. METHODS: This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death. RESULTS: The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free. CONCLUSIONS: Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies.

Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome.

OBJECTIVES: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented. METHODS: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation. RESULTS: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients. CONCLUSIONS: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients.

Prevalence of obstructive sleep apnea in patients with mucopolysaccharidosis types I, II, and VI in a reference center.

PURPOSE: Mucopolysaccharidosis (MPS) encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans in organs and tissues. Respiratory disorders occur in all MPS types. In these patients, the prevalence of obstructive sleep apnea syndrome (OSAS), which may confer additional morbidity, remains overlooked, and the results of the few existing studies are controversial. The present study aimed to characterize the prevalence of OSAS in patients with MPS types I, II, and VI in a reference center. METHODS: Forty-five patients with MPS (I, n=17; II, n=16; and VI; n=12) in the Centro de Referência em Erros Inatos do Metabolismo, who underwent full-night polysomnography, were enrolled in a retrospective study. Demographic data and clinical history were collected from medical records of the first medical consultation. RESULTS: The prevalence of OSAS in patients with MPS was 69.8%. MPS type I patients seemed to be more susceptible to OSA-induced hypoxemia, as indicated by reduced mean SpO2 levels during both NREM and rapid eye movement sleep as well as during SpO2 nadir. CONCLUSIONS: Patients with MPS displayed a high prevalence of OSAS, often with moderate to high severity. Together, our results reinforce the need for OSAS screening in all patients with MPS.

Guidelines for diagnosis and treatment of Hunter Syndrome for clinicians in Latin America.

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase(®), Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients' responses.

Cytogenetic biomonitoring in mucopolyssacharosis I, II and IV patients treated with enzyme replacement therapy.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate genotoxicity and mutagenicity in peripheral blood and buccal mucosal cells in mucopolysaccharidosis (MPS) I, II or VI patients. METHODS: A total of 12 patients with MPS type I, II and VI attended at the Institute of Genetics and Inborn Errors of Metabolism treated with enzyme replacement therapy (ERT) and 10 healthy control volunteers were included in this study. Mechanically exfoliated cells from cheek mucosa (left and right side) were used to micronucleus test and single cell gel (comet) assay in peripheral blood cells. RESULTS: The results of this study detected the presence of genetic damage in peripheral blood for all individuals with MPS treated with ERT, regardless of type of MPS as depicted by tail moment results. In addition, an increased number of micronucleated cells were found in buccal cells of MPS type II patients. It was also observed an increase of other nuclear alterations closely related to cytotoxicity as depicted by the frequency of pyknosis, karyolysis and karyorrhexis in buccal mucosa cells of MPS VI patients (p < 0.05). CONCLUSION: Taken together, such results demonstrate that metabolic alterations induced by the enzymatic deficiency characteristic of MPS associated with ERT therapy can induce genotoxicity and mutagenicity in peripheral blood and buccal mucosa cells, respectively. This effect appears to be more pronounced to MPS II.