Successful use of an eye gaze AAC communication board by a young adult with advanced Sanfilippo Syndrome (MPS IIIA): Case report.

Sanfilippo syndrome (Mucopolysaccharidosis Type III or MPS III) is a family of rare, lysosomal disorders characterized by progressive cognitive and motor deterioration. Even though individuals with MPS III present with complex communication needs, research regarding augmentative and alternative communication (AAC) in this population is scarce. While life expectancy for individuals with MPS IIIA typically does not exceed 20 years of age, this case report involves a 22-year-old adult with postregression MPS IIIA. Prior to this study, the participant could not communicate using speech and only responded to yes/no questions using eye blink responses. The participant was given a low-tech AAC system utilizing eye gaze so that she could respond to a variety of caregiver questions and take conversational turns. The following communication outcomes were measured during each session in which caregivers used the AAC system: number of eye gaze responses, total number of responses (using any means), the percent of responses to questions asked, and the total count of expressive vocabulary words available to the participant with the AAC system. Increases were observed in the number of eye gaze responses per session and in the expressive vocabulary accessible via the eye gaze board. A higher percentage of responses given caregiver questions was noted for the intervention sessions (71%) compared to the baseline sessions (55%). There were also qualitative changes characterized by the types of questions the participant could respond to during conversational exchanges. Despite the progression of MPS IIIA, the results suggest that use of the eye gaze board resulted in quantitative and qualitative changes in functional communication. This case report provides preliminary evidence that AAC can improve communication in a young adult with postregression MPS IIIA.

Successful use of an eye gaze AAC communication board by a young adult with advanced Sanfilippo Syndrome (MPS IIIA): Case Report This article reports a case of a 22-year-old woman who was diagnosed with mucopolysaccharidosis type III (MPS III) or Sanfilippo Syndrome. MPS III is a rare lysosomal disorder characterized by progressive cognitive and motor deterioration. Children with MPS III experience regression in speech and communication skills and speech is typically lost by age eight years. AAC (Augmentative and Alternative Communication) are systems or devices that can be used by individuals with limited to no speech to aid or supplement communication. Even though individuals with MPS III have significant impairment in communication and could potentially benefit from AAC, research regarding the use of AAC (Augmentative and Alternative Communication) by this population is scarce. In this case, an eye-gaze AAC system was introduced to a young adult with postregression MPS IIIA who is well beyond average life expectancy for this disease. Despite the progression of MPS IIIA and complicating medical issues, there were quantitative and qualitative changes and improvement in this woman's functional communication after the eye gaze board was introduced. This case study provides preliminary evidence that AAC use can potentially improve communication in individuals with postregression MPS IIIA.

Behaviours and psychological symptoms of childhood dementia: two cases of psychosocial interventions.

Childhood dementias are a group of rare, fatal neurodegenerative disorders, characterised by global cognitive decline, loss of previously acquired developmental skills and behaviours and psychological symptoms of dementia (BPSD). Batten disease, or neuronal ceroid lipofuscinosis, and Sanfilippo syndrome, or mucopolysaccharidosis type III, are two of the more common forms of childhood dementia disorders worldwide. While psychosocial interventions are the best available therapeutic approach for BPSD management in adult-onset dementia, there is very limited literature or clinical experience in the context of childhood dementia. To address this gap, we conducted a descriptive case analysis of BPSD profiles, associated contributing factors and targeted psychosocial interventions in two cases with childhood dementia disorders (Sanfilippo syndrome and CLN3 (juvenile onset) Batten disease) who were referred to Dementia Support Australia, a national dementia behaviour support service in Australia. Primary BPSD identified in these disorders included physical and verbal aggression and irritability/lability. In these cases, contributing factors to the development of BPSD were not monolithic, encompassing pain, caregiver's approach and over or under-stimulation. Improvement in BPSD were observed using the Neuropsychiatric Inventory-Quesionnaire and globally noted as per the qualitative feedback reported by family and caregivers. Person-centred, multimodal psychosocial interventions were recognised as effective therapies in resolving BPSD in these cases. In conclusion, the case studies described the nature and presentation of BPSD in two common forms of childhood dementia and demonstrated the potential benefits of person-centred psychosocial interventions (delivered through national dementia-specific support programs) in alleviating BPSD such as irritability and aggression in these disorders.

Comprehensive evaluation of pathogenic protein accumulation in fibroblasts from all subtypes of Sanfilippo disease patients.

