Hunter Syndrome Research Articles

Telegenetics aids the diagnosis of Hunter syndrome caused due to a novel IDS variant in rural India, during COVID-19 pandemic

The COVID-19 pandemic resulted in an expanded application of telemedicine globally. This enhanced connectivity also opened newer arenas of availability of super-specialty consultations in remote India. The current report highlights the details of a 15-month-old boy from a rural Maharashtra who was diagnosed with Hunter syndrome (HS i.e., mucopolysaccharidosis (MPS-II) via hybrid model of consultation involving telemedicine. The child was first evaluated by a paediatrician in-person, when he was suspected to have one of the MPS subtypes. This was followed by a virtual and an in-person consultation with the clinical geneticist, following which the suspicion for MPS was sharpened further. Exome sequencing identified a novel insertion in IDS gene c.1080_1081insGAATAA, p.Ile360_Phe361insGluTer confirming HS. The mother was identified to be a carrier for this X-linked disorder. The family was counselled about their available reproductive options for the future. The option of enzyme replacement therapy, as a potential lease of life, for improvement of the somatic symptoms, quality and longevity of life, was offered. However, due to the exorbitant lifelong expense that ERT entailed and the lifelong, weekly-injection schedule; the family declined this option. The report highlights the diagnostic journey of a child with HS, which spanned over barely two months following presentation to the specialist. It demonstrates how prudent integration of telemedicine services in resource-limited and pandemic-challenged settings, can help truncate the diagnostic odysseys often borne by patients of rare diseases. It also calls for attention to fill the existing gaps in meaningful healthcare directed towards rare diseases.

Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid modified AAV8 codon-optimized NAGLU vector.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood-brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.

Radiographic Findings of Mucopolysaccharidosis and Comparison with Bone Mineral Density: A Study from Southeastern Turkey

Introduction: The first aim of this study is to define the severity of radiologic features according to mucopolysaccharidosis (MPS) type. The second aim is to compare spine radiographs with dual-energy X-ray absorptiometry (DXA) scores. Methodology: A total of 64 MPS children were enrolled between January 2017 and March 2021. Patients with a history of surgery, fracture or improper radiographs were excluded. Finally, 48 cases (20 MPS VI, 12 MPS IVA, 7 MPS IIIA, 4 MPS IIIB, 3 MPS II, 2 MPS I) were yielded. Among them, 38 had DXA performed in the same week with radiographs. Demographic and radiographic features and the hip acetabular index were noted. T12-L5 vertebral body heights were measured from lateral spine radiographs and divided by patient height. DXA measurements, bone mineral density and Z-scores were also recorded. Results: Spine and hip findings were most frequently seen in MPS VI and IVA. Oar-shaped ribs were more common in MPS VI, whereas anteromedial beaking of vertebra was predominantly seen in MPS IVA. Femoral head dysplasia is most common in MPS IVA, VI and I. The highest mean acetabular was observed in MPS I. The mean Z-score of L1-L4 vertebrae was low for MPS I (-3.8), IVA (-3.79) and VI (-3.73), but normal for MPS II (0.6) and IIIA (0.23). Correlation between the Z-score and vertebral index was highest in the L1 vertebral body. Conclusion: Interpreting the characteristic radiographic features of different MPS types is important. In addition to dysostosis multiplex, quantitative measurements from radiographs may be beneficial in evaluating disease progression.

Genetic analysis and prenatal diagnosis of a Chinese pedigree affected with mucopolysaccharidosis type II due to deletion of exon 2 of IDS gene

To explore the genetic etiology of a patient with mucopolysaccharidosis type II (MPSII). The IDS gene of the proband and his mother was detected by Sanger sequencing, agarose gel electrophoresis, real-time PCR and multiple ligation-dependent probe amplification (MLPA). Prenatal diagnosis was performed on amniotic fluid sample. Agarose gel electrophoresis, real-time PCR, and MLPA all showed that exon 2 of IDS gene of the proband was deleted, for which his mother was normal. Prenatal diagnosis showed that the fetus was a normal male. The de novo deletion of exon 2 of the IDS gene probably underlay the MPSII in this patient. Above finding has broadened the mutation spectrum of the IDS gene. The combined methods for the detection of IDS gene mutations could make accurate prenatal diagnosis for MPSII.

Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study.

Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks. Six patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator. SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life. SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

The significance of triple-capsid-mutant AAV8 for treatment of Sanfilippo Syndrome Type B.

