MPS I: Early diagnosis, bone disease and treatment, where are we now?

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by α-L-iduronidase deficiency. Patients present with a broad spectrum of disease severity ranging from the most severe phenotype (Hurler) with devastating neurocognitive decline, bone disease and early death to intermediate (Hurler-Scheie) and more attenuated (Scheie) phenotypes, with a normal life expectancy. The most severely affected patients are preferably treated with hematopoietic stem cell transplantation, which halts the neurocognitive decline. Patients with more attenuated phenotypes are treated with enzyme replacement therapy. There are several challenges to be met in the treatment of MPS I patients. First, to optimize outcome, early recognition of the disease and clinical phenotype is needed to guide decisions on therapeutic strategies. Second, there is thus far no effective treatment available for MPS I bone disease. The pathophysiological mechanisms behind bone disease are largely unknown, limiting the development of effective therapeutic strategies. This article is a state of the art that comprehensively discusses three of the most urgent open issues in MPS I: early diagnosis of MPS I patients, pathophysiology of MPS I bone disease, and emerging therapeutic strategies for MPS I bone disease.

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.

Applying the functional independence measure to the assessment of patients with mucopolysaccharidosis / Test de medida de independencia funcional en la evaluación de pacientes con mucopolisacaridosis

Abstract Objective: To assess the functional independence of a group of patients with mucopolysaccharidosis using the Functional Independence Measure as a tool that accomplishes this purpose. Methods: This is a cross-sectional study of patients with mucopolysaccharidosis. Our data was collected between June 2015 and July 2016. In addition to history of present illness and physical examination each study participant was asked to answer a questionnaire to specifically evaluate their functional independence using the functional independence measure. the internal consistency of the functional independence measure was assessed using Cronbach's alpha coefficient. Results: We collected data on 20 patients with mucopolysaccharidosis. The average age was 10.8 (8.67-13.03) years, the average weight was 23.6 (19.91-27.37) kg and the average height was 1 (0.83-1.17) m. The most prevalent type of mucopolysaccharidosis in the study was type VI (n= 14). The average total functional independence measure score was 104.4 (97.61-111.19), the average for the mobility domain was 73.50 (68.22-78.78) and the average for the cognitive function domain was 30.90 (28.68-33.13). The internal consistency of the entire questionnaire was 0.859, with values of 0.966 for the mobility domain and 0.624 for the cognitive function domain. Conclusion: The lowest functional independence measure scores were obtained in the following sub-domains: self-care, locomotion and cognitive function. The functional independence measure questionnaire demonstrated internal consistency for the evaluation of functional independence in patients with mucopolysaccharidosis, being able to value all the affected sub-domains separately.

Resumen Objetivo: Evaluar la independencia funcional de un grupo de pacientes con mucopolisacaridosis utilizando la Medida de Independencia Funcional como herramienta para lograr este propósito. Métodos: Este es un estudio transversal de pacientes con mucopolisacaridosis. Nuestros datos se recopilaron entre junio de 2015 y julio de 2016. Además de la historia de la enfermedad actual y el examen físico, se pidió a cada participante del estudio que respondiera un cuestionario para evaluar específicamente su independencia funcional utilizando la Medida de Independencia Funcional. la consistencia interna de la Medida de Independencia Funcional se evaluó mediante el coeficiente alfa de Cronbach. Resultados: Recopilamos datos de 20 pacientes con mucopolisacaridosis. La edad promedio fue de 10.8 (8.67-13.03) años, el peso promedio fue de 23.6 (19.91-27.37) kg y la altura promedio fue de 1 m (0.83-1.17). El tipo de mucopolisacaridosis más prevalente en el estudio fue el tipo VI (n= 14). El puntaje promedio de la medida de independencia funcional total fue 104.4 (97.61-111.19), el promedio para el dominio de movilidad fue 73.50 (68.22-78.78) y el promedio para el dominio de función cognitiva fue 30.90 (28.68-33.13). La consistencia interna de todo el cuestionario fue de 0.859, con valores de 0.966 para el dominio de movilidad y 0.624 para el dominio de función cognitiva. Conclusión: Las puntuaciones más bajas de la medida de independencia funcional se obtuvieron en los siguientes subdominios: autocuidado, locomoción y función cognitiva. El cuestionario de medida de independencia funcional demostró consistencia interna para la evaluación de la independencia funcional en pacientes con mucopolisacaridosis, pudiendo valorar todos los subdominios afectados por separado.

