scholarly journals Carnitine Inborn Errors of Metabolism

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3251 ◽  
Author(s):  
Mohammed Almannai ◽  
Majid Alfadhel ◽  
Ayman W. El-Hattab
Keyword(s):  
Inborn Errors Of Metabolism ◽  
Treatment Options ◽  
Carnitine Deficiency ◽  
Carnitine Palmitoyltransferase ◽  
Inborn Errors ◽  
Carnitine Transporter ◽  
Carnitine Metabolism ◽  
Carnitine Transport ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii

Carnitine plays essential roles in intermediary metabolism. In non-vegetarians, most of carnitine sources (~75%) are obtained from diet whereas endogenous synthesis accounts for around 25%. Renal carnitine reabsorption along with dietary intake and endogenous production maintain carnitine homeostasis. The precursors for carnitine biosynthesis are lysine and methionine. The biosynthetic pathway involves four enzymes: 6-N-trimethyllysine dioxygenase (TMLD), 3-hydroxy-6-N-trimethyllysine aldolase (HTMLA), 4-N-trimethylaminobutyraldehyde dehydrogenase (TMABADH), and γ-butyrobetaine dioxygenase (BBD). OCTN2 (organic cation/carnitine transporter novel type 2) transports carnitine into the cells. One of the major functions of carnitine is shuttling long-chain fatty acids across the mitochondrial membrane from the cytosol into the mitochondrial matrix for β-oxidation. This transport is achieved by mitochondrial carnitine–acylcarnitine cycle, which consists of three enzymes: carnitine palmitoyltransferase I (CPT I), carnitine-acylcarnitine translocase (CACT), and carnitine palmitoyltransferase II (CPT II). Carnitine inborn errors of metabolism could result from defects in carnitine biosynthesis, carnitine transport, or mitochondrial carnitine–acylcarnitine cycle. The presentation of these disorders is variable but common findings include hypoketotic hypoglycemia, cardio(myopathy), and liver disease. In this review, the metabolism and homeostasis of carnitine are discussed. Then we present details of different inborn errors of carnitine metabolism, including clinical presentation, diagnosis, and treatment options. At the end, we discuss some of the causes of secondary carnitine deficiency.

scholarly journals Fructose and Mannose in Inborn Errors of Metabolism and Cancer

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 479
Author(s):  
Elizabeth L. Lieu ◽  
Neil Kelekar ◽  
Pratibha Bhalla ◽  
Jiyeon Kim
Keyword(s):  
Metabolic Disease ◽  
Inborn Errors Of Metabolism ◽  
Metabolic Diseases ◽  
Treatment Options ◽  
Biochemical Properties ◽  
Biological Molecules ◽  
Diagnostic Tools ◽  
Inborn Errors ◽  
Mannose Metabolism

History suggests that tasteful properties of sugar have been domesticated as far back as 8000 BCE. With origins in New Guinea, the cultivation of sugar quickly spread over centuries of conquest and trade. The product, which quickly integrated into common foods and onto kitchen tables, is sucrose, which is made up of glucose and fructose dimers. While sugar is commonly associated with flavor, there is a myriad of biochemical properties that explain how sugars as biological molecules function in physiological contexts. Substantial research and reviews have been done on the role of glucose in disease. This review aims to describe the role of its isomers, fructose and mannose, in the context of inborn errors of metabolism and other metabolic diseases, such as cancer. While structurally similar, fructose and mannose give rise to very differing biochemical properties and understanding these differences will guide the development of more effective therapies for metabolic disease. We will discuss pathophysiology linked to perturbations in fructose and mannose metabolism, diagnostic tools, and treatment options of the diseases.

