Different Types Of Mucopolysaccharidoses Research Articles

Foramen magnum stenosis in patients with mucopolysaccharidoses: diagnosis and surgical treatment. Review of literature

Cervico-medullary compression and atlantoaxial dislocation syndromes are the dominant clinical manifestations of mucopolysaccharidoses at the craniovertebral level. The review provides an analysis of international literary sources concerning modern aspects of diagnosis and neurosurgical correction of the foramen magnum stenosis in patients with different types of mucopolysaccharidoses. The existing surgical approaches to determining the indications and choosing the method of surgical treatment and some aspects of the use of enzyme replacement therapy and hematopoietic stem cell transplantation are presented. A variety of options for surgical correction of pathology at the craniovertebral level have been demonstrated in patients with different types of mucopolysaccharidosis, however the described recommendations can be considered from the point of view of traditions of the hospitals or personal experience of surgeons, but not as recognized standards of treatment this pathology. Further accumulation of individual observations or clinical series is required to conduct a comparative analysis of the effectiveness of various approaches on a sufficiently large and homogeneous material to determine standards for the diagnosis and treatment of craniovertebral junction pathology in patients with mucopolysaccharidoses.

Quantification of Glycosaminoglycans Using Harmine Extract from Peganum harmala L. in Mucopolysaccharidoses Researches

Background: Harmine is used in the quantification of glycosaminoglycans (GAGs) for the research on mucopolysaccharidoses (MPSs). Although this product is commercially available, researchers may consider preparing it under laboratory conditions when it is unavailable for various reasons. This research aims to extract harmine from Peganum harmala L. seeds and determine whether this extract can be used as a substitute for pure harmine in the quantification of GAGs and, consequently, in the research on MPS. Methods: P. harmala L. seeds were obtained from the plant and extracted using methanol. The harmine extract was then used in a spectrophotometric assay on controls, including patients known of having MPS and healthy subjects and patients suspected of having different types of MPS. Results: One milligram of harmine extract in 1 ml of ethanol is sufficient to produce the chromogen as that obtained by pure harmine. The chromogen exhibits a peak absorbance peak at 510 nm. The concordance between the two forms of harmine reaches 100%, either for abnormal values seen in GAGs from MPS patients or for normal values in those from healthy controls. Suspicion of having MPS was lifted in investigated patients. The harmine extracted from P. harmala L. seeds allowed for accurate and reproducible quantification of the GAGs. Conclusion: This study demonstrates that harmine extract can be used as a reagent for the quantification of GAGs in the research on MPS when pure harmine is unavailable in the same way as pure harmine.

Contribution of vesicle trafficking dysregulation to the pathomechanism of mucopolysaccharidosis

Although mucopolysaccharidoses (MPS) are monogenic diseases, caused by mutations in genes coding for enzymes involved in degradation of glycosaminoglycans (GAGs), recent studies suggested that changes in expressions of various genes might cause secondary and tertiary cellular dysfunctions modulating the course of these diseases. In this report, we demonstrate that vesicle trafficking regulation is affected in fibroblasts derived from patients suffering from 11 different types of MPS due to changes in levels of crucial proteins (estimated by automated Western-blotting) involved in this process, including caveolin, clathrin, huntingtin (Htt), APPL1, EEA1, GOPC, Rab5, and Rab7. Microscopic studies confirmed these results, while investigations of tissue samples derived from the MPS I mouse model indicated differences between various organs in this matter. Moreover, transcriptomic analyses provided a global picture for changes in expressions of genes related to vesicle trafficking in MPS cells. We conclude that vesicle trafficking is dysregulated in MPS cells and changes in this process might contribute to the molecular mechanisms of this disease. Most probably, primary GAG storage might cause a cellular stress response leading to dysregulation of expression of many genes which, in turn, results in changes in cellular processes like vesicle trafficking. This can significantly modulate the course of the disease due to enhancing accumulation of GAGs and altering crucial cellular processes. This hypothesis has been supported by normalization of levels of clathrin in MPS cells treated with either an active form of the deficient GAG-degrading enzyme or a compound (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) indirectly reducing the efficiency of GAG synthesis.

Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses.

Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.

Mandibular condyle morphology among patients with mucopolysaccharidosis: An observational study of panoramic radiographs.