Sanfilippo disease is a lysosomal storage disorder from the group of mucopolysaccharidoses (MPS), characterized by storage of glycosaminoglycans (GAGs); thus, it is also called MPS type III. The syndrome is divided into 4 subtypes (MPS III A, B, C and D). Despite the storage of the same GAG, heparan sulfate (HS), the course of these subtypes can vary considerably. Here, we comprehensively evaluated the levels of protein aggregates (APP, ß-amyloid, p-tau, α-synuclein, TDP43) in fibroblasts derived from patients with all MPS III subtypes, and tested whether lowering GAG levels results in a decrease in the levels of the investigated proteins and the number of aggregates they form. Elevated levels of APP, ß-amyloid, tau, and TDP43 proteins were evident in all MPS III subtypes, and elevated levels of p-tau and α-synuclein were demonstrated in all subtypes except MPS IIIC. These findings were confirmed in the neural tissue of MPS IIIB mice. Fluorescence microscopy studies also indicated a high number of protein aggregates formed by ß-amyloid and tau in all cell lines tested, and a high number of aggregates of p-tau, TDP43, and α-synuclein in all lines except MPS IIIC. Reduction of GAG levels by genistein led to the decrease of levels of all tested proteins and their aggregates except α-synuclein, indicating a relationship between GAG levels and those of some protein aggregates. This work describes for the first time the problem of deposited protein aggregates in all subtypes of Sanfilippo disease and suggests that GAGs are partly responsible for the formation of protein aggregates.

The Role of the Gut Microbiota in Sanfilippo Syndrome's Physiopathology: An Approach in Two Affected Siblings.

Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a rare lysosomal disease caused by congenital enzymatic deficiencies in heparan sulfate (HS) degradation, leading to organ dysfunction. The most severe hallmark of MPS III comprises neurological alterations, although gastrointestinal symptoms (GISs) have also been shown to be relevant in many patients. Here, we explored the contribution of the gut microbiota to MPS III GISs. We analyzed the composition and functionality of the gut microbiota in two MPS III siblings with the same mutation (c.544C > T, c.1080delC, in the SGSH gene) and the same diet, but with differences in their GISs, including recurrent diarrhea in one of them. Using 16S sequencing, we observed that the MPS III patients exhibited decreased alpha diversity and a lower abundance of Lachnospiraceae and Bifidobacteriaceae accompanied by a higher abundance of the Ruminococcaceae and Rikenellaceae families than the healthy control subjects. Comparing siblings, we found an increased abundance of Bacteroidaceae and a lower abundance of Ruminococcaceae and Akkermansiaceae in the GIS-free patient. This patient also had a higher relative abundance of Sus genes (SusA, SusB, SusE, and SusG) involved in glycosaminoglycan metabolism. We found higher HS levels in the stool of the two MPS III patients than in healthy volunteers, particularly in the patient with GISs. Functionally, whole fecal metabolites from the patient with GISs induced oxidative stress in vitro in healthy monocytes. Finally, the Bacteroides thetaiotaomicron strain isolated from MPS III stool samples exhibited HS degradation ability. Overall, our results reveal different microbiota compositions and functionalities in MPS III siblings, who exhibited differential gastrointestinal symptomatology. Our study may serve as a gateway to explore the impact of the gut microbiota and its potential to enhance the quality of life in Sanfilippo syndrome patients.

Initiation of fluoxetine in a pediatric patient with Mucopolysaccharidosis IIIA: Early observations.

Fluoxetine has been identified as a potential treatment for mucopolysaccharidosis IIIA (MPS IIIA), a debilitating and progressive lysosomal storage disorder for which no treatments are approved. In the MPS IIIA mouse model, fluoxetine decreases the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing cognitive deterioration. 1 We treated a single patient, 6 years old, under off-label prescription of fluoxetine, a selective serotonin reuptake inhibitor (SSRI). The primary endpoint was safety. Secondary exploratory assessments included urine quantitative heparan sulfate. Fluoxetine was well-tolerated in this patient and the patient continued treatment following the 12-month monitoring period. The patient experienced an increase in daytime somnolence which resolved with rescheduling fluoxetine administration to bedtime. Quantitative heparan sulfate levels remained elevated during treatment. Parents reported improved sleep latency time and less nighttime waking. These findings support general tolerability and further study of fluoxetine as a potential therapy for MPS IIIA.

