RARE DISEASE
X-linked intellectual disability, Snyder type
X-linked intellectual disability, Snyder type
X-linked intellectual disability, Snyder type
Synonyms: Snyder-Robinson syndrome
Synonyms: Snyder-Robinson syndrome
Synonyms: Snyder-Robinson syndrome
Drug discovery
0
drugs
With orphan designations
Overview
X-linked intellectual disability, Snyder type (Snyder-Robinson syndrome) is a rare X-linked recessive disorder caused by SMS gene mutations, leading to spermine synthase deficiency. It manifests in males with moderate-severe intellectual disability, hypotonia, osteoporosis, kyphoscoliosis, facial asymmetry, and speech impairments. Clinical features include asthenic build, gait abnormalities, and seizures. Diagnosis involves genetic testing for SMS variants, with management focused on symptomatic support [1][3][9][13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
31 drug discovery papers about X-linked intellectual disability, Snyder type, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
31 drug discovery papers about X-linked intellectual disability, Snyder type, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-31 | An improved SMS p.Gly56Ser mouse model of Snyder-Robinson syndrome reveals phenotypic parallels with clinical features.
Snyder-Robinson syndrome (SRS), a rare X-linked disorder caused by pathogenic variants in spermine synthase (SMS), results in spermine deficiency and excessive spermidine accumulation. Previously reported mouse models exhibited reduced birthrate and survival of affected males, greatly limiting their experimental utility. Here we describe a new mouse model carrying the clinically relevant Sms p.Gly56Ser (SmsG56S) allele in which viable males are recovered at Mendelian ratios, enabling generation of adequately powered cohorts. Hemizygous males produce markedly reduced SMS protein across tissues, recreating the biochemical hallmark of SRS, an elevated spermidine:spermine ratio. SmsG56S/Y males exhibit reduced body size, altered body composition, decreased locomotor and exploratory behaviors, and reduced seizure threshold, aligning with clinical features reported in SRS patients. Serum LDL, HDL, and cholesterol levels were reduced, while brain histology revealed modest region-specific astrocytic changes. Comprehensive polyamine profiling revealed tissue-specific biochemical disturbances, highlighting putrescine elevation in the brain and informing development of translational strategies and windows for intervention. Overall, this improved model reproduces multiple key aspects of the human SRS phenotype and provides a robust platform for mechanistic studies and preclinical evaluation of therapies.
2026-06-07 | Metabolic alterations in Snyder-Robinson syndrome lymphoblasts are ameliorated by phenylbutyrate treatment.
Snyder-Robinson syndrome (SRS) is an X-linked polyaminopathy caused by pathogenic variants in the spermine synthase (SMS) gene, resulting in impaired spermine synthesis, accumulation of spermidine, and widespread cellular dysfunction. Although mitochondrial impairment has been implicated in SRS, the impact of SMS deficiency on cellular energy metabolism has not been systematically characterized. In the present study, we performed high-throughput metabolic profiling of 29 patient-derived lymphoblastoid cell lines using Biolog Phenotype Mammalian Microarrays. SRS cells exhibited broad metabolic rewiring, including reduced utilization of galactose, and compensatory increases in the metabolism of d-fructose, maltose, maltotriose, and a- keto-glutaric acid. They also showed attenuated metabolic responses to ionic perturbations and blunted sensitivity to insulin and glucagon, indicating defects in both mitochondrial substrate preference and signal-dependent metabolic regulation. Treatment with phenylbutyrate (PBA), previously shown to modulate polyamine catabolism, partially restored metabolic flexibility and normalized several impaired nutrient pathways. These findings highlight global energy metabolism dysregulation as a hallmark of SRS and support PBA as a promising therapeutic candidate for correcting bioenergetic defects in this disorder.
