Creatine Transporter Deficiency

Mendelian MONDO:0010305 Pathograph 5 Show in embeddings browser Cerebral Creatine Deficiency Syndrome Inborn Error of Metabolism

Creatine transporter deficiency is an X-linked cerebral creatine deficiency syndrome caused by pathogenic variants in SLC6A8, which encodes the sodium-dependent creatine transporter CRTR. Unlike AGAT and GAMT deficiency, the primary defect is not creatine biosynthesis but impaired cellular and CNS creatine uptake. Affected males usually present with developmental delay, intellectual disability, prominent speech-language disorder, behavioral abnormalities, hypotonia, and variable epilepsy or movement disorder. The characteristic diagnostic pattern includes absent or markedly decreased brain creatine on proton magnetic resonance spectroscopy and, especially in males, an elevated urinary creatine-to-creatinine ratio.

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1
Inheritance
3
Pathophys.
8
Phenotypes
5
Pathograph
1
Genes
1
Medical Actions
5
References
👪

Inheritance

1
X-linked inheritance HP:0001417
SLC6A8-related creatine transporter deficiency is inherited in an X-linked manner. Hemizygous males are typically affected, while heterozygous females may be asymptomatic or may have neurodevelopmental manifestations.
X-linked inheritance
Show evidence (2 references)
PMID:20301745 SUPPORT Human Clinical
"SLC6A8) is inherited in an X-linked manner."
GeneReviews directly states X-linked inheritance for SLC6A8-related CRTR deficiency.
PMID:36856349 SUPPORT Human Clinical
"females in SLC6A8 result in creatine transporter deficiency."
Review evidence identifies the sex-specific molecular diagnostic pattern for SLC6A8 deficiency.
⚙

