Mitochondrial trifunctional protein deficiency

Summary

Mitochondrial trifunctional protein deficiency (MONDO:0012172) is a disease caused by variants in HADHB and HADHA, with 3 cohort genes and 4 clinical trials. Top therapeutic interventions include triheptanoin.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: HADHB (GenCC Definitive), HADHA (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,395
• Phenotypes (HPO): 46
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	1-9 / 100 000	1	Europe	Validated

Signs & symptoms

Clinical features (HPO)

46 HPO clinical features (Orphanet curated; top 46 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Very frequent (80-99%)
HP:0003201	Rhabdomyolysis	Very frequent (80-99%)
HP:0003546	Exercise intolerance	Very frequent (80-99%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0001638	Cardiomyopathy	Frequent (30-79%)
HP:0001712	Left ventricular hypertrophy	Frequent (30-79%)
HP:0001985	Hypoketotic hypoglycemia	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002901	Hypocalcemia	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0003756	Skeletal myopathy	Frequent (30-79%)
HP:0006555	Diffuse hepatic steatosis	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009063	Progressive distal muscle weakness	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0011808	Decreased patellar reflex	Frequent (30-79%)
HP:0100626	Chronic hepatic failure	Frequent (30-79%)
HP:0000580	Pigmentary retinopathy	Occasional (5-29%)
HP:0000829	Hypoparathyroidism	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001396	Cholestasis	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0002359	Frequent falls	Occasional (5-29%)
HP:0002878	Respiratory failure	Occasional (5-29%)
HP:0003324	Generalized muscle weakness	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0005180	Tricuspid regurgitation	Occasional (5-29%)
HP:0008110	Equinovarus deformity	Occasional (5-29%)
HP:0008138	Equinus calcaneus	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)
HP:0002476	Primitive reflex	Very rare (<1-4%)
HP:0007067	Distal peripheral sensory neuropathy	Very rare (<1-4%)
HP:0007141	Sensorimotor neuropathy	Very rare (<1-4%)
HP:0025145	Rigors	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial trifunctional protein deficiency
Mondo ID	MONDO:0012172
MeSH	C566945
OMIM	609015
Orphanet	746
DOID	DOID:0111277
ICD-11	1018083832
NCIT	C98991
SNOMED CT	237999008
UMLS	C1969443
MedGen	370665
GARD	0003684
Is cancer (heuristic)	no

Also known as: mitochondrial trifunctional protein deficiency · MTPD · TFP deficiency · TFPD

Data availability: 1,395 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › mitochondrial trifunctional protein deficiency

Related subtypes (28): cortisone reductase deficiency, familial hyperlipidemia, hypolipoproteinemia, steroid inherited metabolic disorder, corticosterone methyloxidase type 1 deficiency, lipoid proteinosis, 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency, vitamin D hydroxylation-deficient rickets, type 1B, pancreatic triacylglycerol lipase deficiency, glucocorticoid resistance, syndromic dyslipidemia, inborn disorder of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation, disorder of plasmalogens biosynthesis, disorder of phospholipids, sphingolipids and fatty acids biosynthesis, inborn disorder of ketolysis, lysosomal lipid storage disorder, sterol metabolism disorder, disorder of sphingolipid biosynthesis, glycosylphosphatidylinositol biosynthesis defect 18, neurodevelopmental disorder with hypotonia and cerebellar atrophy, with or without seizures, developmental and epileptic encephalopathy, 77, developmental and epileptic encephalopathy, 80, developmental and epileptic encephalopathy, 55, inherited fatty acid metabolism disorder, glycosylphosphatidylinositol biosynthesis defect 16, glycosylphosphatidylinositol biosynthesis defect 15, glycosylphosphatidylinositol biosynthesis defect 17, CYP7B1-related disorder of oxysterol accumulation

Subtypes (2): mitochondrial trifunctional protein deficiency 1, mitochondrial trifunctional protein deficiency 2

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

600 retrieved; paginated sample, class counts are floors:

293 likely benign, 159 uncertain significance, 53 pathogenic, 32 likely pathogenic, 31 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 9 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100085	NM_000182.5(HADHA):c.1528G>C (p.Glu510Gln)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065948	NM_000182.5(HADHA):c.2026C>T (p.Arg676Cys)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069908	NM_000182.5(HADHA):c.1523del (p.Leu508fs)	GAREM2	Pathogenic	criteria provided, single submitter
1073572	NM_000182.5(HADHA):c.1319dup (p.Ala441fs)	GAREM2	Pathogenic	criteria provided, single submitter
1075355	NM_000182.5(HADHA):c.1528G>T (p.Glu510Ter)	GAREM2	Pathogenic	criteria provided, single submitter
1163205	NM_000182.5(HADHA):c.1167dup (p.Lys390Ter)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386792	NM_000182.5(HADHA):c.1654dup (p.Ala552fs)	GAREM2	Pathogenic	criteria provided, single submitter
1390752	NM_000182.5(HADHA):c.2200A>T (p.Lys734Ter)	GAREM2	Pathogenic	criteria provided, single submitter
1455936	NM_000182.5(HADHA):c.1491_1495dup (p.Tyr499fs)	GAREM2	Pathogenic	criteria provided, single submitter
1459829	NM_000182.5(HADHA):c.1540del (p.Thr514fs)	GAREM2	Pathogenic	criteria provided, single submitter
188712	NM_000182.5(HADHA):c.1967del (p.Ile655_Leu656insTer)	GAREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
1912385	NM_000182.5(HADHA):c.1893del (p.Lys631fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
194917	NM_000182.5(HADHA):c.2146+1G>A	GAREM2	Pathogenic	criteria provided, multiple submitters, no conflicts
2020384	NM_000182.5(HADHA):c.2010del (p.Asp670fs)	GAREM2	Pathogenic	criteria provided, single submitter
2025539	NC_000002.12:g.26201318_26201321del	GAREM2	Pathogenic	criteria provided, single submitter
203745	NM_000182.5(HADHA):c.1916_1919dup (p.Glu641fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2048816	NM_000182.5(HADHA):c.2020dup (p.Gln674fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2101164	NM_000182.5(HADHA):c.2231del (p.Phe744fs)	GAREM2	Pathogenic	criteria provided, single submitter
2503898	NM_000182.5(HADHA):c.1759_1760del (p.Leu587fs)	GAREM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069465	NM_000182.5(HADHA):c.1990_1993dup (p.Ser665Ter)	HADHA	Pathogenic	criteria provided, single submitter
1070607	NC_000002.11:g.(?26416436)(26418111_?)del	HADHA	Pathogenic	criteria provided, single submitter
1071670	NM_000182.5(HADHA):c.294del (p.Phe98fs)	HADHA	Pathogenic	criteria provided, single submitter
1373566	NM_000182.5(HADHA):c.556C>T (p.Gln186Ter)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1388408	NM_000182.5(HADHA):c.690del (p.Lys230fs)	HADHA	Pathogenic	criteria provided, single submitter
1408580	NM_000182.5(HADHA):c.352_353del (p.Gln118fs)	HADHA	Pathogenic	criteria provided, single submitter
1420102	NM_000182.5(HADHA):c.966_967del (p.Cys322_Glu323delinsTer)	HADHA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427255	NM_000182.5(HADHA):c.2208T>A (p.Tyr736Ter)	HADHA	Pathogenic	criteria provided, single submitter
1435055	NM_000182.5(HADHA):c.310dup (p.Ile104fs)	HADHA	Pathogenic	criteria provided, single submitter
1452112	NM_000182.5(HADHA):c.2020C>T (p.Gln674Ter)	HADHA	Pathogenic	criteria provided, single submitter
1452124	NM_000182.5(HADHA):c.1554del (p.Asp520fs)	HADHA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · 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
HADHB	Definitive	Autosomal recessive	mitochondrial trifunctional protein deficiency	4
HADHA	Strong	Autosomal recessive	mitochondrial trifunctional protein deficiency	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HADHA	Orphanet:243367	Acute fatty liver of pregnancy
HADHA	Orphanet:5	Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
HADHA	Orphanet:746	Mitochondrial trifunctional protein deficiency
HADHB	Orphanet:746	Mitochondrial trifunctional protein deficiency

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
HADHA	HGNC:4801	ENSG00000084754	P40939	Trifunctional enzyme subunit alpha, mitochondrial	gencc,clinvar
HADHB	HGNC:4803	ENSG00000138029	P55084	Trifunctional enzyme subunit beta, mitochondrial	gencc,clinvar
GAREM2	HGNC:27172	ENSG00000157833	Q75VX8	GRB2-associated and regulator of MAPK protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HADHA	Trifunctional enzyme subunit alpha, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.
HADHB	Trifunctional enzyme subunit beta, mitochondrial	Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway.
GAREM2	GRB2-associated and regulator of MAPK protein 2	Probable adapter protein that may provide a link between cell surface epidermal growth factor receptor and the MAPK/ERK signaling pathway.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HADHA	Enzyme (other)	yes	1.1.1.211	Enoyl-CoA_hydra/iso, 3HC_DH_C, 3-OHacyl-CoA_DH_NAD-bd
HADHB	Other/Unknown	no		Thiolase, Thiolase-like, Thiolase_AS
GAREM2	Other/Unknown	no		SAM/pointed_sf, CABIT_dom, GAREM

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
gastrocnemius	1
jejunal mucosa	1
muscle of leg	1
deltoid	1
heart right ventricle	1
left ventricle myocardium	1
caudate nucleus	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HADHA	295	ubiquitous	marker	jejunal mucosa, gastrocnemius, muscle of leg
HADHB	295	ubiquitous	marker	heart right ventricle, left ventricle myocardium, deltoid
GAREM2	187	ubiquitous	yes	ventricular zone, ganglionic eminence, caudate nucleus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHA	4,343
HADHB	4,047
GAREM2	667

Intra-cohort edges

A	B	Sources
HADHA	HADHB	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HADHA	P40939	3
HADHB	P55084	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GAREM2	Q75VX8	61.81

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Beta oxidation of myristoyl-CoA to lauroyl-CoA	2	3806.7×	2e-07	HADHA, HADHB
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	2	3806.7×	2e-07	HADHA, HADHB
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	2	2284.0×	2e-07	HADHA, HADHB
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	2	2284.0×	2e-07	HADHA, HADHB
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	2	2284.0×	2e-07	HADHA, HADHB
Acyl chain remodeling of CL	2	1903.3×	2e-07	HADHA, HADHB
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	2	1903.3×	2e-07	HADHA, HADHB
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	2	1903.3×	2e-07	HADHA, HADHB

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
fatty acid beta-oxidation	2	249.7×	2e-04	HADHA, HADHB
cardiolipin acyl-chain remodeling	1	1404.3×	0.003	HADHA
response to stress	1	802.5×	0.004	GAREM2
neuron projection extension	1	175.5×	0.013	GAREM2
cognition	1	95.2×	0.016	GAREM2
social behavior	1	90.6×	0.016	GAREM2
response to insulin	1	77.0×	0.017	HADHA
cellular response to lipopolysaccharide	1	32.7×	0.034	HADHB
gene expression	1	26.6×	0.037	HADHB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HADHA	0	0
HADHB	0	0
GAREM2	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
HADHA	4	Binding:4
HADHB	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HADHA	1.1.1.211	long-chain-3-hydroxyacyl-CoA dehydrogenase

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	HADHA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HADHB, GAREM2

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)
HADHA	4	—
HADHB	2	—
GAREM2	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
NCT01379625	PHASE2	COMPLETED	Study of Triheptanoin for Treatment of Long-Chain Fatty Acid Oxidation Disorder
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00840112	Not specified	TERMINATED	Vitamin E Treatment for Long-Chain 3-Hydroxyacyl Coenzyme A (CoA) Dehydrogenase (LCHAD) Associated Neuropathy
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TRIHEPTANOIN	4	2