Mucopolysaccharidoses (MPS) are a group of rare metabolic diseases characterized by a wide spectrum of symptoms including progressive condylar resorption. The aim of this study was to quantify the severity of condylar involvement in MPS I individuals in comparison with a group of non-MPS individuals and to describe how condylar changes may vary among the different types of MPS. Fifty panoramic radiographs of MPS patients (13.4±6.2years) with MPS I (n=14), MPS II (n=2), MPS IV (n=8) and MPS VI (n=2) were compared with forty panoramic radiographs of non-MPS individuals. The severity of condylar resorption was evaluated using a qualitative score (grades 0-3) and using the ratio of condylar height to ramus height (CH: RH). All MPS I and VI individuals showed pronounced bilateral degenerative condylar resorption. In contrast, individuals with MPS II and IV exhibited heterogeneous findings. The quantification of condylar height to ramus height revealed that CH: RH was significantly decreased in MPS I as compared to that of non-MPS individuals (P<.001). In contrast, the CH: RH ratios of MPS II and IV showed great variability. Mucopolysaccharidoses subtypes differ with regard to the severity of condylar resorption.

Neuronetworks: Analysis of brain pathology in Mucopolysaccharidoses – A systems biology approach

Mucopolysaccharidoses (MPS) are rare lysosomal storage diseases characterized by defects in the activity of lysosomal hydrolases that degrade glycosaminoglycan, with progressive multisystemic involvement. Neurological damage is present in several MPS types. The relationship between the accumulation of glycosaminoglycans and the neurological disorder presented in these diseases remains unknown. For this purpose, we analyzed distinct types of MPS using publicly available transcriptomic data with a systems biology approach to search for clues about the pathophysiological mechanisms involved in the brain pathology of MPS. The most relevant proteins in the networks and ontology terms related to neurological damage in MPS were identified and compared among diseases. We performed the clustering analysis for GSE111906 (MPSI), GSE95224 (MPSII), GSE23075 (MPSIIIB), GSE15758 (MPSIIIB), and GSE76283 (MPSVII). Regarding biomarker discovery analysis, the top 10 genes were ranked according to the maximal clique centrality. Different ontologies were present in the different types of MPS. Ontologies were also present in all the MPS types, like axon guidance, Calcium signaling, PI3K-Akt signaling pathway, and Wnt signaling pathway. We hypothesize that these pathways are deranged because glycosaminoglycans play an essential role in the extracellular matrix composition, helping to regulate several processes. Systems biology approaches may help to understand the mechanisms of neuropathology in the different types of Mucopolysaccharidoses.

Clinical and hearing function assessment among children with mucopolysacchridosis attending Alexandria university children hospital

Mucopolysaccharidosis (MPS) is a genetic, progressive and clinically heterogeneous disorder that usually involves multiple body systems due to the deficiency of one of the enzymes that play a role in the metabolism of glycosaminoglycans (GAGs), which accumulates in the lysosomes of multiple organs. It involves wide spectrum of clinical manifestations. Hearing dysfunction is a well known clinical association found in most patients with Mucopolysaccharidosis that can’t be underestimated as children acquire language basically by hearing what is being said by those around them, and good hearing is involved in the development of speech and language as well as socialization. Aim of the workThis work aimed at clinical characterization of MPS cases attending genetics clinic at Alexandria University Children Hospital, enzymatic and genetic diagnosis of the cases and detailed evaluation of their hearing function.Subjects and methodsThis descriptive cross sectional study was conducted on seventy-five patients with confirmed diagnosis of different types of Mucopolysaccharidosis diagnosed in the genetics clinic of Alexandria University Children Hospital from the year 2010 till the year 2020.

Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases.

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I (p < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann–Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.

Estimated prevalence of mucopolysaccharidoses from population-based exomes and genomes

BackgroundIn this study, the prevalence of different types of mucopolysaccharidoses (MPS) was estimated based on data from the exome aggregation consortium (ExAC) and the genome aggregation database (gnomAD). The population-based allele frequencies were used to identify potential disease-causing variants on each gene related to MPS I to IX (except MPS II).MethodsWe evaluated the canonical transcripts and excluded homozygous, intronic, 3′, and 5′ UTR variants. Frameshift and in-frame insertions and deletions were evaluated using the SIFT Indel tool. Splice variants were evaluated using SpliceAI and Human Splice Finder 3.0 (HSF). Loss-of-function single nucleotide variants in coding regions were classified as potentially pathogenic, while synonymous variants outside the exon–intron boundaries were deemed non-pathogenic. Missense variants were evaluated by five in silico prediction tools, and only those predicted to be damaging by at least three different algorithms were considered disease-causing.ResultsThe combined frequencies of selected variants (ranged from 127 in GNS to 259 in IDUA) were used to calculate prevalence based on Hardy–Weinberg's equilibrium. The maximum estimated prevalence ranged from 0.46 per 100,000 for MPSIIID to 7.1 per 100,000 for MPS I. Overall, the estimated prevalence of all types of MPS was higher than what has been published in the literature. This difference may be due to misdiagnoses and/or underdiagnoses, especially of the attenuated forms of MPS. However, overestimation of the number of disease-causing variants by in silico predictors cannot be ruled out. Even so, the disease prevalences are similar to those reported in diagnosis-based prevalence studies.ConclusionWe report on an approach to estimate the prevalence of different types of MPS based on publicly available population-based genomic data, which may help health systems to be better prepared to deal with these conditions and provide support to initiatives on diagnosis and management of MPS.

Relationships among Height, Weight, Body Mass Index, and Age in Taiwanese Children with Different Types of Mucopolysaccharidoses.

Background: Children with mucopolysaccharidosis (MPS) generally appear unaffected at birth but may develop multiple clinical manifestations including profound growth impairment as they grow older. Each type of MPS has a variable age at onset and variable rate of progression, however, information regarding growth in Asian children is limited. Methods: This retrospective analysis included 129 Taiwanese patients with MPS (age range, 0.7 to 19.5 years, median age, 7.9 years) from eight medical centers in Taiwan from January 1996 through December 2018. Results: The mean z scores for the first recorded values of height, weight, and body mass index in the patients’ medical records were −4.25, −1.04, and 0.41 for MPS I (n = 9), −2.31, 0.19, and 0.84 for MPS II (n = 49), −0.42, 0.08, and −0.12 for MPS III (n = 27), −6.02, −2.04, and 0.12 for MPS IVA (n = 30), and −4.46, −1.52, and 0.19 for MPS VI (n = 14), respectively. MPS IVA had the lowest mean z scores for both height and weight among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III, which showed the mildest growth retardation. Both z scores for height and weight were negatively correlated with increasing age for all types of MPS (p < 0.01). Of 32 patients younger than 5 years of age, 16 (50%), and 23 (72%) had positive z scores of height and weight, respectively. A substantial number of younger patients with MPS I, II, III, and IVA had a positive height z score. The median age at diagnosis was 3.9 years (n = 115). Conclusions: The patients with MPS IVA had the most significant growth retardation among all types of MPS, followed by MPS VI, MPS I, MPS II, and MPS III. The height and weight of the MPS patients younger than 2–5 years of age were higher than those of healthy individuals, however, their growth significantly decelerated in subsequent years. Understanding the growth curve and potential involved in each type of MPS may allow for early diagnosis and timely management of the disease, which may improve the quality of life.

Normalization of glycosaminoglycan-derived disaccharides detected by tandem mass spectrometry assay for the diagnosis of mucopolysaccharidosis

Mucopolysaccharidosis (MPS) is caused by the deficiency of a specific hydrolytic enzyme that catalyzes the step-wise degradation of glycosaminoglycans (GAGs). In this study, we propose an empirical method to calculate levels of GAG-derived disaccharides based on the quantity (peak areas) of chondroitin sulfate (CS) with the aim of making a diagnosis of MPS more accurate and reducing the occurrence of false positive and false negative results. In this study, levels of urinary GAG-derived disaccharides were measured in 67 patients with different types of MPS and 165 controls without MPS using a tandem mass spectrometry assay. Two different methods of reporting GAG-derived disaccharides were assessed; normalization to urinary CS (in μg/mL), and normalization to μg/mg creatinine. CS-normalization yielded more consistent values than creatinine-normalization. In particular, levels of urinary dermatan sulfate (DS), heparan sulfate (HS), and keratan sulfate (KS) significantly varied because of changes in urine creatinine levels, which were proportional to age but inversely proportional to DS, HS, and KS measurements. Using CS-normalization revealed the actual status of DS, HS, and KS without the influence of factors such as age, urine creatinine, and other physiological conditions. It could discriminate between the patients with MPS and controls without MPS, and also to evaluate changes in GAG levels pre- and post-enzyme replacement therapy.

Genetic testing of Mucopolysaccharidoses disease using multiplex PCR- based panels of STR markers: in silico analysis of novel mutations.

