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Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
LCHADD is a rare condition where the body cannot process long-chain fatty acids, which are an important energy source. It primarily affects infants and children, potentially leading to serious health issues if not managed appropriately.
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Overview
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare genetic condition belonging to a group of disorders known as fatty acid oxidation disorders. These conditions prevent the body from converting certain fats into energy, particularly during periods of fasting or increased energy demand, such as illness or strenuous exercise [PMID:33678519]. Instead of using these fats, the body relies solely on glucose, which can quickly become depleted. LCHADD is one of three related conditions affecting the mitochondrial trifunctional protein complex.
Newborn screening programmes in the UK aim to identify LCHADD early, allowing for timely intervention and management. While LCHADD is a lifelong condition, careful dietary management and other treatments can help prevent serious complications and improve quality of life.
Symptoms & clinical features
Symptoms of LCHADD can vary in severity and typically appear in infancy or early childhood, though in some cases, they may emerge later. The condition often presents during times when the body needs extra energy, such as during illness, fasting, or periods of intense physical activity [PMID:33678519].
Common symptoms can include feeding difficulties, lack of energy (lethargy), vomiting, diarrhoea, and low blood sugar (hypoglycaemia). More severe complications can include liver problems, muscle weakness (myopathy), and issues with the heart muscle (cardiomyopathy). Some individuals may experience damage to nerves in the hands and feet (peripheral neuropathy) or problems with vision [PMID:28751522]. In some cases, severe episodes can lead to coma or be life-threatening.
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Affected organs
LCHADD primarily affects organs that rely heavily on fat for energy, such as the liver, heart, and muscles. The liver can be impacted by fat accumulation and dysfunction, potentially leading to an enlarged liver or liver failure during metabolic crises. The heart muscle may become weakened or enlarged (cardiomyopathy), affecting its ability to pump blood effectively.
Muscles can also be affected, leading to weakness, pain, and damage, particularly during physical exertion. The eyes can experience retinal abnormalities, and the peripheral nerves may be damaged, leading to neuropathy. The brain can be indirectly affected by recurrent episodes of severe hypoglycaemia.
Risks & severity
The severity of LCHADD can vary considerably among affected individuals, even within the same family. Without appropriate management, LCHADD can lead to life-threatening metabolic crises, particularly in infancy. These crises are often triggered by prolonged fasting or illness.
Long-term complications can include progressive heart disease, liver dysfunction, and neurological problems such as peripheral neuropathy and retinopathy. The exact prevalence of LCHADD is estimated to be between 1 in 50,000 and 1 in 100,000 births, though this can vary by population. Early diagnosis and strict adherence to a management plan are crucial for reducing the risk of severe complications and improving long-term outcomes.
Genetic causes
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is caused by pathogenic variants in the HADHA gene. This gene provides instructions for making one part (the alpha subunit) of an important enzyme complex called mitochondrial trifunctional protein (MTP).
This MTP enzyme complex is located in the mitochondria, which are the energy-producing centres within cells. Its role is to help break down long-chain fatty acids into smaller molecules that can then be used by the body for energy [PMID:33678519]. Pathogenic variants in HADHA prevent the MTP complex from functioning correctly, meaning that long-chain fatty acids cannot be adequately processed. This leads to an accumulation of these fats and their byproducts, which can be toxic, while also depriving the body of a vital energy source.
- HADHA hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alphaThe HADHA gene provides instructions for synthesising a component of the mitochondrial trifunctional protein, which plays a crucial role in breaking down long-chain fatty acids for energy.
Inheritance pattern
LCHADD is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the HADHA gene - one from each parent - to develop the condition. People who have only one altered copy of the gene are called carriers.
Carriers typically do not show any symptoms of LCHADD because their one working copy of the gene is sufficient to produce enough functional MTP enzyme. When two carriers have a child together, there is a 25% chance with each pregnancy that the child will inherit two altered copies of the gene and develop LCHADD. There is a 50% chance the child will be a carrier like their parents, and a 25% chance the child will inherit two working copies of the gene and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
LCHADD is often suspected based on symptoms, especially during metabolic crises, or through routine newborn screening programmes. In the UK, newborn blood spot screening includes testing for LCHADD, which allows for early identification before symptoms develop.
A definitive diagnosis of LCHADD is confirmed through genetic testing, which looks for pathogenic variants in the HADHA gene. This testing can be arranged through an NHS clinical genetics service, often following a positive newborn screen or a strong clinical suspicion. Blood tests showing abnormal levels of certain fatty acids or their breakdown products can also support the diagnosis. The NHS Genomic Medicine Service offers genetic testing for LCHADD under specific R-codes, such as R222 (inherited metabolic disorders - targeted testing).
Management & lifestyle
Management of LCHADD focuses on preventing metabolic crises and providing the body with alternative energy sources. A key aspect is dietary modification, particularly avoiding prolonged fasting and consuming a diet low in long-chain fats and rich in medium-chain triglycerides (MCTs) [PMID:28751522]. MCTs are fats that can be processed by the body through a different pathway, bypassing the defective LCHAD enzyme.
Individuals with LCHADD often require frequent meals or snacks and may need special formulas or dietary supplements. During times of illness, an 'emergency regimen' involving increased glucose intake is crucial to prevent hypoglycaemia and metabolic decompensation. Regular follow-up with a metabolic specialist and dietitian is essential to monitor growth, nutritional status, and organ function, and to adjust the management plan as needed. Genetic counsellors can provide support and information to families regarding the inheritance pattern and implications of LCHADD.
UK care pathway
In the UK, individuals suspected of having LCHADD, often identified through newborn screening, are referred to specialist metabolic centres within the NHS. These centres provide comprehensive care, including diagnosis, dietary management, and ongoing monitoring. Genetic testing, typically managed by NHS Genomic Medicine Service laboratories under relevant R-codes (e.g., R222 for inherited metabolic disorders), confirms the diagnosis.
Clinical genetics teams and genetic counsellors play a vital role in explaining the condition, its inheritance, and implications for families. The care pathway involves a multidisciplinary team, including paediatricians, metabolic specialists, dietitians, and other specialists as needed, to ensure holistic patient management.
Frequently asked questions
What is long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)?
LCHADD is a genetic metabolic disorder where the body cannot properly break down long-chain fats into energy. This can lead to serious health problems, especially during periods of fasting or illness, because the body struggles to generate enough energy.
How is LCHADD diagnosed?
LCHADD is often identified through routine newborn screening in the UK. If a screen is positive or symptoms suggest the condition, genetic testing of the HADHA gene is performed to confirm the diagnosis. Blood tests looking at specific fatty acid levels can also support this.
What are the common treatments for LCHADD?
Treatment primarily involves dietary management, such as avoiding long periods without food and reducing intake of long-chain fats. A special diet rich in medium-chain fats (MCTs) is often recommended. During illness, extra glucose (sugar) is given to prevent metabolic crises.
Can people with LCHADD live a normal life?
With early diagnosis and strict adherence to a management plan, individuals with LCHADD can often lead healthy, fulfilling lives. Regular medical follow-ups and dietary adjustments are crucial for preventing complications and maintaining good health.
Is LCHADD inherited?
Yes, LCHADD is an inherited condition. It follows an autosomal recessive pattern, meaning a child must inherit a faulty copy of the HADHA gene from each parent to be affected. Parents who each carry one faulty copy are typically unaffected but can pass the condition on.
References
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- Hua X, Hormel TT, Wang J. Characterizing Long-Chain 3-Hydroxy-Acyl-CoA Dehydrogenase Deficiency (LCHADD) Chorioretinopathy Using OCT and OCTA. Investigative ophthalmology & visual science. 2025. PMID: 40990866
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- Rigaudière F, Delouvrier E, Le Gargasson JF. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and progressive retinopathy: one case report followed by ERGs, VEPs, EOG over a 17-year period. Documenta ophthalmologica. Advances in ophthalmology. 2021. PMID: 33392894
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