Carnitine palmitoyltransferase I deficiency

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Carnitine palmitoyltransferase I deficiency
Other namesCPT-I, CPT1
Carnitine structure.png
Carnitine

Carnitine palmitoyltransferase I deficiency is a rare metabolic disorder that prevents the body from converting certain fats called long-chain fatty acids(LCFA) into energy, particularly during periods without food. [1] It is caused by a mutation in CPT1A on chromosome 11.[ citation needed ]

Contents

Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. People with this disorder have a faulty enzyme, carnitine palmitoyltransferase I, that prevents these long-chain fatty acids from being transported into the mitochondria to be broken down.[ citation needed ]

Symptoms and signs

Signs and symptoms of this disorder include low levels of ketones (hypoketosis) and low blood sugar (hypoglycemia). Together these signs are called hypoketotic hypoglycemia. People with this disorder typically also have an enlarged liver (hepatomegaly), muscle weakness, and elevated levels of carnitine in the blood. [2]

Genetics

Carnitine palmitoyltransferase I deficiency has an autosomal recessive pattern of inheritance. Autorecessive.svg
Carnitine palmitoyltransferase I deficiency has an autosomal recessive pattern of inheritance.

Mutations in the CPT1A gene cause carnitine palmitoyltransferase I deficiency by producing a defective version of an enzyme called carnitine palmitoyltransferase I. Without this enzyme, long-chain fatty acids from food and fats stored in the body cannot be transported into mitochondria to be broken down and processed. As a result, excessive levels of long-chain fatty acids may more rapidly build up in tissues, damaging the liver, heart and/or brain.[ citation needed ] This condition has an autosomal recessive inheritance pattern, which means the defective gene must be inherited from both parents. The parents of a child with an autosomal recessive disorder are carriers of one copy of the defective gene, but are usually not affected by the disorder.[ citation needed ]

The prevalence of mutations associated with this condition reach 68% to 81% in certain arctic coastal populations, suggesting that the condition had some adaptive value in those habitats at some time. [3] [4] Fewer than 50 people have been identified with this condition. [5]

Diagnosis

Genetic testing is necessary for diagnosis.[ citation needed ]

Differential diagnosis

This condition is sometimes mistaken for fatty acid and ketogenesis disorders such as Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD), other long-chain fatty acid oxidation disorders such as Carnitine palmitoyltransferase II deficiency (CPT-II) and Reye syndrome. [6]

Treatment

Treatment for this condition is supportive. There is no cure. Affected people should eat a high-carbohydrate, low-fat diet and avoid fasting. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Carnitine</span> Amino acid active in mitochondria

Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for free energy production, and also participates in removing products of metabolism from cells. Given its key metabolic roles, carnitine is concentrated in tissues like skeletal and cardiac muscle that metabolize fatty acids as an energy source. Generally individuals, including strict vegetarians, synthesize enough L-carnitine in vivo.

<span class="mw-page-title-main">Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy. This can become life-threatening, particularly during periods of fasting.

In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enters the citric acid cycle, generating NADH and FADH2, which are electron carriers used in the electron transport chain. It is named as such because the beta carbon of the fatty acid chain undergoes oxidation and is converted to a carbonyl group to start the cycle all over again. Beta-oxidation is primarily facilitated by the mitochondrial trifunctional protein, an enzyme complex associated with the inner mitochondrial membrane, although very long chain fatty acids are oxidized in peroxisomes.

<span class="mw-page-title-main">Systemic primary carnitine deficiency</span> Medical condition

Systemic primary carnitine deficiency (SPCD) is an inborn error of fatty acid transport caused by a defect in the transporter responsible for moving carnitine across the plasma membrane. Carnitine is an important amino acid for fatty acid metabolism. When carnitine cannot be transported into tissues, fatty acid oxidation is impaired, leading to a variety of symptoms such as chronic muscle weakness, cardiomyopathy, hypoglycemia and liver dysfunction. The specific transporter involved with SPCD is OCTN2, coded for by the SLC22A5 gene located on chromosome 5. SPCD is inherited in an autosomal recessive manner, with mutated alleles coming from both parents.

<span class="mw-page-title-main">Inborn error of lipid metabolism</span> Medical condition

Numerous genetic disorders are caused by errors in fatty acid metabolism. These disorders may be described as fatty oxidation disorders or as a lipid storage disorders, and are any one of several inborn errors of metabolism that result from enzyme defects affecting the ability of the body to oxidize fatty acids in order to produce energy within muscles, liver, and other cell types.

<span class="mw-page-title-main">Carnitine palmitoyltransferase II deficiency</span> Medical condition

Carnitine palmitoyltransferase II deficiency, sometimes shortened to CPT-II or CPT2, is an autosomal recessively inherited genetic metabolic disorder characterized by an enzymatic defect that prevents long-chain fatty acids from being transported into the mitochondria for utilization as an energy source. The disorder presents in one of three clinical forms: lethal neonatal, severe infantile hepatocardiomuscular and myopathic.

<span class="mw-page-title-main">Carnitine-acylcarnitine translocase deficiency</span> Medical condition

Carnitine-acylcarnitine translocase deficiency is a rare, autosomal recessive metabolic disorder that prevents the body from converting long-chain fatty acids into energy, particularly during periods without food. Carnitine, a natural substance acquired mostly through the diet, is used by cells to process fats and produce energy. People with this disorder have a faulty enzyme that prevents long-chain fatty acids from being transported into the innermost part of the mitochondria for processing.

<span class="mw-page-title-main">Mitochondrial trifunctional protein deficiency</span> Medical condition

Mitochondrial trifunctional protein deficiency is an autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats to energy, particularly during periods without food. People with this disorder have inadequate levels of an enzyme that breaks down a certain group of fats called long-chain fatty acids.