The Role of L-Carnitine in Pediatric Cardiomyopathy

1995 ◽  
Vol 10 (2_suppl) ◽  
pp. 2S45-2S51 ◽  
Author(s):  
Susan Winter ◽  
Kenneth Jue ◽  
James Prochazka ◽  
Paul Francis ◽  
Wade Hamilton ◽  
...  
Keyword(s):  
Energy Production ◽  
Inborn Errors Of Metabolism ◽  
Genetic Factors ◽  
Myocardial Dysfunction ◽  
Essential Element ◽  
Carnitine Deficiency ◽  
Inborn Errors ◽  
Pediatric Cardiomyopathy ◽  
Traditional Therapies

Metabolic and genetic factors underlie some forms of cardiomyopathy in childhood. A variety of inborn errors of metabolism can impair mitochondrial energy production, or β-oxidation, in the heart and lead to myocardial dysfunction. L-Carnitine, an essential element of β-oxidation, transports fatty acids across the mitochondrial membrane for energy production. L-Carnitine deficiency syndromes are now well described as secondary to a variety of inborn errors of metabolism and often include cardiomyopathy in the clinical picture. Despite traditional therapies for cardiomyopathy, mortality for this disorder remains at well over 50%. Review of reports of L-carnitine supplementation studies and results from our own trial underscore the importance of its role in cardiac function and demonstrates that there is likely a subpopulation of patients with cardiomyopathy responsive to L-carnitine treatment. (J Child Neurol 1995; 10(Suppl):2S45-2S5 1).

scholarly journals Historical Perspective on Clinical Trials of Carnitine in Children and Adults

2016 ◽  
Vol 68 (Suppl. 3) ◽  
pp. 1-4 ◽  
Author(s):  
Neil R.M. Buist
Keyword(s):  
Clinical Trials ◽  
Inborn Errors Of Metabolism ◽  
Randomized Clinical Trials ◽  
Ethical Issues ◽  
Carnitine Deficiency ◽  
Nutritional Deficiencies ◽  
Inborn Errors ◽  
Treatment Protocols ◽  
The Us ◽  
Primary Carnitine Deficiency

The metabolic roles of carnitine have been greatly clarified over the past 50 years, and it is now well established that carnitine is a key player in mitochondrial generation of energy and metabolism of acetyl coenzyme A. A therapeutic role for carnitine in treatment of nutritional deficiencies in infants and children was first demonstrated in 1958, and since that time it has been used to treat a number of inborn errors of metabolism. Carnitine was approved by the US Food and Drug Administration in 1985 for treatment of ‘primary carnitine deficiency', and later in 1992 for treatment of ‘secondary carnitine deficiency', a definition that included the majority of relevant metabolic disorders associated with low or abnormal plasma carnitine levels. Today, carnitine treatment of inborn errors of metabolism is a safe and integral part of many treatment protocols, and a growing interest in carnitine has resulted in greater recognition of many causes of carnitine depletion. Notwithstanding, there is still a lack of data from randomized clinical trials, even on the use of carnitine in inborn errors of metabolism, although ethical issues may be a contributing factor in this regard.

scholarly journals Gene expression of enzymes regulating ketogenesis and fatty acid metabolism in regenerating rat liver

1994 ◽  
Vol 299 (1) ◽  
pp. 65-69 ◽  
Author(s):  
G Asins ◽  
J L Rosa ◽  
D Serra ◽  
G Gil-Gómez ◽  
J Ayté ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Surgical Stress ◽  
Control Point ◽  
Diabetic Rats ◽  
Carnitine Palmitoyltransferase ◽  
Mrna Levels ◽  
Carnitine Palmitoyltransferase I ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii

Levels of mRNA for mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase, carnitine palmitoyltransferase I (CPT I) and carnitine palmitoyltransferase II (CPT II), fatty acid synthase (FAS) and actin were analysed during liver regeneration. mRNA levels for mitochondrial HMG-CoA synthase decreased rapidly, reaching a minimum 12 h after partial hepatectomy and returning to normal at 24-36 h. In contrast, CPT I, CPT II and FAS mRNAs increased throughout the period examined. Expression of actin increased significantly during regeneration. Levels of mRNA for mitochondrial HMG-CoA synthase also decreased as a result of surgical stress, although the effect of hepatectomy was much greater. We determined the levels of mitochondrial HMG-CoA synthase using specific antibodies. The amount of protein rapidly decreased, although less markedly than the corresponding mRNA levels. These results show that the decrease described in ketogenesis in partially hepatectomized rats correlated with the decrease in the expression of mitochondrial HMG-CoA synthase, suggesting that this enzyme may also be a control point in ketogenesis in the regenerating liver, as it is in normal and diabetic rats.