Pathophysiology

3
SLC6A8 creatine transport defect
Pathogenic SLC6A8 variants impair CRTR-mediated creatine uptake into cells, including high-energy-demand tissues such as brain and muscle. This blocks the transport limb of the creatine pathway while leaving AGAT/GAMT biosynthesis intact.
SLC6A8 hgnc:11055 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC6A8 (hgnc:11055). hgnc:11055 is a gene from the HUGO Gene Nomenclature Committee.
creatine transport GO:0015881 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine transport, annotated with creatine transmembrane transport (GO:0015881). GO:0015881 is a biological process from the Gene Ontology. ↓ DECREASED creatine metabolic process GO:0006600 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal creatine metabolic process (GO:0006600). GO:0006600 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Cerebral creatine depletion Impaired creatine transport reduces brain creatine availability despite intact creatine biosynthesis.
Impaired neuronal energy buffering Reduced intracellular creatine availability compromises energy buffering in developing brain.
Show evidence (2 references)
PMID:38452609 SUPPORT Other
"membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs."
ClinGen VCEP review establishes SLC6A8 as the creatine transporter gene.
PMID:26542286 SUPPORT Other
"further enables cells to incorporate creatine"
Review evidence places CRTR/SLC6A8 at the cellular creatine uptake step.
Cerebral creatine depletion
Brain proton magnetic resonance spectroscopy shows absent or significantly decreased creatine in SLC6A8 deficiency. Blood-brain barrier expression patterns and limited peripheral creatine permeability help explain why oral creatine has limited efficacy for the transporter defect.
creatine transport GO:0015881 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased creatine transport, annotated with creatine transmembrane transport (GO:0015881). GO:0015881 is a biological process from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Impaired neuronal energy buffering Reduced brain creatine limits phosphocreatine-dependent ATP buffering in neurons.
Show evidence (2 references)
PMID:36856349 SUPPORT Human Clinical
"creatine level in brain proton magnetic resonance spectroscopy."
Review evidence states the characteristic brain MRS finding for creatine deficiency disorders including SLC6A8 deficiency.
PMID:26861125 SUPPORT Other
"by microcapillary endothelial cells at the blood-brain barrier, but is absent"
CNS transport review supports limited creatine delivery across the blood-brain barrier in transporter-related disease.
Impaired neuronal energy buffering
Creatine and phosphocreatine provide rapid ATP buffering in high-energy tissues. Reduced CNS creatine availability from the transporter defect perturbs brain energy homeostasis and contributes to neurodevelopmental and seizure phenotypes.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
ATP metabolic process GO:0046034 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ATP metabolic process (GO:0046034). GO:0046034 is a biological process from the Gene Ontology. ⚠ ABNORMAL phosphocreatine metabolic process GO:0006603 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phosphocreatine metabolic process (GO:0006603). GO:0006603 is a biological process from the Gene Ontology. ↓ DECREASED
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (2 references)
PMID:38452609 SUPPORT Other
"Creatine uptake is very important especially in high energy demanding organs"
ClinGen VCEP review links creatine uptake to brain and muscle energy demand.
PMID:26542286 SUPPORT Other
"developmental delay, intellectual disability, behavioral disorders)."
Review evidence links primary creatine disorders to altered brain function and neurodevelopmental manifestations.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Creatine Transporter Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Musculoskeletal 1
Hypotonia FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and"
GeneReviews lists hypotonia among clinical findings in affected males with CRTR deficiency.
Nervous System 6
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"CRTR deficiency in affected males (reported in ~130 individuals) in addition to"
GeneReviews identifies developmental delay as a core clinical finding in affected males.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"males with CRTR deficiency have been reported to have severe intellectual"
GeneReviews reports severe intellectual disability in most adult males.
Seizure FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"intractable) and behavior disorders (e.g., attention deficit and/or"
GeneReviews states that epilepsy is part of the male CRTR deficiency phenotype.
Delayed speech and language development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"dysfunction or intellectual disability and speech-language disorder are common"
GeneReviews identifies speech-language disorder as a common feature of creatine deficiency disorders.
Atypical behavior FREQUENT HP:0000708 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atypical behavior (HP:0000708). HP:0000708 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"intractable) and behavior disorders (e.g., attention deficit and/or"
GeneReviews lists behavior disorders among clinical findings in affected males with CRTR deficiency.
Movement disorder OCCASIONAL Abnormality of movement HP:0100022 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Movement disorder, annotated with Abnormality of movement (HP:0100022). HP:0100022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301745 SUPPORT Human Clinical
"(less commonly) a movement disorder."
GeneReviews reports movement disorder as a less common feature of male CRTR deficiency.
Other 1
Reduced brain creatine level by MRS VERY_FREQUENT HP:0025051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced brain creatine level by MRS (HP:0025051). HP:0025051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36856349 SUPPORT Human Clinical
"creatine level in brain proton magnetic resonance spectroscopy."
Review evidence describes the characteristic reduced brain creatine MRS finding.
🧬

Genetic Associations

1
SLC6A8 pathogenic variants
Gene: SLC6A8 hgnc:11055 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC6A8 (hgnc:11055). hgnc:11055 is a gene from the HUGO Gene Nomenclature Committee.
X-linked inheritance
Show evidence (2 references)
PMID:20301745 SUPPORT Human Clinical
"hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular"
GeneReviews establishes SLC6A8 molecular diagnosis for CRTR deficiency.
PMID:38452609 SUPPORT Other
"variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS"
ClinGen VCEP review supports SLC6A8-related CCDS as a curated gene-disease relationship.
💊

Medical Actions

1
Creatine precursor supplementation
Action: nutritional supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is nutritional supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Creatine transporter deficiency is treated with creatine monohydrate plus arginine and glycine supplementation in some protocols, but clinical improvement has not been proven; this differs from the clearer treatment responsiveness of AGAT and GAMT biosynthesis defects.
Mechanism Target:
MODULATES Cerebral creatine depletion — Supplementation attempts to improve creatine availability, but transporter impairment limits CNS benefit.
Show evidence (1 reference)
PMID:36856349 SUPPORT Human Clinical
"creatine transporter deficiency is treated with arginine and glycine"
Review evidence documents the treatment approach and explicitly notes lack of proven improvement.
{ }