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

Applying the functional independence measure to the assessment of patients with mucopolysaccharidosis.

OBJECTIVE: To assess the functional independence of a group of patients with mucopolysaccharidosis using the Functional Independence Measure as a tool that accomplishes this purpose. METHODS: This is a cross-sectional study of patients with mucopolysaccharidosis. Our data was collected between June 2015 and July 2016. In addition to history of present illness and physical examination each study participant was asked to answer a questionnaire to specifically evaluate their functional independence using the functional independence measure. the internal consistency of the functional independence measure was assessed using Cronbach's alpha coefficient. RESULTS: We collected data on 20 patients with mucopolysaccharidosis. The average age was 10.8 (8.67-13.03) years, the average weight was 23.6 (19.91-27.37) kg and the average height was 1 (0.83-1.17) m. The most prevalent type of mucopolysaccharidosis in the study was type VI (n= 14). The average total functional independence measure score was 104.4 (97.61-111.19), the average for the mobility domain was 73.50 (68.22-78.78) and the average for the cognitive function domain was 30.90 (28.68-33.13). The internal consistency of the entire questionnaire was 0.859, with values of 0.966 for the mobility domain and 0.624 for the cognitive function domain. CONCLUSION: The lowest functional independence measure scores were obtained in the following sub-domains: self-care, locomotion and cognitive function. The functional independence measure questionnaire demonstrated internal consistency for the evaluation of functional independence in patients with mucopolysaccharidosis, being able to value all the affected sub-domains separately.

OBJETIVO: Evaluar la independencia funcional de un grupo de pacientes con mucopolisacaridosis utilizando la Medida de Independencia Funcional como herramienta para lograr este propósito. MÉTODOS: Este es un estudio transversal de pacientes con mucopolisacaridosis. Nuestros datos se recopilaron entre junio de 2015 y julio de 2016. Además de la historia de la enfermedad actual y el examen físico, se pidió a cada participante del estudio que respondiera un cuestionario para evaluar específicamente su independencia funcional utilizando la Medida de Independencia Funcional. la consistencia interna de la Medida de Independencia Funcional se evaluó mediante el coeficiente alfa de Cronbach. RESULTADOS: Recopilamos datos de 20 pacientes con mucopolisacaridosis. La edad promedio fue de 10.8 (8.67-13.03) años, el peso promedio fue de 23.6 (19.91-27.37) kg y la altura promedio fue de 1 m (0.83-1.17). El tipo de mucopolisacaridosis más prevalente en el estudio fue el tipo VI (n= 14). El puntaje promedio de la medida de independencia funcional total fue 104.4 (97.61-111.19), el promedio para el dominio de movilidad fue 73.50 (68.22-78.78) y el promedio para el dominio de función cognitiva fue 30.90 (28.68-33.13). La consistencia interna de todo el cuestionario fue de 0.859, con valores de 0.966 para el dominio de movilidad y 0.624 para el dominio de función cognitiva. CONCLUSIÓN: Las puntuaciones más bajas de la medida de independencia funcional se obtuvieron en los siguientes subdominios: autocuidado, locomoción y función cognitiva. El cuestionario de medida de independencia funcional demostró consistencia interna para la evaluación de la independencia funcional en pacientes con mucopolisacaridosis, pudiendo valorar todos los subdominios afectados por separado.

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BACKGROUND: Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. METHODS: This 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. RESULTS: The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. CONCLUSIONS: Laronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made.

A flexible multi-domain test with adaptive weights and its application to clinical trials.

