Salivary Metabolites in Patients with Mucopolysaccharidosis

ABSTRACT Objective: To identify the salivary metabolites profile of Mucopolysaccharidosis (MPS) types I, II, IV, and VI patients. Material and Methods: The participants were asked to refrain from eating and drinking for one hour before sampling, performed between 7:30 and 9:00 a.m. Samples were centrifuged at 10.000 × g for 60 min at 4°C, and the supernatants (500µl) were stored at −80°C until NMR analysis. The salivary proton nuclear magnetic resonance (1H-NMR) spectra were acquired in a 500 MHz spectrometer, and TOCSY experiments were used to confirm and assign metabolites. Data were analyzed descriptively. Results: Differences in salivary metabolites were found among MPS types and the control, such as lactate, propionate, alanine, and N-acetyl sugar. Understanding these metabolite changes may contribute to precision medicine and early detection of mucopolysaccharidosis and its monitoring. Conclusion: The composition of low molecular weight salivary metabolites of mucopolysaccharidosis subjects may present specific features compared to healthy controls.

Dysregulation of genes coding for proteins involved in metabolic processes in mucopolysaccharidoses, evidenced by a transcriptomic approach.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSD) caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans (GAGs). Most types of these severe disorders are characterized by neuronopathic phenotypes. Although lysosomal accumulation of GAGs is the primary metabolic defect in MPS, secondary alterations in biochemical processes are considerable and influence the course of the disease. Early hypothesis suggested that these secondary changes might be due to lysosomal storage-mediated impairment of activities of other enzymes, and subsequent accumulation of various compounds in cells. However, recent studies indicated that expression of hundreds of genes is changed in MPS cells. Therefore, we asked whether metabolic effects observed in MPS are caused primarily by GAG-mediated inhibition of specific biochemical reactions or appear as results of dysregulation of expression of genes coding for proteins involved in metabolic processes. Transcriptomic analyses of 11 types of MPS (using RNA isolated from patient-derived fibroblasts), performed in this study, showed that a battery of the above mentioned genes is dysregulated in MPS cells. Some biochemical pathways might be especially affected by changes in expression of many genes, including GAG metabolism and sphingolipid metabolism which is especially interesting as secondary accumulation of various sphingolipids is one of the best known additional (while significantly enhancing neuropathological effects) metabolic defects in MPS. We conclude that severe metabolic disturbances, observed in MPS cells, can partially arise from changes in the expression of many genes coding for proteins involved in metabolic processes.

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.

Bone Biomarkers in Mucopolysaccharidoses.

The accumulation of glycosaminoglycans (GAGs) in bone and cartilage leads to progressive damage in cartilage that, in turn, reduces bone growth by the destruction of the growth plate, incomplete ossification, and growth imbalance. The mechanisms of pathophysiology related to bone metabolism in mucopolysaccharidoses (MPS) include impaired chondrocyte function and the failure of endochondral ossification, which leads to the release of inflammatory cytokines via the activation of Toll-like receptors by GAGs. Although improvements in the daily living of patients with MPS have been achieved with enzyme replacement, treatment for the bone disorder is limited. There is an increasing need to identify biomarkers related to bone and cartilage to evaluate the progressive status and to monitor the treatment of MPS. Recently, new analysis methods, such as proteomic analysis, have identified new biomarkers in MPS. This review summarizes advances in clinical bone metabolism and bone biomarkers.

The experiences and support needs of siblings of people with mucopolysaccharidosis.

The mucopolysaccharidoses (MPS) are a group of rare genetic disorders characterized by progressive multisystem disease. We sought to identify the perceptions and support needs of siblings, who often have lifelong relationships and assume important roles for their brothers and sisters with MPS. We designed an online survey to ask siblings about their experiences through a series of Likert statements and open-ended questions. A mixed methods approach was used to analyze the results. We analyzed eligible responses from 97 participants, ages 18.1-61.2 years, who have brothers and sisters with MPS I, II, III, IV, and VI. Participants reported serving as caregivers for their siblings with MPS, at all ages. While over 62% of siblings often felt sad because they have a brother or sister with MPS, over 90% of siblings reported that they like their brothers and sisters and expressed feelings of pride. Siblings wanted information about MPS, guidance for caregiving activities, genetic counseling, and opportunities to connect with other siblings. Families and professionals should acknowledge the unique experiences and needs of siblings, include siblings in medical conversations and care plans when appropriate, and connect siblings to resources for informational and emotional support.

Homozygous missense VPS16 variant is associated with a novel disease, resembling mucopolysaccharidosis-plus syndrome in two siblings.

Disorders of intracellular trafficking are a group of inherited disorders, which often display multisystem phenotypes. Vacuolar protein sorting (VPS) subunit C, composed of VPS11, VPS18, VPS16, and VPS33A proteins, is involved in tethering of endosomes, lysosomes, and autophagosomes. Our group and others have previously described patients with a specific homozygous missense VPS33A variant, exhibiting a storage disease phenotype resembling mucopolysaccharidosis (MPS), termed "MPS-plus syndrome." Here, we report two siblings from a consanguineous Turkish-Arabic family, who have overlapping features of MPS and intracellular trafficking disorders, including short stature, coarse facies, developmental delay, peripheral neuropathy, splenomegaly, spondylar dysplasia, congenital neutropenia, and high-normal glycosaminoglycan excretion. Whole exome sequencing and familial segregation analyses led to the homozygous NM_022575.3:c.540G>T; p.Trp180Cys variant in VPS16 in both siblings. Multiple bioinformatic methods supported the pathogenicity of this variant. Different monoallelic null VPS16 variants and a homozygous missense VPS16 variant had been previously associated with dystonia. A biallelic intronic, probably splice-altering variant in VPS16, causing an MPS-plus syndrome-like disease has been very recently reported in two individuals. The siblings presented herein display no dystonia, but have features of a multisystem storage disorder, representing a novel MPS-plus syndrome-like disease, associated for the first time with VPS16 missense variants.

Gene Expression-Related Changes in Morphologies of Organelles and Cellular Component Organization in Mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are inherited metabolic diseases characterized by accumulation of incompletely degraded glycosaminoglycans (GAGs) in lysosomes. Although primary causes of these diseases are mutations in genes coding for enzymes involved in lysosomal GAG degradation, it was demonstrated that storage of these complex carbohydrates provokes a cascade of secondary and tertiary changes affecting cellular functions. Potentially, this might lead to appearance of cellular disorders which could not be corrected even if the primary cause of the disease is removed. In this work, we studied changes in cellular organelles in MPS fibroblasts relative to control cells. All 11 types and subtypes of MPS were included into this study to obtain a complex picture of changes in organelles in this group of diseases. Two experimental approaches were employed, transcriptomic analyses and electron microscopic assessment of morphology of organelles. We analyzed levels of transcripts of genes grouped into two terms included into the QuickGO database, 'Cellular component organization' (GO:0016043) and 'Cellular anatomical entity' (GO:0110165), to find that number of transcripts with significantly changed levels in MPS fibroblasts vs. controls ranged from 109 to 322 (depending on MPS type) in GO:0016043, and from 70 to 208 in GO:0110165. This dysregulation of expression of genes crucial for proper structures and functions of various organelles was accompanied by severe changes in morphologies of lysosomes, nuclei, mitochondria, Golgi apparatus, and endoplasmic reticulum. Interestingly, some observed changes occurred in all/most MPS types while others were specific to particular disease types/subtypes. We suggest that severe changes in organelles in MPS cells might arise from dysregulation of expression of a battery of genes involved in organelles' structures and functions. Intriguingly, normalization of GAG levels by using recombinant human enzymes specific to different MPS types corrected morphologies of some, but not all, organelles, while it failed to improve regulation of expression of selected genes. These results might suggest reasons for inability of enzyme replacement therapy to correct all MPS symptoms, particularly if initiated at advanced stages of the disease.