Source YAML

click to show 
name: Creatine Transporter Deficiency
category: Mendelian
creation_date: '2026-07-05T00:00:00Z'
synonyms:
- SLC6A8-related creatine deficiency syndrome
- SLC6A8-related creatine transporter deficiency
- CRTR deficiency
- X-linked creatine deficiency syndrome
- Cerebral creatine deficiency syndrome type 1
description: >
  Creatine transporter deficiency is an X-linked cerebral creatine deficiency
  syndrome caused by pathogenic variants in SLC6A8, which encodes the
  sodium-dependent creatine transporter CRTR. Unlike AGAT and GAMT deficiency,
  the primary defect is not creatine biosynthesis but impaired cellular and CNS
  creatine uptake. Affected males usually present with developmental delay,
  intellectual disability, prominent speech-language disorder, behavioral
  abnormalities, hypotonia, and variable epilepsy or movement disorder. The
  characteristic diagnostic pattern includes absent or markedly decreased brain
  creatine on proton magnetic resonance spectroscopy and, especially in males,
  an elevated urinary creatine-to-creatinine ratio.
disease_term:
  preferred_term: creatine transporter deficiency
  term:
    id: MONDO:0010305
    label: creatine transporter deficiency
parents:
- Cerebral Creatine Deficiency Syndrome
- Inborn Error of Metabolism
references:
- reference: PMID:20301745
  title: Creatine Deficiency Disorders.
  tags:
  - GeneReviews
- reference: PMID:36856349
  title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
- reference: PMID:38452609
  title: "ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes."
- reference: PMID:26861125
  title: "Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?"
- reference: PMID:26542286
  title: Creatine biosynthesis and transport in health and disease.
inheritance:
- name: X-linked inheritance
  description: >
    SLC6A8-related creatine transporter deficiency is inherited in an X-linked
    manner. Hemizygous males are typically affected, while heterozygous females
    may be asymptomatic or may have neurodevelopmental manifestations.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SLC6A8) is inherited in an X-linked manner."
    explanation: GeneReviews directly states X-linked inheritance for SLC6A8-related CRTR deficiency.
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "females in SLC6A8 result in creatine transporter deficiency."
    explanation: Review evidence identifies the sex-specific molecular diagnostic pattern for SLC6A8 deficiency.
pathophysiology:
- name: SLC6A8 creatine transport defect
  description: >
    Pathogenic SLC6A8 variants impair CRTR-mediated creatine uptake into cells,
    including high-energy-demand tissues such as brain and muscle. This blocks
    the transport limb of the creatine pathway while leaving AGAT/GAMT
    biosynthesis intact.
  genes:
  - preferred_term: SLC6A8
    term:
      id: hgnc:11055
      label: SLC6A8
  biological_processes:
  - preferred_term: creatine transport
    term:
      id: GO:0015881
      label: creatine transmembrane transport
    modifier: DECREASED
  - preferred_term: creatine metabolic process
    term:
      id: GO:0006600
      label: creatine metabolic process
    modifier: ABNORMAL
  chemical_entities:
  - preferred_term: creatine
    term:
      id: CHEBI:16919
      label: creatine
    modifier: DECREASED
  evidence:
  - reference: PMID:38452609
    reference_title: "ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs."
    explanation: ClinGen VCEP review establishes SLC6A8 as the creatine transporter gene.
  - reference: PMID:26542286
    reference_title: Creatine biosynthesis and transport in health and disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "further enables cells to incorporate creatine"
    explanation: Review evidence places CRTR/SLC6A8 at the cellular creatine uptake step.
  downstream:
  - target: Cerebral creatine depletion
    causal_link_type: DIRECT
    description: Impaired creatine transport reduces brain creatine availability despite intact creatine biosynthesis.
  - target: Impaired neuronal energy buffering
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Decreased CNS creatine limits the creatine/phosphocreatine energy-buffering system.
    description: Reduced intracellular creatine availability compromises energy buffering in developing brain.
- name: Cerebral creatine depletion
  description: >
    Brain proton magnetic resonance spectroscopy shows absent or significantly