Sanfilippo Syndrome Type-B remains an untreatable childhood neurodegenerative disease with great burden for both patient and caregiver. Very few clinical trials have been undertaken to treat the disease, and none of these have yet yielded clinically obtainable products for patients. Caused by a simple enzyme function deficiency, Sanfilippo Syndrome Type-B has been considered a great prospect for gene-therapy interventions. Adeno-associated virus (AAV) remains a major choice for therapeutic gene delivery due to its relatively low-immunogenicity, versatility and tissue tropism. However, many clinical trials with AAV continue to use wild-type capsids, which in many cases are not able to reach stable transgene expression for long enough to be clinically effective in most cases. Previous research in AAV gene-therapy has created a litany of novel AAV capsids that can improve overall transduction efficiency far above that of wild-type AAV capsids. One such example is the triple-capsid mutant AAV8 (TCM8), which has been shown to exhibit transgene expression far superior to other capsids in Sanfilippo mouse models, specifically. Originally designed to bypass capsid ubiquitination intracellularly, mouse studies suggest this TCM8 vector outperforms both AAV5 and AAV9 when delivered to the central nervous system. This implies it as an ideal contender for an effective gene-therapy clinical trial candidate and has the potential to advance the progress of Sanfilippo Syndrome treatment. Here we provide commentary on the TCM8 vector and its context in the field of Sanfilippo Syndrome Type-B research.

Adults with lysosomal storage diseases in the undiagnosed diseases network.

ObjectivesTo review the referral and clinical characteristics of adult patients diagnosed with lysosomal storage diseases (LSD) through the Undiagnosed Diseases Network (UDN).MethodsRetrospective review of both application and evaluation records for adults admitted to the UDN with a final diagnosis of a lysosomal storage disease.ResultsTen patients were identified. Final diagnoses included late onset Tay Sachs, attenuated MPS I, MPS IIIA, MPS IIIB, and MPS IIIC. Most patients presented with neurocognitive changes. Prior to referral, all patients had been evaluated by neurology, four patients underwent phenotype specific panel testing that did not include the causative gene, and four patients had non‐diagnostic clinical exome sequencing.ConclusionsLSDs figure highly in the differential diagnosis of neurometabolic disorders in pediatric onset progressive diseases. In adults, their subtle initial presentations overlap with symptoms of more common disorders and less practitioner awareness may lead to prolonged diagnostic challenges.

Clinical Case of Drug Allergy to Enzyme Replacement Therapy in a Patient with Mucopolysaccharidosis Type II

Background. Enzyme replacement therapy (ERT) with iduronate-2-sulfatase recombinant forms (idursulfase and idursulfase beta) is effective for the management of mucopolysaccharidosis type II (MPS II). Patients with Hunter syndrome require lifelong ERT that can negate endogenous enzyme deficiency. However, hypersensitivity reactions may occur during ERT, and they significantly complicate the implementation of vital therapy.Clinical case description. This article describes clinical case of a child with hypersensitivity reaction to ERT. The patient with confirmed diagnosis of MPS II was administrated with idursulfase. Then, the drug was replaced with idursulfase beta due to the allergic reaction. Thus, even after the drug change, side effects maintained without sustained improvement with underlying glucocorticosteroids (GCS), antihistamines and with decreased infusion rate. Concerning the vital need to continue ERT, this patient with drug allergy to this pharmacotherapeutic group was further administered with combined therapy of cyclosporine and omalizumab. Personalised protocol for the administration of idursulfase beta with desensitization was developed. Such experience was firstly described In Russian patient.Conclusion. The presented personalised combination therapy made it possible to prevent hypersensitivity reactions during ERT in the patient with MPS II.

Mutational spectrum of the iduronate-2-sulfatase gene in Mexican patients with Hunter syndrome.

Hunter syndrome, or mucopolysaccharidosis type II (MPS II), is caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS), which is responsible for degrading heparan and dermatan sulfate. The IDS gene is located on chromosome Xq28; pathological variants in this gene mostly consist of missense mutations and small and larger deletions, which produce different phenotypes. However, there is only one record in our population concerning the molecular mechanism of this disease; a genotype-phenotype description is not available. There were included 24 unrelated male patients; clinical features were recorded at a database, fluorometric IDS enzyme activity testing was done for each individual, followed by Sanger sequencing to identify mutations. The mutational spectrum was found in 16 out of 24 Mexican patients with MPS II, and its range of phenotypes was described. The most frequent variants were of the missense type. The most affected exons were exon 3 (c.275T>G, c.284_287del, c.325T>C), exon 8 (c.1035G>C, c.550G>A), exon 9 (c.1403G>C, c.1229_1229del), and exon 7 (c.979A>C; this variant has not been previously reported). Exon 5 (c.438C>T, a non-pathogenic variant) was the least frequent. It was also found that the most severely affected patients were those with large deletions (2 out of 24) [rsaIDS: IDSP1 (P164)x0, FMR1, AFF2 (P164)x2] involving genes and pseudogenes. We found 2 patients with a synonymous mutation in exon 4. Our results confirmed reports in the literature, since the most frequent variants were reported in exons 3 and 8. However, this result varies from one previous report in our population, which mentions large deletions and rearrangements as the most frequent alterations, since complex rearrangements were not found. According to what has been previously found, the most severely affected patients are those in which a whole gene has been deleted.

