What is Carnitine Palmitoyltransferase 1A Deficiency?

Causes and symptoms
CPT1: The gene and its functions
Diagnosis and treatment
References
Further reading

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare condition characterized by mitochondrial fatty acid b-oxidation. It follows the autosomal recessive pattern of inheritance. When energy needs are elevated, clinical manifestations usually emerge in a person who is also suffering from a fever or gastrointestinal disease. Symptoms of CPT1A typically appear rapidly. Hypoketotic hypoglycemic encephalopathy, metabolic acidosis, and liver failure are common early signs of this illness. Bougneres and colleagues discovered carnitine palmitoyltransferase-1A deficiency in 1981.

Causes and symptoms

The CPT-1 gene is located on chromosome 11q13. The CPT-1 gene has several pathogenic allelic variants. Private mutations, including missense, nonsense, insertion, and deletion mutations, account for the bulk of the variances observed in patients. In both the Hutterite and Inuit groups, unique mutations have been discovered. The Inuit variation mutation has been identified as a missense mutation that causes the proline at position 479 to be replaced with leucine (P479L). The arctic variation-specific mutation of P479L has been observed in Alaskan, Canadian, and Greenlandic Inuit people.

Acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that cause CPT1A deficiency, and hepatic encephalopathy, in which individuals (usually children) present with hypoketotic hypoglycemia and sudden onset of liver failure, are two of the recognized phenotypes. Hypoglycemia, absence or low levels of ketones, and high serum concentrations of liver transaminases, ammonia, and total carnitine are common symptoms of hepatic encephalopathy. Individuals appear developmentally and intellectually normal between episodes of hepatic encephalopathy unless past metabolic decompensation has resulted in brain impairment.

Classic CPT-1A deficiency usually manifests itself between the ages of birth and 18 months. When the arctic version is present, it is frequently asymptomatic. Patients will exhibit a wide range of symptoms. Hypoglycemia in newborns is a common occurrence. Fasting-induced lethargy and seizures are common in children who are not present during the newborn period.

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In certain situations, the presentation has been lethal. Alterations in mental status, seizures, coma, hepatomegaly, fever, vomiting, and diarrhea are just a few of the symptoms. Hypoketotic hypoglycemia, hyperammonemia, high liver function tests, elevated free fatty acids, and low urine ketones are all possible results of laboratory tests. In youngsters, the symptoms generally resemble those of Reye syndrome. Although cardiac and skeletal muscles are involved in many long-chain fatty acid oxidation defects, this has not been observed in patients with CPT-1A deficiency.

CPT1: The gene and its functions

Carnitine palmitoyltransferase-1A is a mitochondrial enzyme found on the outer membrane. CPT-1 is responsible for converting long-chain fatty acyl molecules to acylcarnitines. Carnitine acylcarnitine translocase transports the acylcarnitine through the inner mitochondrial membrane and into the mitochondrial matrix once it has been converted to acylcarnitine. The CPT-2 enzyme converts acylcarnitine back into a long-chain fatty acyl molecule once inside, allowing for -oxidation. When glycogen stores are reduced due to fasting or illness, the liver's -oxidation and generation of ketones provide an alternate fuel source. This method enables metabolism in peripheral tissues that are unable to oxidize fatty acids and must rely on ketogenesis for energy.

Carnitine palmitoyltransferase-1A is the only CPT-1 gene identified to be defective in humans, and it is exclusive to the liver isoform of CPT-1. Fasting is difficult for those with CPT-1A deficiency because there isn't enough enzyme activity to allow lipids to be used for energy when glucose levels decrease, especially during times of stress. As the glucose stores are depleted, the body enters a state of hypoglycemia.

Diagnosis and treatment

When molecular genetic testing is not definitive, the diagnosis of CPT1A is confirmed in a proband by the discovery of biallelic pathogenic mutations in CPT1A on molecular genetic testing or decreased carnitine palmitoyltransferase 1 (CPT 1) enzyme activity on cultured skin fibroblasts. In most people with CPT1A deficiency, residual enzyme activity is between 1% and 5%.

On the expanded newborn screen, tandem mass spectrometry (MS/MS) is used to make the diagnosis. The findings of the MS/MS will show an increase in free carnitine. CPT-1A deficiency may be discovered at greater rates with the second newborn test done at 14 days of age due to birth stress and transplacental carnitine transfer. Encephalopathy with hypoglycemia and low ketone levels are two further diagnostic tests. Serum transaminases, ammonia, liver function tests, and free fatty acids may all be increased in patients with the typical type. Urine organic acid tests can detect low ketone levels.

A diet heavy in carbs and low in fat is advantageous for patients with the classic type. A high-fat diet may protect against hypoglycemia in the case of the arctic variety. Supplementing with MCT oils (medium-chain triglycerides) may also be necessary. Older patients are required to take at least one-third of their total calories from MCT. Suppose the patient does not adhere to the diet and receives frequent feedings. In that case, they run the danger of experiencing repeated bouts of metabolic crisis, which can lead to mental retardation or learning difficulties. Even if they are asymptomatic, patients with CPT-1A deficiency should have their liver enzymes and liver function checked at clinic appointments.

Hypoglycemia can lead to brain impairment, so it's important to avoid it. Acute fatty liver of pregnancy should be observed in heterozygous pregnant women. Carnitine palmitoyltransferase-1A deficiency is an autosomal recessive disorder, so families should seek genetic counseling to understand the condition better.

References

1. Lee, B. H., Kim, Y. M., Kim, J. H., Kim, G. H., Kim, J. M., Kim, J. H., Woo, K. H., Yang, S. H., Kim, C. J., Choi, I. H., & Yoo, H. W. (2015). Atypical manifestation of carnitine palmitoyltransferase 1A deficiency: hepatosplenomegaly and nephromegaly. Journal of pediatric gastroenterology and nutrition, 60(3), e19–e22. https://doi.org/10.1097/MPG.0b013e3182a95a42
2. Dykema, Deanna M. (2012). Carnitine Palmitoyltransferase-1A Deficiency. Advances in Neonatal Care, 12(1), 23–27. doi:10.1097/anc.0b013e318242df6d
3. Gobin, S.; Thuillier, L.; Jogl, G.; Faye, A.; Tong, L.; Chi, M.; Bonnefont, J.-P.; Girard, J.; Prip-Buus, C. (2003). Functional and Structural Basis of Carnitine Palmitoyltransferase 1A Deficiency. Journal of Biological Chemistry, 278(50), 50428–50434. doi:10.1074/jbc.M310130200
4. Bennett MJ, Santani AB. (1993). Carnitine Palmitoyltransferase 1A Deficiency. In: GeneReviews®. University of Washington, Seattle, Seattle (WA). PMID: 20301700.

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