long chain 3-hydroxyacyl-CoA dehydrogenase deficiency

disease

On this page

Also known as 3-hydroxyacyl-CoA dehydrogenase long chain deficiencyfatty liver, acute, of pregnancyHELLP syndrome, maternal, of pregnancyLCHAD deficiencyLCHADDlong-chain 3-hydroxy acyl CoA dehydrogenase deficiencylong-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiencylong-chain 3-OH acyl-CoA dehydrogenase deficiencytrifunctional protein deficiency type 1

Summary

long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (MONDO:0012173) is a disease caused by HADHA (GenCC Definitive), with 3 cohort genes and 7 clinical trials. Top therapeutic interventions include glycerin.

At a glance

Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
Causal gene: HADHA (GenCC Definitive)
Cohort genes: 3
ClinVar variants: 1,102
Phenotypes (HPO): 25
Clinical trials: 7

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	8	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.4	United States	Validated
Prevalence at birth	1-9 / 1 000 000	0.5	Germany	Validated
Prevalence at birth	1-9 / 100 000	2	Sweden	Validated
Prevalence at birth	1-9 / 1 000 000	0.84	Poland	Validated
Prevalence at birth	1-9 / 100 000	1.09	Estonia	Validated
Prevalence at birth	1-9 / 1 000 000	0.5	Israel	Validated
Prevalence at birth	1-9 / 1 000 000	0.3	Specific population	Validated
Prevalence at birth	1-9 / 100 000	1.24	Czech Republic	Validated
Prevalence at birth	1-9 / 100 000	1	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000613	Photophobia	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0001985	Hypoketotic hypoglycemia	Very frequent (80-99%)
HP:0000512	Abnormal electroretinogram	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0000577	Exotropia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001939	Abnormality of metabolism/homeostasis	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0000488	Retinopathy	Occasional (5-29%)
HP:0000532	Chorioretinal abnormality	Occasional (5-29%)
HP:0000533	Chorioretinal atrophy	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000662	Nyctalopia	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002611	Cholestatic liver disease	Occasional (5-29%)
HP:0007703	Abnormality of retinal pigmentation	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0030856	Posterior staphyloma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	long chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Mondo ID	MONDO:0012173
OMIM	609016
Orphanet	5
DOID	DOID:0061186
ICD-11	760613381
NCIT	C129929
SNOMED CT	726021008
UMLS	C3711645
MedGen	778253
GARD	0006867
Is cancer (heuristic)	no

Also known as: 3-hydroxyacyl-CoA dehydrogenase long chain deficiency · fatty liver, acute, of pregnancy · HELLP syndrome, maternal, of pregnancy · LCHAD deficiency · LCHADD · long chain 3-hydroxyacyl-CoA dehydrogenase deficiency · long-chain 3-hydroxy acyl CoA dehydrogenase deficiency · long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency · long-chain 3-OH acyl-CoA dehydrogenase deficiency · trifunctional protein deficiency type 1

Data availability: 1,102 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

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 › long chain 3-hydroxyacyl-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

600 retrieved; paginated sample, class counts are floors:

364 likely benign, 89 uncertain significance, 50 pathogenic, 41 likely pathogenic, 27 pathogenic/likely pathogenic, 12 conflicting classifications of pathogenicity, 10 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
2675968	NM_000182.5(HADHA):c.1533dup (p.Ile512fs)	GAREM2	Pathogenic	criteria provided, single submitter
2921383	NM_000182.5(HADHA):c.2011del (p.Glu671fs)	GAREM2	Pathogenic	criteria provided, single submitter
2922371	NM_000182.5(HADHA):c.1361_1364dup (p.Lys455delinsAsnTer)	GAREM2	Pathogenic	criteria provided, single submitter
2934638	NM_000182.5(HADHA):c.1231_1235del (p.Lys411fs)	GAREM2	Pathogenic	criteria provided, single submitter
2941242	NM_000182.5(HADHA):c.2039_2040dup (p.Phe681fs)	GAREM2	Pathogenic	criteria provided, single submitter
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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
HADHA	Definitive	Autosomal recessive	long chain 3-hydroxyacyl-CoA dehydrogenase 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
HMGCL	Orphanet:20	3-hydroxy-3-methylglutaric aciduria

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
GAREM2	HGNC:27172	ENSG00000157833	Q75VX8	GRB2-associated and regulator of MAPK protein 2	clinvar
HMGCL	HGNC:5005	ENSG00000117305	P35914	Hydroxymethylglutaryl-CoA lyase, mitochondrial	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.
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.
HMGCL	Hydroxymethylglutaryl-CoA lyase, mitochondrial	Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase that catalyzes a cation-dependent cleavage of (S)-3-hydroxy-3-methylglutaryl-CoA into acetyl-CoA and acetoacetate, a key step in ketogenesis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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)	2	8.0×	0.039
Other/Unknown	1	0.6×	0.914

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
GAREM2	Other/Unknown	no		SAM/pointed_sf, CABIT_dom, GAREM
HMGCL	Enzyme (other)	yes	4.1.3.4	HMG_CoA_lyase_AS, PYR_CT, Aldolase_TIM

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
caudate nucleus	1
ganglionic eminence	1
ventricular zone	1
liver	1
mucosa of transverse colon	1
right lobe of liver	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
GAREM2	187	ubiquitous	yes	ventricular zone, ganglionic eminence, caudate nucleus
HMGCL	295	ubiquitous	marker	right lobe of liver, liver, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HADHA	4,343
HMGCL	2,440
GAREM2	667

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HMGCL	P35914	4
HADHA	P40939	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: 10. 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	1	1903.3×	0.001	HADHA
Beta oxidation of palmitoyl-CoA to myristoyl-CoA	1	1903.3×	0.001	HADHA
Beta oxidation of lauroyl-CoA to decanoyl-CoA-CoA	1	1142.0×	0.001	HADHA
Beta oxidation of octanoyl-CoA to hexanoyl-CoA	1	1142.0×	0.001	HADHA
Beta oxidation of hexanoyl-CoA to butanoyl-CoA	1	1142.0×	0.001	HADHA
Acyl chain remodeling of CL	1	951.7×	0.001	HADHA
mitochondrial fatty acid beta-oxidation of unsaturated fatty acids	1	951.7×	0.001	HADHA
Beta oxidation of decanoyl-CoA to octanoyl-CoA-CoA	1	951.7×	0.001	HADHA
Synthesis of Ketone Bodies	1	713.8×	0.002	HMGCL
Peroxisomal protein import	1	86.5×	0.012	HMGCL

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
cardiolipin acyl-chain remodeling	1	1404.3×	0.003	HADHA
ketone body biosynthetic process	1	936.2×	0.003	HMGCL
L-leucine catabolic process	1	802.5×	0.003	HMGCL
response to stress	1	802.5×	0.003	GAREM2
neuron projection extension	1	175.5×	0.013	GAREM2
fatty acid beta-oxidation	1	124.8×	0.015	HADHA
cognition	1	95.2×	0.015	GAREM2
social behavior	1	90.6×	0.015	GAREM2
response to insulin	1	77.0×	0.016	HADHA
mitochondrion organization	1	50.6×	0.022	HMGCL
lipid metabolic process	1	30.5×	0.032	HMGCL

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
HADHA	0	0
GAREM2	0	0
HMGCL	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
HADHA	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HADHA	1.1.1.211	long-chain-3-hydroxyacyl-CoA dehydrogenase
HMGCL	4.1.3.4	hydroxymethylglutaryl-CoA lyase

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	2	HADHA, HMGCL
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	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	—
GAREM2	0	—
HMGCL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01494051	PHASE1/PHASE2	COMPLETED	High Protein Diet in Patients With Long-chain Fatty Acid Oxidation Disorders
NCT05411835	EARLY_PHASE1	COMPLETED	Oral Ketones and Exercise Among Patients With Long-chain Fatty Acid Oxidation Disorders
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT02517307	Not specified	COMPLETED	Fatty Acid Oxidation Defects and Insulin Sensitivity
NCT02635269	Not specified	UNKNOWN	Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
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
GLYCERIN	4	1

Cohort genes: HADHA, GAREM2, HMGCL
Drugs: Glycerin