Cerebral creatine deficiency syndrome

Summary

Cerebral creatine deficiency syndrome (MONDO:0000456) is a disease with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 541
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral creatine deficiency syndrome
Mondo ID	MONDO:0000456
OMIM	300352
Orphanet	79172
DOID	DOID:0050798
UMLS	C5244016
MedGen	1826001
GARD	0018952
Is cancer (heuristic)	no

Also known as: CCDS · CDS · cerebral creatine deficiency syndrome · creatine deficiency syndrome

Data availability: 541 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › cerebral creatine deficiency syndrome

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Subtypes (3): creatine transporter deficiency, AGAT deficiency, guanidinoacetate methyltransferase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

541 retrieved; paginated sample, class counts are floors:

239 likely benign, 186 uncertain significance, 56 pathogenic, 27 likely pathogenic, 17 pathogenic/likely pathogenic, 10 benign, 3 benign/likely benign, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069228	NM_000156.6(GAMT):c.59G>A (p.Trp20Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070918	NM_000156.6(GAMT):c.356dup (p.Asp119fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073500	NM_000156.6(GAMT):c.324_325del (p.His108fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073697	NM_000156.6(GAMT):c.307del (p.Ala103fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075552	NM_000156.6(GAMT):c.64del (p.Ala22fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075655	NM_000156.6(GAMT):c.289C>T (p.Gln97Ter)	GAMT	Pathogenic	criteria provided, multiple submitters, no conflicts
1076411	NM_000156.6(GAMT):c.414_415del (p.Ser140fs)	GAMT	Pathogenic	criteria provided, single submitter
1312506	NM_000156.6(GAMT):c.497T>C (p.Leu166Pro)	GAMT	Pathogenic	reviewed by expert panel
1374093	NM_000156.6(GAMT):c.305G>A (p.Trp102Ter)	GAMT	Pathogenic	criteria provided, single submitter
1374768	NM_000156.6(GAMT):c.432_433dup (p.His145fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1382497	NM_000156.6(GAMT):c.402C>A (p.Tyr134Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1391239	NM_000156.6(GAMT):c.432G>A (p.Trp144Ter)	GAMT	Pathogenic	reviewed by expert panel
1409758	NM_000156.6(GAMT):c.526dup (p.Glu176fs)	GAMT	Pathogenic	reviewed by expert panel
1422935	NM_000156.6(GAMT):c.504C>G (p.Tyr168Ter)	GAMT	Pathogenic	criteria provided, single submitter
1452336	NM_000156.6(GAMT):c.470_476del (p.Phe157fs)	GAMT	Pathogenic	criteria provided, single submitter
1452750	NM_000156.6(GAMT):c.2T>C (p.Met1Thr)	GAMT	Pathogenic	criteria provided, single submitter
1453224	NM_000156.6(GAMT):c.440_441dup (p.Gln148fs)	GAMT	Pathogenic	criteria provided, single submitter
1454624	NC_000019.9:g.(?1398895)(1401475_?)del	GAMT	Pathogenic	criteria provided, single submitter
1454825	NM_000156.6(GAMT):c.534dup (p.Lys179fs)	GAMT	Pathogenic	criteria provided, single submitter
