RARE DISEASE
Sanfilippo syndrome type C
Sanfilippo syndrome type C
Sanfilippo syndrome type C
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Synonyms: HGSNAT deficiency, Heparan-alpha-glucosaminide N-acetyltransferase deficiency, MPS3C, MPSIIIC, Mucopolysaccharidosis type 3C, Mucopolysaccharidosis type IIIC
Drug discovery
2
drugs
With orphan designations
Overview
Sanfilippo syndrome type C (MPS IIIC) is a rare autosomal recessive lysosomal storage disorder caused by HGSNAT gene mutations, leading to deficient heparan-alpha-glucosaminide N-acetyltransferase enzyme activity [6][11][14]. This results in heparan sulfate accumulation, causing progressive neurodegeneration [9][19]. Key features include developmental regression, hyperactivity, sleep disturbances, seizures, and severe cognitive decline [6][11][19]. Life expectancy typically extends to adolescence or early adulthood, with death often due to respiratory complications [6][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
112 drug discovery papers about Sanfilippo syndrome type C, with 6 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
112 drug discovery papers about Sanfilippo syndrome type C, with 6 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | NDST1 as a substrate-reduction target in Mucopolysaccharidosis type IIIC: virtual screening, microsecond molecular dynamics, and peptide design
ABSTRACT Mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) is a rare lysosomal storage disorder caused by loss-of-function mutations in HGSNAT , which encodes an enzyme involved in heparan sulfate (HS) degradation, leading to impaired HS catabolism, lysosomal accumulation, and progressive neurodegeneration. Because enzyme replacement therapies have limited penetration across the blood–brain barrier, substrate-reduction therapy represents an alternative therapeutic strategy. Here, N-deacetylase/N-sulfotransferase 1 (NDST1), a key enzyme responsible for HS biosynthesis, was investigated as a potential substrate-reduction target. A structure-based computational pipeline was used to identify and evaluate inhibitors targeting the NDST1 sulfotransferase domain. Approximately 4.1 million drug-like compounds and FDA-approved drugs were screened by molecular docking, followed by pharmacokinetic filtering, molecular dynamics simulations, and MM/PBSA binding free energy calculations. In parallel, peptide binders targeting the same site were generated using diffusion-based protein design and evaluated using molecular dynamics and MM/GBSA analysis. Four chemically distinct small-molecule scaffolds and three peptide candidates were identified as stable binders to the NDST1 active site. The lead small-molecule candidate exhibited a predicted binding free energy of −13.36 ± 5.87 kcal mol −1 . These provide a focused set of candidates for further investigation and support the feasibility of targeting NDST1 as a substrate-reduction strategy for MPS IIIC.
2026-08-01 | A Rare Septuagenarian Patient with a Mild Form of Mucopolysaccharidosis Type IIIC with Ocular Manifestations, a Case Report
Purpose: We present an atypical case of mucopolysaccharidosis (MPS) type IIIC to contribute to the growing understanding of its clinical heterogeneity and expand the known phenotypic spectrum of the disorder. This report describes one of the oldest known patients with genetically confirmed MPS IIIC. Case presentation: The patient received genetic testing in her seventies, revealing variations in the HGSNAT and NAGLU genes, two genes associated with MPS III. Her clinical presentation consisted primarily of retinal dystrophy, diagnosed via clinical presentation in addition to OCT and ERG. The patient also showed signs of peripheral neuropathy which were initially presumed to be idiopathic. She did not exhibit the typical behavioral involvement and craniofacial abnormalities expected of MPS type IIIC. Conclusions: This presentation broadens the recognized clinical spectrum of MPS IIIC and may facilitate earlier diagnosis in adults with similar, seemingly idiopathic findings. Improved recognition of such atypical cases may support timely genetic testing and potential therapeutic options.
2026-07-23 | Extracellular vesicles derived from cells overexpressing HGSNAT rescue defects in Mucopolysaccharidosis IIIC neurons
Summary Mucopolysaccharidosis III type C (MPS IIIC) is a rare neurological lysosomal storage disorder caused by genetic deficiency of the lysosomal membrane enzyme, heparan-α-glucosaminide N-acetyltransferase (HGSNAT). To assess the feasibility of therapeutic strategies based on cross-correction of neurons by HGSNAT secreted from transplanted cells overexpressing the enzyme, we generated induced cortical neurons (iCN) from induced pluripotent stem cells (iPSCs) derived from MPS IIIC patients. The neurons were treated with extracellular vesicles (EV) purified from the culture medium conditioned by human endothelial cells transduced with a lentiviral vector encoding EGFP-tagged HGSNAT (LV-HGSNAT-EGFP). The isolated EV showed supraphysiologic HGSNAT activity levels and efficiently delivered the enzyme to the lysosomes of MPS IIIC iCN reducing lysosomal size and restoring normal synaptic protein levels. EV-mediated delivery of HGSNAT to neurons was further confirmed by the analysis of MPS IIIC iCN either co-cultured with iPSC-derived MPS IIIC microglia (iMGL) transduced with LV-HGSNAT-EGFP or treated with the iMGL conditioned medium. MPS IIIC iCN co-cultured with iMGL overexpressing HGSNAT achieved a complete phenotypic rescue, including normalization of lysosomal size, and the levels of heparan sulfate, G M2 -ganglioside, synaptic proteins and brain-derived neurotropic factor. Treatment of MPS IIIC iCNs with conditioned medium led to a partial defects correction. Our findings reveal the translational potential of EV-mediated enzyme delivery in MPS IIIC patients treated with LV-mediated haematopoietic progenitor stem cell gene therapy.