<span class="mw-page-title-main">Very long-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Very long-chain acyl-coenzyme A dehydrogenase deficiency is a fatty-acid metabolism disorder which prevents the body from converting certain fats to energy, particularly during periods without food.

<span class="mw-page-title-main">Biotinidase deficiency</span> Medical condition

Biotinidase deficiency is an autosomal recessive metabolic disorder in which biotin is not released from proteins in the diet during digestion or from normal protein turnover in the cell. This situation results in biotin deficiency.

Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous chemical imbalance called acidosis. It is a metabolic myopathy, categorized under fatty acid metabolism disorder as that is the bioenergetic system that it affects the most. It also affects choline metabolism.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Short-chain acyl-coenzyme A dehydrogenase deficiency</span> Medical condition

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

<span class="mw-page-title-main">Palmitoylcarnitine</span> Chemical compound

Palmitoylcarnitine is an ester derivative of carnitine involved in the metabolism of fatty acids. During the tricarboxylic acid cycle (TCA), fatty acids undergo a process known as β-oxidation to produce energy in the form of ATP. β-oxidation occurs primarily within mitochondria, however the mitochondrial membrane prevents the entry of long chain fatty acids (>C10), so the conversion of fatty acids such as palmitic acid is key. Palmitic acid is brought to the cell and once inside the cytoplasm is first converted to Palmitoyl-CoA. Palmitoyl-CoA has the ability to freely pass the outer mitochondrial membrane, but the inner membrane is impermeable to the Acyl-CoA and thioester forms of various long-chain fatty acids such as palmitic acid. The palmitoyl-CoA is then enzymatically transformed into palmitoylcarnitine via the Carnitine O-palmitoyltransferase family. The palmitoylcarnitine is then actively transferred into the inner membrane of the mitochondria via the carnitine-acylcarnitine translocase. Once inside the inner mitochondrial membrane, the same Carnitine O-palmitoyltransferase family is then responsible for transforming the palmitoylcarnitine back to the palmitoyl-CoA form.

<span class="mw-page-title-main">Carnitine O-palmitoyltransferase</span>

Carnitine O-palmitoyltransferase is a mitochondrial transferase enzyme involved in the metabolism of palmitoylcarnitine into palmitoyl-CoA. A related transferase is carnitine acyltransferase.

<span class="mw-page-title-main">Acyl-CoA</span> Group of coenzymes that metabolize fatty acids

Acyl-CoA is a group of CoA-based coenzymes that metabolize carboxylic acids. Fatty acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way, fats are converted to ATP, the common biochemical energy carrier.

3-hydroxyacyl-coenzyme A dehydrogenase deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during fasting. Normally, through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to metabolize fats and convert them to energy. People with 3-hydroxyacyl-coenzyme A dehydrogenase deficiency have inadequate levels of an enzyme required for a step that metabolizes groups of fats called medium chain fatty acids and short chain fatty acids; for this reason this disorder is sometimes called medium- and short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD) deficiency.

<span class="mw-page-title-main">Carnitine palmitoyltransferase II</span> Mammalian protein found in humans

Carnitine O-palmitoyltransferase 2, mitochondrial is an enzyme that in humans is encoded by the CPT2 gene.

<span class="mw-page-title-main">Carnitine palmitoyltransferase I</span> Enzyme found in humans

Carnitine palmitoyltransferase I (CPT1) also known as carnitine acyltransferase I, CPTI, CAT1, CoA:carnitine acyl transferase (CCAT), or palmitoylCoA transferase I, is a mitochondrial enzyme responsible for the formation of acyl carnitines by catalyzing the transfer of the acyl group of a long-chain fatty acyl-CoA from coenzyme A to l-carnitine. The product is often palmitoylcarnitine, but other fatty acids may also be substrates. It is part of a family of enzymes called carnitine acyltransferases. This "preparation" allows for subsequent movement of the acyl carnitine from the cytosol into the intermembrane space of mitochondria.

<span class="mw-page-title-main">Fatty-acid metabolism disorder</span> Medical condition

A broad classification for genetic disorders that result from an inability of the body to produce or utilize an enzyme or transport protein that is required to oxidize fatty acids. They are an inborn error of lipid metabolism, and when it affects the muscles also a metabolic myopathy.

References

  1. Bennett, Michael J.; Santani, Avni B. (1993-01-01). "Carnitine Palmitoyltransferase 1A Deficiency". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C. (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301700.update 2010
  2. "Carnitine palmitoyl transferase 1 deficiency | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2022-01-27. Retrieved 2018-10-27.
  3. Clemente, Florian; al., et. (2014-11-06). "A Selective Sweep on a Deleterious Mutation in CPT1A in Arctic Populations". The American Journal of Human Genetics. 95 (5). AJHG: 584–589. doi:10.1016/j.ajhg.2014.09.016. PMC   4225582 . PMID   25449608.
  4. Greenberg, Cheryl; al., et. (2009-04-09). "The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations". Molecular Genetics and Metabolism. 96 (4): 201–7. doi:10.1016/j.ymgme.2008.12.018. PMID   19217814.
  5. Reference, Genetics Home. "CPT I deficiency". Genetics Home Reference.
  6. Bennett, Michael; Stanley, Charles (2011-03-01). "Carnitine palmitoyl transferase 1A deficiency". Orphanet. Retrieved 2014-12-04.
  7. Bennett, Michael J.; Santani, Avni B. (1993). "Carnitine Palmitoyltransferase 1A Deficiency". GeneReviews®. University of Washington, Seattle. PMID   20301700.

This article incorporates public domain text from The U.S. National Library of Medicine