The design of a clinical trial is often complicated by the multi-systemic nature of the disease; a single endpoint often cannot capture the spectrum of potential therapeutic benefits. Multi-domain outcomes which take into account patient heterogeneity of disease presentation through measurements of multiple symptom/functional domains are an attractive alternative to a single endpoint. A multi-domain test with adaptive weights is proposed to synthesize the evidence of treatment efficacy over numerous disease domains. The test is a weighted sum of domain-specific test statistics with weights selected adaptively via a data-driven algorithm. The null distribution of the test statistic is constructed empirically through resampling and does not require estimation of the covariance structure of domain-specific test statistics. Simulations show that the proposed test controls the type I error rate, and has increased power over other methods such as the O'Brien and Wei-Lachin tests in scenarios reflective of clinical trial settings. Data from a clinical trial in a rare lysosomal storage disorder were used to illustrate the properties of the proposed test. As a strategy of combining marginal test statistics, the proposed test is flexible and readily applicable to a variety of clinical trial scenarios.

Neonatal nonviral gene editing with the CRISPR/Cas9 system improves some cardiovascular, respiratory, and bone disease features of the mucopolysaccharidosis I phenotype in mice.

Mucopolysaccharidosis type I (MPS I) is caused by deficiency of alpha-L-iduronidase (IDUA), leading to multisystemic accumulation of glycosaminoglycans (GAG). Untreated MPS I patients may die in the first decades of life, mostly due to cardiovascular and respiratory complications. We previously reported that the treatment of newborn MPS I mice with intravenous administration of lipossomal CRISPR/Cas9 complexes carrying the murine Idua gene aiming at the ROSA26 locus resulted in long-lasting IDUA activity and GAG reduction in various tissues. Following this, the present study reports the effects of gene editing in cardiovascular, respiratory, bone, and neurologic functions in MPS I mice. Bone morphology, specifically the width of zygomatic and femoral bones, showed partial improvement. Although heart valves were still thickened, cardiac mass and aortic elastin breaks were reduced, with normalization of aortic diameter. Pulmonary resistance was normalized, suggesting improvement in respiratory function. In contrast, behavioral abnormalities and neuroinflammation still persisted, suggesting deterioration of the neurological functions. The set of results shows that gene editing performed in newborn animals improved some manifestations of the MPS I disorder in bone, respiratory, and cardiovascular systems. However, further studies will be imperative to find better delivery strategies to reach "hard-to-treat" tissues to ensure better systemic and neurological effects.

Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I).

Mucopolysaccharidosis Type I (MPS I) is a rare genetic lysosomal storage disease caused by a mutation of IDUA gene. IDUA codes for α-L-iduronidase (IDUA), a lysosomal hydrolase that degrades glycosaminoglycans (GAGs): heparan sulphate and dermatan sulphate. GAGs are structural and signalling molecules that have a crucial role in controlling a variety of cell functions and their interaction with the extracellular matrix. Because of GAG's widespread action in cellular metabolism, MPS I is a progressive and disabling multisystemic disorder. Nowadays, the therapies available allowed patients to reach the adult life and the consequences of the disease in their reproductive system are mostly unknown. We aimed to investigate whether IDUA disruption influences sexual behaviour and sexual steroid production in male and female MPS I mice. We used 3 and 6-month-old male and 3-month-old female Idua+/_ and Idua-/- mice to evaluate typical rodent copulatory behaviours. In males we observed the frequency and latency of mounts, intromissions and ejaculations. In females, we evaluated the lordosis quotient. We also analysed the locomotor capacity of mice in the open field test, since mobility is essential for copulatory behaviour. We also quantified steroidal hormonal levels in plasmatic samples. We detected an increase in the latencies of intromissions in Idua-/- males when compared to Idua+/_. However, the number of intromissions was not statistically different between groups. No parameter of female sexual behaviour was statistically different between control and knockout females. In both sexes, we detected diminished mobility in Idua-/- mice. Plasma hormone levels did not differ between Idua+/_ and Idua-/- mice, both in males and females. Although the motor disability predicted to MPS I animals, we concluded that in the considered time point of MPS I progression studied, mice are able to perform sexual behaviour.

Case series of patients under biweekly treatment with laronidase: a report of a single center experience / Série de casos de pacientes em tratamento com laronidase quinzenal: relato da experiência de um centro

ABSTRACT Objective: To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of laronidase of 1.2 mg/kg every other week. Methods: We participated in a dose-optimization trial for laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. Results: Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event. Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.