Impaired mitophagy in Sanfilippo a mice causes hypertriglyceridemia and brown adipose tissue activation

Lysosomal storage diseases result in various developmental and physiological complications, including cachexia. To study the causes for the negative energy balance associated with cachexia, we assessed the impact of sulfamidase deficiency and heparan sulfate storage on energy homeostasis and metabolism in a mouse model of type IIIa mucopolysaccharidosis (MPS IIIa, Sanfilippo A syndrome). At 12-weeks of age, MPS IIIa mice exhibited fasting and postprandial hypertriglyceridemia compared with wildtype mice, with a reduction of white and brown adipose tissues. Partitioning of dietary [3H]triolein showed a marked increase in intestinal uptake and secretion, whereas hepatic production and clearance of triglyceride-rich lipoproteins did not differ from wildtype controls. Uptake of dietary triolein was also elevated in brown adipose tissue (BAT), and notable increases in beige adipose tissue occurred, resulting in hyperthermia, hyperphagia, hyperdipsia, and increased energy expenditure. Furthermore, fasted MPS IIIa mice remained hyperthermic when subjected to low temperature but became cachexic and profoundly hypothermic when treated with a lipolytic inhibitor. We demonstrated that the reliance on increased lipid fueling of BAT was driven by a reduced ability to generate energy from stored lipids within the depot. These alterations arose from impaired autophagosome–lysosome fusion, resulting in increased mitochondria content in beige and BAT. Finally, we show that increased mitochondria content in BAT and postprandial dyslipidemia was partially reversed upon 5-week treatment with recombinant sulfamidase. We hypothesize that increased BAT activity and persistent increases in energy demand in MPS IIIa mice contribute to the negative energy balance observed in patients with MPS IIIa.

Generation of an induced pluripotent stem cells line, CSSi014-A 9407, carrying the variant c.479C>T in the human iduronate 2-sulfatase (hIDS) gene

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare X-linked inherited lysosomal storage disorder presenting a wide genetic heterogeneity. It is due to pathogenic variants in the IDS gene, causing the deficit of the lysosomal hydrolase iduronate 2-sulfatase, degrading the glycosaminoglycans (GAGs) heparan- and dermatan-sulfate. Based on the presence/absence of neurocognitive signs, commonly two forms are recognized, the severe and the attenuate ones. Here we describe a line of induced pluripotent stem cells, generated from dermal fibroblasts, carrying the mutation c.479C>T, and obtained from a patient showing an attenuated phenotype. The line will be useful to study the disease neuropathogenesis.

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects.SIGNIFICANCE STATEMENTThis work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.

Glucosamine amends CNS pathology in mucopolysaccharidosis IIIC mouse expressing misfolded HGSNAT.

The majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have missense variants causing misfolding of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), which are potentially treatable with pharmacological chaperones. To test this approach, we generated a novel HgsnatP304L mouse model expressing misfolded HGSNAT Pro304Leu variant. HgsnatP304L mice present deficits in short-term and working/spatial memory 2-4 mo earlier than previously described constitutive knockout Hgsnat-Geo mice. HgsnatP304L mice also show augmented severity of neuroimmune response, synaptic deficits, and neuronal storage of misfolded proteins and gangliosides compared with Hgsnat-Geo mice. Expression of misfolded human Pro311Leu HGSNAT protein in cultured hippocampal Hgsnat-Geo neurons further reduced levels of synaptic proteins. Memory deficits and majority of brain pathology were rescued in mice receiving HGSNAT chaperone, glucosamine. Our data for the first time demonstrate dominant-negative effects of misfolded HGSNAT Pro304Leu variant and show that they are treatable by oral administration of glucosamine. This suggests that patients affected with mutations preventing normal folding of the enzyme can benefit from chaperone therapy.

MUCOPOLYSACCHARIDOSIS TYPE 2: NARRATIVE REVIEW

Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare, progressive, multisystemic lysosomal storage disease caused by deciency of iduronate 2 sulfatase, an enzyme responsible for the degradation of the mucopolysaccharides dermatan (DS) and keratan sulfate (QS), causing their accumulation at the lysosomal level. It is an X-linked disease, therefore it is common to nd most cases in men, rarely in women, it is considered an orphan disease given an incidence of approximately 1/100,000 live births. Various phenotypes of severe (2/3) and attenuated disease have been described. The diagnosis is based on clinical ndings and the measurement of mucopolysaccharides DS and QS in urine, which are elevated, conrmed by determining the enzyme deciency in serum, leukocytes and broblasts. It has been observed that in patients with enzyme replacement therapy somatic symptoms have decreased, however there are several studies of alternative therapies in the future, including gene therapy as an alternative in the future.