Identification of Orthosteric and Allosteric Pharmacological Chaperones for Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal inherited disease caused by mutations in gene encoding the lysosomal enzyme N-acetyl-alpha-glucosaminidase (NAGLU). These mutations result in reduced NAGLU activity, preventing it from catalyzing the hydrolysis of the glycosaminoglycan heparan sulfate (HS). There are currently no approved treatments for MPS IIIB. A novel approach in the treatment of lysosomal storage diseases is the use of pharmacological chaperones (PC). In this study, we used a drug repurposing approach to identify and characterize novel potential PCs for NAGLU enzyme. We modeled the interaction of natural and artificial substrates within the active cavity of NAGLU (orthosteric site) and predicted potential allosteric sites. We performed a virtual screening for both the orthosteric and the predicted allosteric site against a curated database of human tested molecules. Considering the binding affinity and predicted blood-brain barrier permeability and gastrointestinal absorption, we selected atovaquone and piperaquine as orthosteric and allosteric PCs. The PCs were evaluated by their capacity to bind NAGLU and the ability to restore the enzymatic activity in human MPS IIIB fibroblasts These results represent novel PCs described for MPS IIIB and demonstrate the potential to develop novel therapeutic alternatives for this and other protein deficiency diseases.

Clinical and Molecular Characterization of Mucopolysaccharidosis Type 3A and 3B in a Turkish Series.

Introduction: Sanfilippo syndrome or mucopolysaccharidosis type 3 (MPS-3) is a rare condition and its epidemiological data are still not defined. MPS-3 is linked to a deficiency in enzymes involved in heparan sulfate degradation. This biomolecule is neurotoxic and its accumulation underlies the severe central nervous system degeneration observed in this disease. Methods: Here, we describe 15 Turkish patients with MPS-3A or MPS-3B subtypes. Clinical data upon the diagnosis and during the follow-up as well as molecular characterization are reported. Results: Two and ten distinct variants were identified in SGSH and NAGLU gene sequences, respectively. Six variants (NAGLU NM_000263.3:c.532-?_c.764+?del, NAGLU NM_000263.3: c.509G>T, NAGLU NM_000263.3: c.700C>G, NAGLU NM_000263.3:c.507_516 del, NAGLU NM dises_000263.3: c.1354 G>A, NAGLU NM_000263.3: c.200T>C) have been previously published and 6 are novel (SGSH NM_000199.4: c.80T>G, SGSH NM_000199.4: c.7_16del, NAGLU NM_000263.3: c.224_235del, NAGLU NM_000263.3: c.904G>T, NAGLU NM_000263.3: c.626C>T, NAGLU NM_000263.3: c.1241A>G). SGSH NM_000199.4:c.7_16del variation might be caused by a founder effect. Conclusion: Due to the high rate of consanguinity in Turkey, the incidence of Sanfilippo syndrome might be higher compared to other populations worldwide. Our results contribute to the characterization of rare diseases in Turkey and to improve our knowledge of the clinical, molecular, and epidemiological aspects of MPS-3 disease.

Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Current Concepts in the Management of Sanfilippo Syndrome (MPS III): A Narrative Review.

Sanfilippo syndrome is a childhood-onset (1-4 years) autosomal recessive lysosomal storage disease that presents as a neurodegenerative disease by targeting the brain and spinal cord. It is also known as mucopolysaccharidosis III. Mucopolysaccharidosis III is divided into four subtypes (A, B, C, or D). It can cause delayed speech, behavior problems, and features of autism spectrum disorder. Sanfilippo syndrome is of a higher prevalence within consanguineous families that carry its gene alteration. If both parents have a nonfunctional copy of a gene linked to this condition, their children will have a 25% (1 in 4) chance of developing the disease. In Saudi Arabia, the incidence rate is estimated at 2 per 100,000 live births. Recent research focused on promising treatment approaches, such as gene therapy, modified enzyme replacement therapy, and stem cells. These approaches work by exogenous administration of the proper version of the mutant enzyme (enzyme replacement therapy), cleaning the defective enzyme in individuals with glycolipid storage disorders (substrate reduction therapy), or using a pharmacological chaperone to target improperly folded proteins. However, there is currently no approved curative medication for Sanfilippo syndrome that can effectively halt or reverse the disorder.