The Mucopolysaccharidoses (MPS) are group of inherited metabolic diseases caused by the deficiency of enzymes required to degrade glycosaminoglycans (GAGs) in the lysosomes. GAGs are sulfated polysaccharides involving repeating disaccharides, uronic acid and hexosamines including chondroitin sulfate (CS), dermatan sulfate (DS), heparan sulfate (HS) and keratan sulfate (KS). Hyaluronan is excluded in terms of being non-sulfated in the GAG family. Different types of mutations have been identified as the causative agent in all types of MPS. Herein, we planned to investigate the pathogenic mutations in different types of MPS including type I (IDUA gene), IIIA (SGSH) and IIIB (NAGLU) in the eight Iranian patients. Autozygosity mapping was performed to identify the potential pathogenic variants in these 8 patients indirectly with the clinical diagnosis of MPSs. so three panels of STR (Short Tandem Repeat) markres flanking IDUA, SGSH and NAGLU genes were selected for multiplex PCR amplification. Then in each family candidate gene was sequenced to identify the pathogenic mutation. Our study showed two novel mutations c.469T > C and c.903C > G in the IDUA gene, four recurrent mutations: c.1A > C in IDUA, c.220C > T, c.1298G > A in SGSH gene and c.457G > A in the NAGLU gene. The c.1A > C in IDUA was the most common mutation in our study. In silico analysis were performed as well to predict the pathogenicity of the novel variants.

The relationships between urinary glycosaminoglycan levels and phenotypes of mucopolysaccharidoses.

BackgroundThe aim of this study was to use the liquid chromatography/tandem mass spectrometry (LC‐MS/MS) method to quantitate levels of three urinary glycosaminoglycans (GAGs; dermatan sulfate [DS], heparan sulfate [HS], and keratan sulfate [KS]) to help make a correct diagnosis of mucopolysaccharidosis (MPS).MethodsWe analyzed the relationships between phenotypes and levels of urinary GAGs of 79 patients with different types of MPS.ResultsThe patients with mental retardation (n = 21) had significantly higher levels of HS than those without mental retardation (n = 58; 328.8 vs. 3.2 μg/ml, p < 0.001). The DS levels in the patients with hernia, hepatosplenomegaly, claw hands, coarse face, valvular heart disease, and joint stiffness were higher than those without. Twenty patients received enzyme replacement therapy (ERT) for 1–12.3 years. After ERT, the KS level decreased by 90% in the patients with MPS IVA compared to a 31% decrease in the change of dimethylmethylene blue (DMB) ratio. The DS level decreased by 79% after ERT in the patients with MPS VI compared to a 66% decrease in the change of DMB ratio.ConclusionsThe measurement of GAG fractionation biomarkers using the LC‐MS/MS method is a more sensitive and reliable tool than the DMB ratio for MPS high‐risk screening, diagnosis, subclass identification, and monitoring the efficacy of ERT.

Aortic root dilatation in patients with mucopolysaccharidoses and the impact of enzyme replacement therapy.

Mucopolysaccharidoses (MPS) are disorders characterized by impaired glycosaminoglycan (GAG) catabolism as a consequence of a deficiency or the absence of lysosomal enzymes directly involved in their degradation. Multiple organ systems are involved in MPS, including the cardiovascular system. Recently, aortic root dilatation (ARD) has been described in these patients. Thus, we reviewed aortic root diameter measurements in 69 MPS patients from a single center from 2000 to 2016. Aortic root diameter z scores were calculated based on data published by Colan et al. according to the body surface area (BSA) determined using the Haycock formula. The overall incidence of ARD in MPS patients was 39.1%. Higher mean z scores were present in patients with MPS IVA and VI when compared to MPS I and II. Aortic root z scores were higher in older MPS IVA patients, which may suggest a progressive ARD change in this MPS type. No significant differences were found before and after enzyme replacement therapy (ERT) in 11 patients with available data (2 with MPS I; 4 with MPS II; 2 with MPS IVA, and 3 with MPS VI). This work provides further evidence that ARD is common in different types of MPS, being especially evident in MPS IVA, but with a significant occurrence also in MPS VI.

EPILEPSY IN CHILDREN WITH MUCOPOLYSACCHARIDOSIS: EPIDEMIOLOGY, CLINICAL AND ELECTROENCEPHALOGRAPHIC FEATURES

The current knowledge of the causes and progression of epilepsy in patients with different types of mucopolysaccharidosis are presented. The article discusses the dynamics of electroencephalographic changes with age and in connection with the disease progression.