1458883	NM_000156.6(GAMT):c.536del (p.Lys179fs)	GAMT	Pathogenic	criteria provided, single submitter
1460109	NM_000156.6(GAMT):c.350G>A (p.Trp117Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705080	NM_000156.6(GAMT):c.475del (p.Leu159fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1998188	NM_000156.6(GAMT):c.65del (p.Ala22fs)	GAMT	Pathogenic	criteria provided, single submitter
2003951	NM_000156.6(GAMT):c.332_338del (p.Ile111fs)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2030841	NC_000019.10:g.1399939del	GAMT	Pathogenic	criteria provided, single submitter
205584	NM_000156.6(GAMT):c.522G>A (p.Trp174Ter)	GAMT	Pathogenic	reviewed by expert panel
2060742	NM_000156.6(GAMT):c.60G>A (p.Trp20Ter)	GAMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2083318	NM_000156.6(GAMT):c.289del (p.Gln97fs)	GAMT	Pathogenic	criteria provided, multiple submitters, no conflicts
2084043	NM_000156.6(GAMT):c.370del (p.Leu124fs)	GAMT	Pathogenic	criteria provided, single submitter
2089258	NM_000156.6(GAMT):c.608_621del (p.Arg203fs)	GAMT	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCF3	Orphanet:33110	Autosomal non-syndromic agammaglobulinemia
TCF3	Orphanet:585956	B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3)
TCF3	Orphanet:641375	B-lymphoblastic leukemia/lymphoma with t(17;19)
GAMT	Orphanet:382	Guanidinoacetate methyltransferase deficiency
NDUFS7	Orphanet:2609	Isolated complex I deficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCF3	HGNC:11633	ENSG00000071564	P15923	Transcription factor E2-alpha	clinvar
TCF7L1	HGNC:11640	ENSG00000152284	Q9HCS4	Transcription factor 7-like 1	clinvar
ABCA7	HGNC:37	ENSG00000064687	Q8IZY2	Phospholipid-transporting ATPase ABCA7	clinvar
GAMT	HGNC:4136	ENSG00000130005	Q14353	Guanidinoacetate N-methyltransferase	clinvar
NDUFS7	HGNC:7714	ENSG00000115286	O75251	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TCF3	Transcription factor E2-alpha	Transcriptional regulator involved in the initiation of neuronal differentiation and mesenchymal to epithelial transition.
TCF7L1	Transcription factor 7-like 1	Participates in the Wnt signaling pathway.
ABCA7	Phospholipid-transporting ATPase ABCA7	Catalyzes the translocation of specific phospholipids from the cytoplasmic to the extracellular/lumenal leaflet of membrane coupled to the hydrolysis of ATP.
GAMT	Guanidinoacetate N-methyltransferase	Converts guanidinoacetate to creatine, using S-adenosylmethionine as the methyl donor.
NDUFS7	NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transporter	1	15.6×	0.251
Enzyme (other)	1	2.4×	0.634
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCF3	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TCF7L1	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
ABCA7	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC2_TM
GAMT	Enzyme (other)	yes	2.1.1.2	GuanidinoAc_N-MeTrfase, RMT2_dom, SAM-dependent_MTases_sf
NDUFS7	Other/Unknown	no		NADH_UbQ_OxRdtase-like_20kDa, NADH_UQ_OxRdtase_20Kd_su