2026-01-24 | Polyamine dysregulation converges with RASopathies on RAS/MAPK and sensory processing phenotypes in Drosophila
ABSTRACT RASopathies are developmental conditions associated with cognitive and sensory processing impairments. They are caused by pathogenic variants in genes that result in overactivation of the RAS/MAPK signaling pathway. Genes linked to this pathway have been reported to be enriched among Drosophila models with habituation deficits, a behavioral phenotype reflecting sensory filtering. To identify hidden RASopathies – monogenic disorders that converge on RAS/MAPK overactivation without being classically linked to the pathway – we generated 89 and screened 41 viable habituation-deficient Drosophila RNAi models for RAS/MAPK overactivation, measured as an increased phosphorylated ERK to ERK ratio. This screen identified Sms , the ortholog of human spermine synthase ( SMS ), implicated in Snyder-Robinson syndrome. RAS/MAPK overactivation along with hyperreactivity and habituation impairments are confirmed in a full loss-of-function mutant. A RNAi screen targeting polyamine pathway genes identified Sat (human SAT1/2 , SATL1 ) to reproduce these phenotypes. Knockdown of Sms or Sat in GABAergic neurons impaired habituation, implicating polyamine metabolism in inhibitory circuit function. These findings reveal previously unrecognized convergence between polyamine dysregulation and RASopathies, suggesting shared therapeutic opportunities through modulation of either pathway. SUMMARY STATEMENT Using Drosophila , we uncovered polyamine metabolism genes, Sms and Sat , as modulators of RAS/MAPK and sensory processing, revealing a shared mechanism between polyaminopathies and RASopathies that may inform unified therapies.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-05-18 | Methods to study polyamine metabolism during osteogenesis.
Mammalian polyamines, namely putrescine, spermidine, and spermine, have been implicated in many cellular homeostatic processes. Polyamines play a critical role in skeletal health as evidenced by recent studies and by skeletal disorders caused by polyamine imbalances, such as Snyder-Robinson Syndrome (SRS). However, very little is still known about the role of polyamines within bone development, homeostasis, and metabolism. Human bone marrow derived mesenchymal stromal cells (MSCs) provide a unique opportunity to study polyamines at a cellular and molecular level within the context of osteogenic differentiation and calcium deposition. Through in vitro work, mechanistic understanding of the role of polyamines within osteogenesis as well as the consequences of polyamine imbalance can provide new insights into potential therapeutics for those experiencing polyaminopathies. This chapter describes procedures to develop a human primary cell culture system and quantify osteoblastogenesis as a function of polyamine modulation.
proteins
2026-07-01 | Snyder-Robinson Syndrome Presenting with Severe Osteoporosis and Fragility Fracture: A Case Report and Literature Review
Background/Objective Snyder-Robinson syndrome (SRS) is an extremely rare X-linked genetic disorder caused by mutations in the spermine synthase (SMS) gene. SMS gene encodes spermine synthase enzyme which is essential for producing spermine, a polyamine that plays a crucial role in various cellular functions like growth and repair. Patients often present with intellectual disability, hypotonia, seizures, scoliosis, and progressive bone fragility. Case report: We report the case of a 22-year-old male that presented with multiple fragility fractures and osteogenesis imperfecta-like features that was ultimately confirmed to have Snyder-Robinson Syndrome. Discussion: Despite long-term bisphosphonate therapy, patient developed more fragility fractures and transitioned to anabolic therapy with abaloparatide with stable laboratory parameters and no new interval fractures. Conclusion This case highlights the endocrine related manifestations of the syndrome, therapeutic challenges, and the importance of multidisciplinary management in rare metabolic bone disorders.
2025-05-18 | Gene replacement therapy to restore polyamine metabolism in a Snyder-Robinson syndrome mouse model.
Polyamines, including putrescine, spermidine, and spermine, are organic cations essential for cell growth, proliferation, and tissue regeneration. Their levels are tightly regulated by a set of enzymes controlling their biosynthesis, catabolism, and interconversion. Dysregulation of polyamine metabolism is associated with a group of rare genetic neurodevelopmental disorders collectively known as "polyaminopathies", including Snyder-Robinson Syndrome (SRS). SRS is an X-linked recessive disorder caused by mutations in the SMS gene, which encodes the spermine synthase enzyme. The lack of spermine synthase leads to aberrant polyamine levels and neurological impairments, as observed in patients and animal models. Currently, there are no available treatment options for SRS. Due to its monogenic nature, SRS is an excellent candidate for gene replacement therapy. The recent success of Zolgensma in treating children with Spinal Muscular Atrophy and the establishment of Platform Vector Gene Therapy (Pave-GT) initiative at the National Institute of Health (NIH) offer a framework to adapt-and-apply the same gene delivery system for multiple rare disease gene therapies. This chapter outlines strategies for delivering a functional copy of the SMS gene using an adeno-associated viral (AAV) vector, as well as methods to evaluate the molecular efficacy of this approach in an SRS mouse model. Our ultimate goal is to establish a versatile platform for genetic interventions targeting SRS and other polyaminopathies.
