Long-chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

Long-chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency is a long-chain fatty-acid oxidation disorder presenting with hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, skeletal myopathy, rhabdomyolysis and exercise intolerance. Survivors may develop progressive peripheral neuropathy and pigmentary retinopathy despite good metabolic control.
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Genetics

Autosomal recessive disease caused by biallelic pathogenic variants in HADHA, which encodes the alpha subunit of mitochondrial trifunctional protein. The recurrent c.1528G>C, p.Glu510Gln variant is common in isolated LCHAD deficiency.

Molecular Mechanism

Loss of long-chain 3-hydroxyacyl-CoA dehydrogenase activity blocks mitochondrial beta-oxidation of long-chain fatty acids. Energy failure during fasting or illness and accumulation of long-chain 3-hydroxyacyl intermediates injure liver, heart, skeletal muscle, peripheral nerves and retina.

Therapy

Treatment requires avoidance of fasting, rapid provision of glucose during illness, restriction of long-chain fat and supplementation with medium-chain triglyceride or FDA-approved triheptanoin. Exercise and pregnancy require specialist planning; no approved gene therapy exists.

CCP Activity

CCP is developing and characterizing an LCHAD-deficiency model. Gene-replacement concept is under design.  

Mouse Models Mouse Models & Gene Cards

Mouse ModelsGene Cards
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