Expression context

Cohort genes with no expression data: 0.

5 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	2
hindlimb stylopod muscle	2
embryo	1
ganglionic eminence	1
ventricular zone	1
aorta	1
popliteal artery	1
tibial artery	1
adenohypophysis	1
granulocyte	1
pituitary gland	1
right lobe of liver	1
apex of heart	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCF3	294	ubiquitous	marker	ganglionic eminence, ventricular zone, embryo
TCF7L1	230	ubiquitous	marker	popliteal artery, tibial artery, aorta
ABCA7	231	ubiquitous	marker	granulocyte, adenohypophysis, pituitary gland
GAMT	258	ubiquitous	marker	hindlimb stylopod muscle, right lobe of liver, gastrocnemius
NDUFS7	286	ubiquitous	marker	hindlimb stylopod muscle, apex of heart, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NDUFS7	3,621
GAMT	2,166
TCF7L1	1,635
ABCA7	1,520
TCF3	457

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDUFS7	O75251	7
ABCA7	Q8IZY2	6
TCF3	P15923	5
GAMT	Q14353	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCF7L1	Q9HCS4	52.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 5 evidence-associated genes (5 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Binding of TCF/LEF:CTNNB1 to target gene promoters	1	228.4×	0.049	TCF7L1
RUNX3 regulates WNT signaling	1	228.4×	0.049	TCF7L1
Creatine metabolism	1	207.6×	0.049	GAMT
Repression of WNT target genes	1	142.8×	0.049	TCF7L1
Specification of the neural plate border	1	126.9×	0.049	TCF7L1
ABC transporters in lipid homeostasis	1	120.2×	0.049	ABCA7
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	114.2×	0.049	TCF7L1
TGFBR3 expression	1	91.4×	0.050	TCF3
Myogenesis	1	76.1×	0.050	TCF3
Signaling by TGFBR3	1	73.7×	0.050	TCF3
Transcriptional Regulation by MECP2	1	63.4×	0.050	GAMT
Beta-catenin independent WNT signaling	1	58.6×	0.050	TCF7L1
Transcriptional regulation by RUNX3	1	54.4×	0.050	TCF7L1
Gastrulation	1	51.9×	0.050	TCF7L1
RNA Polymerase II Transcription	2	9.0×	0.050	TCF3, TCF7L1
Deactivation of the beta-catenin transactivating complex	1	46.6×	0.052	TCF7L1
MITF-M-dependent gene expression	1	36.2×	0.053	TCF7L1
Ca2+ pathway	1	35.7×	0.053	TCF7L1
Degradation of beta-catenin by the destruction complex	1	34.6×	0.053	TCF7L1
Complex I biogenesis	1	33.1×	0.053	NDUFS7
Transcriptional regulation by RUNX1	1	29.3×	0.053	TCF3
ABC-family protein mediated transport	1	24.3×	0.053	ABCA7
Formation of the beta-catenin:TCF transactivating complex	1	24.0×	0.053	TCF7L1
Negative Regulation of CDH1 Gene Transcription	1	24.0×	0.053	TCF3
TCF dependent signaling in response to WNT	1	23.6×	0.053	TCF7L1
Signaling by TGFB family members	1	23.1×	0.053	TCF3
MITF-M-regulated melanocyte development	1	22.8×	0.053	TCF7L1
Signaling by WNT	1	22.4×	0.053	TCF7L1
Regulation of PD-L1(CD274) transcription	1	21.8×	0.053	TCF7L1
CHD1 and CHD2 subfamily	1	21.8×	0.053	TCF3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
creatine biosynthetic process	1	1685.2×	0.010	GAMT
positive regulation of engulfment of apoptotic cell	1	1685.2×	0.010	ABCA7
creatine metabolic process	1	842.6×	0.010	GAMT
electron transport coupled proton transport	1	842.6×	0.010	NDUFS7
apolipoprotein A-I-mediated signaling pathway	1	842.6×	0.010	ABCA7
positive regulation of phospholipid efflux	1	842.6×	0.010	ABCA7
B cell lineage commitment	1	674.1×	0.010	TCF3
regulation of amyloid precursor protein catabolic process	1	674.1×	0.010	ABCA7
immunoglobulin V(D)J recombination	1	561.7×	0.010	TCF3
plasma membrane raft organization	1	561.7×	0.010	ABCA7
negative regulation of amyloid precursor protein biosynthetic process	1	421.3×	0.010	ABCA7
amyloid-beta clearance by cellular catabolic process	1	421.3×	0.010	ABCA7
positive regulation of amyloid-beta clearance	1	421.3×	0.010	ABCA7
amyloid-beta formation	1	374.5×	0.010	ABCA7
high-density lipoprotein particle assembly	1	337.0×	0.011	ABCA7
negative regulation of PERK-mediated unfolded protein response	1	280.9×	0.012	ABCA7
phospholipid efflux	1	224.7×	0.014	ABCA7
negative regulation of endocytosis	1	187.2×	0.015	ABCA7
regulation of Wnt signaling pathway	1	177.4×	0.015	TCF7L1
negative regulation of amyloid-beta formation	1	177.4×	0.015	ABCA7
positive regulation of protein localization to cell surface	1	153.2×	0.017	ABCA7
regulation of multicellular organism growth	1	129.6×	0.018	GAMT
positive regulation of cholesterol efflux	1	124.8×	0.018	ABCA7
phospholipid translocation	1	124.8×	0.018	ABCA7
obsolete positive regulation of DNA-binding transcription factor activity	1	120.4×	0.018	TCF3
cholesterol efflux	1	105.3×	0.019	ABCA7
regulation of DNA-templated transcription	2	12.6×	0.019	TCF3, TCF7L1
positive regulation of cell cycle	1	88.7×	0.022	TCF3
regulation of lipid metabolic process	1	86.4×	0.022	ABCA7
mitochondrial respiratory chain complex I assembly	1	82.2×	0.022	NDUFS7

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCF3	0	0
TCF7L1	0	0
ABCA7	0	0
GAMT	0	0
NDUFS7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
NDUFS7	5	Binding:5
GAMT	2	ADMET:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GAMT	2.1.1.2	guanidinoacetate N-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	ABCA7, GAMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	TCF3, TCF7L1, NDUFS7

Undrugged target profiles

5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TCF3	0	—
TCF7L1	0	—
ABCA7	0	—
GAMT	2	—
NDUFS7	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening