Carnitine-acylcarnitine translocase deficiency

Summary

Carnitine-acylcarnitine translocase deficiency (MONDO:0008918) is a disease caused by SLC25A20 (GenCC Definitive), with 3 cohort genes and 4 clinical trials. Top therapeutic interventions include triheptanoin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC25A20 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 308
• Phenotypes (HPO): 30
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		60	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0001254	Lethargy	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001638	Cardiomyopathy	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0001987	Hyperammonemia	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002615	Hypotension	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0003162	Fasting hypoglycemia	Very frequent (80-99%)
HP:0003201	Rhabdomyolysis	Very frequent (80-99%)
HP:0003215	Dicarboxylic aciduria	Very frequent (80-99%)
HP:0003234	Decreased circulating carnitine concentration	Very frequent (80-99%)
HP:0004756	Ventricular tachycardia	Very frequent (80-99%)
HP:0008331	Elevated creatine kinase after exercise	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0045045	Elevated plasma acylcarnitine levels	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000961	Cyanosis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0002045	Hypothermia	Occasional (5-29%)
HP:0002882	Sudden episodic apnea	Occasional (5-29%)
HP:0100520	Oliguria	Occasional (5-29%)
HP:0100602	Preeclampsia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	carnitine-acylcarnitine translocase deficiency
Mondo ID	MONDO:0008918
MeSH	C562812
OMIM	212138
Orphanet	159
DOID	DOID:0111585
ICD-11	677949122
NCIT	C133086
SNOMED CT	238003000
UMLS	C0342791
MedGen	91000
GARD	0001123
Is cancer (heuristic)	no

Also known as: CACT deficiency · CACTD · carnitine-acylcarnitine translocase deficiency

Data availability: 308 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of energy metabolism › disorder of fatty acid and ketone body metabolism › disorder of fatty acid oxidation and ketogenesis › carnitine-acylcarnitine translocase deficiency

Related subtypes (9): very long chain acyl-CoA dehydrogenase deficiency, systemic primary carnitine deficiency disease, 3-hydroxy-3-methylglutaric aciduria, 3-hydroxy-3-methylglutaryl-CoA synthase deficiency, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, acyl-CoA dehydrogenase 9 deficiency, acyl-CoA dehydrogenase deficiency, 3-hydroxyacyl-CoA dehydrogenase deficiency, long chain acyl-CoA dehydrogenase 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

308 retrieved; paginated sample, class counts are floors:

131 likely benign, 77 uncertain significance, 43 pathogenic, 28 likely pathogenic, 13 pathogenic/likely pathogenic, 10 conflicting classifications of pathogenicity, 3 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3246864	NC_000003.11:g.(?48895920)(49570632_?)del	AMT	Pathogenic	criteria provided, single submitter
3246860	NC_000003.11:g.(?48895143)(49213234_?)del	ARIH2	Pathogenic	criteria provided, single submitter
12132	NM_000387.6(SLC25A20):c.897dup (p.Asn300fs)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
12133	NM_000387.6(SLC25A20):c.200_326+1del	SLC25A20	Pathogenic	no assertion criteria provided
12134	SLC25A20, 110-BP DEL	SLC25A20	Pathogenic	no assertion criteria provided
12135	NM_000387.6(SLC25A20):c.496C>T (p.Arg166Ter)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
12136	NM_000387.6(SLC25A20):c.84del (p.His29fs)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
12137	NM_000387.6(SLC25A20):c.199-10T>G	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
12138	NM_000387.6(SLC25A20):c.713A>G (p.Gln238Arg)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
126507	NM_000387.6(SLC25A20):c.576G>A (p.Trp192Ter)	SLC25A20	Pathogenic	no assertion criteria provided
126508	NM_000387.6(SLC25A20):c.106-2A>T	SLC25A20	Pathogenic	no assertion criteria provided
1301321	NM_000387.6(SLC25A20):c.528del (p.Met177fs)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
1348719	NM_000387.6(SLC25A20):c.533G>A (p.Arg178Gln)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1377642	NM_000387.6(SLC25A20):c.48del (p.Gly17fs)	SLC25A20	Pathogenic	criteria provided, single submitter
1722350	NM_000387.6(SLC25A20):c.823C>T (p.Arg275Ter)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723815	NM_000387.6(SLC25A20):c.842C>T (p.Ala281Val)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2031549	NM_000387.6(SLC25A20):c.106-2A>G	SLC25A20	Pathogenic	criteria provided, single submitter
203941	NM_000387.6(SLC25A20):c.10C>T (p.Gln4Ter)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2133196	NM_000387.6(SLC25A20):c.645dup (p.Gly216fs)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422997	NC_000003.11:g.(?48929393)(48929525_?)del	SLC25A20	Pathogenic	criteria provided, single submitter
2422998	NC_000003.11:g.(?48916771)(48921577_?)del	SLC25A20	Pathogenic	criteria provided, single submitter
2678861	NM_000387.6(SLC25A20):c.706C>T (p.Arg236Ter)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
2678862	NM_000387.6(SLC25A20):c.121C>T (p.Gln41Ter)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678863	NM_000387.6(SLC25A20):c.542del (p.Pro181fs)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678867	NM_000387.6(SLC25A20):c.843+4_843+50del	SLC25A20	Pathogenic	criteria provided, single submitter
2678874	NM_000387.6(SLC25A20):c.125del (p.Pro42fs)	SLC25A20	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678875	NM_000387.6(SLC25A20):c.191_192del (p.Leu63_Phe64insTer)	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts
2705051	NM_000387.6(SLC25A20):c.510_514dup (p.Thr172fs)	SLC25A20	Pathogenic	criteria provided, single submitter
2729645	NM_000387.6(SLC25A20):c.1A>G (p.Met1Val)	SLC25A20	Pathogenic	criteria provided, single submitter
2734532	NM_000387.6(SLC25A20):c.718+1G>C	SLC25A20	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SLC25A20	Definitive	Autosomal recessive	carnitine-acylcarnitine translocase deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A20	Orphanet:159	Carnitine-acylcarnitine translocase deficiency
AMT	Orphanet:289857	Neonatal glycine encephalopathy
AMT	Orphanet:289860	Infantile glycine encephalopathy
AMT	Orphanet:289863	Atypical glycine encephalopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC25A20	HGNC:1421	ENSG00000178537	O43772	Mitochondrial carnitine/acylcarnitine carrier protein	gencc,clinvar
AMT	HGNC:473	ENSG00000145020	P48728	Aminomethyltransferase, mitochondrial	clinvar
ARIH2	HGNC:690	ENSG00000177479	O95376	E3 ubiquitin-protein ligase ARIH2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A20	Mitochondrial carnitine/acylcarnitine carrier protein	Mediates the electroneutral exchange of acylcarnitines (O-acyl-(R)-carnitine or L-acylcarnitine) of different acyl chain lengths (ranging from O-acetyl-(R)-carnitine to long-chain O-acyl-(R)-carnitines) with free carnitine ((R)-carnitine o…
AMT	Aminomethyltransferase, mitochondrial	The glycine cleavage system catalyzes the degradation of glycine.
ARIH2	E3 ubiquitin-protein ligase ARIH2	E3 ubiquitin-protein ligase, which catalyzes ubiquitination of target proteins together with ubiquitin-conjugating enzyme E2 UBE2L3.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC25A20	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, Mitochondrial_Carrier
AMT	Enzyme (other)	yes	1.4.1.27	GCVT_N, GcvT, GcvT_C
ARIH2	Transcription factor	no	2.3.2.31	Znf_RING, IBR_dom, Znf_RING/FYVE/PHD

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	2
right lobe of liver	2
mucosa of transverse colon	1
liver	1
right uterine tube	1
gastrocnemius	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A20	276	ubiquitous	marker	right lobe of liver, mucosa of transverse colon, apex of heart
AMT	140	broad	yes	right lobe of liver, liver, right uterine tube
ARIH2	289	ubiquitous	marker	apex of heart, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARIH2	1,781
SLC25A20	1,757
AMT	1,716

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ARIH2	O95376	5
AMT	P48728	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A20	O43772	89.02

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycine degradation	1	543.8×	0.017	AMT
Carnitine shuttle	1	253.8×	0.018	SLC25A20
Fatty acid metabolism	1	43.8×	0.068	SLC25A20
Class I MHC mediated antigen processing & presentation	1	23.4×	0.095	ARIH2
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.125	ARIH2
Metabolism of lipids	1	10.5×	0.125	SLC25A20
Adaptive Immune System	1	9.9×	0.125	ARIH2
Immune System	1	4.3×	0.237	ARIH2
Metabolism	1	3.9×	0.237	SLC25A20

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
glycine catabolic process	1	2808.7×	0.003	AMT
developmental cell growth	1	2808.7×	0.003	ARIH2
glycine decarboxylation via glycine cleavage system	1	1872.4×	0.003	AMT
carnitine shuttle	1	1404.3×	0.003	SLC25A20
carnitine transmembrane transport	1	936.2×	0.003	SLC25A20
mitochondrial transport	1	401.2×	0.006	SLC25A20
hematopoietic stem cell proliferation	1	216.1×	0.010	ARIH2
obsolete positive regulation of protein targeting to mitochondrion	1	165.2×	0.011	ARIH2
protein K63-linked ubiquitination	1	89.2×	0.019	ARIH2
protein K48-linked ubiquitination	1	56.2×	0.027	ARIH2
protein polyubiquitination	1	38.5×	0.035	ARIH2
ubiquitin-dependent protein catabolic process	1	24.8×	0.047	ARIH2
in utero embryonic development	1	24.0×	0.047	SLC25A20
proteasome-mediated ubiquitin-dependent protein catabolic process	1	17.4×	0.060	ARIH2
protein ubiquitination	1	13.8×	0.071	ARIH2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC25A20	0	0
AMT	0	0
ARIH2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
SLC25A20	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMT	1.4.1.27, 2.1.2.10	glycine cleavage system, aminomethyltransferase
ARIH2	2.3.2.31	RBR-type E3 ubiquitin transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	AMT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SLC25A20, ARIH2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC25A20	1	—
AMT	0	—
ARIH2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02214160	PHASE2	COMPLETED	Long-Chain Fatty Acid Oxidation Disorders (LC-FAOD) Extension Study for Subjects Previously Enrolled in Triheptanoin Studies
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	1