rs137852769 — HADHA p.Glu510Gln

HADHA p.Glu510Gln — The Common LCHAD Deficiency Variant

The mitochondrial trifunctional protein (MTP)¹¹ mitochondrial trifunctional protein (MTP)
MTP is a hetero-octameric enzyme complex in the inner mitochondrial membrane consisting of four HADHA-encoded alpha subunits and four HADHB-encoded beta subunits. Together they catalyze the last three steps of long-chain fatty acid beta-oxidation. is the enzymatic workhorse for burning long-chain dietary fats. The HADHA alpha subunit alone carries three distinct catalytic activities: long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), and long-chain 3-ketoacyl-CoA thiolase. The p.Glu510Gln substitution (c.1528G>C, NM_000182.5) specifically abolishes the LCHAD activity while leaving the other two activities partially intact — a distinction that defines isolated LCHAD deficiency as a phenotypically distinct disorder from complete MTP deficiency.

This glutamic-to-glutamine change at position 510 is by far the most prevalent pathogenic HADHA variant in European populations, accounting for the large majority of LCHAD deficiency cases worldwide. In the Kashubian ethnic group of northern Poland, carrier frequency reaches 1 in 57 individuals²² 1 in 57 individuals
Nedoszytko et al., PLoS One, 2017 — the Kashubian founder effect suggests a single ancestral mutation event; general Polish carrier rate is approximately 1 in 187, reflecting a documented founder effect. Globally the heterozygous carrier frequency is approximately 1 in 275 people, making LCHAD deficiency one of the more common fatty acid oxidation disorders after MCAD deficiency.

The Mechanism

Glutamate 510 sits within the catalytic core of the LCHAD domain, where its negatively charged carboxylate side chain participates in the proton transfer mechanism of 3-hydroxyacyl-CoA dehydrogenation. Replacing glutamate with glutamine removes the charge while preserving volume — a conservative substitution at the sequence level but catastrophic for catalysis. The result is near-complete loss of LCHAD activity; homozygous cells cannot oxidize long-chain 3-hydroxyacyl-CoA intermediates (C12–C18 chain length).

When LCHAD fails, long-chain fatty acids cannot complete beta-oxidation. Toxic long-chain 3-hydroxyacylcarnitine species (particularly C16:OH and C18:OH acylcarnitines) accumulate in plasma and tissues. These are not merely inert intermediates — they are detergent-like molecules that disrupt mitochondrial membrane integrity, cardiac conduction, retinal pigment epithelial cells, and peripheral nerve myelin sheaths. Cells that rely heavily on long-chain fat for energy (cardiac muscle, skeletal muscle, retina, liver) are disproportionately affected.

The Evidence

Clinical spectrum in homozygotes: A multi-center study of LCHAD and MTP-deficient patients³³ LCHAD and MTP-deficient patients
Olpin et al., J Inherit Metab Dis, 2005 — comprehensive biochemical and clinical profiling across the phenotypic spectrum established that isolated LCHAD deficiency from the Glu510Gln mutation produces a moderately severe phenotype spanning neonatal presentation (cardiomyopathy, hypoketotic hypoglycemia) to a later-onset neuromyopathic form.

Outcomes under modern management: In a cohort of 67 individuals diagnosed through newborn screening⁴⁴ 67 individuals diagnosed through newborn screening
Mütze et al., Ann Clin Transl Neurol, 2024 — 54 screened, 13 symptomatic; LCHAD and MTP deficiency combined, all screened LCHAD patients survived. However, even with early intervention, 94% had a symptomatic disease course, 82% developed myopathy, 17% retinopathy, and 22% peripheral neuropathy — underscoring that dietary treatment prevents death but does not fully prevent long-term morbidity. Dietary adherence declined from 75% in infancy to only 12% by age 10, a major clinical challenge.

Retinopathy and visual outcomes: Among 40 patients stratified by diagnosis pathway⁵⁵ 40 patients stratified by diagnosis pathway
Gillingham et al., J Inherit Metab Dis, 2024 — 12 symptomatic, 28 via NBS or family history, early diagnosis through newborn screening produced significantly better visual acuity, ERG amplitudes, contrast sensitivity, and visual fields than symptomatic diagnosis. Despite this advantage, chorioretinopathy progressed with age in both groups. An Austrian cohort of 14 Glu510Gln homozygotes showed retinopathy in 57%, cardiomyopathy in 50%, and hepatopathy in 36%⁶⁶ retinopathy in 57%, cardiomyopathy in 50%, and hepatopathy in 36%
Karall et al., Orphanet J Rare Dis, 2015 — all patients homozygous for c.1528G>C, majority identified by NBS, with a median of 9 hospitalizations per patient.

The unique maternal-fetal link: LCHAD deficiency is distinctive among metabolic disorders for its effect on the carrier mother during pregnancy. When a carrier mother gestates an affected (homozygous) fetus, the fetus floods the maternal circulation with long-chain 3-hydroxyacylcarnitines it cannot process. In a heterozygous mother whose own LCHAD capacity is already reduced by 50%, this metabolic load overwhelms hepatic processing⁷⁷ this metabolic load overwhelms hepatic processing
Bellig, Adv Neonatal Care, 2004; Ibdah et al., Mol Genet Metab, 2000 and causes HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) or acute fatty liver of pregnancy (AFLP) in the third trimester — conditions with significant maternal and fetal mortality. This makes LCHAD deficiency one of the few recessive disorders where the heterozygous state has a clinically documented, albeit pregnancy-specific, phenotype.

Practical Actions

For homozygous individuals, management is lifelong and centers on eliminating the long-chain fat substrate: a diet restricted to no more than 15–30% of energy from long-chain fat, with medium-chain triglycerides supplying the remainder of fat-based energy. MCT oil and triheptanoin (C7 triglyceride, Dojolvi) are metabolized via MCAD and MCKAT without requiring HADHA activity. Fasting must be avoided — when glucose stores are depleted, the body cannot substitute long-chain fat oxidation. Every hospitalization, surgical procedure, or febrile illness requires IV dextrose supplementation. Long-chain 3-hydroxyacylcarnitine monitoring (C16:OH, C18:OH acylcarnitines) guides dietary adequacy.

Annual ophthalmology evaluation with retinal imaging (OCT, ERG) is essential given the high retinopathy rate, even in well-managed patients. Periodic nerve conduction studies detect subclinical peripheral neuropathy before it becomes symptomatic.

Carrier mothers planning pregnancy should inform their obstetrician and undergo carrier testing of their partner. If both partners are carriers, LCHAD-deficient fetuses can be detected prenatally; affected neonates must be identified within days of birth to begin dietary treatment before metabolic crisis.

Interactions

The Glu510Gln variant can occur in compound heterozygosity with other HADHA pathogenic variants, producing variable phenotypic severity depending on the second allele's residual activity. Variants causing complete MTP deficiency (abolishing all three alpha-subunit activities) produce a more severe phenotype than Glu510Gln homozygosity.

Pathway partners include HADHB (encoding the MTP beta subunit harboring thiolase activity); biallelic HADHB mutations cause the isolated MTP neuropathic/myopathic phenotype without LCHAD deficiency's characteristic retinopathy. Other fatty acid oxidation enzymes — ACADVL (rs113994167), ACADM — act upstream in the same pathway; concurrent variants there amplify the metabolic burden.