Novel gene-specific Bayesian Gaussian mixture model to predict the missense variants pathogenicity of Sanfilippo syndrome.

MPS III is an autosomal recessive lysosomal storage disease caused mainly by missense variants in the NAGLU, GNS, HGSNAT, and SGSH genes. The pathogenicity interpretation of missense variants is still challenging. We aimed to develop unsupervised clustering-based pathogenicity predictor scores using extracted features from eight in silico predictors to predict the impact of novel missense variants of Sanfilippo syndrome. The model was trained on a dataset consisting of 415 uncertain significant (VUS) missense NAGLU variants. Performance The SanfilippoPred tool was evaluated by validation and test datasets consisting of 197-labelled NAGLU missense variants, and its performance was compared versus individual pathogenicity predictors using receiver operating characteristic (ROC) analysis. Moreover, we tested the SanfilippoPred tool using extra-labelled 427 missense variants to assess its specificity and sensitivity threshold. Application of the trained machine learning (ML) model on the test dataset of labelled NAGLU missense variants showed that SanfilippoPred has an accuracy of 0.93 (0.86-0.97 at CI 95%), sensitivity of 0.93, and specificity of 0.92. The comparative performance of the SanfilippoPred showed better performance (AUC = 0.908) than the individual predictors SIFT (AUC = 0.756), Polyphen-2 (AUC = 0.788), CADD (AUC = 0.568), REVEL (AUC = 0.548), MetaLR (AUC = 0.751), and AlphMissense (AUC = 0.885). Using high-confidence labelled NAGLU variants, showed that SanfilippoPred has an 85.7% sensitivity threshold. The poor correlation between the Sanfilippo syndrome phenotype and genotype represents a demand for a new tool to classify its missense variants. This study provides a significant tool for preventing the misinterpretation of missense variants of the Sanfilippo syndrome-relevant genes. Finally, it seems that ML-based pathogenicity predictors and Sanfilippo syndrome-specific prediction tools could be feasible and efficient pathogenicity predictors in the future.

Mucopolysaccharidosis (MPS IIIA) mice have increased lung compliance and airway resistance, decreased diaphragm strength, and no change in alveolar structure.

Mucopolysaccharidosis type IIIA (MPS IIIA) is characterized by neurological and skeletal pathologies caused by reduced activity of the lysosomal hydrolase, sulfamidase, and the subsequent primary accumulation of undegraded heparan sulfate (HS). Respiratory pathology is considered secondary in MPS IIIA and the mechanisms are not well understood. Changes in the amount, metabolism, and function of pulmonary surfactant, the substance that regulates alveolar interfacial surface tension and modulates lung compliance and elastance, have been reported in MPS IIIA mice. Here we investigated changes in lung function in 20-wk-old control and MPS IIIA mice with a closed and open thoracic cage, diaphragm contractile properties, and potential parenchymal remodeling. MPS IIIA mice had increased compliance and airway resistance and reduced tissue damping and elastance compared with control mice. The chest wall impacted lung function as observed by an increase in airway resistance and a decrease in peripheral energy dissipation in the open compared with the closed thoracic cage state in MPS IIIA mice. Diaphragm contractile forces showed a decrease in peak twitch force, maximum specific force, and the force-frequency relationship but no change in muscle fiber cross-sectional area in MPS IIIA mice compared with control mice. Design-based stereology did not reveal any parenchymal remodeling or destruction of alveolar septa in the MPS IIIA mouse lung. In conclusion, the increased storage of HS which leads to biochemical and biophysical changes in pulmonary surfactant also affects lung and diaphragm function, but has no impact on lung or diaphragm structure at this stage of the disease.NEW & NOTEWORTHY Heparan sulfate storage in the lungs of mucopolysaccharidosis type IIIA (MPS IIIA) mice leads to changes in lung function consistent with those of an obstructive lung disease and includes an increase in lung compliance and airway resistance and a decrease in tissue elastance. In addition, diaphragm muscle contractile strength is reduced, potentially further contributing to lung function impairment. However, no changes in parenchymal lung structure were observed in mice at 20 wk of age.

Expanding the phenotypic and genotypic spectrum of patients with HGSNAT-related retinopathy.