    decreased creatine in SLC6A8 deficiency. Blood-brain barrier expression
    patterns and limited peripheral creatine permeability help explain why oral
    creatine has limited efficacy for the transporter defect.
  biological_processes:
  - preferred_term: creatine transport
    term:
      id: GO:0015881
      label: creatine transmembrane transport
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  chemical_entities:
  - preferred_term: creatine
    term:
      id: CHEBI:16919
      label: creatine
    modifier: DECREASED
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "creatine level in brain proton magnetic resonance spectroscopy."
    explanation: Review evidence states the characteristic brain MRS finding for creatine deficiency disorders including SLC6A8 deficiency.
  - reference: PMID:26861125
    reference_title: "Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "by microcapillary endothelial cells at the blood-brain barrier, but is absent"
    explanation: CNS transport review supports limited creatine delivery across the blood-brain barrier in transporter-related disease.
  downstream:
  - target: Impaired neuronal energy buffering
    causal_link_type: DIRECT
    description: Reduced brain creatine limits phosphocreatine-dependent ATP buffering in neurons.
- name: Impaired neuronal energy buffering
  description: >
    Creatine and phosphocreatine provide rapid ATP buffering in high-energy
    tissues. Reduced CNS creatine availability from the transporter defect
    perturbs brain energy homeostasis and contributes to neurodevelopmental and
    seizure phenotypes.
  biological_processes:
  - preferred_term: ATP metabolic process
    term:
      id: GO:0046034
      label: ATP metabolic process
    modifier: ABNORMAL
  - preferred_term: phosphocreatine metabolic process
    term:
      id: GO:0006603
      label: phosphocreatine metabolic process
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:38452609
    reference_title: "ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Creatine uptake is very important especially in high energy demanding organs"
    explanation: ClinGen VCEP review links creatine uptake to brain and muscle energy demand.
  - reference: PMID:26542286
    reference_title: Creatine biosynthesis and transport in health and disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "developmental delay, intellectual disability, behavioral disorders)."
    explanation: Review evidence links primary creatine disorders to altered brain function and neurodevelopmental manifestations.
phenotypes:
- name: Global developmental delay
  frequency: VERY_FREQUENT
  description: Developmental delay is a common manifestation of creatine transporter deficiency in affected males.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CRTR deficiency in affected males (reported in ~130 individuals) in addition to"
    explanation: GeneReviews identifies developmental delay as a core clinical finding in affected males.
- name: Intellectual disability
  frequency: VERY_FREQUENT
  description: Intellectual disability is a core neurodevelopmental manifestation.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "males with CRTR deficiency have been reported to have severe intellectual"
    explanation: GeneReviews reports severe intellectual disability in most adult males.
- name: Seizure
  frequency: FREQUENT
  description: Epilepsy with variable seizure types may occur and can be intractable.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intractable) and behavior disorders (e.g., attention deficit and/or"
    explanation: GeneReviews states that epilepsy is part of the male CRTR deficiency phenotype.
- name: Hypotonia
  frequency: FREQUENT
  description: Hypotonia is reported among affected males with creatine transporter deficiency.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and"
    explanation: GeneReviews lists hypotonia among clinical findings in affected males with CRTR deficiency.
- name: Delayed speech and language development
  frequency: VERY_FREQUENT
  description: Speech-language delay is a common neurodevelopmental manifestation across creatine deficiency disorders including CRTR deficiency.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysfunction or intellectual disability and speech-language disorder are common"
    explanation: GeneReviews identifies speech-language disorder as a common feature of creatine deficiency disorders.
- name: Atypical behavior
  frequency: FREQUENT
