Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

LCHADD deficiency, or long-chain 3-hydroxyacyl CoA dehydrogenase deficiency, is a disease that affects the metabolic process through which our body obtains energy from certain fats, especially during periods of fasting.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is an autosomal recessive inherited disorder of metabolism included in the group of monogenic mitochondrial disorders of long-chain fatty acid oxidation. LCHADD is a rare disease with a prevalence of approximately one case per 250,000 population.

In LCHADD, there is an impairment of mitochondrial beta-oxidation, which is a metabolic pathway involving several enzymes that generates acetyl-CoA and energy from fatty acids. The acetyl-CoA produced can enter the Krebs cycle and produce energy. When beta-oxidation is impaired, the accumulation of potentially toxic unoxidized acyl-CoA esters occurs and the acyl-CoA groups are transferred to other molecules forming acyl-conjugates that are unable to enter the usual biochemical pathways. Some of the acyl-conjugates, such as acylcarnitine, pass into the blood and are excreted in the urine. Screening that analyzes the acylcarnitine profile using a dried blood spot (Guthrie card) is a well-known and commonly used method that allows neonatal screening.

Symptoms

Symptoms appear immediately in early infancy, during periods of fasting, and include lethargy, hypoglycemia or low blood sugar levels, weak muscle tone (hypotonia), febrile infections and gastroenteritis, liver problems and retinal abnormalities. Known irreversible long-term complications are peripheral neuropathy, retinopathy and heart disease.

Disease management

The treatment of LCHADD is lifelong and is based on the avoidance of long periods of fasting and a diet free of long-chain fatty acids. In addition, L-carnitine supplementation and anaplerotic therapy, which is based on providing a substrate for the citric acid cycle that prevents deficient fatty acid oxidation, are used. One example is triheptanoin, a synthetic medium-chain triglyceride, which is being studied for long-chain fatty acid oxidation disorders.

Genes analyzed

HADHA

Bibliography

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IJlst L, Ruiter JP, Hoovers JM, et al . Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. J Clin Invest. 1996 Aug 15;98(4):1028-33.

Karall D, Brunner-Krainz M, Kogelnig K, et al . Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD). Orphanet J Rare Dis. 2015 Feb 22;10:21.

Liewluck T, Mundi MS, Mauermann ML. Mitochondrial trifunctional protein deficiency: a rare cause of adult-onset rhabdomyolysis. Muscle Nerve. 2013 Dec;48(6):989-91.

Lotz-Havla AS, Röschinger W, Schiergens K, et al . Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Orphanet J Rare Dis. 2018 Jul 20;13(1):122.

Shirley M. Triheptanoin: First Approval. Drugs. 2020 Oct;80(15):1595-1600.

Vockley J, Longo N, Madden M, et al . Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study. Clin Nutr ESPEN. 2021 Feb;41:293-298.