RARE DISEASE
Multiple sulfatase deficiency
Multiple sulfatase deficiency
Multiple sulfatase deficiency
Synonyms: Austin disease, MSD, Mucosulfatidosis
Synonyms: Austin disease, MSD, Mucosulfatidosis
Synonyms: Austin disease, MSD, Mucosulfatidosis
Drug discovery
1
drug
With orphan designation
Overview
Multiple sulfatase deficiency (MSD) is an ultra-rare autosomal recessive lysosomal storage disorder caused by SUMF1 gene mutations, impairing post-translational activation of sulfatase enzymes [1][2][4]. This results in widespread accumulation of sulfated substrates (e.g., glycosaminoglycans, sulfatides), causing multi-system manifestations: neurodevelopmental regression, leukodystrophy, ichthyosis, skeletal anomalies (dysostosis multiplex), and organomegaly [1][9][12]. Classified into neonatal (most severe), late-infantile (most common), and juvenile forms, prognosis is poor with progressive neurodegeneration and reduced life expectancy [2][6][7].
Burden
High morbidity: Progressive neurologic deterioration (motor/cognitive regression, seizures), multisystem complications (hepatosplenomegaly, skeletal deformities) [1][12][19]
Mortality: Median survival ~13 years; neonatal forms often fatal within 1–2 years [2][7][19]
Caregiver burden: Intensive daily care needs due to rapid functional decline and complex medical requirements [12][19]
Therapies
Supportive care: Multidisciplinary management (physiotherapy, skin care, seizure control, and organ-specific monitoring) [2][12]
Experimental therapies: Ex vivo hematopoietic stem cell gene therapy (lentiviral SUMF1 delivery) shows biochemical and functional improvements in preclinical models [3][13][18]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
50 drug discovery papers about Multiple sulfatase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
50 drug discovery papers about Multiple sulfatase deficiency, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | New structures of human formylglycine-generating enzyme reveal features important for catalysis, disease and structure-based drug design.
The formylglycine-generating enzyme (FGE) post-translationally modifies the active site of all human sulfatases. Mutations in the SUMF1 gene encoding FGE may lead to catalytically inactive FGE or destabilize the protein. The resulting lack of sulfatase modification causes the rare disease multiple sulfatase deficiency (MSD). Previously, FGE required elastase treatment for crystallization and the structures lacked copper, although FGE is a copper-dependent enzyme. Here, we show that highly active human FGE purified from insect cells natively contains one copper ion and we report six new crystal structures revealing previously unobserved features. Several structures contain the catalytic copper ion coordinated almost linearly by the two catalytic cysteines. A structure of the MSD-causing E130D variant shows distortions in coordination of a structural Ca2+ explaining its lower stability. As part of exploratory ligand-soaking experiments, a structure of FGE soaked with N-acetyl cysteine methyl ester shows the binding of a small molecule to a site other than the active site highlighting a potential binding site to be explored in the development of pharmacological chaperones for FGE. Crystallization of FGE without elastase treatment resulted in a structure in which the previously missing loop is well defined in the electron density and partly covers the active site, indicating that it needs to adopt a different conformation for substrate binding. This assumption is supported by a second structure in which the loop faces away from the active site and leaves the substrate binding groove open and by the occasional occurrence of crystals in which the loop becomes disordered.
2026-01-01 | N-acetyl-L-leucine in Neurological Disorders: Mechanisms, Evidence, and Therapeutic Perspectives.
