RARE DISEASE
Creatine deficiency syndrome
Creatine deficiency syndrome
Creatine deficiency syndrome
Synonyms: CCDS, CDS, Cerebral creatine deficiency syndrome
Synonyms: CCDS, CDS, Cerebral creatine deficiency syndrome
Synonyms: CCDS, CDS, Cerebral creatine deficiency syndrome
Drug discovery
2
drugs
With orphan designations
Overview
Creatine deficiency syndrome (CDS) encompasses inherited disorders of creatine metabolism, including GAMT deficiency, AGAT deficiency, and X-linked creatine transporter deficiency (CTD). These conditions disrupt cerebral creatine synthesis or transport, causing global developmental delay, intellectual disability, seizures, movement disorders, and behavioral abnormalities (e.g., autism). Diagnosis relies on brain MRI spectroscopy, urine creatine/creatinine ratios, and genetic testing. While creatine supplementation effectively treats AGAT/GAMT deficiencies, CTD lacks definitive therapies, though gene therapy and novel formulations are under investigation [1][2][8][11].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
60 drug discovery papers about Creatine deficiency syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
60 drug discovery papers about Creatine deficiency syndrome, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-10 | A novel homozygous missense variant in the GAMT gene causing cerebral creatine deficiency syndrome 2 in an Iranian patient: molecular dynamics insights and literature review
Cerebral creatine deficiency syndrome 2 (CCDS2; OMIM #612,736) is a rare autosomal recessive neurometabolic disorder caused by variants in the GAMT gene, leading to deficient creatine synthesis in the brain. Here, we report a 17-year-old Iranian Fars female patient from a consanguineous marriage presenting with severe intellectual disability, inability to walk, muscle atrophy, and epileptiform EEG activity. Whole-exome sequencing identified a previously unreported homozygous missense variant in GAMT (NM_000156.6: c.326A > G, p.Lys109Arg), classified as likely pathogenic according to ACMG guidelines. The affected lysine residue at position 109 is highly conserved across species. Molecular dynamics (MD) simulations over 100 ns revealed that the p.Lys109Arg substitution induces a more compact global conformation (lower RMSD and Rg) but drastically alters the dynamic coupling network. Compared to wild-type, the mutant exhibited a substantially higher standard deviation in the cross-correlation matrix (0.323 vs. 0.236) and a markedly increased number of both strongly positive (4,006 vs. 1,574) and strongly negative (3,326 vs. 576) correlated residue pairs, indicating the emergence of extensive long-range allosteric perturbations that may disrupt functional dynamics and stability. Our report highlights the value of MD simulations as a tool to evaluate the structural consequences of genetic variants.
2026-06-18 | Stage- and Region-Dependent Proteomic Alterations in a Mouse Model of Creatine Transporter Deficiency.
SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the blood-brain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G>C (G561R) variant of Slc6a8, which corresponds to a variant identified in SLC6A8 in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G>C point mutation into the mouse Slc6a8 gene using the CRISPR/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.
2026-04-02 | Transporters for Creatine and Related Guanidino Compounds: Their Relevance to Brain Health and Disorders.
Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.
2025-11-24 | Complete data for neurochemical and behavioral assessment in a mouse model of creatine transporter deficiency.
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT −/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.
2025-09-02 | Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na+/Cl--dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
2026-08-10 | A novel homozygous missense variant in the GAMT gene causing cerebral creatine deficiency syndrome 2 in an Iranian patient: molecular dynamics insights and literature review
Cerebral creatine deficiency syndrome 2 (CCDS2; OMIM #612,736) is a rare autosomal recessive neurometabolic disorder caused by variants in the GAMT gene, leading to deficient creatine synthesis in the brain. Here, we report a 17-year-old Iranian Fars female patient from a consanguineous marriage presenting with severe intellectual disability, inability to walk, muscle atrophy, and epileptiform EEG activity. Whole-exome sequencing identified a previously unreported homozygous missense variant in GAMT (NM_000156.6: c.326A > G, p.Lys109Arg), classified as likely pathogenic according to ACMG guidelines. The affected lysine residue at position 109 is highly conserved across species. Molecular dynamics (MD) simulations over 100 ns revealed that the p.Lys109Arg substitution induces a more compact global conformation (lower RMSD and Rg) but drastically alters the dynamic coupling network. Compared to wild-type, the mutant exhibited a substantially higher standard deviation in the cross-correlation matrix (0.323 vs. 0.236) and a markedly increased number of both strongly positive (4,006 vs. 1,574) and strongly negative (3,326 vs. 576) correlated residue pairs, indicating the emergence of extensive long-range allosteric perturbations that may disrupt functional dynamics and stability. Our report highlights the value of MD simulations as a tool to evaluate the structural consequences of genetic variants.
2026-06-18 | Stage- and Region-Dependent Proteomic Alterations in a Mouse Model of Creatine Transporter Deficiency.
