Hunter Syndrome Research Articles

Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients.

Objectives Sanfilippo syndrome (Mucopolysaccharidosis III, MPS III) is a rare autosomal recessive hereditary disease, which is caused by lysosomal enzyme deficiency. This study was operated to investigate clinical and molecular characteristics of patients with MPS III, which will improve the diagnosis and treatment of MPS III. Method Thirty four patients with MPS III were assessed using clinical evaluation, questionnaire, and scoring system. Results Among the 34 patients, 14 had MPS IIIA, 19 had MPS III B, and one had MPS III C. Speech delay (100%) and intellectual disability (100%) were the most prevalent clinical manifestations in this cohort, followed by hyperactivity (94.12%), hirsutism (91.18%), enlarged head circumference (73.52%), repeated diarrhea (67.64%), sparse teeth (67.64%), and Mongolian spots (64.71%). There were two clinical manifestations that were significantly different between IIIA and IIIB: Hepatosplenomegaly and serrated teeth. The most common initial symptoms at diagnosis were speech delay (52.94%), hyperactivity (35.29%), and mental retardation (29.41%). Genetic analysis of 25 patients was conducted, which identified 12 novel mutations. Conclusion When language retardation, mental retardation, and rough facial features occurred, MPS III should be considered. At same time, more examination should be operated, such as examination of changes in cranial magnetic resonance imaging of cerebral cortex atrophy. Hepatosplenomegaly and serrated teeth could be used clinically to preliminarily distinguish IIIA from IIIB.

Safety and efficacy of idursulfase in the treatment of mucopolysaccharidosis II (Hunter syndrome): a post-marketing study in Japan

ABSTRACT Objectives Enzyme replacement therapy with idursulfase has been shown to improve somatic signs and symptoms of mucopolysaccharidosis type II (MPS II). Idursulfase is available in Japan (since 2007), based on the outcome of clinical trials conducted in the United States, but data from Japanese patients are limited. Methods This was a postmarketing study of Japanese MPS II patients treated with 0.5 mg/kg intravenous idursulfase weekly, conducted over a period of 8 years after initial administration. Assessments included the safety profile, survival rate, degree of clinical improvement, change in urinary uronic acid (UA) concentration, and 6-minute walk test (6MWT). Results The safety and efficacy analysis populations included 145 and 143 patients, respectively. The incidence of serious adverse events was 42.8% and the incidence of adverse drug reactions was 48.3%. The 7-year survival rate was 82.7%. Improvements in the clinical features of hepatosplenomegaly, skin, joint, and respiratory disorders were reported (per investigator’s assessment). The mean change in urinary UA concentration was −128.39 mg/g creatinine, and that of 6MWT walking distance was +31.8 m. Conclusion Long-term idursulfase treatment was well tolerated, and effective in improving clinical features, reducing urinary UA, and slowing disease progression in Japanese MPS II patients.

Murine cellular model of mucopolysaccharidosis, type IIIB (MPS IIIB) – A preliminary study with particular emphasis on the non-oxidative l-cysteine metabolism

The lack of the N-alpha-glucosaminidase (Naglu) is responsible for the incidence of a rare disease - mucopolysaccharidosis, type IIIB (MPS IIIB). To date, studies have been conducted based on cells derived from patients suffering from MPS or using in vivo MPS mouse models. These limitations have allowed for defining our research goal - to create and characterize the first in vitro murine cellular MPS IIIB model. In the current work we present a new, stable cell line with confirmed accumulation of glycosaminoglycans. The line stability was achieved by immortalization using a lentivirus carrying the T-antigens of SV40. The Naglu−/− cells were confirmed to produce no Naglu enzyme. To confirm the proper functioning of the in vitro MPS IIIB model, we determined the activity and expression of cystathionine γ-lyase, rhodanese and 3-mercaptopyruvate sulfurtransferase, as well as the level of low molecular-weight thiols (reduced and oxidized glutathione, cysteine and cystine). The results were referred to our earlier findings originating from the studies on the tissues of the Naglu−/− mice that were used to create the lines. The results obtained in the Naglu−/− cells were in accordance with the results found in the mouse model of MPS IIIB. It suggests that the presented murine Naglu−/− cell lines might be a convenient in vitro model of MPS IIIB.

Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102, an intravenous AAV9-based gene therapy for Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA) (4898)

Transpher A, a multicenter, single-dose, phase 1/2 clinical trial of ABO-102, an intravenous AAV9-based gene therapy for Sanfilippo Syndrome Type A (Mucopolysaccharidosis IIIA) (4898)

Safety, Tolerability, and Preliminary Evidence of Biopotency in Transpher B, a Multicenter, Singledose, Phase 1/2 Clinical Trial of ABO-101 Gene Therapy for Sanfilippo Syndrome Type B (Mucopolysaccharidosis IIIB) (5175)

Safety, Tolerability, and Preliminary Evidence of Biopotency in Transpher B, a Multicenter, Singledose, Phase 1/2 Clinical Trial of ABO-101 Gene Therapy for Sanfilippo Syndrome Type B (Mucopolysaccharidosis IIIB) (5175)

FDA orphan drug designations for lysosomal storage disorders - a cross-sectional analysis.

To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N = 23) months. The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included "me-too"-enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease.

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann–Pick disease type A and B, and of GM2 and glucosylceramide in Niemann–Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

Hunter syndrome revisited

Hunter syndrome revisited

SEVERE HUNTER DISEASE: ABOUT A CASE

16Mar 2020 SEVERE HUNTER DISEASE: ABOUT A CASE Souad Maher , Siham El Haddad , Nazik Allali and Latifa Chat Pediatric Radiology Department, Pediatric Hospital -Rabat University Hospital Center, Faculty of Medecine and Pharmacy-Mohamed V University - Rabat.

Décès et engagement du pronostic vital chez les enfants et les adolescents ayant un trouble psychiatrique : revue de la littérature et exemple dans un service universitaire d’hospitalisation pédopsychiatrique

BackgroundDeath is a rare event in child psychiatry and still not widely studied. MethodsHere, we report a review of literature concerning mortality in child psychiatry and a retrospective study (begun in 2007) of the implementation of “mortality and morbidity reviews” carried out in a university hospital within several inpatient units. ResultsThe review pulled together 73 studies, all of them confirming the excess mortality of children and adolescents in child psychiatry, whether in the general/non-specific populations (ex : hospitalized patients) or in specific populations (e.g. : autistic patients). The causes of excess mortality are undoubtedly suicide but also many natural causes (e.g. : complications due to addiction or anorexia nervosa). Our study includes 11 patients (mean average age=15.5 years; 9 girls and 2 boys) and saw 5 deaths and 14 life-threatening situations. Again, suicides and serious suicide attempts were very common (n=8 including 2 deaths), but the study also describes somatic causes, complications of pathological behaviour (n=5 : undernutrition in the context of anorexia, water poisoning) or underlying somatic disease (n=5, including 2 deaths related to Sanfilippo disease and infiltrative brain lymphoma). ConclusionAs with adult psychiatry, children and adolescents with mental disorders appear to have a lower life expectancy compared to the general population. Nevertheless, death in child psychiatry remains a rare phenomenon, especially when it happens in hospital care. Our study shows that cases of death or life-threatening situations in hospitalized child psychiatry are due to somatic diseases (that are more or less entangled with psychiatric disorders) or due to suicides.

Hematopoietic stem cell transplantation in mucopolysaccharidosis type IIIA: A case description and comparison with a genotype-matched control group

BackgroundMucopolysaccharidosis type IIIA (MPS IIIA, Sanfilippo A syndrome) is a chronic progressive neurodegenerative storage disorder caused by a deficiency of lysosomal sulfamidase. The clinical hallmarks are sleep disturbances, behavioral abnormalities and loss of cognitive, speech and motor abilities. Affected children show developmental slowing from the second year of life, dementia occurs by the age of 5 years followed by death in the second decade of life. Only a few studies concerning HSCT in MPS IIIA have been published and do not document a clear benefit of treatment. MethodsThe present study summarizes the clinical outcome of a girl with MPS IIIA who received HSCT at the age of 2.5 years. Her clinical course was compared with the natural history of six untreated MPS IIIA patients carrying the same mutations (p.R74C and p. R245H) in the SGSH-gene. ResultsEight years after successful HSCT, the patient showed a global developmental delay. However, cognitive abilities continued to develop, albeit very slowly. There was no sign of regression. She could talk in short sentences, had good motor abilities and performed basic daily living activities by herself. She did not present with sleeping problems, but behavioral abnormalities were profound. In contrast, the six untreated patients with identical mutations in the SGSH-gene showed the typical progressive course of disease with early and continuous loss of abilities. ConclusionsThe present data suggest a beneficial effect of HSCT performed at an early stage of MPS IIIA on cognitive skills, motor function and quality of life.

A New Mutation in IDS Gene Causing Hunter Syndrome: A Case Report

RationaleMucopolysaccharidosis type II (Hunter syndrome) is an X-linked multisystem disorder, caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S). The clinical manifestations of this disease are severe skeletal deformities, airway obstruction, cardiomyopathy, and neurologic deterioration.PatientThe patient was 5 years and 6 months boy, with developmental delay, hearing loss, hepatosplenomegaly, and skeletal dysplasia. He was diagnosed with mucopolysaccharidosis type II based on clinical manifestations, biochemical and genetic analysis.OutcomesThe patient carries a new mutation (c.879-1210_1007-218del) in hemizygosis in the IDS gene, which was defined as pathogenic according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology guidelines and as responsible for the mucopolysaccharidosis type II phenotype in the patient.

Retinal Degeneration in MPS-IIIA Mouse Model.

Mucopolysaccharidosis type IIIA (MPS-IIIA, Sanfilippo A) is one of the most severe lysosomal storage disorder (LSD) caused by the inherited deficiency of sulfamidase, a lysosomal sulfatase enzyme involved in the stepwise degradation of heparan sulfates (HS). MPS-IIIA patients show multisystemic problems, including a strong impairment of central nervous system (CNS), mild somatic involvement, and ocular manifestations that result in significant visual impairment. Despite the CNS and somatic pathology have been well characterized, studies on visual system and function remain partially explored. Here, we characterized the retina morphology and functionality in MPS-IIIA mouse model and analyzed how the SGSH deficiency affects the autophagic flux. MPS-IIIA mice exhibited a progressive retinal dystrophy characterized by significant alterations in visual function. The photoreceptor degeneration was associated with HS accumulation and a block of autophagy pathway. These events caused a reactive microgliosis, and a development of apoptotic processes in MPS-IIIA mouse retina. Overall, this study provides the first phenotypic spectrum of retinal disorders in MPS-IIIA and significantly contributes for diagnosis, counseling, and potential therapies development.

Синдром протяженной делеции при тяжелой форме мукополисахаридоза II типа

В статье отражены современные представления о сочетании нескольких наследственных синдромов в результате протяженной делеции Х хромосомы на примере мукополисахаридоза II типа и умственной отсталости. Проанализированы описания встречающихся в литературе сочетаний моногенных синдромов, обозначаемых как «сопряженные» или «протяженные» генные синдромы, а также понятие «смежные» гены. Протяженные генные синдромы, обусловленные делецией участка X хромосомы у мальчиков, приводят к структурной и функциональной нуллисомии, поэтому необходимы исследования числа копий генов с целью определения точного генетического дефекта. Суммированы данные литературы и собственные наблюдения, касающиеся вопросов этиологии, патогенеза, сроков манифестации и клинической симптоматики болезни, методов диагностики, современного лечения и профилактики мукополисахаридоза II типа. Мукополисахаридоз II типа относится к заболеваниям из группы лизосомных болезней накопления с мультиорганным поражением. Описан клинический случай синдрома Хантера с протяженной делецией хромосомы Х и ранним дебютом клинических проявлений комбинированного стеноза позвоночного канала и миелопатии шейного отдела спинного мозга вследствие накопления гликозаминогликанов (ГАГ) в оболочках спинного мозга. Смешанный тетрапарез при мукополисахаридозе II типа наблюдается реже, чем при других мукополисахаридозах и, как правило, манифестирует в более старшем возрасте. Высказано предположение, что тяжелый фенотип с сочетанием неврологической симптоматики и умственнной отсталости связан с протяженной делецией хромосомы Х, включающей полную делецию гена IDS. В алгоритм обследования пациентов с несиндромальной умственной отсталостью входят анализ кариотипа, ДНК-диагностика синдрома ломкой хромосомы Х и хромосомный микроматричный анализ. Показано, что при обследовании мальчиков с умственной отсталостью в этот алгоритм дополнительно следует включить биохимические тесты - определение ГАГ в моче и анализ ферментов лизосом, что позволит с большей эффективностью выявлять больных с мукополисахаридоз II типа. This article presented below reflects modern ideas about the combination of several hereditary syndromes as a result of an contiguous deletion of the X chromosome by the example of mucopolysaccharidosis type II and mental retardation. Monogenic syndromes occurring in the literature in combination, marked as contiguous gene syndromes, have been analyzed, along with what the notion of contiguous geneshas been described. Contiguous gene syndromes due to the deletion of the X chromosome region in boys lead to structural and functional nullisomy, thus confirming the significance of studying the number of copies of genes in order to determine the exact genetic defect. The data of the literature and our own observations concerning issues of etiology, pathogenesis, time of manifestation and clinical symptoms of the disease, diagnostic methods, treatment and prevention of mucopolysaccharidosis type II are summarized. Mucopolysaccharidosis type II refers to а group of lysosomal storage diseases with multiorgan lesions. Here is described a clinical case of Hunter syndrome with a long deletion of the X chromosome and an early manifestation of a combined stenosis of the spinal canal, the development of myelopathy of the cervical spinal cord as a result of the accumulation of glycosaminoglycans in the membranes of the spinal cord. The described case with the clinical picture of mixed tetraparesis is a rarer symptom with type II mucopolysaccharidosis than with other mucopolysaccharidosis and, as a rule, manifests at an older age. It was suggested that such a phenotypic correlation in patients with mucopolysaccharidosis type II, as a severe phenotype with neurological symptoms with a complete deletion of the IDS gene. The algorithm for examining patients with non-syndromic mental retardation includes the analysis of karyotype, DNA-diagnosis of fragile X chromosome, and chromosome analysis. It is shown that a survey is needed to exclude MPS II in boys with mental retardation and the inclusion of simple biochemical tests in these algorithms - determination of GAG in urine and analysis of lysosomal enzymes, which will more effectively identify patients with MPS type II.

Bow Hunter's Syndrome: Complete Microsurgical Decompression of Vertebral Artery by Far Lateral Retrocondylar Approach: 3-Dimensional Operative Video.

This 50-yr-old man had a 15-yr history of presyncopal episodes that were precipitated by turning his head to the right, and had worsened recently. Cerebral angiogram demonstrated complete cessation of anterograde flow in left vertebral artery (VA) at the level of the C1 sulcus arteriosus while turning head to right, indicating dynamic compression at the C1 level. Patient underwent left extreme lateral retrocondylar approach, partial C1 laminectomy and opening of the C1 foramen with complete microsurgical decompression of the VA. After skin incision, meticulous muscle dissection was performed and superior and inferior oblique muscles were disconnected from the tubercle of C1. The VA was exposed, and three areas of constriction were visible, first at the atlanto-occipital membrane laterally; second, located more medially as the artery curved around the occipital condyle to enter the posterior fossa; and third, located anterior to C2 nerve root. The artery was dissected from all the surrounding tissues, preserving the C2 nerve root, and the Cl foramen was opened completely. The Cl lamina was also partially resected and grooved to allow free placement of the VA. The VA was also decompressed near the C2 foramen. Postoperative computed tomography angiogram of the head and neck showed complete decompression of VA. The patient had no episodes of presyncope or dizziness while turning head to right and his mRs was 0 at 8 mo follow up. This 3D video shows the technical nuances of decompression of V3 segment of VA in bow hunters's syndrome. Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides.

Neuronal and Astrocytic Differentiation from Sanfilippo C Syndrome iPSCs for Disease Modeling and Drug Development.

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.

Proteomic Analysis of Mucopolysaccharidosis IIIB Mouse Brain.

Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363.

An exonic insertion in the NAGLU gene causing Mucopolysaccharidosis IIIB in Schipperke dogs

Mucopolysaccharidosis (MPS) IIIB (Sanfilippo syndrome B; OMIM 252920), is a lysosomal storage disease with progressive neurological signs caused by deficient activity of alpha-N-acetylglucosaminidase (NAGLU, EC 3.2.1.50). Herein we report the causative variant in the NAGLU gene in Schipperke dogs and a genotyping survey in the breed. All six exons and adjacent regions of the NAGLU gene were sequenced from six healthy appearing and three affected Schipperkes. DNA fragment length and TaqMan assays were used to genotype privately owned Schipperkes. A single variant was found in exon 6 of MPS IIIB affected Schipperkes: an insertion consisting of a 40–70 bp poly-A and an 11 bp duplication of the exonic region preceding the poly-A (XM_548088.6:c.2110_2111ins[A(40_70);2100_2110]) is predicted to insert a stretch of 13 or more lysines followed by either an in-frame insertion of a repeat of the four amino acids preceding the lysines, or a frameshift. The clinically affected Schipperkes were homozygous for this insertion, and the sequenced healthy dogs were either heterozygous or homozygous for the wild-type allele. From 2003–2019, 3219 Schipperkes were genotyped. Of these, 1.5% were homozygous for this insertion and found to be clinically affected, and 23.6% were heterozygous for the insertion and were clinically healthy, the remaining 74.9% were homozygous for the wild-type and were also clinically healthy. The number of dogs homozygous and heterozygous for the insertion declined rapidly after the initial years of genotyping, documenting the benefit of a DNA screening program in a breed with a small gene pool. In conclusion, a causative NAGLU variant in Schipperke dogs with MPS IIIB was identified and was found at high frequency in the breed. Through genotyping and informed breeding practices, the prevalence of canine MPS IIIB has been drastically reduced in the Schipperke population worldwide.

Mucopolysaccharidosis type II: Enzyme Replacement Therapy Efficiency

Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is the hereditary lysosomal storage disease caused by pathological variants in IDS gene. Such variants lead to iduronate-2-sulfatase enzyme deficiency and glycosaminoglycan catabolism disorder. Major clinical signs are central nervous system lesion, disorders of musculoskeletal system, cardiovascular and respiratory systems pathologies, hepatosplenomegaly, hearing impairment. Enzyme replacement therapy (ERT) makes it possible to adjust metabolic processes in lysosomes of many organs and tissues, to improve clinical signs due to partial restoring of the damaged enzyme function. Cardiovascular pathology is the main cause of death in patients with MPS. In this regard we have studied efficiency of ERT with idursulfase and its effects on the cardiovascular system in 55 patients with MPS II. It has been shown that ERT started from an early age can significantly improve children's condition, reduce or event prevent cardiac involvement. Treatment gaps from 1 to 7 months due to economic or organizational factors in 12 patients caused worsening course of the disease.

Haematopoietic stem cell gene therapy with IL‐1Ra rescues cognitive loss in mucopolysaccharidosis IIIA

Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)‐1β and interleukin‐1 receptor antagonist (IL‐1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease‐specific 2‐O‐sulphated heparan sulphate was essential for priming an IL‐1β response via the Toll‐like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL‐1β secretion. IL‐1 blockade in mucopolysaccharidosis IIIA mice using IL‐1 receptor type 1 knockout or haematopoietic stem cell gene therapy over‐expressing IL‐1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL‐1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL‐1Ra as a potential neuronopathic lysosomal disease treatment.