N-acetyl-L-leucine (NALL), a stereospecific derivative of the essential amino acid L-leucine, has attracted increasing attention as a candidate therapy for neurological disorders. Preclinical and clinical studies suggest both symptomatic and neuroprotective effects. This review summarizes evidence on the mechanisms of action, preclinical findings, and clinical outcomes of NALL, and discusses its therapeutic prospects in neurological health and disease. A structured literature search of PubMed, Scopus, and Google Scholar was conducted to identify preclinical and clinical studies evaluating N-acetyl-L-leucine (NALL) in neurological disorders. Preclinical studies demonstrated that NALL enhances mitochondrial bioenergetics, reduces oxidative stress, restores lysosomal and autophagic function, and modulates neuroinflammation. In rodent models, NALL improved motor coordination, neuronal survival, and recovery following traumatic brain injury. Clinical trials in Niemann-Pick disease type C and GM2 gangliosidoses showed improvements in motor function, quality of life, and disease progression, with sustained benefit during extension phases. Preliminary evidence also suggests possible roles in multiple sclerosis, ataxia telangiectasia, Parkinson’s disease, and multiple sulfatase deficiency. NALL was consistently well tolerated with a favorable safety profile. NALL shows multimodal mechanisms and promising translational potential for both rare and common neurological disorders. While early evidence is encouraging, larger randomized trials are required to confirm efficacy, define optimal dosing, and determine its place in neurological therapeutics.
2025-04-12 | Repurposing Tazarotene for Multiple Sulfatase Deficiency: A Path TowardClinical Application
Despite increasing research efforts, Multiple Sulfatase Deficiency (MSD, MIM #272200) remains an untreatable disease with a high unmet medical need. Various therapeutic approaches, including gene therapy and hematopoietic stem cell transplantation, have been explored. Among them, small-molecule drug identification has been a key strategy for therapy development. Drug repurposing—repositioning existing medications for new indications—
offers a fast-track route to treatment by leveraging existing knowledge on formulation, toxicity, dosage, safety, and side effects. This significantly reduces the time and cost associated with early pharmacological and clinical development. A high-throughput drug screening on MSD patient-derived cells identified tazarotene, a third-generation retinoic acid derivative, as a potential therapeutic candidate capable of reversing disease pathology in vitro. Currently approved for topical treatment of plaque psoriasis and acne, tazarotene was previously evaluated for oral administration in clinical trials (Phase I–III) with approximately 1,500 participants. While proven efficacious for its intended indications, oral tazarotene was not licensed by the FDA due to post-marketing safety monitoring concerns.As part of the REMEDI4ALL initiative, an EU-funded consortium of 24 partners—including academia,
industry, patient organizations, and regulatory agencies—tazarotene has been selected as a demonstrator project for drug repurposing. REMEDI4ALL has facilitated a target product profile and gap analysis, leading to reformulation, evaluation, and production of oral tazarotene for clinical development in MSD. Collaboration with the pharmaceutical industry ensures
access to existing toxicity, preclinical, and clinical data, aiding regulatory processes. These efforts have culminated in scientific advice meetings with regulators, paving the way for the first clinical trial in MSD patients, scheduled to begin by the end of 2025.
2025-01-10 | Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series.
Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome. Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells. There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition. These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
2026-08-11 | New structures of human formylglycine-generating enzyme reveal features important for catalysis, disease and structure-based drug design.
The formylglycine-generating enzyme (FGE) post-translationally modifies the active site of all human sulfatases. Mutations in the SUMF1 gene encoding FGE may lead to catalytically inactive FGE or destabilize the protein. The resulting lack of sulfatase modification causes the rare disease multiple sulfatase deficiency (MSD). Previously, FGE required elastase treatment for crystallization and the structures lacked copper, although FGE is a copper-dependent enzyme. Here, we show that highly active human FGE purified from insect cells natively contains one copper ion and we report six new crystal structures revealing previously unobserved features. Several structures contain the catalytic copper ion coordinated almost linearly by the two catalytic cysteines. A structure of the MSD-causing E130D variant shows distortions in coordination of a structural Ca2+ explaining its lower stability. As part of exploratory ligand-soaking experiments, a structure of FGE soaked with N-acetyl cysteine methyl ester shows the binding of a small molecule to a site other than the active site highlighting a potential binding site to be explored in the development of pharmacological chaperones for FGE. Crystallization of FGE without elastase treatment resulted in a structure in which the previously missing loop is well defined in the electron density and partly covers the active site, indicating that it needs to adopt a different conformation for substrate binding. This assumption is supported by a second structure in which the loop faces away from the active site and leaves the substrate binding groove open and by the occasional occurrence of crystals in which the loop becomes disordered.
2026-01-01 | N-acetyl-L-leucine in Neurological Disorders: Mechanisms, Evidence, and Therapeutic Perspectives.
N-acetyl-L-leucine (NALL), a stereospecific derivative of the essential amino acid L-leucine, has attracted increasing attention as a candidate therapy for neurological disorders. Preclinical and clinical studies suggest both symptomatic and neuroprotective effects. This review summarizes evidence on the mechanisms of action, preclinical findings, and clinical outcomes of NALL, and discusses its therapeutic prospects in neurological health and disease. A structured literature search of PubMed, Scopus, and Google Scholar was conducted to identify preclinical and clinical studies evaluating N-acetyl-L-leucine (NALL) in neurological disorders. Preclinical studies demonstrated that NALL enhances mitochondrial bioenergetics, reduces oxidative stress, restores lysosomal and autophagic function, and modulates neuroinflammation. In rodent models, NALL improved motor coordination, neuronal survival, and recovery following traumatic brain injury. Clinical trials in Niemann-Pick disease type C and GM2 gangliosidoses showed improvements in motor function, quality of life, and disease progression, with sustained benefit during extension phases. Preliminary evidence also suggests possible roles in multiple sclerosis, ataxia telangiectasia, Parkinson’s disease, and multiple sulfatase deficiency. NALL was consistently well tolerated with a favorable safety profile. NALL shows multimodal mechanisms and promising translational potential for both rare and common neurological disorders. While early evidence is encouraging, larger randomized trials are required to confirm efficacy, define optimal dosing, and determine its place in neurological therapeutics.
2025-04-12 | Repurposing Tazarotene for Multiple Sulfatase Deficiency: A Path TowardClinical Application
Despite increasing research efforts, Multiple Sulfatase Deficiency (MSD, MIM #272200) remains an untreatable disease with a high unmet medical need. Various therapeutic approaches, including gene therapy and hematopoietic stem cell transplantation, have been explored. Among them, small-molecule drug identification has been a key strategy for therapy development. Drug repurposing—repositioning existing medications for new indications—
offers a fast-track route to treatment by leveraging existing knowledge on formulation, toxicity, dosage, safety, and side effects. This significantly reduces the time and cost associated with early pharmacological and clinical development. A high-throughput drug screening on MSD patient-derived cells identified tazarotene, a third-generation retinoic acid derivative, as a potential therapeutic candidate capable of reversing disease pathology in vitro. Currently approved for topical treatment of plaque psoriasis and acne, tazarotene was previously evaluated for oral administration in clinical trials (Phase I–III) with approximately 1,500 participants. While proven efficacious for its intended indications, oral tazarotene was not licensed by the FDA due to post-marketing safety monitoring concerns.As part of the REMEDI4ALL initiative, an EU-funded consortium of 24 partners—including academia,
industry, patient organizations, and regulatory agencies—tazarotene has been selected as a demonstrator project for drug repurposing. REMEDI4ALL has facilitated a target product profile and gap analysis, leading to reformulation, evaluation, and production of oral tazarotene for clinical development in MSD. Collaboration with the pharmaceutical industry ensures
access to existing toxicity, preclinical, and clinical data, aiding regulatory processes. These efforts have culminated in scientific advice meetings with regulators, paving the way for the first clinical trial in MSD patients, scheduled to begin by the end of 2025.
2025-01-10 | Bone marrow transplantation reverses metabolic alterations in multiple sulfatase deficiency: a case series.
Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome. Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells. There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition. These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.
2024-10-25 | Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model.
Multiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD. To test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive). After 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain. Our results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Multiple sulfatase deficiency.
1 orphan drug designation for Multiple sulfatase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant serotype 9 adeno-associated virus encoding codon optimized human sulfatase modifying factor 1 | gene therapies | FDA | 2024-09-20 | — | National Center for Advancing Translational Sciences, National Institutes of Health |
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