Sanfilippo Syndrome

Sanfilippo syndrome (mucopolysaccharidosis type III) is a lysosomal disorder caused by a defect in the catabolism of heparan sulfate. Mucopolysaccharidosis type III is the most common type of all mucopolysaccharidoses. The pathogenic basis of the disease consists of the storage of undegraded substrate in the central nervous system. Progressive cognitive decline resulting in dementia and behavioural abnormalities are the main clinical characteristics of Sanfilippo syndrome. Mucopolysaccharidosis type III may be misdiagnosed as other forms of developmental delay, attention deficit/hyperactivity disorder and autistic spectrum disorders because of lack of somatic symptoms, presence of mild and atypical forms of the disease. Patients with Sanfilippo syndrome may have comparatively low urinary glycosaminoglycans levels resulting in false negative urinary assay. Definitive diagnosis is made by enzyme assay on leucocytes and cultured fibroblasts. There is currently no effective treatment of mucopolysaccharidosis type III, though ongoing researches of gene, substrate reduction and intrathecal enzyme replacement therapies expect getting curative method to alter devasting damage of central nervous system in near future.

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Lysosomal storage diseases. Mucopolysaccharidosis type III, sanfilippo syndrome

Pediatrician (St Petersburg) ◽

10.17816/ped12469-81 ◽

2021 ◽

Vol 12 (4) ◽

pp. 69-81

Author(s):

V. N. Gorbunova ◽

N. V. Buchinskaya

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Heparan Sulfate ◽

Mucopolysaccharidosis Type ◽

Sanfilippo Syndrome ◽

Biochemical Basis ◽

Type Iii ◽

Mucopolysaccharidosis Type Iii ◽

The Central Nervous System ◽

Inactivating Mutations

The review describes the clinical, biochemical and molecular genetic characteristics of autosomal recessive mucopolysaccharidosis type III, or Sanfilippo syndrome. This is a genetically heterogeneous group of rare, but similar in nature, diseases caused by a deficiency of one of the four lysosomal enzymes involved in the degradation of heparan sulfate. All types of mucopolysaccharidosis III are characterized by severe degeneration of the central nervous system in combination with mild somatic manifestations, which is explained by the accumulation of high concentrations of heparan sulfate in the lysosomes of various cells, including the central nervous system. The primary biochemical defect in the most common type of mucopolysaccharidosis IIIA, occurring with a frequency of 1 : 105 and presented in 60% of all cases of the disease, is heparan-N-sulfatase, or sulfamidase deficiency. Mucopolysaccharidosis IIIB type occurs twice less often and accounts for about 30% of all cases of Sanfilippo syndrome. It is caused by the presence of inactivating mutations in the lysosomal -N-acetylglucosaminidase gene. Mucopolysaccharidosis IIIC and IIID are 4% and 6%, and occur at frequencies of 0.7 and 1.0 : 106. Mucopolysaccharidosis IIIC is caused by inactivating mutations in the gene of membrane-bound lysosomal acetyl-CoA:-glucosaminid-N-acetyltransferase, or N-acetyltransferase. Mucopolysaccharidosis IIID is based on the deficiency of lysosomal N-acetylglucosamine-6-sulfatase. The role of experimental models in the study of the biochemical basis of the pathogenesis of Sanfilippo syndrome and the development of various therapeutic approaches are discussed. The possibility of neonatal screening, early diagnosis, prevention and pathogenetic therapy of these severe lysosomal diseases are considered. As an example, a clinical case of diagnosis and treatment of a child with type IIIB mucopolysaccharidosis is presented.

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New Advanced Strategies for the Treatment of Lysosomal Diseases Affecting the Central Nervous System

Current Pharmaceutical Design ◽

10.2174/1381612825666190708213159 ◽

2019 ◽

Vol 25 (17) ◽

pp. 1933-1950 ◽

Cited By ~ 3

Author(s):

Maria R. Gigliobianco ◽

Piera Di Martino ◽

Siyuan Deng ◽

Cristina Casadidio ◽

Roberta Censi

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Polymeric Nanoparticles ◽

Genetic Diseases ◽

Point Of View ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Lysosomal Diseases ◽

The Central Nervous System ◽

Enzyme Delivery

Lysosomal Storage Disorders (LSDs), also known as lysosomal diseases (LDs) are a group of serious genetic diseases characterized by not only the accumulation of non-catabolized compounds in the lysosomes due to the deficiency of specific enzymes which usually eliminate these compounds, but also by trafficking, calcium changes and acidification. LDs mainly affect the central nervous system (CNS), which is difficult to reach for drugs and biological molecules due to the presence of the blood-brain barrier (BBB). While some therapies have proven highly effective in treating peripheral disorders in LD patients, they fail to overcome the BBB. Researchers have developed many strategies to circumvent this problem, for example, by creating carriers for enzyme delivery, which improve the enzyme’s half-life and the overexpression of receptors and transporters in the luminal or abluminal membranes of the BBB. This review aims to successfully examine the strategies developed during the last decade for the treatment of LDs, which mainly affect the CNS. Among the LD treatments, enzyme-replacement therapy (ERT) and gene therapy have proven effective, while nanoparticle, fusion protein, and small molecule-based therapies seem to offer considerable promise to treat the CNS pathology. This work also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs.

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Differential Effects of Three CanonicalToxoplasmaStrains on Gene Expression in Human Neuroepithelial Cells

Infection and Immunity ◽

10.1128/iai.00947-10 ◽

2010 ◽

Vol 79 (3) ◽

pp. 1363-1373 ◽

Cited By ~ 38

Author(s):

Jianchun Xiao ◽

Lorraine Jones-Brando ◽

C. Conover Talbot ◽

Robert H. Yolken

Keyword(s):

Gene Expression ◽

Central Nervous System ◽

Nervous System ◽

Nucleotide Metabolism ◽

Neural Cells ◽

Type I ◽

Type Ii ◽

Type Iii ◽

Neuroepithelial Cells ◽

The Central Nervous System

ABSTRACTStrain type is one of the key factors suspected to play a role in determining the outcome ofToxoplasmainfection. In this study, we examined the transcriptional profile of human neuroepithelioma cells in response to representative strains ofToxoplasmaby using microarray analysis to characterize the strain-specific host cell response. The study of neural cells is of interest in light of the ability ofToxoplasmato infect the brain and to establish persistent infection within the central nervous system. We found that the extents of the expression changes varied considerably among the three strains. Neuroepithelial cells infected withToxoplasmatype I exhibited the highest level of differential gene expression, whereas type II-infected cells had a substantially smaller number of genes which were differentially expressed. Cells infected with type III exhibited intermediate effects on gene expression. The three strains also differed in the individual genes and gene pathways which were altered following cellular infection. For example, gene ontology (GO) analysis indicated that type I infection largely affects genes related to the central nervous system, while type III infection largely alters genes which affect nucleotide metabolism; type II infection does not alter the expression of a clearly defined set of genes. Moreover, Ingenuity Pathways Analysis (IPA) suggests that the three lineages differ in the ability to manipulate their host; e.g., they employ different strategies to avoid, deflect, or subvert host defense mechanisms. These observed differences may explain some of the variation in the neurobiological effects of different strains ofToxoplasmaon infected individuals.

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