RESUMO Objetivo: Descrever a manutenção dos níveis de glicosaminoglicano (GAG) excretados na urina e da estabilização clínica em pacientes com mucopolissacaridose do tipo I (MPS I) com o uso da laronidase num regime de dose alternativo de 1,2 mg/kg a cada duas semanas. Método: Alguns pacientes do nosso serviço participaram de um estudo de otimização de dose da laronidase para o tratamento da MPS I no qual foram comparados quatro esquemas terapêuticos: 0,58 mg/kg/semana, 1,2 mg/kg a cada duas semanas, 1,2 mg/kg/semana e 1,8 mg/kg a cada duas semanas. Após o término do estudo, todos os pacientes passaram a receber a terapia de reposição enzimática (TRE) na dose padrão de bula, que é de 0,58 mg/kg/semana, e nesse regime alguns pais se queixaram da dificuldade em comparecer ao centro todas as semanas, além da dificuldade de se obter acesso para punção venosa. Com base nessas queixas, oito pacientes passaram a receber a TRE no regime alternativo de 1,2 mg/kg a cada duas semanas. Foi feito o estudo retrospectivo de dados de prontuário de pacientes com MPS I que fizeram TRE com laronidase nas doses 0,58 mg/kg/semana e 1,2 mg/kg a cada duas semanas. Resultados: Os pacientes mantiveram-se clinicamente estáveis, não apresentaram aumento dos níveis de GAG urinários nem eventos adversos durante o regime alternativo de dose. Conclusões: A mudança para o esquema de 1,2 mg/kg de laronidase a cada duas semanas foi segura e não acarretou piora clínica nos pacientes que já estavam em TRE na dose padrão.

CASE SERIES OF PATIENTS UNDER BIWEEKLY TREATMENT WITH LARONIDASE: A REPORT OF A SINGLE CENTER EXPERIENCE.

OBJECTIVE: To report the stabilization of urinary glycosaminoglicans (GAG) excretion and clinical improvements in patients with mucopolysaccharidosis type I (MPS I) under an alternative dose regimen of laronidase of 1.2 mg/kg every other week. METHODS: We participated in a dose-optimization trial for laronidase in MPS-I patients using four alternative regimens: 0.58 mg/kg every week, 1.2 mg/kg every two weeks, 1.2 mg/kg every week and 1.8 mg/kg every other week (EOW). After the trial ended, the patients resumed the recommended dose and regimen of 0.58 mg/kg every week. Under this regimen, some patients presented difficulties in venous access and were unable to commute weekly to the treatment center. Therefore, we used an alternative regimen that consisted of 1.2 mg/kg EOW in eight patients. A retrospective study of medical records of MPS-I patients who underwent both enzyme replacement therapy (ERT) regimens, of 0.58 mg/kg every week and 1.2 mg/kg EOW, was done. RESULTS: Patients remained clinically stable under the alternative regimen, did not present elevation of urinary GAG nor any adverse event.Conclusions: The switch of dose regimen to 1.2 mg/kg EOW of laronidase was safe, and did not cause any clinical worsening in patients who had been previously under standard dose ERT.

Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.

OBJECTIVE: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I. METHODS: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls. RESULTS: The MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT. CONCLUSIONS: We found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

Intrathecal enzyme replacement for Hurler syndrome: biomarker association with neurocognitive outcomes.