scholarly journals Muscle Carnitine Palmitoyltransferase II (CPT II) Deficiency: A Conceptual Approach

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1784
Author(s):  
Pushpa Raj Joshi ◽  
Stephan Zierz
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Carnitine Palmitoyltransferase ◽  
Tween 20 ◽  
Acid Oxidation ◽  
Malonyl Coa ◽  
Cpt I ◽  
Carnitine Palmitoyltransferase Ii ◽  
Triton X ◽  
Cpt Ii Deficiency

Carnitine palmitoyltransferase (CPT) catalyzes the transfer of long- and medium-chain fatty acids from cytoplasm into mitochondria, where oxidation of fatty acids takes place. Deficiency of CPT enzyme is associated with rare diseases of fatty acid metabolism. CPT is present in two subforms: CPT I at the outer mitochondrial membrane and carnitine palmitoyltransferase II (CPT II) inside the mitochondria. Deficiency of CPT II results in the most common inherited disorder of long-chain fatty acid oxidation affecting skeletal muscle. There is a lethal neonatal form, a severe infantile hepato-cardio-muscular form, and a rather mild myopathic form characterized by exercise-induced myalgia, weakness, and myoglobinuria. Total CPT activity (CPT I + CPT II) in muscles of CPT II-deficient patients is generally normal. Nevertheless, in some patients, not detectable to reduced total activities are also reported. CPT II protein is also shown in normal concentration in patients with normal CPT enzymatic activity. However, residual CPT II shows abnormal inhibition sensitivity towards malonyl-CoA, Triton X-100 and fatty acid metabolites in patients. Genetic studies have identified a common p.Ser113Leu mutation in the muscle form along with around 100 different rare mutations. The biochemical consequences of these mutations have been controversial. Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme. The recombinant enzyme experiments that we recently conducted have shown that CPT II enzyme is extremely thermoliable and is abnormally inhibited by different emulsifiers and detergents such as malonyl-CoA, palmitoyl-CoA, palmitoylcarnitine, Tween 20 and Triton X-100. Here, we present a conceptual overview on CPT II deficiency based on our own findings and on results from other studies addressing clinical, biochemical, histological, immunohistological and genetic aspects, as well as recent advancements in diagnosis and therapeutic strategies in this disorder.

scholarly journals Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle

2016 ◽  
Vol 68 (Suppl. 3) ◽  
pp. 5-9 ◽  
Author(s):  
Nicola Longo
Keyword(s):  
Newborn Screening ◽  
Carnitine Deficiency ◽  
The Body ◽  
Molecular Testing ◽  
Inner Mitochondrial Membrane ◽  
Inborn Errors ◽  
Irreversible Damage ◽  
Carnitine Transport ◽  
Patients At Risk ◽  
Primary Carnitine Deficiency

Carnitine is needed for transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. Carnitine can be synthesized by the body and is also obtained in the diet through consumption of meat and dairy products. Defects in carnitine transport such as those caused by defective activity of the OCTN2 transporter encoded by the SLC22A5 gene result in primary carnitine deficiency, and newborn screening programmes can identify patients at risk for this condition before irreversible damage. Initial biochemical diagnosis can be confirmed through molecular testing, although direct study of carnitine transport in fibroblasts is very useful to confirm or exclude primary carnitine deficiency in individuals with genetic variations of unknown clinical significance or who continue to have low levels of carnitine despite negative molecular analyses. Genetic defects in carnitine biosynthesis do not generally result in low plasma levels of carnitine. However, deletion of the trimethyllysine hydroxylase gene, a key gene in carnitine biosynthesis, has been associated with non-dysmorphic autism. Thus, new roles for carnitine are emerging that are unrelated to classic inborn errors of metabolism.

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