BACKGROUND: Variants in HGSNAT have historically been associated with syndromic mucopolysaccharidosis type IIIC (MPSIIIC) but more recent studies demonstrate cases of HGSNAT-related non-syndromic retinitis pigmentosa. We describe and expand the genotypic and phenotypic spectrum of this disease. MATERIALS AND METHODS: This is a retrospective, observational, case series of 11 patients with pericentral retinitis pigmentosa due to variants in HGSNAT gene without a syndromic diagnosis of MPSIIIC. We reviewed ophthalmologic data extracted from medical records, genetic testing, color fundus photos, fundus autofluorescence (FAF), and optical coherence tomography (OCT). RESULTS: Of the 11 patients, the mean age was 52 years (range: 26-78). The mean age of ophthalmologic symptoms onset was 45 years (range: 15-72). The visual acuity varied from 20/20 to 20/80 (mean 20/30 median 20/20). We described five novel variants in HGSNAT: c.715del (p.Arg239Alafs *37), c.118 G>A (p.Asp40Asn), c.1218_1220delinsTAT, c.1297A>G (p.Asn433Asp), and c.1726 G>T (p.Gly576*). CONCLUSIONS: HGSNAT has high phenotypic heterogeneity. Data from our cohort showed that all patients who had at least one variant of c.1843 G>A (p.Ala615Thr) presented with the onset of ocular symptoms after the fourth decade of life. The two patients with onset of ocular symptoms before the fourth decade did not carry this variant. This may suggest that c.1843 G>A variant is associated with a later onset of retinopathy.

Increasing Sanfilippo Syndrome Awareness through Children's Literature and Music.

There is an ongoing effort to increase rare disease awareness amongst healthcare providers. This front is important and can help to address several challenges faced by rare disease patients, such as lengthy diagnosis times, difficulty in finding adequate providers of medical services and experts, and adequate treatment if one exists. On another front, there is the need for awareness among citizens and their support in the advocacy for public policies towards rare disease patients and families. Awareness campaigns are prevalent in social networks and fundraising events. In this poster, we present a complementary approach to engage society and promote rare disease awareness through children's literature and music. A Portuguese teenager wrote a book ('My Life with my sister'), describing simple and daily moments spent with her teenage sister affected by Sanfilippo syndrome. A professional illustrator designed and illustrated the book. The book is bilingual in Portuguese and English. The author, with the assistance of her music teacher, also composed a song which was recorded with the participation of professional musicians and made into a video clip telling their story and the books. The book and song promote the inclusion and love for people affected by rare diseases and their families. To increase outreach, sister organizations translated the book, adapted the song, and published/ recorded the material in Brazilian Portuguese and French. The proceeds from the sales go towards the Sanfilippo foundations in their respective countries to fund common research projects. The material is being advertised on social media, television, interviews, newspapers, podcasts, libraries, schools, bookshops, book fairs, and others. To date, more than eight hundred books have been sold to individuals and companies. The interviews and video clips add to more than twelve hundred views. The target audience is children, parents, teachers but also companies, and their employees.

Extensive and Persistent Dermal Melanocytosis in a Male Carrier of Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome): A Case Report.

Congenital dermal melanocytosis (DM) represents a common birthmark mainly found in children of Asian and darker skin phototype descent, clinically characterized by an oval blue-grey macule or macules, commonly located on the lumbosacral area. In rare DM cases, when presenting with diffuse macules persisting during the first years of life, it could represent a cutaneous feature of mucopolysaccharidoses (MPS). Extensive congenital DM is actually associated with Hurler syndrome (MPS type I) and Hunter syndrome (MPS type II), although several reports also described this association with MPS type VI and other lysosomal storage disorders (LySD), including GM1 gangliosidosis, mucolipidosis, Sandhoff disease, and Niemann-Pick disease. Here, we present the case of a two-year-old boy presenting with extensive dermal melanocytosis, generalized hypertrichosis, and chronic itch, harboring a heterozygous variant of uncertain significance, NM_152419.3: c.493C>T (p.Pro165Ser), in the exon 4 of HGSNAT gene, whose mutations are classically associated with MPS IIIC, also known as Sanfilippo syndrome. This is the first report that highlights the association between extensive congenital DM and MPS type IIIC, as well as a pathogenetic link between heterozygous LySD carrier status and congenital DM. We speculate that some cases of extensive congenital DM could be related to heterozygous LySD carriers, as a manifestation of a mild clinical phenotype.

Generalized pairwise comparisons of prioritized outcomes are a powerful and patient-centric analysis of multi-domain scores.