PURPOSE: Abnormalities in cerebrospinal fluid (CSF) have been reported in Hurler syndrome, a fatal neurodegenerative lysosomal disorder. While no biomarker has predicted neurocognitive response to treatment, one of these abnormalities, glycosaminoglycan nonreducing ends (NREs), holds promise to monitor therapeutic efficacy. A trial of intrathecal enzyme replacement therapy (ERT) added to standard treatment enabled tracking of CSF abnormalities, including NREs. We evaluated safety, biomarker response, and neurocognitive correlates of change. METHODS: In addition to intravenous ERT and hematopoietic cell transplantation, patients (N = 24) received intrathecal ERT at four peritransplant time points; CSF was evaluated at each point. Neurocognitive functioning was quantified at baseline, 1 year, and 2 years posttransplant. Changes in CSF biomarkers and neurocognitive function were evaluated for an association. RESULTS: Over treatment, there were significant decreases in CSF opening pressure, biomarkers of disease activity, and markers of inflammation. Percent decrease in NRE from pretreatment to final intrathecal dose posttransplant was positively associated with percent change in neurocognitive score from pretreatment to 2 years posttransplant. CONCLUSION: Intrathecal ERT was safe and, in combination with standard treatment, was associated with reductions in CSF abnormalities. Critically, we report evidence of a link between a biomarker treatment response and neurocognitive outcome in Hurler syndrome.

Hurler-Scheie syndrome in Niger: a case series.

BACKGROUND: Hurler-Scheie syndrome is an intermediate form of mucopolysaccharidosis type I which is a rare lysosomal storage disorder caused by the deficiency or complete absence of enzyme alpha-L-iduronidase activity. We report the first documented cases of Hurler-Scheie syndrome observed in Niger in a Touareg family. CASE PRESENTATION: We studied the case of two 12-year-old twin Touareg boys and their 10-year-old Touareg sister whose parents are first-degree cousins, and there was no history of similar cases in their previous generations. The diagnosis of Hurler-Scheie syndrome was considered in these patients on the basis of clinical and radiological arguments, with the highlighting of a deficiency of enzyme alpha-L-iduronidase in serum and leukocytes. The twins had presented the first symptoms at the age of 24 months and the diagnosis of Hurler-Scheie syndrome was made at the age of 12 years. In their younger sister, the first symptoms were observed at the age of 3 years and the diagnosis was made at the age of 10 years. The three probands were born after a normal full-term pregnancy and a spontaneous vaginal delivery according to their parents. Their birth weight, height, and head circumference were within normal limits according to their parents. The three probands were brought in for consultation for stunted growth, joint stiffness with gait disorders, deformities of the thoracolumbar spine, recurrent otitis media, decreased hearing, increased abdominal volume, snoring during sleep, and facial dysmorphism. CONCLUSIONS: Even in countries with limited access to diagnostic means, a good knowledge of the clinical manifestations of the disease can help to guide the diagnosis of mucopolysaccharidosis type I.

Beneath the floor: re-analysis of neurodevelopmental outcomes in untreated Hurler syndrome.

BACKGROUND: Hurler syndrome (MPS IH), the severe, neurodegenerative form of type one mucopolysaccharidosis, is associated with rapid neurocognitive decline during toddlerhood and multi-system dysfunction. It is now standardly treated with hematopoietic cell transplantation (HCT), which halts accumulating disease pathology and prevents early death. While norm-based data on developmental functioning in untreated children have previously demonstrated neurocognitive decline, advances in methodology for understanding the cognitive functioning of children with neurodegenerative diseases have highlighted that the previous choice of scores to report results was not ideal. Specifically, the lowest possible norm-based score is 50, which obscures the complete range of cognitive functioning at more advanced stages of neurodeterioration. To a set of cognitive data collected on a sample of untreated children, we applied a modern method of score analysis, calculating a developmental quotient based on age equivalent scores, to reveal the full range of cognitive functioning beneath this cutoff of 50, uncovering new information about the rapidity of decline and the profound impairment in these children. RESULTS: Among 39 observations for 32 patients with untreated Hurler syndrome, the full array of cognitive functioning below 50 includes many children in the severely to profoundly impaired range. The loss of skills per time unit was 14 points between age 1 and 2. There was a very large range of developmental quotients corresponding to the norm-based cutoff of 50. CONCLUSIONS: This report enables clarification of functioning at levels that extend beneath the floor of 50 in previous work. At the dawn of newborn screening and amidst a proliferation of new therapies for MPS I, these data can provide crucial benchmark information for developing treatments, particularly for areas of the world where transplant may not be available.

Long-term outcomes of systemic therapies for Hurler syndrome: an international multicenter comparison.

