Issues of COVID-19-related distance learning for children with neuronopathic mucopolysaccharidoses.

The COVID-19 pandemic has impacted the education of children around the world, forcing a large proportion of teaching to be carried out remotely. The implications of this disruption have yet to be fully elucidated, but initial assessments suggest that COVID-19-related school closures and reliance on virtual learning may have a long-term negative impact on educational attainment and future earnings as well as life expectancy of children in the United States. Among children with neurodegenerative disorders, such as neuronopathic mucopolysaccharidoses (MPS disorders), the effects of the pandemic are likely to be even greater. We aim to shine a spotlight on the impact of COVID-19 on the education, treatment and general wellbeing of children and families affected by MPS disorders by highlighting the important role that educators and therapists play in supporting the neurocognitive function and quality of life of children with neuronopathic MPS disorders. This article will serve as a resource that caregivers, educators, clinicians and therapists can use when considering how best to advocate for children with neuronopathic MPS disorders in circumstances where in-school teaching or in-clinic treatment is compromised or not possible. Given that the current pandemic is likely to have a prolonged course and impact and that similar epidemics and pandemics are a near certainty in the future, it is essential that steps are taken to support the learning and care of children with neuronopathic MPS disorders. We must prioritize strategies to safely resume this fragile community's access to in-person education and supportive care, and to address gaps that have emerged during prolonged pauses in access, whenever possible.

MPSBase: Comprehensive repository of differentially expressed genes for mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are lysosomal storage diseases (LSDs) caused by the deficiency of enzymes essential for the metabolism of extracellular matrix components called glycosaminoglycans (GAGs). To understand the physiopathology and alterations due to the lysosomal accumulation resulting from enzymatic deficiencies and their secondary outcomes can improve the diagnosis and treatment of rare genetic diseases. This work presents a database for differentially expressed genes from different public MPS data. We developed our database, including 13 studies previously deposited in the GEO (https://www.ncbi.nlm.nih.gov/geo/). The website is hosted in the UFRGS data processing center (CPD) and is available at . The site was constructed in PHP, and the analyses were performed in R. The organisms represented by the datasets are Canis lupus familiaris, Homo sapiens, Mus musculus, and Rattus norvegicus. The user can search for the differentially expressed genes and ontologies by species, MPS type, or tissue type. For each comparison, a heatmap with the 50 top differentially expressed genes is available as well as dot plots for the 30 top ontologies divided by biological process, cellular component, KEGG pathways, and molecular function. This data is also fully available in tables. There are 54 possible comparisons involving about 5000 to 10,000 genes each. This website is the only specific database for MPS with filtering and presenting their results in a one-click approach to the best of our knowledge. The development of such analytical and automated strategies accessible to health professionals is essential for fostering MPS research. The MPSBase is a web user-friendly, comprehensive repository of differentially expressed genes and ontologies regarding the MPS data.

Urinary glycosaminoglycans as a potential biomarker for evaluating treatment efficacy in subjects with mucopolysaccharidoses.

Accumulations of glycosaminoglycans (GAGs) that result from deficiencies in lysosomal hydrolases are characteristic of mucopolysaccharidoses (MPS). Enzyme replacement therapies (ERTs) are now available for several MPS diseases (MPS I, MPS II, MPS IVA, MPS VI, and MPS VII), but assessment of the efficacy of treatment can be challenging because these are rare, progressive, and highly heterogeneous diseases; because some clinical manifestations may be irreversible if treatment initiation is delayed; and because determining the benefits of a treatment to prevent those manifestations may take prolonged periods of time. In addition to accumulation of GAGs in tissues, elevated urinary GAG (uGAG) levels are evident and are reduced rapidly after initiation of ERT. Studies in MPS animal models and clinical studies in subjects with MPS diseases have revealed correlations between reductions of uGAG levels and clinical effects of ERTs. In this article, we review the growing body of evidence to support the potential for the use of uGAG levels as predictive biomarkers of treatment efficacy.

Failures of Endochondral Ossification in the Mucopolysaccharidoses.