Combination of two rare genetically determinated diseases, associated with poor prognosis, in a 2-year-old child

This article presents the case of a combination of two genetically determined diseases in one early age patient: long QT syndrome type 1 and mucopolysaccharidosis type IIIA.

Bayesian model of disease progression in mucopolysaccaridosis IIIA.

Mucopolysaccaridosis IIIA (MPS IIIA) is a rare genetic disease that afflicts children and leads to neurocognitive degeneration. We develop a Bayesian disease progression model (DPM) of MPS IIIA that characterizes the pattern of cognitive growth and decline in this disease. The DPM is a repeated measures model that incorporates a nonlinear developmental trajectory and shape-invariant random effects. This approach quantifies the pattern of cognitive development in MPS IIIA and addresses differences in biological age, length of follow-up, and clinical outcomes across natural history subjects. The DPM can be used in clinical trials to estimate the percent slowing in disease progression for treatment relative to natural history. Simulations demonstrate that the DPM provides substantial improvements in power relative to alternative analyses.

Clinical Characteristics and Healthcare Resource Utilization for Patients with Mucopolysaccharidosis II (MPS II) in the United States: A Retrospective Chart Review.

Background: Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, X-linked, life-limiting lysosomal storage disease characterized by a deficiency in the activity of the enzyme iduronate-2-sulfatase. Accumulation of glycosaminoglycans in tissues and organs throughout the body causes cellular damage, leading to multisystemic disease manifestations. Patients generally require multidisciplinary care across a wide range of specialties. Objectives: The aims of this study were to assess the healthcare needs of patients with MPS II and to explore the impact of treatment on disease burden and healthcare resource utilization. Methods: A retrospective review of medical charts from 19 US sites was performed. Data were analyzed from 140 male patients diagnosed with MPS II (defined as a documented deficiency in iduronate-2-sulfatase) between 1997 and 2017. The prevalence and age at onset of clinical manifestations and extent and frequency of healthcare resource use were evaluated. Results: Of the patients in this study, 77.1% had received enzyme replacement therapy with intravenous idursulfase and 62.1% had cognitive impairment. The clinical burden among patients was substantial: almost all patients had ear, nose, and throat abnormalities (95.7%); musculoskeletal abnormalities (95.0%); and joint stiffness or abnormalities (90.7%). Of the most prevalent disease manifestations, facial dysmorphism and hepatosplenomegaly were documented the earliest (median age at first documentation of 3.8 years in both cases). Hospitalizations, emergency department visits, and outpatient visits were reported for 51.2%, 58.5%, and 93.5% of patients, respectively, with a frequency of 0.1, 0.2, and 3.0 per patient per year, respectively. Surgery was also common, with 91.1% of patients having undergone at least 1 surgical procedure. The clinical burden and prevalence and frequency of resource use were generally similar in patients who had received enzyme replacement therapy and in those who had not. Conclusions: These results add to our understanding of the natural history of MPS II and indicate that the disease burden and healthcare needs of patients with this progressive disease are extensive. Increased understanding of disease burden and resource use may enable the development of models of healthcare resource utilization in patients with MPS II and contribute to improvements in disease management and patient care.

Updated results of Transpher A, a multicenter, single-dose, Phase 1/2 clinical trial of ABO-102 investigational gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA) (S39.008)

Updated results of Transpher A, a multicenter, single-dose, Phase 1/2 clinical trial of ABO-102 investigational gene therapy for Sanfilippo syndrome type A (mucopolysaccharidosis IIIA) (S39.008)

Management of a difficult airway in Hunters syndrome.

Management of a difficult airway in Hunters syndrome.

Current and Future Treatment of Mucopolysaccharidosis (MPS) Type II: Is Brain-Targeted Stem Cell Gene Therapy the Solution for This Devastating Disorder?

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare, x-linked recessive, progressive, multi-system, lysosomal storage disease caused by the deficiency of iduronate-2-sulfatase (IDS), which leads to the pathological storage of glycosaminoglycans in nearly all cell types, tissues and organs. The condition is clinically heterogeneous, and most patients present with a progressive, multi-system disease in their early years. This article outlines the pathology of the disorder and current treatment strategies, including a detailed review of haematopoietic stem cell transplant outcomes for MPSII. We then discuss haematopoietic stem cell gene therapy and how this can be employed for treatment of the disorder. We consider how preclinical innovations, including novel brain-targeted techniques, can be incorporated into stem cell gene therapy approaches to mitigate the neuropathological consequences of the condition.