Hip pathologies in mucopolysaccharidosis type III.

BACKGROUND: Mucopolysaccharidosis type III (MPS III) comprises a group of rare lysosomal storage diseases. Although musculoskeletal symptoms are less pronounced than in other MPS subtypes, pathologies of hip and spine have been reported in MPS III patients. The purpose of this study was to describe hip pathologies and influencing parameters in MPS III patients. METHODS: A retrospective chart review was performed for 101 MPS III patients. Thirty-two patients met the inclusion criteria of enzymatically or genetically confirmed diagnosis and anteroposterior radiograph of the hips. Modified Ficat classification, Wiberg's center-edge angle, and Reimer's migration percentage were measured. RESULTS: The mean age at data assessment was 11.0 years (SD 5.7). Osteonecrosis of the femoral head was observed in 17/32 patients. No statistically significant association was found between these changes and age, sex, or MPS III subtype. Patients with a severe phenotype showed significantly higher rates of osteonecrosis (14/17) than patients with an intermediate phenotype. Hip dysplasia was present in 9/32 patients and was significantly associated with osteonecrosis of the femoral head (p = 0.04). CONCLUSIONS: The present study demonstrates a high rate of hip pathologies in MPS III patients. Hip dysplasia and severe phenotype were significantly correlated with osteonecrosis of the femoral head. Therefore, radiographs of the hips are highly recommended in baseline and follow-up assessments of MPS III patients. TRIAL REGISTRATION: Retrospectively registered.

The point-of-care use of a facial phenotyping tool in the genetics clinic: Enhancing diagnosis and education with machine learning.

Computer-assisted pattern recognition platforms, such as Face2Gene® (F2G), can facilitate the diagnosis of children with rare genetic syndromes by comparing a patient's features to known genetic diagnoses. Our work designed, implemented, and evaluated an innovative model of care in clinical genetics in a heterogeneous and multicultural patient population that utilized this facial phenotyping software at the point-of-care. We assessed the performance of F2G by comparing the suggested diagnoses to the patient's confirmed molecular diagnosis. Providers' overall experiences with the technology and trainees' educational experiences were assessed with questionnaires. We achieved an overall diagnostic yield of 57%. This increased to 82% when cases diagnosed with syndromes not recognized by F2G were removed. The mean rank of a confirmed diagnosis in the top 10 was 2.3 (CI 1.5-3.2) and the mean gestalt score 37.6%. The most commonly suggested diagnoses were Noonan syndrome, mucopolysaccharidosis, and 22q11.2 deletion syndrome. Our qualitative assessment revealed that clinicians and trainees saw value using the tool in practice. Overall, this work helped to implement an innovative patient care delivery model in clinical genetics that utilizes a facial phenotyping tool at the point-of-care. Our data suggest that F2G has utility in the genetics clinic as a clinical decision support tool in diverse populations, with a majority of patients having their eventual diagnosis listed in the top 10 suggested syndromes based on a photograph alone. It shows promise for further integration into clinical care and medical education, and we advocate for its continued use, adoption and refinement along with transparent and accountable industrial partnerships.

Changes in cellular processes occurring in mucopolysaccharidoses as underestimated pathomechanisms of these diseases.

Mucopolysaccharidoses (MPS) are a group of genetic disorders belonging to lysosomal storage diseases. They are caused by genetic defects leading to a lack or severe deficiency of activity of one of lysosomal hydrolases involved in degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate in lysosomes, which results in dysfunctions of cells, tissues, and organs. Until recently, it was assumed that GAG accumulation in cells is the major, if not the only, mechanism of pathogenesis in MPS, as GAGs may be a physical ballast for lysosomes causing inefficiency of cells due to a large amount of a stored material. However, recent reports suggest that in MPS cells there are changes in many different processes, which might be even more important for pathogenesis than lysosomal accumulation of GAGs per se. Moreover, there are many recently published results indicating that lysosomes not only are responsible for degradation of various macromolecules, but also play crucial roles in the regulation of cellular metabolism. Therefore, it appears plausible that previous failures in treatment of MPS (i.e., possibility to correct only some symptoms and slowing down of the disease rather than fully effective management of MPS) might be caused by underestimation of changes in cellular processes and concentration solely on decreasing GAG levels in cells.

The abnormal accumulation of heparan sulfate in patients with mucopolysaccharidosis prevents the elastolytic activity of cathepsin V.

Mucopolysaccharidosis (MPS) are rare inherited diseases characterized by accumulation of lysosomal glycosaminoglycans, including heparan sulfate (HS). Patients exhibit progressive multi-visceral dysfunction and shortened lifespan mainly due to a severe cardiac/respiratory decline. Cathepsin V (CatV) is a potent elastolytic protease implicated in extracellular matrix (ECM) remodeling. Whether CatV is inactivated by HS in lungs from MPS patients remained unknown. Herein, CatV colocalized with HS in MPS bronchial epithelial cells. HS level correlated positively with the severity of respiratory symptoms and negatively to the overall endopeptidase activity of cysteine cathepsins. HS bound tightly to CatV and impaired its activity. Withdrawal of HS by glycosidases preserved exogenous CatV activity, while addition of Surfen, a HS antagonist, restored elastolytic CatV-like activity in MPS samples. Our data suggest that the pathophysiological accumulation of HS may be deleterious for CatV-mediated ECM remodeling and for lung tissue homeostasis, thus contributing to respiratory disorders associated to MPS diseases.

Changes in expressions of genes involved in the regulation of cellular processes in mucopolysaccharidoses as assessed by fibroblast culture-based transcriptomic analyses.

Recent studies indicated that apart from lysosomal storage of glycosaminoglycans (GAGs), secondary and tertiary changes in cellular processes may significantly contribute to development of disorders and symptoms occurring in mucopolysaccharidoses (MPS), a group of lysosomal storage diseases in which neurodegeneration is specific for most types and subtypes. In this report, using transcriptomic data, we demonstrate that regulation of hundreds of genes coding for proteins involved in regulations of various cellular processes is changed in cells derived from patients suffering from all types and subtypes of MPS. Among such genes there are 10 which expression is significantly changed in 9 or more (out of 11) MPS types/subtypes; they include IER3IP1, SAR1A, TMEM38B, PLCB4, SIN3B, ABHD5, SH3BP5, CAPG, PCOLCE2, and MN1. Moreover, there are several genes whose expression is changed over log2 > 4 times in some MPS types relative to control cells. The above analysis indicates that significant changes in expression of genes coding for various regulators of cellular processes may considerably contribute to development of cellular dysfunctions, and further appearance of specific symptoms of MPS, including neurodegeneration.

Transcriptomic analyses suggest that mucopolysaccharidosis patients may be less susceptible to COVID-19.

We used transcriptomic (RNA-seq) analyses to determine whether patients suffering from all types and subtypes of mucopolysaccharidosis (MPS), a severe inherited metabolic disease, may be more susceptible to coronavirus disease 2019 (COVID-19). The expression levels of genes encoding proteins potentially involved in SARS-CoV-2 development were estimated in MPS cell lines. Four genes (GTF2F2, RAB18, TMEM97, PDE4DIP) coding for proteins potentially facilitating virus development were down-regulated, while two genes (FBN1, MFGE8), the products of which potentially interfere with virus propagation, were up-regulated in most MPS types. Although narrowing of respiratory tract and occurrence of thick mucus, characteristic of MPS, are risk factors for COVID-19, transcriptomic analyses suggest that MPS cells might be less, rather than more, susceptible to SARS-CoV-2 infection.

Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

A systematic review and meta-analysis of published cases reveals the natural disease history in multiple sulfatase deficiency.

Multiple Sulfatase Deficiency (MSD, MIM#272200) is an ultra-rare lysosomal storage disorder arising from mutations in the SUMF1 gene, which encodes the formylglycine-generating enzyme (FGE). FGE is necessary for the activation of sulfatases, a family of enzymes that are involved in the degradation of sulfated substrates such as glycosaminoglycans and sulfolipids. SUMF1 mutations lead to functionally impaired FGE and individuals with MSD demonstrate clinical signs of single sulfatase deficiencies, including metachromatic leukodystrophy (MLD) and several mucopolysaccharidosis (MPS) subtypes. Comprehensive information related to the natural history of MSD is missing. We completed a systematic literature review and a meta-analysis on data from published cases reporting on MSD. As available from these reports, we extracted clinical, genetic, biochemical, and brain imaging information. We identified 75 publications with data on 143 MSD patients with a total of 53 unique SUMF1 mutations. The mean survival was 13 years (95% CI 9.8-16.2 years). Seventy-five clinical signs and 11 key clusters of signs were identified. The most frequently affected organs systems were the nervous, skeletal, and integumentary systems. The most frequent MRI features were abnormal myelination and cerebral atrophy. Individuals with later onset MSD signs and survived longer than those with signs at birth. Less severe mutations, low disease burden and achievement of independent walking positively correlated with longer survival. Despite the limitations of our approach, we were able to define clinical characteristics and disease outcomes in MSD. This work will provide the foundation of natural disease history data needed for future clinical trial design.

Multiple Sulfatase Deficiency: A Disease Comprising Mucopolysaccharidosis, Sphingolipidosis, and More Caused by a Defect in Posttranslational Modification.

Multiple sulfatase deficiency (MSD, MIM #272200) is an ultra-rare disease comprising pathophysiology and clinical features of mucopolysaccharidosis, sphingolipidosis and other sulfatase deficiencies. MSD is caused by impaired posttranslational activation of sulfatases through the formylglycine generating enzyme (FGE) encoded by the sulfatase modifying factor 1 (SUMF1) gene, which is mutated in MSD. FGE is a highly conserved, non-redundant ER protein that activates all cellular sulfatases by oxidizing a conserved cysteine in the active site of sulfatases that is necessary for full catalytic activity. SUMF1 mutations result in unstable, degradation-prone FGE that demonstrates reduced or absent catalytic activity, leading to decreased activity of all sulfatases. As the majority of sulfatases are localized to the lysosome, loss of sulfatase activity induces lysosomal storage of glycosaminoglycans and sulfatides and subsequent cellular pathology. MSD patients combine clinical features of all single sulfatase deficiencies in a systemic disease. Disease severity classifications distinguish cases based on age of onset and disease progression. A genotype- phenotype correlation has been proposed, biomarkers like excreted storage material and residual sulfatase activities do not correlate well with disease severity. The diagnosis of MSD is based on reduced sulfatase activities and detection of mutations in SUMF1. No therapy exists for MSD yet. This review summarizes the unique FGE/ sulfatase physiology, pathophysiology and clinical aspects in patients and their care and outlines future perspectives in MSD.

Newborn screening of mucopolysaccharidoses: past, present, and future.

