Long Chain Fatty Acid Oxidation Disorder (LC-FAOD)

Long chain fatty acid oxidation disorder (LCFAOD) is a group of 6 genetic autosomal recessive metabolic disorders characterized by impaired fat metabolism and energy deficiency. These are carnitine palmitoyltransferase 1 (CPT1) deficiency, carnitine palmitoyltransferase 2 (CPT2) deficiency, carnitine-acylcarnitine translocase (CACT) deficiency, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency, long-chain 3-hydroxy-acyl-CoA dehydrogenase (LCHAD) deficiency, and trifunctional protein (TFP) deficiency.¹

Persistent or Recurring Symptoms

The persistent or recurring symptoms of LCFAOD usually include fatigue, muscle pain, cramps, weakness, and brain fog. These can be brought on by fasting, illness, sustained exercise, and physiologic stress.²  

These chronic symptoms can lead to hypotonia, and in some types of disease retinopathy and peripheral neuropathy. 

Acute Energy Crises

Illness or fasting can trigger acute energy crises in patients with LCFAOD, which may lead to hospitalization and in severe cases, sudden death. However, these crises can also occur spontaneously.² 

Symptoms in Infants 

Symptoms of a metabolic crisis in infants include neurologic distress, which manifests as extreme sleepiness, coma, and Reye’s syndrome. Changes in heartbeat and appetite or dietary requirements, as well as muscle weakness, may also occur.²

Symptoms by Disease Type

CPT1 Deficiency

The symptoms of CPT1 deficiency include hypoglycemia and hypoketotic hypoglycemia. The disease can also cause sudden liver failure, which can cause hepatic encephalopathy. Abnormal laboratory findings include increased liver enzymes, hyperammonemia, and carnitine in the blood.³

The symptoms of the disease usually appear in childhood but they can also cause abnormal findings during pregnancy. These can include maternal fatty liver, hypoglycemia, abnormal liver enzymes, hyperammonemia, and increased susceptibility to bleeding.

CPT2 Deficiency

The most common symptoms of CPT2 deficiency are muscle weakness and reduced carnitine O-palmitoyltransferase levels seen in as much as 99% of patients. Other symptoms include decreased plasma carnitine, elevated plasma acylcarnitine, elevated serum creatine kinase, exercise intolerance and exercise-induced myalgia, hyperlipidemia, myoglobinuria, myopathy, and red-brown urine. Other rare symptoms include cold-induced muscle cramps, abdominal pain, exercise-induced muscle cramps, headache, hepatomegaly, painful muscle spasms, renal tubular epithelial necrosis, rhabdomyolysis, seizures, chronic kidney disease, and tubulointerstitial nephritis.⁴

In very rare cases (1% to 4% of patients) abnormality in the basal ganglia, agenesis of the corpus callosum, heart arrhythmia, cardiomyopathy, cerebellar vermis hypoplasia, cerebral or hepatic calcification, coma, cystic renal dysplasia, liver failure, hydrocephalus may occur. Too much cerebrospinal fluid in the brain, hypoketotic hypoglycemia, pachygyria, polycystic kidney dysplasia, and polymicrogyria may also occur.

CACT Deficiency

The first symptoms of CACT deficiency are seizures caused by hypoketotic hypoglycemia, arrhythmia, and respiratory problems. These usually appear within the first few hours after birth.⁵

Other symptoms of the disease include hyperammonemia, hepatomegaly, cardiomyopathy, arrhythmias, muscle weakness, and developmental delays.

VLCAD Deficiency

VLCAD deficiency can present in one of three forms. The first is the severe, early-onset form and is characterized by cardiomyopathy, pericardial effusion, heart arrhythmias, hypotonia, hepatomegaly, and intermittent hypoglycemia.⁶

In hepatic or hypoketotic hypoglycemic VLCAD deficiency, hepatomegaly usually occurs in early childhood. Patients can feel weak, shaky, or dizzy. 

The third and most common form of VLCAD deficiency is the later-onset episodic myopathic form, symptoms of which may include intermittent rhabdomyolysis, muscle cramps, muscle pain, and exercise intolerance.

LCHAD Deficiency

Almost all patients with LCHAD deficiency experience hypoketotic hypoglycemia and photophobia. Other symptoms of the disease include exotropia, developmental delays, hepatomegaly, hypertrophic cardiomyopathy, peripheral neuropathy, and vision loss.⁷

In rarer cases, the following symptoms can occur: retinal pigmentation abnormalities, cholestatic liver disease, chorioretinal atrophy, failure to thrive, faltering weight, feeding issues, hypotonia, intellectual disability, myopia, nyctalopia, posterior staphyloma, retinopathy, and seizures.

TFP Deficiency

The symptoms of TFP deficiency include feeding difficulties, lethargy, hypoglycemia, hypotonia, and hepatic problems. These usually appear in early infancy. Symptoms that may also appear later in life include hypotonia, muscle pain, rhabdomyolysis, and peripheral neuropathy. These symptoms can be triggered by fasting or illness.⁸

Age of Onset of Symptoms

The cardiac symptoms of LCFAOD usually appear in the neonatal period or early childhood. In VLCAD, CPT2, LCHAD, and TFP deficiency may appear later in life in periods of crisis and may be accompanied by pericardial effusion.⁹

Hepatic symptoms usually appear within the first 2 years of life but may present later in the case of CPT1, CPT2, LCHAD, and CACT deficiency. Muscular symptoms appear in early childhood and may also be triggered by endurance, fasting, and physiologic stress.

Neuropathy is usually not detected until the teenage years or adulthood. Children with TFP and LCHAD deficiency may miss key developmental milestones. They may also present with retinal changes at around age 2. 

TFP and CPT2 deficiency may cause respiratory distress in neonates.⁹

References

1. Knottnerus SJG, Bleeker JC, Wüst RCI, et al. Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle. Rev Endocr Metab Disord. 19, 93–106 (2018). doi:10.1007/s11154-018-9448-1
2. Understand What Causes LC-FAOD and How It Impacts the Body. FAOD in Focus. Accessed June 3, 2021.
3. Carnitine Palmitoyltransferase 1A Deficiency. National Organization of Rare Disorders. 2020. Accessed June 3, 2021. 
4. Carnitine palmitoyltransferase 2 deficiency. Genetic and Rare Diseases Information Center. Accessed June 3, 2021.
5. Carnitine-acylcarnitine translocase deficiency. Medline Plus. August 18, 2020. Accessed June 3, 2021.
6. Leslie ND, Valencia A, Strauss AW, Zhang K. Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency. GeneReviews. June 3, 2021.
7. LCHAD deficiency. Genetic and Rare Diseases Information Center. Accessed June 3, 2021.
8. Mitochondrial trifunctional protein deficiency. Medline Plus. 2020. Accessed June 3, 2021.
9. Merritt JL, MacLeod E, Jurecka A, Hainline B. Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord. 2020;21(4):479-493. doi:10.1007/s11154-020-09568-3

Reviewed by Harshi Dhingra, MD, on 7/1/2021.

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Ozge Ozkaya, MSc, PhD

Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.