BACKGROUND: Generalized pairwise comparisons (GPC) can be used to assess the net benefit of new treatments for rare diseases. We show the potential of GPC through simulations based on data from a natural history study in mucopolysaccharidosis type IIIA (MPS IIIA). METHODS: Using data from a historical series of untreated children with MPS IIIA aged 2 to 9 years at the time of enrolment and followed for 2 years, we performed simulations to assess the operating characteristics of GPC to detect potential (simulated) treatment effects on a multi-domain symptom assessment. Two approaches were used for GPC: one in which the various domains were prioritized, the other with all domains weighted equally. The net benefit was used as a measure of treatment effect. We used increasing thresholds of clinical relevance to reflect the magnitude of the desired treatment effects, relative to the standard deviation of the measurements in each domain. RESULTS: GPC were shown to have adequate statistical power (80% or more), even with small sample sizes, to detect treatment effects considered to be clinically worthwhile on a symptom assessment covering five domains (expressive language, daily living skills, and gross-motor, sleep and pain). The prioritized approach generally led to higher power as compared with the non-prioritized approach. CONCLUSIONS: GPC of prioritized outcomes is a statistically powerful as well as a patient-centric approach for the analysis of multi-domain scores in MPS IIIA and could be applied to other heterogeneous rare diseases.

Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing.

Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and in silico analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including NAGLU, SGSH, GALNS, GNPTG as well as the genes VWA3B, BTD, and GNPTG which have not previously associated with MPS. One family had causal variants in both GALNS and BTD. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs.

Clinical, biochemical, and molecular characterization of mucopolysaccharidosis type III in 34 Egyptian patients.

Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disorder characterized by progressive neurocognitive deterioration. There are four MPS III subtypes (A, B, C, and D) that are clinically indistinguishable with variable rates of progression. A retrospective analysis was carried out on 34 patients with MPS III types at Cairo University Children's Hospital. We described the clinical, biochemical, and molecular spectrum of MPS III patients. Of 34 patients, 22 patients had MPS IIIB, 7/34 had MPS IIIC, 4/34 had MPS IIIA, and only 1 had MPS IIID. All patients presented with developmental delay/intellectual disability, and speech delay. Ataxia was reported in a patient with MPS IIIC, and cerebellar atrophy in a patient with MPS IIIA. We reported 25 variants in the 4 MPS III genes, 11 of which were not previously reported. This is the first study to analyze the clinical and genetic spectrum of MPS III patients in Egypt. This study explores the genetic map of MPS III in the Egyptian population. It will pave the way for a national registry for rare diseases in Egypt, a country with a high rate of consanguineous marriage and consequently a high rate of autosomal recessive disorders.

Economic Burden of Sanfilippo Syndrome in the United States.

Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. Design and Setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Main Outcome Measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death. Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome. Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.

Increased pituitary volumes in patients with Sanfilippo syndrome (mucopolysaccharidosis type 3, MPS III).

PURPOSE: To evaluate apparent pituitary gland enlargement in patients with Sanfilippo syndrome observed at our institution. METHODS: Twelve patients with Sanfilippo syndrome with brain MRI were studied. Anterior, posterior, and whole pituitary volumes were estimated using the prolate ellipsoid volume calculation method (π/6 × L × W × H). Convexity along the upper pituitary margin (Elster's grade) was also measured. These values were compared to two age- and sex-matched groups (normal controls and patients with Hurler syndrome) using one-way ANOVA followed by Tukey's post hoc analysis for multiple comparisons. RESULTS: In the Sanfilippo cohort, the mean whole pituitary volume was 529.9 mm, the mean anterior pituitary volume was 333.4 mm, and the mean posterior pituitary volume was 59.1 mm with Elster's grade of 4.2. In the control cohort, the mean whole pituitary volume was 217.4 mm, the mean anterior pituitary volume was 154.8 mm, and the mean posterior pituitary volume was 28.4 mm with Elster's grade of 2.5. In the Hurler syndrome cohort, the mean whole pituitary volume was 310.0 mm, the mean anterior pituitary volume was 178.2 mm, and the mean posterior pituitary volume was 35.4 mm with Elster's grade of 3.5. CONCLUSION: In our cohort of patients with Sanfilippo syndrome, whole, anterior, and posterior pituitary volumes and degree of convexity along the upper pituitary border were all significantly greater than controls. The cause of these morphological changes is unclear, as is clinical correlation of the findings.