2026-06-26 | Pathogenic Variants in HGSNAT associated with Autosomal Recessive Retinitis Pigmentosa without Overt Sanfilippo Syndrome.
Biallelic variants in the HGSNAT gene are associated with Sanfilippo syndrome, a rare lysosomal storage disorder caused by deficiency of heparan acetyl CoA glucosamine N-Acetyl-transferase enzyme(HGSNAT). The syndrome is characterized by multiple systemic findings, including progressive neurological and retinal degeneration. Retinitis pigmentosa due to HGSNAT gene variants are rarely reported without systemic manifestations. Here we describe two patients with retinitis pigmentosa and reduced enzymatic activity. One of our patients also had hearing loss. We also present a review of the literature for cases of non-syndromic retinal dystrophy associated with HGSNAT variants in the discussion. The first patient with retinitis pigmentosa and hearing loss has two variants of uncertain significance in the HGSNAT gene(p.Thr522Met and p.Cys79Arg). HGSNAT enzyme activity was 0.43nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). Our second patient with isolated retinitis pigmentosa has two heterozygous pathogenic variants in HGSNAT (p.Arg124Trp and p.Ala615Thr). HGSNAT enzyme activity was 1.13nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). The retinal findings are consistent with HGSNAT-related disease. The first case is the second report of retinitis pigmentosa and hearing loss linked to HGSNAT-related disease. Both cases showed reduced HGSNAT enzyme activity in blood. Although more evidence is needed to definitively link adult-onset hearing loss to HGSNAT variants, it may be due to reduced enzyme activity.
2026-04-29 | Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.
Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.
2026-08-11 | NDST1 as a substrate-reduction target in Mucopolysaccharidosis type IIIC: virtual screening, microsecond molecular dynamics, and peptide design
ABSTRACT Mucopolysaccharidosis IIIC (Sanfilippo syndrome type C) is a rare lysosomal storage disorder caused by loss-of-function mutations in HGSNAT , which encodes an enzyme involved in heparan sulfate (HS) degradation, leading to impaired HS catabolism, lysosomal accumulation, and progressive neurodegeneration. Because enzyme replacement therapies have limited penetration across the blood–brain barrier, substrate-reduction therapy represents an alternative therapeutic strategy. Here, N-deacetylase/N-sulfotransferase 1 (NDST1), a key enzyme responsible for HS biosynthesis, was investigated as a potential substrate-reduction target. A structure-based computational pipeline was used to identify and evaluate inhibitors targeting the NDST1 sulfotransferase domain. Approximately 4.1 million drug-like compounds and FDA-approved drugs were screened by molecular docking, followed by pharmacokinetic filtering, molecular dynamics simulations, and MM/PBSA binding free energy calculations. In parallel, peptide binders targeting the same site were generated using diffusion-based protein design and evaluated using molecular dynamics and MM/GBSA analysis. Four chemically distinct small-molecule scaffolds and three peptide candidates were identified as stable binders to the NDST1 active site. The lead small-molecule candidate exhibited a predicted binding free energy of −13.36 ± 5.87 kcal mol −1 . These provide a focused set of candidates for further investigation and support the feasibility of targeting NDST1 as a substrate-reduction strategy for MPS IIIC.
2026-08-01 | A Rare Septuagenarian Patient with a Mild Form of Mucopolysaccharidosis Type IIIC with Ocular Manifestations, a Case Report
Purpose: We present an atypical case of mucopolysaccharidosis (MPS) type IIIC to contribute to the growing understanding of its clinical heterogeneity and expand the known phenotypic spectrum of the disorder. This report describes one of the oldest known patients with genetically confirmed MPS IIIC. Case presentation: The patient received genetic testing in her seventies, revealing variations in the HGSNAT and NAGLU genes, two genes associated with MPS III. Her clinical presentation consisted primarily of retinal dystrophy, diagnosed via clinical presentation in addition to OCT and ERG. The patient also showed signs of peripheral neuropathy which were initially presumed to be idiopathic. She did not exhibit the typical behavioral involvement and craniofacial abnormalities expected of MPS type IIIC. Conclusions: This presentation broadens the recognized clinical spectrum of MPS IIIC and may facilitate earlier diagnosis in adults with similar, seemingly idiopathic findings. Improved recognition of such atypical cases may support timely genetic testing and potential therapeutic options.