SLC6A8 encodes the creatine transporter (CRT), which mediates creatine transport across the plasma membrane in the brain, including the blood-brain barrier and neurons. Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, leads to cerebral creatine depletion and cognitive impairment. Here, we investigated the developmental molecular mechanisms underlying CTD using the pathogenic c.1681G>C (G561R) variant of Slc6a8, which corresponds to a variant identified in SLC6A8 in a patient with CTD. In vitro analyses using HEK293 cells expressing mutant mouse CRT carrying the G561R variant demonstrated impaired N-glycan maturation and plasma membrane localization of the transporter, resulting in markedly reduced creatine uptake, consistent with previous reports on the corresponding human CRT variant. To investigate the in vivo effects of this pathogenic variant, we generated CRT-G561R knock-in mice by introducing the c.1681G>C point mutation into the mouse Slc6a8 gene using the CRISPR/Cas9 system. These male mice exhibited severe reductions in brain creatine levels, postnatal growth retardation, and impaired spatial memory, despite preserved gross brain morphology. Quantitative proteomic analyses of the hippocampus and cerebral cortex during postnatal development revealed region-dependent protein alterations in CTD. The hippocampus showed pronounced early postnatal remodeling involving proteins related to actin cytoskeleton organization and vesicle-mediated membrane trafficking, whereas the cerebral cortex exhibited a more gradual response involving creatine biosynthesis-related enzymes and later-emerging mitochondrial pathways, including the mitochondrial translation machinery. These findings demonstrate stage- and region-dependent proteomic remodeling during postnatal brain development in CTD.
2026-04-02 | Transporters for Creatine and Related Guanidino Compounds: Their Relevance to Brain Health and Disorders.
Creatine, α-N-methyl-guanidino-acetic acid, plays a fundamental role in the storage and regeneration of high-energy phosphate in the brain. Defects in the creatine transporter gene (CRT/SLC6A8) result in a significant reduction in brain creatine levels and severe neurological symptoms such as intellectual disability. Clarifying creatine dynamics in the brain is essential to increase our understanding of CRT deficiency syndrome (CRTD) pathology and the development of CRTD therapeutics. This review comprehensively summarizes the pathophysiological roles of transporters in dynamics of creatine and related guanidine compounds in the brain barriers and brain parenchyma. Brain creatine dynamics are regulated by the cooperative actions of various influx and efflux transporters of creatine, guanidinoacetate, creatinine, and creatine biosynthetic enzymes. These transporters include CRT/SLC6A8 as a creatine/guanidinoacetate/creatinine influx transporter, MCT12/SLC16A12, and SLC22A15 for creatine efflux transport, TauT/SLC6A6, GAT2/SLC6A13, and GAT3/SLC6A11 for guanidinoacetate influx transport, and OCT3/SLC22A3 for creatinine influx transport. Transporters and creatine biosynthetic enzymes, such as arginine-glycine amidinotransferase and guanidinoacetate N-methyltransferase, exhibit cell-type specific spatio-temporal expression at the brain barrier and in neurons, astrocytes, and oligodendrocytes. To date, no effective therapeutics have been developed for the treatment of CRTD. The link between low brain creatine level and the mechanism of neurological dysfunction remains unclear. Creatine prodrugs, molecular chaperones, and adeno-associated virus-based gene therapies are potential therapeutic options for CRTD. Advanced technologies, such as omics and genetic engineering, will open new avenues for CRTD therapeutics.
2025-11-24 | Complete data for neurochemical and behavioral assessment in a mouse model of creatine transporter deficiency.
Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and behavioral disturbances, language and speech impairment ( OMIM #300352). CCDS1 is still an untreatable pathology that can be very invalidating for patients and caregivers. Only two murine models of CCDS1, one of which is an ubiquitous knockout mouse, are currently available to study the possible mechanisms underlying the pathologic phenotype of CCDS1 and to develop therapeutic strategies. Given the importance of validating phenotypes and efficacy of promising treatments in more than one mouse model we have generated a new murine model of CCDS1 obtained by ubiquitous deletion of 5-7 exons in the Slc6a8 gene. We showed a remarkable Cr depletion in the murine brain tissues and cognitive defects, thus resembling the key features of human CCDS1. These results confirm that CCDS1 can be well modeled in mice. This CrT −/y murine model will provide a new tool for increasing the relevance of preclinical studies to the human disease.
2025-09-02 | Structural insights into the substrate uptake and inhibition of the human creatine transporter (hCRT).
Creatine plays a vital role in cellular energy production and adenosine triphosphate (ATP) homeostasis and has also been identified as a neurotransmitter in the mammalian brain. Creatine is transported into cells by the human creatine transporter (hCRT) (SLC6A8), an Na+/Cl--dependent symporter encoded on the X chromosome. Mutations in hCRT cause cerebral creatine deficiency syndrome 1, a neurological disorder marked by intellectual disability, speech delay, and seizures. Beyond its role in the brain and muscle, hCRT is highly expressed in metabolically active tumors. Many cancer cells, including colorectal cancer and glioblastoma, upregulate hCRT to sustain intracellular creatine levels and buffer ATP under energy stress. Pharmacological blockade of hCRT by RGX202 has been shown to impair tumor growth by disrupting energy homeostasis. Here, we report the high-resolution cryo-Electron Microscopy (cryo-EM) structures of human hCRT in three states: apo, creatine-bound, and RGX202-bound. hCRT adopts a canonical LeuT-fold with 12 transmembrane helices and two pseudosymmetric inverted repeats. Creatine is coordinated in the central substrate-binding site through interactions with transmembrane helices TM1, TM3, TM6, and TM8, while the inhibitor RGX202 occupies the same binding pocket, engaging in overlapping contacts that competitively block creatine access. Our structural and mechanistic findings clarify substrate recognition and inhibitory binding of hCRT, providing a molecular rationale for targeting hCRT in both inherited metabolic diseases and cancer therapy.
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
2 orphan drug designations for Creatine deficiency syndrome.
2 orphan drug designations for Creatine deficiency syndrome.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Dodecyl creatine ester, dodecyl creatine ester hydrochloride | small molecules | EMA | 2021-02-19 | — | Ceres Brain Therapeutics S.A.S. |
Cyclocreatine | small molecules | EMA | 2016-06-27 | — | Pharma Gateway AB |
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