Mucopolysaccharidoses (MPS) are a subtype of lysosomal storage disorders (LSDs) characterized by the deficiency of the enzyme involved in the breakdown of glycosaminoglycans (GAGs). Mucopolysaccharidosis type I (MPS I, Hurler Syndrome) was endorsed by the U.S. Secretary of the Department of Health and Human Services for universal newborn screening (NBS) in February 2016. Its endorsement exemplifies the need to enhance the accuracy of diagnostic testing for disorders that are considered for NBS. The progression of MPS disorders typically incudes irreversible CNS involvement, severe bone dysplasia, and cardiac and respiratory issues. Patients with MPS have a significantly decreased quality of life if untreated and require timely diagnosis and management for optimal outcomes. NBS provides the opportunity to diagnose and initiate treatment plans for MPS patients as early as possible. Most newborns with MPS are asymptomatic at birth; therefore, it is crucial to have biomarkers that can be identified in the newborn. At present, there are tiered methods and different instrumentation available for this purpose. The screening of quick, cost-effective, sensitive, and specific biomarkers in patients with MPS at birth is important. Rapid newborn diagnosis enables treatments to maximize therapeutic efficacy and to introduce immune tolerance during the neonatal period. Currently, newborn screening for MPS I and II has been implemented and/or in pilot testing in several countries. In this review article, historical aspects of NBS for MPS and the prospect of newborn screening for MPS are described, including the potential tiers of screening.

Pathogenesis of Mucopolysaccharidoses, an Update.

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.

Underestimated Aspect of Mucopolysaccharidosis Pathogenesis: Global Changes in Cellular Processes Revealed by Transcriptomic Studies.

Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders caused by deficiency in enzymes involved in degradation of glycosaminoglycans (GAGs), are examples (and models) of monogenic diseases. Accumulation of undegraded GAGs in lysosomes was supposed to be the major cause of MPS symptoms; however, their complexity and variability between particular types of the disease can be hardly explained by such a simple storage mechanism. Here we show that transcriptomic (RNA-seq) analysis of the material derived from fibroblasts of patients suffering from all types and subtypes of MPS, supported by RT-qPCR results, revealed surprisingly large changes in expression of genes involved in various cellular processes, indicating complex mechanisms of MPS. Although each MPS type and subtype was characterized by specific changes in gene expression profile, there were genes with significantly changed expression relative to wild-type cells that could be classified as common for various MPS types, suggesting similar disturbances in cellular processes. Therefore, both common features of all MPS types, and differences between them, might be potentially explained on the basis of changes in certain cellular processes arising from disturbed regulations of genes' expression. These results may shed a new light on the mechanisms of genetic diseases, indicating how a single mutation can result in complex pathomechanism, due to perturbations in the network of cellular reactions. Moreover, they should be considered in studies on development of novel therapies, suggesting also why currently available treatment methods fail to correct all/most symptoms of MPS. We propose a hypothesis that disturbances in some cellular processes cannot be corrected by simple reduction of GAG levels; thus, combined therapies are necessary which may require improvement of these processes.

Posterior fossa horns; a new calvarial finding of mucopolysaccharidoses with well-known cranial MRI features

Background/aim: Mucopolysaccharidoses (MPS) are a group of hereditary metabolic diseases. The aim of this study was to share the previously unreported calvarial finding of internal hypertrophy of the occipitomastoid sutures (IHOMS) together with some other well-known cranial MRI findings in this patient series. Materials and methods: A retrospective evaluation was conducted of 80 cranial MRIs of patients who had been diagnosed and followed up with MPS from 2008 to 2019 in our center. Of these patients, 11 had Hurler, 14 had Hunter, 24 had Sanfilippo, 15 had Morquio, 14 had Maroteaux­Lamy, and 2 had Sly disease. The cranial MRIs were assessed in two main groups as parenchymal intradural cranial MRI findings and extradural calvarial findings. Results: The most common parenchymal intradural cranial MRI findings were white matter signal alterations (n = 51, 63%) and perivascular space enlargements (n = 39, 48%). The most common extradural calvarial findings were J-shaped sella (n = 45, 56%) and tympanic effusion (n = 44, 55%). Although IHOMS was defined in a relatively small number of the patients (n = 12, 15%), the prevalence rate was high in MPS type I (n = 6, 54%). Conclusion: The abnormal cranial MRI findings of the MPS patients, including the newly identified IHOMS, may provide diagnostic clues to differentiate the type of the disease in radiological imaging.