Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world

Background Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world.Methods Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n=118) compared with patients from the rest of the world [ROW (n=727)].Results Phenotype distribution differed among patients in Latin America compared to ROW(Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). the frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%.Conclusion These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.MPS I Registry team at Genzyme CorporationHosp Nacl Pediat JP Garrahan, Unidad Errores Congenitos Metab, Buenos Aires, DF, ArgentinaHosp Especialidades UMAE 25, Monterrey, MexicoGenzyme Corp, Latin Amer Grp, Registry Program, Rio de Janeiro, BrazilUniv Rosario, Fdn Univ Ciencias Salud, Bogota, ColombiaUniv Valparaiso, Fac Med, Neurol Infantil Programa Formac Neuropediat, Valparaiso, ChileUniv Chile, INTA, Lab Genet & Enfermedades Metab, Santiago, ChileUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilGenzyme Corp, Latin Amer Grp, Compassionate Use Program, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilWeb of Scienc

Childhood onset of Scheie syndrome, the attenuated form of mucopolysaccharidosis I

Scheie syndrome is the most attenuated and rarest form of mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder. Only small patient series have previously been reported. Using natural history data from the uniquely large population of 78 Scheie patients enrolled in the MPS I Registry, we characterized the onset and prevalence of clinical manifestations and explored reasons for delayed diagnosis of the disease. Median patient age was 17.5 years; 46% of the patients were male, and 88% were Caucasian. Of 25 MPS I-related clinical features, cardiac valve abnormalities, joint contractures, and corneal clouding were each reported by >80% and all three by 53% of patients. Carpal tunnel syndrome, hernia, coarse facial features, and hepatomegaly were each reported by >50% of patients. Age at onset of the clinical features varied widely between individuals, but the median age at onset was 3 years for hernia and between 5 and 12 years for most features, including coarse facial features, hepatomegaly, joint contractures, bone deformities, cardiac valve abnormalities, cognitive impairment, and corneal clouding. Carpal tunnel syndrome, cardiomyopathy, and myelopathy arose more commonly during adolescence or adulthood. Delays up to 47 years intervened between symptom onset and disease diagnosis, and the longest delays were associated with later age at symptom onset and symptom onset before 1980. In summary, Scheie syndrome usually emerges during childhood, and recognition of attenuated MPS I requires awareness of the multisystemic disease manifestations and their diverse presentation. Given the availability of etiologic treatment, prompt diagnosis is important

Atypical clinical presentation of mucopolysaccharidosis type II (Hunter syndrome): a case report

<p>Abstract</p> <p>Introduction</p> <p>We present a very rare case of mucopolysaccharidosis with atypical presentation such as mild mental retardation, an acrocephalic head and no corneal clouding. The purpose of presenting this case is to highlight the distinctive manifestation of mucopolysaccharidosis type II (Hunter syndrome).</p> <p>Case presentation</p> <p>A 10-year-old East Asian boy presented with abdominal distension of five years' duration and complained of shortness of breath on and off for the same period. On examination his head was large and his head circumference was 54.5 cm. His neck was short, he had coarse facial features, a depressed nasal bridge and small stubby fingers with flexion of distal interphalangeal joints, and a low arched palate was observed. There was mild mental retardation.</p> <p>Conclusion</p> <p>Based on clinical findings and radiological features it is possible to diagnose a case of mucopolysaccharidosis.</p> <p>Careful and systemic approach is needed to accurately diagnose the exact type as enzymatic studies are not available in most centers.</p

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study.

ObjectiveTo assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA).MethodsPatients with Morquio A aged ≥5&nbsp;years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0&nbsp;mg/kg/every other week (qow), elosulfase alfa 2.0&nbsp;mg/kg/week (weekly) or placebo for 24&nbsp;weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated.ResultsAt week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95&nbsp;% CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95&nbsp;% CI -17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95&nbsp;% CI -2.1, 4.4; P = 0.494) for weekly and -0.5 stairs/min (95&nbsp;% CI -3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24&nbsp;weeks in both regimens. In the weekly dose group, 22.4&nbsp;% of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3&nbsp;% of all infusions in this group) over 6&nbsp;months. No adverse events led to permanent treatment discontinuation.ConclusionsElosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile

Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases