Novel therapies for mucopolysaccharidosis type III.
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ABSTRACT:
SUBMITTER: Seker Yilmaz B
PROVIDER: S-EPMC8436764 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundMucopolysaccharidosis (MPS) type III (Sanfilippo syndrome) comprises a group of rare, lysosomal storage diseases caused by the deficiency of one of four enzymes involved in the degradation of heparan sulfate. The clinical hallmark of the disease is severe neurological deterioration leading to dementia and death in the second decade of life. Adult MPS patients are generally of short stature. To date there is no clear description of the physical development of MPS III patients. The aim of this study was to document growth reference data for MPS III patients. We collected growth data of 182 German MPS III patients and were able to develop growth charts for this cohort. Growth curves for height, weight, head circumference, and body mass index were calculated and compared to German reference charts.ResultsBirth height, weight and head circumference were within the physiological ranges. Both genders were significantly taller than healthy children at 2 years of age, while only male patients were taller at the age of four. Growth velocity decelerated after the ages of 4.5 and 5 years for female and male patients, respectively. Both genders were significantly shorter than the reference group at the age of 17.5 years. Head circumference was larger compared to healthy matched controls within the first 2 years of life and remained enlarged until physical maturity.ConclusionMPS III is a not yet treatable severe neuro-degenerative disease, developing new therapeutic strategies might change the course of the disease significantly. The present charts contribute to the understanding of the natural history of MPS III. Specific growth charts represent an important tool for families and physicians as the expected height at physical maturity can be estimated and therapeutic effects can be monitored.
| S-EPMC6498678 | biostudies-literature
Project description:Homozygous or compound heterozygous mutation in the gene encoding N-alpha-acetylglucosaminidase (NAGLU) on chromosome 17q21 results in Sanfilippo B, resulting in excess accumulation of intralysosomal glycosaminoglycans (mucopolysaccharides) in various tissues. We wish to report a novel homozygous variant in a child with features of Sanfilippo syndrome B.
| S-EPMC5986016 | biostudies-other
Project description:Mucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area.An international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III.Improving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research.
| S-EPMC5485703 | biostudies-literature
Project description:Both non-epileptic sleep disturbances and epilepsy are common in patients with mucopolysaccharidoses (MPS), so diagnosis of sleep-related hypermotor epilepsy in these patients is a tackling issue. We present a case of an adult patient with MPS IIIB (Sanfilippo syndrome), who presented with numerous nocturnal events of sudden awakening and hypermotor behavior, which had been previously regarded as parasomnias. Overnight video-EEG captured numerous stereotypical seizures with ictal pattern in the frontal regions, which led the diagnosis of SHE. The patient was started with carbamazepine, which resulted in a substantial reduction in the number of seizures. Our report provides further support for use of overnight video-EEG in the differential diagnosis of sleep-related disorders in MPS, yet true incidence of SHE in MPS patients remains unknown.
| S-EPMC8663726 | biostudies-literature
Project description:Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: ?-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-?. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: ?-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease.
| S-EPMC4306821 | biostudies-literature
Project description:Mucopolysaccharidosis type IIIC or Sanfilippo syndrome type C (MPS IIIC, MIM #252930) is an autosomal recessive disorder caused by deficiency of the lysosomal membrane enzyme, heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT, EC 2.3.1.78), which catalyses transmembrane acetylation of the terminal glucosamine residues of heparan sulfate prior to their hydrolysis by alpha-N-acetylglucosaminidase. Lysosomal storage of undegraded heparan sulfate in the cells of affected patients leads to neuronal death causing neurodegeneration and is accompanied by mild visceral and skeletal abnormalities, including coarse facies and joint stiffness. Surprisingly, the majority of MPS IIIC patients carrying missense mutations are as severely affected as those with splicing errors, frame shifts or nonsense mutations resulting in the complete absence of HGSNAT protein.In order to understand the effects of the missense mutations in HGSNAT on its enzymatic activity and biogenesis, we have expressed 21 mutant proteins in cultured human fibroblasts and COS-7 cells and studied their folding, targeting and activity. We found that 17 of the 21 missense mutations in HGSNAT caused misfolding of the enzyme, which is abnormally glycosylated and not targeted to the lysosome, but retained in the endoplasmic reticulum. The other 4 mutants represented rare polymorphisms which had no effect on the activity, processing and targeting of the enzyme. Treatment of patient cells with a competitive HGSNAT inhibitor, glucosamine, partially rescued several of the expressed mutants. Altogether our data provide an explanation for the severity of MPS IIIC and suggest that search for pharmaceutical chaperones can in the future result in therapeutic options for this disease.
| S-EPMC2757673 | biostudies-literature
Project description:BackgroundMucopolysaccharidosis type III (MPS III) is an autosomal recessive lysosomal storage disorder characterised by progressive neurocognitive deterioration. MPS III subtypes are clinically indistinguishable, with a wide range of symptoms and variable severity. The natural history of this disorder within an Asian population has not yet been extensively studied. This study investigated the natural history of Korean patients with MPS III.MethodsThirty-four patients from 31 families diagnosed with MPS III from January 1997 to May 2020 in Samsung Medical Centre were enrolled. Clinical, molecular, and biochemical characteristics were retrospectively collected from the patients' medical records and via interviews.Results18 patients had MPS IIIA, 14 had IIIB, and two had IIIC. Twenty (58.9%) patients were male. Mean age at symptom onset was 2.8 ± 0.8 years and at diagnosis was 6.3 ± 2.2 years. All patients with MPS IIIA and IIIB were classified into the rapidly progressing (RP) phenotype. The most common symptom at diagnosis was language retardation (88.2%), followed by motor retardation (76.5%), general retardation (64.7%), and hyperactivity (41.2%). Language retardation was more predominant in IIIA, and motor retardation was more predominant in IIIB. The mean age of the 13 deceased patients at the time of the study was 14.4 ± 4.1 years. The age at diagnosis and lag time were significantly older and longer in the non-survivor group compared with the survivor group (p = 0.029 and 0.045, respectively). Genetic analysis was performed in 24 patients with MPS III and identified seven novel variants and three hot spots.ConclusionThis study is the first to analyse the genetic and clinical characteristics of MPS III patients in Korea. Better understanding of the natural history of MPS III might allow early diagnosis and timely management of the disease and evaluation of treatment outcomes in future clinical trials for MPS III.
| S-EPMC9145712 | biostudies-literature
Project description:BACKGROUND:Metabolomics represent a valuable tool to recover biological information using body fluids and may help to characterize pathophysiological mechanisms of the studied disease. This approach has not been widely used to explore inherited metabolic diseases. This study investigates mucopolysaccharidosis type III (MPS III). A thorough and holistic understanding of metabolic remodeling in MPS III may allow the development, improvement and personalization of patient care. METHODS:We applied both targeted and untargeted metabolomics to urine samples obtained from a French cohort of 49 patients, consisting of 13 MPS IIIA, 16 MPS IIIB, 13 MPS IIIC, and 7 MPS IIID, along with 66 controls. The analytical strategy is based on ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Twenty-four amino acids have been assessed using tandem mass spectrometry combined with liquid chromatography. Multivariate data modeling has been used for discriminant metabolite selection. Pathway analysis has been performed to retrieve metabolic pathways impairments. RESULTS:Data analysis revealed distinct biochemical profiles. These metabolic patterns, particularly those related to the amino acid metabolisms, allowed the different studied groups to be distinguished. Pathway analysis unveiled major amino acid pathways impairments in MPS III mainly arginine-proline metabolism and urea cycle metabolism. CONCLUSION:This represents one of the first metabolomics-based investigations of MPS III. These results may shed light on MPS III pathophysiology and could help to set more targeted studies to infer the biomarkers of the affected pathways, which is crucial for rare conditions such as MPS III.
| S-EPMC6122730 | biostudies-literature
Project description:BackgroundMucopolysaccharidosis type III (MPS III, Sanfilippo disease) is a life-limiting recessive lysosomal storage disorder caused by a deficiency in the enzymes involved in degrading glycosaminoglycan heparan sulfate. MPS III is characterized by progressive deterioration of the central nervous system. Respiratory tract infections have been reported as frequent and as the most common cause of death, but gastrointestinal (GI) manifestations have not been acknowledged as a cause of concern. The aim of this study was to determine the incidence of GI problems as a primary cause of death and to review GI symptoms reported in published studies.MethodsCauses of death from 221 UK death certificates (1957-2020) were reviewed and the literature was searched to ascertain reported GI symptoms.ResultsGI manifestations were listed in 5.9% (n = 13) of death certificates. Median (IQR) age at death was 16.7 (5.3) years. Causes of death included GI failure, GI bleed, haemorrhagic pancreatitis, perforation due to gastrostomies, paralytic ileus and emaciation. Twenty-one GI conditions were reported in 30 studies, mostly related to functional GI disorders, including diarrhoea, dysphagia, constipation, faecal incontinence, abdominal pain/distension and cachexia.ConclusionsGI manifestations may be an under-recognized but important clinical feature of MPS III. Early recognition of GI symptoms and timely interventions is an important part of the management of MPS III patients.
| S-EPMC8509825 | biostudies-literature
Project description:Preconception expanded carrier screening (ECS) aims to detect carrier couples of autosomal recessive (AR) disorders before pregnancy in order to increase reproductive autonomy of prospective parents. Genetic knowledge and knowledge gained from experience influence decision making on participation in genetic testing and understanding carrier test results. In this study we assessed whether parents and relatives of patients with the severe AR condition mucopolysaccharidosis type III (MPS III), who are expected to have genetic and experiential knowledge, have more positive attitudes toward ECS than the Dutch reference group. Parents of all MPS III patients known to the Dutch expert center were invited to participate and asked to invite first and second degree relatives. The online questionnaire started with an educational text, and assessed attitudes toward ECS, genetic knowledge and perceived MPS III severity. Results were compared with the Dutch population. Parents and relatives of MPS III patients (n = 159) scored higher on the genetic knowledge test and perceived MPS III as more severe compared with the general Dutch population (n = 781). Parents and relatives reported to be more likely to participate in ECS (84.3% and 62.5%, respectively) compared with the public (31%) (p < 0.001). Being a relative of a MPS III patient was the strongest variable in the regression analyses for intended ECS participation. Our results show that genetic knowledge influences ECS decision making. Therefore, appropriate information on ECS and genetic counseling is needed to enable prospective parents from the general population, including relatives of patients with severe hereditary disorders, to make informed decisions.
| S-EPMC7609293 | biostudies-literature