PURPOSE OF REVIEW: The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders characterized by abnormal accumulation of glycosaminoglycans (GAGs) in cells and tissues. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. In this review, we outline the current understanding of the cellular and molecular mechanisms underlying failures of endochondral ossification in MPS and discuss associated treatment challenges and opportunities. RECENT FINDINGS: Studies in MPS patients and animal models have demonstrated that skeletal cells and tissues exhibit significantly elevated GAG storage from early in postnatal life and that this is associated with impaired cartilage-to-bone conversion in primary and secondary ossification centers, and growth plate dysfunction. Recent studies have begun to elucidate the underlying cellular and molecular mechanisms, including impaired chondrocyte proliferation and hypertrophy, diminished growth factor signaling, disrupted cell cycle progression, impaired autophagy, and increased cell stress and apoptosis. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy fail to normalize endochondral ossification in MPS. Emerging treatments including gene therapy and small molecule-based approaches hold significant promise in this regard. Failures of endochondral ossification contribute to skeletal deformity and short stature in MPS patients, increasing mortality and reducing quality of life. Early intervention is crucial for effective treatment, and there is a critical need for new approaches that normalize endochondral ossification by directly targeting affected cells and signaling pathways.

Ganglioside GM2 catabolism is inhibited by storage compounds of mucopolysaccharidoses and by cationic amphiphilic drugs.

The catabolism of ganglioside GM2 is dependent on the lysosomal enzyme ß-hexosaminidase A and a supporting lipid transfer protein, the GM2 activator protein. A genetically based disturbance of GM2 catabolism, leads to several subtypes of the GM2 gangliosidosis: Tay-Sachs disease, Sandhoff disease, the AB-variant and the B1-variant, all of them having GM2 as major lysosomal storage compound. Further on it is known that the gangliosides GM2 and GM3 accumulate as secondary storage compounds in mucopolysaccharidoses, especially in Hunter disease, Hurler disease, Sanfilippo disease and Sly syndrome, with chondroitin sulfate as primary storage compound. The exact mechanism of ganglioside accumulation in mucopolysaccaridoses is still a matter of debate. Here, we show that chondroitin sulfate strongly inhibits the catabolism of membrane-bound GM2 by ß-hexosaminidase A in presence of GM2 activator protein in vitro already at low micromolar concentrations. In contrast, hyaluronan, the major storage compound in mucopolysaccharidosis IX, a milder disease without secondary ganglioside accumulation, is a less effective inhibitor. On the other hand, hydrolysis of micellar-bound GM2 by ß-hexosaminidase A without the assistance of GM2AP was not impeded by chondroitin sulfate implicating that the inhibition of GM2 hydrolysis by chondroitin sulfate is most likely based on an interaction with GM2AP, the GM2AP-GM2 complex or the GM2-carrying membranes. We also studied the influence of some cationic amphiphilic drugs (desipramine, chlorpromazine, imipramine and chloroquine), provoking drug induced phospholipidosis and found that all of them inhibited the hydrolysis of GM2 massively.

Growth impairment and limited range of joint motion in children should raise suspicion of an attenuated form of mucopolysaccharidosis: expert opinion.

Growth impairment together with bone and joint involvement is common to most patients with mucopolysaccharidosis (MPS) disorders. The genetic basis for these metabolic disorders involves various enzyme deficiencies responsible for the catabolism of glycosaminoglycans (GAGs). The incomplete degradation and subsequent accumulation of GAGs result in progressive tissue damage throughout the body. Bone ossification is particularly affected, with the consequent onset of dysostosis multiplex which is the underlying cause of short stature. Joint manifestations, whether joint contractures (MPS I, II, VI, VII) or hyperlaxity (MPS IV), affect fine motor skills and quality of life. Subtle decreases in growth velocity can begin as early as 2-4 years of age. Pediatricians are in the front line to recognize or suspect MPS. However, given the rarity of the disorders and variable ages of symptom onset depending on disease severity, recognition and diagnostic delays remain a challenge, especially for the attenuated forms. Prompt diagnosis and treatment can prevent irreversible disease outcomes.Conclusion: We present a diagnostic algorithm based on growth velocity decline and bone and joint involvement designed to help pediatricians recognize early manifestations of attenuated forms of MPS. We illustrate the paper with examples of abnormal growth curves and subtle radiographic nuances. What is Known: • As mucopolysaccharidoses (MPSs) are rare genetic disorders infrequently seen in clinical practice, there can be a lag between symptom onset and diagnosis, especially of attenuated forms of the disease. • This highlights the need for increased disease awareness to recognize early clinical signs and subsequently initiate early treatment to improve outcomes (normal height potential) and possibly prevent or delay the development of irreversible disease manifestations. What is New: • Growth impairment co-presenting with limited range of joint motion and radiographic anomalies in children should raise suspicions of possible attenuated MPS (AMPS). • Experts present a diagnostic algorithm with detailed focus on the decline in growth velocity, delayed puberty and limitation in joint mobility seen in children with AMPS, to shorten time-to-diagnosis and treatment and potentially improve patient outcome.

Clinical presentation and diagnosis of mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are estimated to affect1 in 25,000 live births although specific rates vary between the ethnic origin and country. MPS are a group of lysosomal storage disorders, which cause the buildup of GAG(s) due to insufficient or absent GAG-degrading enzymes. With seven types of MPS disorders and eleven subtypes, the MPS family presents unique challenges for early clinical diagnosis due to the molecular and clinical heterogeneity between groups and patients. Novel methods of early identification, particularly newborn screening through mass spectrometry, can change the flow of diagnosis, allowing enzyme and GAG quantification before the presentation of clinical symptoms improving outcomes. Genetic testing of patients and their families can also be conducted preemptively. This testing enables families to make informed decisions about family planning, leading to prenatal diagnosis. In this review, we discuss the clinical symptoms of each MPS type as they initially appear in patients, biochemical and molecular diagnostic methods, and the future of newborn screening for this group of disorders.

Growth impairment in mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that affect regulation of glycosaminoglycan (GAG) processing. In MPS, the lysosomes cannot efficiently break down GAGs, and the specific GAGs accumulated depend on the type of MPS. The level of impairment of breakdown varies between patients, making this one of the many factors that lead to a range of clinical presentations even in the same type of MPS. These clinical presentations usually involve skeletal dysplasia, in which the most common feature is bone growth impairment and successive short stature. Growth impairment occurs due to the deposition and retention of GAGs in bone and cartilage. The accumulation of GAGs in these tissues leads to progressive damage in cartilage that in turn reduces bone growth by destruction of the growth plate, incomplete ossification, and imbalance of growth. Imbalance of growth leads to various skeletal abnormalities including disproportionate dwarfism with short neck and trunk, prominent forehead, rigidity of joints, tracheal obstruction, kyphoscoliosis, pectus carinatum, platyspondyly, round-shaped vertebral bodies or beaking sign, underdeveloped acetabula, wide flared iliac, coxa valgus, flattered capital femoral epiphyses, and genu valgum. If left untreated, skeletal abnormalities including growth impairment result in a significant impact on these patients' quality of life and activity of daily living, leading to high morbidity and severe handicap. This review focuses on growth impairment in untreated patients with MPS. We comprehensively describe the growth abnormalities through height, weight, growth velocity, and BMI in each type of MPS and compare the status of growth with healthy age-matched controls. The timing, the degree, and the difference in growth impairment of each MPS are highlighted to understand the natural course of growth and to evaluate future therapeutic efficacy.

Children with mucopolysaccharidosis risk progressive visual dysfunction despite haematopoietic stem cell transplants.

AIM: This prospective study assessed the long-term ocular and visual outcomes of children with mucopolysaccharidoses type I Hurler syndrome (MPS IH) who were treated with haematopoietic stem cell transplants (HSCT). METHODS: Clinical ophthalmological assessments were performed on eight patients at the St Erik Eye Hospital, Huddinge, Stockholm, Sweden, from 2001-2018: The median age at diagnosis and HSCT were 12.2 (range 5.0-16.4) and 16.7 (8.0-20.4) months. The last eye examination was at a median of 13.4 (6.3-19.0) years and follow-up lasted a median of 12.0 (5.0-17.4) years. RESULTS: Poor visual acuity, poor night vision and, or, photophobia were reported by six children. The best corrected visual acuity at the last visit was a median of 0.4 and 0.5 in the right and left eye and had declined significantly in two patients. Corneal opacities had increased despite HSCT in five patients. High hyperopia, at a median of +6 Dioptres, occurred in all patients and stiff corneas in all four patients that were measured. The patients' corrected intraocular pressures were normal. Retinal degeneration was identified in two patients. CONCLUSION: Despite HSCT, the long-term follow-up of patients with MPS IH showed reduced visual acuity due to corneal opacities or retinal degeneration.

Safety of anesthesia for children with mucopolysaccharidoses: A retrospective analysis of 54 patients.

BACKGROUND: Complications are common during anesthesia for patients with mucopolysaccharidoses. San Gerardo Hospital (Italy) is a reference center for mucopolysaccharidoses with a dedicated pediatric anesthesia service. AIMS: This study aims to evaluate the safety of anesthesia for mucopolysaccharidoses patients, describe their anesthetic management at our institution, and assess risk factors for complications. METHODS: The anesthetic charts of mucopolysaccharidoses patients admitted from January 1999 to December 2014 were retrospectively analyzed. We retrieved patients' demographics; location and type of the procedure; anesthetic approach airway management and occurrence of difficult intubation and complications and outcome at hospital discharge. A generalized linear mixed model was performed to assess risk factors for complications and difficult intubation. RESULTS: Fifty-four consecutive children were included. The anesthetic charts of 232 procedures (52% radio-diagnostics, 15% orthopedics, 15% ear-nose-throat surgery, 10% neurosurgery, and 8% general surgery) were analyzed. Each patient underwent a median of 4 (1-6) procedures. The median age at the first procedure was 2 (1-5), and overall age was 5 (2-8) years old. One hundred and twenty-five (54%) procedures were performed in remote locations. General anesthesia was utilized for 100 (43%) procedures. No death was recorded. Twenty-one (9%) procedures had respiratory complications. Remote location anesthesia was associated with increased risk for complications (odds ratio 5.405 [1.355-28.571], P = .016). All planned intubations (n = 65) were successful. Nineteen (29%) of those were defined difficult. All emergency intubations (n = 3) failed and were rescued by laryngeal mask airways. Older age was associated with an increased risk of difficult intubation (OR 1.200 [1.019-1.436], P = .028). CONCLUSION: Patients with mucopolysaccharidoses are at high risk for anesthesia-related complications. Remote location anesthesia is associated with increased risk for complications, and older age is associated with increased risk for difficult intubation.

Cognitive and adaptive measurement endpoints for clinical trials in mucopolysaccharidoses types I, II, and III: A review of the literature.

Sensitive, reliable measurement instruments are critical for the evaluation of disease progression and new treatments that affect the brain in the mucopolysaccharidoses (MPS). MPS I, II, and III have early onset clinical phenotypes that affect the brain during development and result in devastating cognitive decline and ultimately death without treatment. Comparisons of outcomes are hindered by diverse protocols and approaches to assessment including applicability to international trials necessary in rare diseases. We review both cognitive and adaptive measures with the goal of providing evidence to a Delphi panel to come to a consensus about recommendations for clinical trials for various age groups. The results of the consensus panel are reported in an accompanying article. The following data were gathered (from internet resources and from test manuals) for each measure and summarized in the discussion: reliability, validity, date and adequacy of normative data, applicability of the measure's metrics, cross cultural validity including translations and adaptations, feasibility in the MPS population, familiarity to sites, sensitivity to change, and interpretability. If, resulting from this consensus, standard protocols are used for both natural history and treatment studies, patients, their families, and health care providers will benefit from the ability to compare study outcomes.

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.

Myocardial deformation in pediatric patients with mucopolysaccharidoses: A two-dimensional speckle tracking echocardiography study.

BACKGROUND: Mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders caused by deficiency of required glycosaminoglycans breakdown enzymes, inducing cardiac involvement. Little is known about myocardial deformation involvement in MPS. Our aim was to assess biventricular structure and function in asymptomatic children with MPS using standard echo Doppler and 2D speckle tracking (STE). METHODS: Fifteen MPS children (one type I, six type II, three type III A, one III B, three IV A, one VI), asymptomatic for cardiac symptoms, and 15 age and sex-matched healthy controls underwent echo Doppler and STE. Left ventricular (LV) wall thicknesses, diameters, and mass were normalized by z-score. LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS) at papillary muscles, LV twisting, and right ventricular (RV) GLS were measured. RESULTS: The two groups were comparable for body mass index, heart rate, and blood pressure. LV mass index and relative wall thickness were higher in MPS. Ejection fraction (EF), and s' velocity did not differ between the two groups. E/A ratio was lower and E/e' higher in MPS. Tricuspid annular plane systolic excursion, RV s' and e' were lower in MPS. LV GLS did not differ between the two groups, but GCS (P=.014), GRS (P=.023), twisting (P=.012), and RV GLS (P<.001) were lower in the MPS group. CONCLUSIONS: LV strain abnormalities are detectable in MPS pediatric patients, independently of MPS type, when EF is still normal. RV GLS is also involved consensually with TAPSE reduction. STE can be useful for detection of subclinical myocardial damage in MPS.

The Carotid Intima-Media Thickness and Arterial Stiffness of Pediatric Mucopolysaccharidosis Patients Are Increased Compared to Both Pediatric and Adult Controls.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a "structural vascular age" of at least 40 years old.

Pathogenesis and treatment of spine disease in the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS, such as hematopoietic stem cell transplantation and enzyme replacement therapy, have shown limited efficacy for improving spinal manifestations in patients and animal models. Therefore, there is a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine - the discs, vertebrae, odontoid process and dura - contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments.

Emerging drugs for the treatment of mucopolysaccharidoses.

INTRODUCTION: Despite being reported for the first time almost one century ago, only in the last few decades effective have treatments become available for the mucopolysaccharidoses (MPSs), a group of 11 inherited metabolic diseases that affect lysosomal function. These diseases are progressive, usually severe, and, in a significant number of cases, involve cognitive impairment. AREAS COVERED: This review will not cover established treatments such as bone marrow/hematopoietic stem cell transplantation and classic intravenous enzyme replacement therapy (ERT), whose long-term outcomes have already been published (MPS I, MPS II, and MPS VI), but it instead focuses on emerging therapies for MPSs. That includes intravenous ERT for MPS IVA and VII, intrathecal ERT, ERT with fusion proteins, substrate reduction therapy, gene therapy, and other novel approaches. EXPERT OPINION: The available treatments have resulted in improvements for several disease manifestations, but they still do not represent a cure for these diseases; thus, it is important to develop alternative methods to approach the unmet needs (i.e. bone disease, heart valve disease, corneal opacity, and central nervous system (CNS) involvement). The work in progress with novel approaches makes us confident that in 2017, when MPS will commemorate 100 years of its first report, we will be much closer to an effective cure for these challenging conditions.

Neuroimaging Findings in Patients with Mucopolysaccharidosis: What You Really Need to Know.