2026-07-23 | Extracellular vesicles derived from cells overexpressing HGSNAT rescue defects in Mucopolysaccharidosis IIIC neurons
Summary Mucopolysaccharidosis III type C (MPS IIIC) is a rare neurological lysosomal storage disorder caused by genetic deficiency of the lysosomal membrane enzyme, heparan-α-glucosaminide N-acetyltransferase (HGSNAT). To assess the feasibility of therapeutic strategies based on cross-correction of neurons by HGSNAT secreted from transplanted cells overexpressing the enzyme, we generated induced cortical neurons (iCN) from induced pluripotent stem cells (iPSCs) derived from MPS IIIC patients. The neurons were treated with extracellular vesicles (EV) purified from the culture medium conditioned by human endothelial cells transduced with a lentiviral vector encoding EGFP-tagged HGSNAT (LV-HGSNAT-EGFP). The isolated EV showed supraphysiologic HGSNAT activity levels and efficiently delivered the enzyme to the lysosomes of MPS IIIC iCN reducing lysosomal size and restoring normal synaptic protein levels. EV-mediated delivery of HGSNAT to neurons was further confirmed by the analysis of MPS IIIC iCN either co-cultured with iPSC-derived MPS IIIC microglia (iMGL) transduced with LV-HGSNAT-EGFP or treated with the iMGL conditioned medium. MPS IIIC iCN co-cultured with iMGL overexpressing HGSNAT achieved a complete phenotypic rescue, including normalization of lysosomal size, and the levels of heparan sulfate, G M2 -ganglioside, synaptic proteins and brain-derived neurotropic factor. Treatment of MPS IIIC iCNs with conditioned medium led to a partial defects correction. Our findings reveal the translational potential of EV-mediated enzyme delivery in MPS IIIC patients treated with LV-mediated haematopoietic progenitor stem cell gene therapy.
2026-06-26 | Pathogenic Variants in HGSNAT associated with Autosomal Recessive Retinitis Pigmentosa without Overt Sanfilippo Syndrome.
Biallelic variants in the HGSNAT gene are associated with Sanfilippo syndrome, a rare lysosomal storage disorder caused by deficiency of heparan acetyl CoA glucosamine N-Acetyl-transferase enzyme(HGSNAT). The syndrome is characterized by multiple systemic findings, including progressive neurological and retinal degeneration. Retinitis pigmentosa due to HGSNAT gene variants are rarely reported without systemic manifestations. Here we describe two patients with retinitis pigmentosa and reduced enzymatic activity. One of our patients also had hearing loss. We also present a review of the literature for cases of non-syndromic retinal dystrophy associated with HGSNAT variants in the discussion. The first patient with retinitis pigmentosa and hearing loss has two variants of uncertain significance in the HGSNAT gene(p.Thr522Met and p.Cys79Arg). HGSNAT enzyme activity was 0.43nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). Our second patient with isolated retinitis pigmentosa has two heterozygous pathogenic variants in HGSNAT (p.Arg124Trp and p.Ala615Thr). HGSNAT enzyme activity was 1.13nmol/17hr/mg(normal:5.8-45nmol/17hr/mg protein). The retinal findings are consistent with HGSNAT-related disease. The first case is the second report of retinitis pigmentosa and hearing loss linked to HGSNAT-related disease. Both cases showed reduced HGSNAT enzyme activity in blood. Although more evidence is needed to definitively link adult-onset hearing loss to HGSNAT variants, it may be due to reduced enzyme activity.
2026-04-29 | Short-Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With MPS III.
Mucopolysaccharidosis type III (MPS III) is a group of autosomal recessive neurodegenerative lysosomal storage disorders that causes progressive cognitive and physical impairment, predominantly in child/early adulthood. The median age of death is 17 years as there is no safe, effective treatment approved. Using faithful Drosophila and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up-regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down-regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short-term studies, food enriched with 5 mM spermidine improved overall fly activity and climbing ability. A 4-week study in pre-symptomatic MPS IIIA mice (3- or 6-mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer-term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.
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Drug Discovery Landscape
2 orphan drug designations for Sanfilippo syndrome type C.
2 orphan drug designations for Sanfilippo syndrome type C.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector 9-containing the human heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT) gene (AAV9- HGSNAT) | gene therapies | FDA | 2019-01-16 | — | Phoenix Nest, Inc. |
Adeno-associated viral vector serotype 9 containing the human HGSNAT gene | gene therapies | EMA | 2015-05-21 | — | Cochamo Pharma Limited |
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