Recent scientific articles relevant to Sanfilippo Syndrome: June 9, 2022, digest

“The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy”

Published: Front. Pharmacol., May 13, 2022 Authors: Anna-Maria Wiesinger, Brian Bigger, Roberto Giugliani, Maurizio Scarpa, Tobias Moser, Christina Lampe, Christoph Kampmann, and Florian B. Lagler “Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).” Conclusion: “Lysosomal storage appears to have a prominent impact on the inflammatory cytopathology of MPS. Primary and secondary accumulation of undegraded substrates and probably many more factors may initiate a self-propagating innate immune response in MPS—finally leading to inflammation and clinical deterioration. We face a complex interplay between multiple processes on a cellular and humoral level. Patients affected by MPSs show a wide spectrum of clinical features and disease severity. Understanding the pathomechanism in each MPS type and subtype can reveal insights on how to better treat and manage the disease. The complexity of the pathogenic cascade in MPS disease provides a number of potential clinical intervention points. Perhaps several different targets have to be addressed together to receive a benefit in clinical features, especially concerning CNS pathology. Combining therapies which target different aspects of the pathogenic cascade has shown neuroprotective effects in a neurodegenerative mouse model of the neurodegenerative LSD Niemann Pick disease type C1 (Williams et al., 2014). This approach may be valuable in MPSs as well. Currently, several promising therapeutic approaches are under investigation, including biologicals and small molecules. Immunomodulatory drugs, within the meaning of repurposing, are emerging tools for specific and/or adjuvant use in patients with MPS disease. For this purpose, additional and larger clinical trials are needed to investigate benefits of different immunomodulatory agents in MPS. On the other hand, clearly structured and evidence-based individual treatment trials are required, as each MPS patient differs phenotypically among another. Therefore, the understanding of the role of inflammation in the cytopathology of patients with MPS is necessary to gain new (adjuvant) treatment approaches, causing reduction of symptoms and enhancing quality of life.” Read more: Access the publication

“Highly diverse phenotypes of mucopolysaccharidosis type IIIB sibling patients: effects of an additional mutation in the AUTS2 gene”

Published: Journal of Applied Genetics, May 8, 2022 Authors: Paulina Anikiej-Wiczenbach, Arkadiusz Mański, Katarzyna Milska-Musa, Monika Limanówka, Jolanta Wierzba, Aleksander Jamsheer, Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska, and Grzegorz Węgrzyn Abstract: “Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo syndrome type B) is an inherited metabolic disease caused by mutations in the NAGLU gene, encoding α-N-acetylglucosaminidase. Accumulation of undegraded heparan sulfate (one of glycosaminoglycans) arises from deficiency in this enzyme and leads to severe symptoms, especially related to dysfunctions of the central nervous system. Here, we describe a case of two siblings with highly diverse phenotypes, despite carrying the same mutations (c.1189 T > G/c.1211G > A (p.Phe397Val/p.Trp404Ter)) and similar residual activities of α-N-acetylglucosaminidase; the younger patient reveals more severe phenotype; thus, these differences cannot be explained by the age and progression of the disease. Surprisingly, the whole exome sequencing analysis indicated the presence of an additional mutation in one allele of the AUTS2 gene (c.157G > A (p.Ala53Thr)) in the younger patient but not in the older one. Since mutations in this gene are usually dominant and cause delayed development and intellectual disability, it is likely that the observed differences between the MPS IIIB siblings are due to the potentially pathogenic AUTS2 variant, present in one of them. This case confirms also that simultaneous occurrence of two ultra-rare diseases in one patient is actual, despite a low probability of such a combination. Moreover, it is worth noting that apart from the genotype–phenotype correlation and the importance of the residual activity of the deficient enzyme, efficiency of glycosaminoglycan synthesis and global secondary changes in expression of hundreds of genes may considerably modulate the course and severity of MPS, especially Sanfilippo disease.” Read more: Access the abstract