Mucopolysaccharidosis (MPS) is an inherited metabolic disease and a member of the group of lysosomal storage disorders. Its hallmark is a deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). The products of GAG degradation accumulate within lysosomes and in the extracellular space, thereby interfering with the degradation of other macromolecules. This process leads to chronic degeneration of cells, which in turn affects multiple organs and systems. There are seven distinct types of MPS (I, II, III, IV, VI, VII, and IX), which are divided into subtypes according to the deficient enzyme and the severity of the clinical picture. Although clinical manifestations vary considerably among the different types of MPS, the central nervous system (CNS) is characteristically affected, and magnetic resonance (MR) imaging is the method of choice to evaluate brain and spinal cord abnormalities. Enlarged perivascular spaces, white matter lesions, hydrocephalus, brain atrophy, cervical spinal canal stenosis with or without spinal cord compression and myelopathy, and bone abnormalities in the skull and spine (dysostosis multiplex) are typical imaging findings described in the literature and reviewed in this article. The differential diagnosis of MPS is limited because the constellation of imaging findings is highly suggestive. Thus, radiologists should be aware of its typical neuroimaging findings so they can recognize cases not yet diagnosed, exclude other metabolic diseases, monitor CNS findings over time, and assess treatment response. (©)RSNA, 2016.

[Mucopolysaccharidosis: clinical features, diagnosis and management]. / Mucopolisacaridosis: características clínicas, diagnóstico y de manejo.

The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment.

Early initiation of enzyme replacement therapy for the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS), a group of rare genetic disorders caused by defects in glycosaminoglycan (GAG) catabolism, are progressive, multi-systemic diseases with a high burden of morbidity. Enzyme replacement therapy (ERT) is available for MPS I, II, and VI, and may improve walking ability, endurance, and pulmonary function as evidenced by data from pivotal trials and extension studies. Despite these demonstrable benefits, cardiac valve disease, joint disease, and skeletal disease, all of which cause significant morbidity, do not generally improve with ERT if pathological changes are already established. Airway disease improves, but usually does not normalize. These limitations can be well understood by considering the varied functions of GAG in the body. Disruption of GAG catabolism has far-reaching effects due to the triggering of secondary pathogenic cascades. It appears that many of the consequences of these secondary pathogenic events, while they may improve on treatment, cannot be fully corrected even with long-term exposure to enzyme, thereby supporting the treatment of patients with MPS before the onset of clinical disease. This review examines the data from clinical trials and other studies in human patients to explore the limits of ERT as currently used, then discusses the pathophysiology, fetal tissue studies, animal studies, and sibling reports to explore the question of how early to treat an MPS patient with a firm diagnosis. The review is followed by an expert opinion on the rationale for and the benefits of early treatment.

Current and potential therapeutic strategies for mucopolysaccharidoses.

WHAT IS KNOWN AND OBJECTIVE: Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic diseases caused by genetic defects in the production of lysosomal enzymes. MPSs are clinically heterogeneous and are characterized by progressive deterioration in visceral, skeletal and neurological functions. This article aims to review the classification and pathophysiology of MPSs and discuss current therapies and new targeted agents under development. METHODS: A Medline search through PubMed was performed for relevant articles and treatment guidelines on MPSs published in English for years 1970 to September of 2013 inclusive. The references listed in the identified articles, prescribing information of the drugs approved for the treatment of MPSs, as well as recent clinical trial information posted on Clinicaltrials.gov website, were reviewed. RESULTS AND DISCUSSION: Until recently, supportive care was the only option available for the management of MPSs. In the early 2000s, enzyme replacement therapy (ERT) was approved by the United States Food and Drug Administration (FDA) for the treatment of MPS I, II and VI. Clinical trials of ERT showed substantial improvements in patients' somatic symptoms; however, no benefit was found in the neurological symptoms because the enzymes do not readily cross the blood-brain barrier (BBB). Haematopoietic stem cell transplantation (HSCT), another potentially curative treatment, is not routinely advocated in clinical practice due to its high risk profile and lack of evidence for efficacy, except in preserving cognition and prolonging survival in young patients with severe MPS I. In recent years, substrate reduction therapy (SRT) and gene therapy have been rapidly gaining greater recognition as potential therapeutic avenues. WHAT IS NEW AND CONCLUSION: Enzyme replacement therapy (ERT) is effective for the treatment of many somatic symptoms, particularly walking ability and respiratory function, and remains the mainstay of MPS treatment. The usefulness of HSCT has not been established adequately for most MPSs. Although still under investigation, SRT and gene therapy are promising MPS treatments that may prevent the neurodegeneration not affected by ERT.