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Sanfilippo disease/mucopolysaccharidosis type III
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The defective enzyme in type D Sanfilippo disease is in α-N-acetylglucosamine-6-sulfatase [50, 51]. Glucosamine residues in heparan sulfate can be either N-sulfated or O-sulfated, and there are specific sulfatases for each residue. Defective activity of either leads to accumulation and to the Sanfilippo syndrome. The glucosamine-6-sulfatase has been purified [52] and its cDNA has been cloned [11]. Its structure is homologous to other sulfatases. Immunoprecipitation studies have demonstrated cross-reactive material in the Sanfilippo B-syndrome [53]. The enzyme is also involved in the degradation of keratan sulfate, but patients do not excrete keratan sulfate, because this block may be obviated by other enzymes. Patients excrete N-acetylglucosamine sulfate, as well as heparan sulfate [54].
Cognitive symptoms related to memory
Published in Aurora Lassaletta, Ruth Clarke, The Invisible Brain Injury, 2019
I’ve realised that, if I want to commit something that I have read to memory and recall it later, I can’t read it quickly, or even quite quickly – the way I used to – because I can’t take in information that way anymore. I recently wanted to explain to a friend what Sanfilippo syndrome was, because a month and half earlier my son and I had quickly read a plan to help research into this rare disease, which we wanted to support. I was perplexed when I couldn’t explain anything about the syndrome, because at the time I hadn’t spent long looking at it in depth.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Sanfilippo syndrome is a group of four autosomal recessive lysosomal storage diseases resulting from a failure to degrade heparan sulphate. The four biochemical subtypes of MPS III (types A–D) are caused by the deficiency of one of the four enzymes required for the removal of N-acetylglucosamine at the non-reducing end of the saccharide chain. Heparan-N-sulfamidase is deficient in MPS IIIA, a-N-acetylglucosaminidase is deficient in MPS IIIB, acetylCoA:alpha-glucosaminide N-acetyl transferase is deficient in MPS IIIC and N-acetylglucosamine 6-sulfatase is deficient in MPS IIID. Type C and D are uncommon.
Enzyme replacement combinational therapy: effective treatments for mucopolysaccharidoses
Published in Expert Opinion on Biological Therapy, 2021
Azam Safary, Hakimeh Moghaddas-Sani, Mostafa Akbarzadeh-Khiavi, Alireza Khabbazzi, Mohammad A. Rafi, Yadollah Omidi
Tralesinidase alfa (BMN-250) as a novel recombinant fusion enzyme is being developed for targeted therapy of MPS IIIB (Sanfilippo B) by BioMarin Pharmaceutical Company [96]. The Sanfilippo syndrome type B is a pediatric neurodegenerative MPS, characterized by the lysosomal accumulation of partially degraded HS [97]. In comparison with other forms of MPS disorders, the skeletal abnormalities of the MPS IIIB are mild and the involvement of CNS is the primary manifestation of the disease. The symptoms typically occur in early childhood, except for the mild forms in which the symptoms may not be present until the adulthood of the patient [32]. Tralesinidase alfa is a combination of alpha-N-acetylglucosaminidase (NAGLU)-tagged insulin-like growth factor 2 (IGF2) molecules (NAGLU-IGF2), which can effectively bind to the IGF2/M6P receptors and transport from the surface of MPS IIIB fibroblasts to the lysosome through glycosylation-independent lysosomal trafficking pathway [96]. The recombinant NAGLU obtained from CHO cells was shown to possess very little mannose glycan, which strongly limits the cellular uptake and lysosomal delivery of this enzyme [98]. Thus, IGF2 peptide, through interaction with cation-independent M6PRs, can promote targeted delivery of the NAGLU-IGF2 into astrocytes, cortical neurons, and primary fibroblasts of MPS IIIB [99]. In a preclinical study, intracerebroventricular (ICV) administration of tralesinidase alfa into the CSF resulted in enzyme uptake into the brain and the clearance of HS in the animal model with Sanfilippo syndrome type B. The ICV administration route is a CNS-directed enzyme replacement therapy, which has been explored to bypass the BBB and restore the NAGLU function in the brain [100]. Besides, the preliminary results from the first human study (NCT02754076) demonstrate that the ICV administration of tralesinidase alfa can lead to decrease in the HS level in the CNS and improve the developmental quotient (DQ) of the subjects [101]. Clinical trials on the long-term safety and efficacy of ICV-BMN-250 in MPS IIIB patients are currently being evaluated (NCT03784287). Additionally, Alexion Pharmaceuticals Company compeleted a phase I/II trials for IV administration of recombinant α-N-acetylglucosaminidase (SBC-103) in the MPS-IIIB (NCT02324049; NCT02618512) [102].