2015-06-15 | Wnt-related SynGAP1 is a neuroprotective factor of glutamatergic synapses against Aβ oligomers
Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Aβ oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored. That is why we aim to study the relationship between Wnt-5a and miRNAs in glutamatergic synapses. We performed in silico analysis which predicted that miR-101b may inhibits the expression of SynGAP1, a Ras GTPase-activating protein critical for the development of cognition and proper synaptic function. Through overexpression of miR-101b, we showed that miR-101b is able to regulate the expression of SynGAP1 in an hippocampal cell line. Moreover and consistent with a decrease of miR-101b, Wnt-5a enhances SynGAP expression in cultured hippocampal neurons. Additionally, Wnt-5a increases the activity of SynGAP in a time-dependent manner, with a similar kinetic to CaMKII phosphorylation. This also, correlates with a modulation in the SynGAP clusters density. On the other hand, Aβ oligomers permanently decrease the number of SynGAP clusters. Interestingly, when neurons are co-incubated with Wnt-5a and Aβ oligomers, we do not observe the detrimental effect of Aβ oligomers, indicating that, Wnt-5a protects neurons from the synaptic failure triggered by Aβ oligomers. Overall, our findings suggest that SynGAP1 is part of the signaling pathways induced by Wnt-5a. Therefore, possibility exists that SynGAP is involved in the synaptic protection against Aβ oligomers
2013-02-28 | Enhancing Human Spermine Synthase Activity by Engineered Mutations
Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an artificial engineering of a more efficient SMS variant by transferring sequence information from another organism. It is confirmed experimentally that the variant, bearing four amino acid substitutions, is catalytically more active than the wild type. The increased functionality is attributed to enhanced monomer stability, lowering the pKa of proton donor catalytic residue, optimized spatial distribution of the electrostatic potential around the SMS with respect to substrates, and increase of the frequency of mechanical vibration of the clefts presumed to be the gates toward the active sites. The study demonstrates that wild type SMS is not particularly evolutionarily optimized with respect to the reaction spermidine → spermine. Having in mind that currently there are no variations (non-synonymous single nucleotide polymorphism, nsSNP) detected in healthy individuals, it can be speculated that the human SMS function is precisely tuned toward its wild type and any deviation is unwanted and disease-causing.
2013-01-29 | Enhancing Human Spermine Synthase Activity by Site Directed Mutations
Spermine Synthase (SMS) is an enzyme converting spermidine into spermine, both of which are polyamines controlling normal cell growth and development. Several missense mutations in human SMS (HsSMS) are known to cause Snyder-Robinson Syndrome (SRS) by either destabilizing the monomer/dimer conformation or directly affecting the hydrogen bond network in the active sites. Recently a comparison of protein sequence and crystal structure between the HsSMS and its homologous protein Thermotoga maritima (Tm) spermidine synthase (TmSRM) was performed. Tm is the only bacterium known to grow at a high temperature as well as 90°C, and the half-life of TmSRM is longer than 25h under this temperature. In contrast, HsSMS is much less stable than TmSRM under the same temperature. Sequence alignment between HsSMS and TmSRM suggests that some key residues may be essential players for the elevate stability of TmSRM. Such key residues were identified based on various biophysical and sequence criteria and four mutations (S165D, L175E, T178H and C206R) were selected for HsSMS. Both in silico and in vitro experiments indicated that these four mutations strongly stabilize the monomer structure and dramatically improve the efficiency of SPM synthesis. The enhanced reaction rate in the mutant HsSMS is attributed to the increase of the strength of negative electrostatic potential, calculated with DelPhi, in the dimer cleft between HsSMS units, which presumably facilitates the substrate delivery to the active site. The work was supported by a grant from the Institute of General Medical Sciences, National Institutes of Health, and the grant number is 1R01GM093937.
gene therapies
2025-12-18 | Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.
Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.
small molecules
2026-07-31 | An improved SMS p.Gly56Ser mouse model of Snyder-Robinson syndrome reveals phenotypic parallels with clinical features.
Snyder-Robinson syndrome (SRS), a rare X-linked disorder caused by pathogenic variants in spermine synthase (SMS), results in spermine deficiency and excessive spermidine accumulation. Previously reported mouse models exhibited reduced birthrate and survival of affected males, greatly limiting their experimental utility. Here we describe a new mouse model carrying the clinically relevant Sms p.Gly56Ser (SmsG56S) allele in which viable males are recovered at Mendelian ratios, enabling generation of adequately powered cohorts. Hemizygous males produce markedly reduced SMS protein across tissues, recreating the biochemical hallmark of SRS, an elevated spermidine:spermine ratio. SmsG56S/Y males exhibit reduced body size, altered body composition, decreased locomotor and exploratory behaviors, and reduced seizure threshold, aligning with clinical features reported in SRS patients. Serum LDL, HDL, and cholesterol levels were reduced, while brain histology revealed modest region-specific astrocytic changes. Comprehensive polyamine profiling revealed tissue-specific biochemical disturbances, highlighting putrescine elevation in the brain and informing development of translational strategies and windows for intervention. Overall, this improved model reproduces multiple key aspects of the human SRS phenotype and provides a robust platform for mechanistic studies and preclinical evaluation of therapies.
2026-06-07 | Metabolic alterations in Snyder-Robinson syndrome lymphoblasts are ameliorated by phenylbutyrate treatment.
Snyder-Robinson syndrome (SRS) is an X-linked polyaminopathy caused by pathogenic variants in the spermine synthase (SMS) gene, resulting in impaired spermine synthesis, accumulation of spermidine, and widespread cellular dysfunction. Although mitochondrial impairment has been implicated in SRS, the impact of SMS deficiency on cellular energy metabolism has not been systematically characterized. In the present study, we performed high-throughput metabolic profiling of 29 patient-derived lymphoblastoid cell lines using Biolog Phenotype Mammalian Microarrays. SRS cells exhibited broad metabolic rewiring, including reduced utilization of galactose, and compensatory increases in the metabolism of d-fructose, maltose, maltotriose, and a- keto-glutaric acid. They also showed attenuated metabolic responses to ionic perturbations and blunted sensitivity to insulin and glucagon, indicating defects in both mitochondrial substrate preference and signal-dependent metabolic regulation. Treatment with phenylbutyrate (PBA), previously shown to modulate polyamine catabolism, partially restored metabolic flexibility and normalized several impaired nutrient pathways. These findings highlight global energy metabolism dysregulation as a hallmark of SRS and support PBA as a promising therapeutic candidate for correcting bioenergetic defects in this disorder.
2026-01-24 | Polyamine dysregulation converges with RASopathies on RAS/MAPK and sensory processing phenotypes in Drosophila
ABSTRACT RASopathies are developmental conditions associated with cognitive and sensory processing impairments. They are caused by pathogenic variants in genes that result in overactivation of the RAS/MAPK signaling pathway. Genes linked to this pathway have been reported to be enriched among Drosophila models with habituation deficits, a behavioral phenotype reflecting sensory filtering. To identify hidden RASopathies – monogenic disorders that converge on RAS/MAPK overactivation without being classically linked to the pathway – we generated 89 and screened 41 viable habituation-deficient Drosophila RNAi models for RAS/MAPK overactivation, measured as an increased phosphorylated ERK to ERK ratio. This screen identified Sms , the ortholog of human spermine synthase ( SMS ), implicated in Snyder-Robinson syndrome. RAS/MAPK overactivation along with hyperreactivity and habituation impairments are confirmed in a full loss-of-function mutant. A RNAi screen targeting polyamine pathway genes identified Sat (human SAT1/2 , SATL1 ) to reproduce these phenotypes. Knockdown of Sms or Sat in GABAergic neurons impaired habituation, implicating polyamine metabolism in inhibitory circuit function. These findings reveal previously unrecognized convergence between polyamine dysregulation and RASopathies, suggesting shared therapeutic opportunities through modulation of either pathway. SUMMARY STATEMENT Using Drosophila , we uncovered polyamine metabolism genes, Sms and Sat , as modulators of RAS/MAPK and sensory processing, revealing a shared mechanism between polyaminopathies and RASopathies that may inform unified therapies.
2025-11-01 | Spermine synthase in Snyder-Robinson syndrome and cancer.
Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.
2025-05-18 | Methods to study polyamine metabolism during osteogenesis.
Mammalian polyamines, namely putrescine, spermidine, and spermine, have been implicated in many cellular homeostatic processes. Polyamines play a critical role in skeletal health as evidenced by recent studies and by skeletal disorders caused by polyamine imbalances, such as Snyder-Robinson Syndrome (SRS). However, very little is still known about the role of polyamines within bone development, homeostasis, and metabolism. Human bone marrow derived mesenchymal stromal cells (MSCs) provide a unique opportunity to study polyamines at a cellular and molecular level within the context of osteogenic differentiation and calcium deposition. Through in vitro work, mechanistic understanding of the role of polyamines within osteogenesis as well as the consequences of polyamine imbalance can provide new insights into potential therapeutics for those experiencing polyaminopathies. This chapter describes procedures to develop a human primary cell culture system and quantify osteoblastogenesis as a function of polyamine modulation.
proteins
2026-07-01 | Snyder-Robinson Syndrome Presenting with Severe Osteoporosis and Fragility Fracture: A Case Report and Literature Review
Background/Objective Snyder-Robinson syndrome (SRS) is an extremely rare X-linked genetic disorder caused by mutations in the spermine synthase (SMS) gene. SMS gene encodes spermine synthase enzyme which is essential for producing spermine, a polyamine that plays a crucial role in various cellular functions like growth and repair. Patients often present with intellectual disability, hypotonia, seizures, scoliosis, and progressive bone fragility. Case report: We report the case of a 22-year-old male that presented with multiple fragility fractures and osteogenesis imperfecta-like features that was ultimately confirmed to have Snyder-Robinson Syndrome. Discussion: Despite long-term bisphosphonate therapy, patient developed more fragility fractures and transitioned to anabolic therapy with abaloparatide with stable laboratory parameters and no new interval fractures. Conclusion This case highlights the endocrine related manifestations of the syndrome, therapeutic challenges, and the importance of multidisciplinary management in rare metabolic bone disorders.
2025-05-18 | Gene replacement therapy to restore polyamine metabolism in a Snyder-Robinson syndrome mouse model.
Polyamines, including putrescine, spermidine, and spermine, are organic cations essential for cell growth, proliferation, and tissue regeneration. Their levels are tightly regulated by a set of enzymes controlling their biosynthesis, catabolism, and interconversion. Dysregulation of polyamine metabolism is associated with a group of rare genetic neurodevelopmental disorders collectively known as "polyaminopathies", including Snyder-Robinson Syndrome (SRS). SRS is an X-linked recessive disorder caused by mutations in the SMS gene, which encodes the spermine synthase enzyme. The lack of spermine synthase leads to aberrant polyamine levels and neurological impairments, as observed in patients and animal models. Currently, there are no available treatment options for SRS. Due to its monogenic nature, SRS is an excellent candidate for gene replacement therapy. The recent success of Zolgensma in treating children with Spinal Muscular Atrophy and the establishment of Platform Vector Gene Therapy (Pave-GT) initiative at the National Institute of Health (NIH) offer a framework to adapt-and-apply the same gene delivery system for multiple rare disease gene therapies. This chapter outlines strategies for delivering a functional copy of the SMS gene using an adeno-associated viral (AAV) vector, as well as methods to evaluate the molecular efficacy of this approach in an SRS mouse model. Our ultimate goal is to establish a versatile platform for genetic interventions targeting SRS and other polyaminopathies.
2015-06-15 | Wnt-related SynGAP1 is a neuroprotective factor of glutamatergic synapses against Aβ oligomers
Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Aβ oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored. That is why we aim to study the relationship between Wnt-5a and miRNAs in glutamatergic synapses. We performed in silico analysis which predicted that miR-101b may inhibits the expression of SynGAP1, a Ras GTPase-activating protein critical for the development of cognition and proper synaptic function. Through overexpression of miR-101b, we showed that miR-101b is able to regulate the expression of SynGAP1 in an hippocampal cell line. Moreover and consistent with a decrease of miR-101b, Wnt-5a enhances SynGAP expression in cultured hippocampal neurons. Additionally, Wnt-5a increases the activity of SynGAP in a time-dependent manner, with a similar kinetic to CaMKII phosphorylation. This also, correlates with a modulation in the SynGAP clusters density. On the other hand, Aβ oligomers permanently decrease the number of SynGAP clusters. Interestingly, when neurons are co-incubated with Wnt-5a and Aβ oligomers, we do not observe the detrimental effect of Aβ oligomers, indicating that, Wnt-5a protects neurons from the synaptic failure triggered by Aβ oligomers. Overall, our findings suggest that SynGAP1 is part of the signaling pathways induced by Wnt-5a. Therefore, possibility exists that SynGAP is involved in the synaptic protection against Aβ oligomers
2013-02-28 | Enhancing Human Spermine Synthase Activity by Engineered Mutations
Spermine synthase (SMS) is an enzyme which function is to convert spermidine into spermine. It was shown that gene defects resulting in amino acid changes of the wild type SMS cause Snyder-Robinson syndrome, which is a mild-to-moderate mental disability associated with osteoporosis, facial asymmetry, thin habitus, hypotonia, and a nonspecific movement disorder. These disease-causing missense mutations were demonstrated, both in silico and in vitro, to affect the wild type function of SMS by either destabilizing the SMS dimer/monomer or directly affecting the hydrogen bond network of the active site of SMS. In contrast to these studies, here we report an artificial engineering of a more efficient SMS variant by transferring sequence information from another organism. It is confirmed experimentally that the variant, bearing four amino acid substitutions, is catalytically more active than the wild type. The increased functionality is attributed to enhanced monomer stability, lowering the pKa of proton donor catalytic residue, optimized spatial distribution of the electrostatic potential around the SMS with respect to substrates, and increase of the frequency of mechanical vibration of the clefts presumed to be the gates toward the active sites. The study demonstrates that wild type SMS is not particularly evolutionarily optimized with respect to the reaction spermidine → spermine. Having in mind that currently there are no variations (non-synonymous single nucleotide polymorphism, nsSNP) detected in healthy individuals, it can be speculated that the human SMS function is precisely tuned toward its wild type and any deviation is unwanted and disease-causing.
2013-01-29 | Enhancing Human Spermine Synthase Activity by Site Directed Mutations
Spermine Synthase (SMS) is an enzyme converting spermidine into spermine, both of which are polyamines controlling normal cell growth and development. Several missense mutations in human SMS (HsSMS) are known to cause Snyder-Robinson Syndrome (SRS) by either destabilizing the monomer/dimer conformation or directly affecting the hydrogen bond network in the active sites. Recently a comparison of protein sequence and crystal structure between the HsSMS and its homologous protein Thermotoga maritima (Tm) spermidine synthase (TmSRM) was performed. Tm is the only bacterium known to grow at a high temperature as well as 90°C, and the half-life of TmSRM is longer than 25h under this temperature. In contrast, HsSMS is much less stable than TmSRM under the same temperature. Sequence alignment between HsSMS and TmSRM suggests that some key residues may be essential players for the elevate stability of TmSRM. Such key residues were identified based on various biophysical and sequence criteria and four mutations (S165D, L175E, T178H and C206R) were selected for HsSMS. Both in silico and in vitro experiments indicated that these four mutations strongly stabilize the monomer structure and dramatically improve the efficiency of SPM synthesis. The enhanced reaction rate in the mutant HsSMS is attributed to the increase of the strength of negative electrostatic potential, calculated with DelPhi, in the dimer cleft between HsSMS units, which presumably facilitates the substrate delivery to the active site. The work was supported by a grant from the Institute of General Medical Sciences, National Institutes of Health, and the grant number is 1R01GM093937.
gene therapies
2025-12-18 | Genetic and Phenotypic Features of the Five Known Polyaminopathies: A Critical Narrative Review.
Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.
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