  description: Affected males may have behavioral problems such as attention deficit, hyperactivity, autistic features, impulsivity, or social anxiety.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "intractable) and behavior disorders (e.g., attention deficit and/or"
    explanation: GeneReviews lists behavior disorders among clinical findings in affected males with CRTR deficiency.
- name: Movement disorder
  frequency: OCCASIONAL
  description: Movement disorder is a less common neurologic manifestation in affected males.
  phenotype_term:
    preferred_term: Movement disorder
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(less commonly) a movement disorder."
    explanation: GeneReviews reports movement disorder as a less common feature of male CRTR deficiency.
- name: Reduced brain creatine level by MRS
  frequency: VERY_FREQUENT
  description: Brain proton magnetic resonance spectroscopy shows absent or markedly decreased creatine.
  phenotype_term:
    preferred_term: Reduced brain creatine level by MRS
    term:
      id: HP:0025051
      label: Reduced brain creatine level by MRS
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "creatine level in brain proton magnetic resonance spectroscopy."
    explanation: Review evidence describes the characteristic reduced brain creatine MRS finding.
genetic:
- name: SLC6A8 pathogenic variants
  gene_term:
    preferred_term: SLC6A8
    term:
      id: hgnc:11055
      label: SLC6A8
  inheritance:
  - name: X-linked inheritance
  features: >
    SLC6A8 encodes the creatine transporter CRTR. Pathogenic hemizygous variants
    in males and heterozygous variants in females cause creatine transporter
    deficiency, with affected males typically showing the more severe
    neurodevelopmental phenotype.
  evidence:
  - reference: PMID:20301745
    reference_title: Creatine Deficiency Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemizygous or heterozygous pathogenic variant in SLC6A8 identified by molecular"
    explanation: GeneReviews establishes SLC6A8 molecular diagnosis for CRTR deficiency.
  - reference: PMID:38452609
    reference_title: "ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "variant classification guidelines for GAMT-, GATM-, and SLC6A8-related CCDS"
    explanation: ClinGen VCEP review supports SLC6A8-related CCDS as a curated gene-disease relationship.
treatments:
- name: Creatine precursor supplementation
  description: >
    Creatine transporter deficiency is treated with creatine monohydrate plus
    arginine and glycine supplementation in some protocols, but clinical
    improvement has not been proven; this differs from the clearer treatment
    responsiveness of AGAT and GAMT biosynthesis defects.
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Cerebral creatine depletion
    treatment_effect: MODULATES
    description: Supplementation attempts to improve creatine availability, but transporter impairment limits CNS benefit.
  evidence:
  - reference: PMID:36856349
    reference_title: "Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "creatine transporter deficiency is treated with arginine and glycine"
    explanation: Review evidence documents the treatment approach and explicitly notes lack of proven improvement.
notes: >-
  WP-013 audit result: AGAT deficiency and GAMT deficiency already had local
  disease entries. This entry adds the missing SLC6A8 creatine transporter
  deficiency anchor and distinguishes it mechanistically from AGAT/GAMT
  biosynthesis defects. The GATM aggregation syndrome seed is represented as
  the FRTS1 subtype of Fanconi renotubular syndrome rather than folded into
  AGAT deficiency.
📚

References & Deep Research

References

5
PMID:20301745
Creatine Deficiency Disorders.
No top-level findings curated for this source.
PMID:36856349
Creatine Deficiency Disorders: Phenotypes, Genotypes, Diagnosis, and Treatment Outcomes.
No top-level findings curated for this source.
PMID:38452609
ClinGen variant curation expert panel recommendations for classification of variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromes.
No top-level findings curated for this source.
PMID:26861125
Creatine synthesis and exchanges between brain cells: What can be learned from human creatine deficiencies and various experimental models?
No top-level findings curated for this source.
PMID:26542286
Creatine biosynthesis and transport in health and disease.
No top-level findings curated for this source.