TREATMENT OF A PATIENT WITH MUCOPOLYSACCHARIDOSES TYPE II (HUNTER SYNDROME) COMPLICATED BY CRANIOVERTEBRAL SPINAL CANAL STENOSIS

Formation of spinal canal stenosis at T12-L1 level, rarely at the level of craniovertebral junction, is a typical spinal disorder in different types of mucopolysaccharidoses that is a serious complication due to tetraparesis and tetraplegia development. Clinical, roentgenologic and therapeutic aspects of the mucopolysaccharidoses type II course in a 23 months old boy as well as the results of two-step surgical treatment for the cervical spine stabilization and elimination of spinal canal stenosis at the level of craniovertebral junction are presented.

Mucopolysaccharidoses: overview of neuroimaging manifestations.

The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have autosomal-recessive transmission with the exception of mucopolysaccharidosis II, which is X-linked. Each individual disorder has a wide spectrum of phenotypic variation, depending on the specific mutation, from very mild to very severe. The skeletal and central nervous systems are particularly affected. The typical clinical presentation includes organomegaly, dysostosis multiplex with short trunk dwarfism, mental retardation and developmental delay. In this article, we review the neuroimaging manifestations of the different types of mucopolysaccharidoses including the dysostosis multiplex of the skull and spine as well as the various central nervous system complications. These include white matter injury, enlargement of the perivascular spaces, hydrocephalus, brain atrophy, characteristic enlargement of the subarachnoid spaces as well as compressive myelopathy. The correlation between several of the neuroimaging features and disease severity remains controversial, without well-established imaging biomarkers at this time. Imaging has, however, a crucial role in monitoring disease progression, in particular craniocervical junction stenosis, cord compression and hydrocephalus, because this allows for timely intervention before permanent damage occurs.

Treatment of a patient with mucopolysaccharidoses type II (Hunter syndrome) complicated by craniovertebral spinal canal stenosis

Formation of spinal canal stenosis at T12-L1 level, rarely at the level of craniovertebral junction, is a typical spinal disorder in different types of mucopolysaccharidoses that is a serious complication due to tetraparesis and tetraplegia development. Clinical, roentgenologic and therapeutic aspects of the mucopolysaccharidoses type II course in a 23 months old boy as well as the results of two-step surgical treatment for the cervical spine stabilization and elimination of spinal canal stenosis at the level of craniovertebral junction are presented.

Anesthesia Risk and the Mucopolysaccharidoses: A Challenging and Changing Landscape

The mucopolysaccharidoses (MPS) are well known to present a high risk of anesthesia. Predominantly, this risk is not only related to upper airway issues but also to multilevel airway obstruction, respiratory morbidity, and cardiac issues. Before disease-specific treatment became available, the management of the untreated patients with MPS was regarded as the worst airway problem in pediatric anesthetic practice. The last 20 to 30 years have seen great advances in the treatment of the different types of MPS with hematopoietic stem cell transplantation (HSCT) being offered to children with MPS I Hurler sundrome since the 1980s, and more recently enzyme replacement therapy (ERT) becoming available for many MPS subtypes.These treatments have undoubtedly affected the relative risk involved with an anesthetic. HSCT improves markedly the upper airway and cardiac myocardial function and there is evidence that airway management is much more straightforward. ERT, on the other hand, improves obstructive sleep apnea and exercise tolerance, but the overall effect on the risk of anesthesia is less obvious and airway complications during anesthesia remain at a high level. The impact of improved anesthetic management in the same time frame is borne out by a reduced failed intubation rate in the literature.The management of the MPS patients necessitates a multidisciplinary approach presently widely practiced in pediatric centers, but successful modes of therapy increasing their life span have pushed many of the extreme anesthetic challenges into adult practice where most anesthetists will be unfamiliar with the problem. This is a problem that needs to be addressed, and solutions to this issue could be collaborative working between pediatric and adult practitioners or an international network of experts available for advice.

Surgical management of neurological manifestations of mucopolysaccharidosis disorders.

The mucopolysaccharidosis (MPS) disorders are ultra-rare lysosomal storage disorders associated with progressive accumulation of glycosaminoglycans (GAGs) in cells and tissues throughout the body. Clinical manifestations and progression rates vary widely across and within the different types of MPS. Neurological symptoms occur frequently, and may result directly from brain damage caused by infiltration of GAGs, or develop secondary to somatic manifestations such as spinal cord compression, hydrocephalus, and peripheral nerve entrapment. Management of secondary neurological manifestations often requires surgical correction of the underlying somatic cause. The present review discusses the surgical management of neurological disease in patients with MPS, including diagnostic imaging. Background information is derived from presentations and discussions during a meeting on the brain in MPS, attended by an international group of experts (April 28-30, 2016, Stockholm, Sweden), and additional literature searches.