PURPOSE: Early treatment is critical for mucopolysaccharidosis type I (MPS I), justifying its incorporation into newborn screening. Enzyme replacement therapy (ERT) treats MPS I, yet presumptions that ERT cannot penetrate the blood-brain barrier (BBB) support recommendations that hematopoietic cell transplantation (HCT) treat the severe, neurodegenerative form (Hurler syndrome). Ethics precludes randomized comparison of ERT with HCT, but insight into this comparison is presented with an international cohort of patients with Hurler syndrome who received long-term ERT from a young age. METHODS: Long-term survival and neurologic outcomes were compared among three groups of patients with Hurler syndrome: 18 treated with ERT monotherapy (ERT group), 54 who underwent HCT (HCT group), and 23 who received no therapy (Untreated). All were followed starting before age 5 years. A sensitivity analysis restricted age of treatment below 3 years. RESULTS: Survival was worse when comparing ERT versus HCT, and Untreated versus ERT. The cumulative incidences of hydrocephalus and cervical spinal cord compression were greater in ERT versus HCT. Findings persisted in the sensitivity analysis. CONCLUSION: As newborn screening widens treatment opportunity for Hurler syndrome, this examination of early treatment quantifies some ERT benefit, supports presumptions about BBB impenetrability, and aligns with current guidelines to treat with HCT.

Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of IV laronidase for MPS I. METHODS: A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. RESULTS: The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant-NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 µg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. CONCLUSIONS: Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.

Cognitive endpoints for therapy development for neuronopathic mucopolysaccharidoses: Results of a consensus procedure.

The design and conduct of clinical studies to evaluate the effects of novel therapies on central nervous system manifestations in children with neuronopathic mucopolysaccharidoses is challenging. Owing to the rarity of these disorders, multinational studies are often needed to recruit enough patients to provide meaningful data and statistical power. This can make the consistent collection of reliable data across study sites difficult. To address these challenges, an International MPS Consensus Conference for Cognitive Endpoints was convened to discuss approaches for evaluating cognitive and adaptive function in patients with mucopolysaccharidoses. The goal was to develop a consensus on best practice for the design and conduct of clinical studies investigating novel therapies for these conditions, with particular focus on the most appropriate outcome measures for cognitive function and adaptive behavior. The outcomes from the consensus panel discussion are reported here.

Intranasal Adeno-Associated Virus Mediated Gene Delivery and Expression of Human Iduronidase in the Central Nervous System: A Noninvasive and Effective Approach for Prevention of Neurologic Disease in Mucopolysaccharidosis Type I.

Mucopolysaccharidosis type I (MPS I) is a progressive, multi-systemic, inherited metabolic disease caused by deficiency of α-L-iduronidase (IDUA). Current treatments for this disease are ineffective in treating central nervous system (CNS) disease due to the inability of lysosomal enzymes to traverse the blood-brain barrier. A noninvasive and effective approach was taken in the treatment of CNS disease by intranasal administration of an IDUA-encoding adeno-associated virus serotype 9 (AAV9) vector. Adult IDUA-deficient mice aged 3 months were instilled intranasally with AAV9-IDUA vector. Animals sacrificed 5 months post instillation exhibited IDUA enzyme activity levels that were up to 50-fold that of wild-type mice in the olfactory bulb, with wild-type levels of enzyme restored in all other parts of the brain. Intranasal treatment with AAV9-IDUA also resulted in the reduction of tissue glycosaminoglycan storage materials in the brain. There was strong IDUA immunofluorescence staining of tissue sections observed in the nasal epithelium and olfactory bulb, but there was no evidence of the presence of transduced cells in other portions of the brain. This indicates that reduction of storage materials most likely occurred as a result of enzyme diffusion from the olfactory bulb and the nasal epithelium into deeper areas of the brain. At 8 months of age, neurocognitive testing using the Barnes maze to assess spatial navigation demonstrated that treated IDUA-deficient mice were no different from normal control animals, while untreated IDUA-deficient mice exhibited significant learning and navigation deficits. This novel, noninvasive strategy for intranasal AAV9-IDUA instillation could potentially be used to treat CNS manifestations of human MPS I.