Hypoglycemia, Hypotonia, and Cardiomyopathy: The Evolving Clinical Picture of Long-Chain Acyl-CoA Dehydrogenase Deficiency

Inherited defects in fatty acid oxidation, which have been described and diagnosed with increasing frequency in the last decade, are most commonly attributed to a deficiency in the activity of medium-chain acyl-CoA dehydrogenase. Few cases of the related enzyme defect of long-chain acyl-CoA dehydrogenase activity have been reported. An infant with documented long-chain acyl-CoA dehydrogenase deficiency is described with a detailed metabolic profile, long-term clinical follow-up, and response to treatment. This patient is compared with the seven previously published cases of this disorder in order to stress the unique features of the initial presentation, more subtle late manifestations of the disease, and clinical and biochemical differentiation from the more common medium-chain acyl-CoA dehydrogenase deficiency. This report stresses the enlarging spectrum of the clinical presentation and natural history of this defect in fatty acid oxidation.

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Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids

Frontiers in Genetics ◽

10.3389/fgene.2020.598976 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alexandre Umpierrez Amaral ◽

Moacir Wajner

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Calcium Homeostasis ◽

Acid Oxidation ◽

Cultured Fibroblasts ◽

Medium Chain ◽

Chain Acyl ◽

Energy Deprivation ◽

Long Chain

Deficiencies of medium-chain acyl-CoA dehydrogenase, mitochondrial trifunctional protein, isolated long-chain 3-hydroxyacyl-CoA dehydrogenase, and very long-chain acyl-CoA dehydrogenase activities are considered the most frequent fatty acid oxidation defects (FAOD). They are biochemically characterized by the accumulation of medium-chain, long-chain hydroxyl, and long-chain fatty acids and derivatives, respectively, in tissues and biological fluids of the affected patients. Clinical manifestations commonly include hypoglycemia, cardiomyopathy, and recurrent rhabdomyolysis. Although the pathogenesis of these diseases is still poorly understood, energy deprivation secondary to blockage of fatty acid degradation seems to play an important role. However, recent evidence indicates that the predominant fatty acids accumulating in these disorders disrupt mitochondrial functions and are involved in their pathophysiology, possibly explaining the lactic acidosis, mitochondrial morphological alterations, and altered mitochondrial biochemical parameters found in tissues and cultured fibroblasts from some affected patients and also in animal models of these diseases. In this review, we will update the present knowledge on disturbances of mitochondrial bioenergetics, calcium homeostasis, uncoupling of oxidative phosphorylation, and mitochondrial permeability transition induction provoked by the major fatty acids accumulating in prevalent FAOD. It is emphasized that further in vivo studies carried out in tissues from affected patients and from animal genetic models of these disorders are necessary to confirm the present evidence mostly achieved from in vitro experiments.

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Medium-Chain Acyl-CoA Dehydrogenase Deficiency in an Infant with Dilated Cardiomyopathy

Cardiology Research and Practice ◽

10.4061/2009/281389 ◽

2009 ◽

Vol 2009 ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Marcello Marcì ◽

Patrizia Ajovalasit

Keyword(s):

Fatty Acid ◽

Dilated Cardiomyopathy ◽

Dehydrogenase Deficiency ◽

Acid Oxidation ◽

Inherited Disorders ◽

Mitochondrial Fatty Acid Oxidation ◽

Medium Chain ◽

Mitochondrial Fatty Acid ◽

Chain Acyl ◽

Long Chain

We report about an infant affected by dilated cardiomyopathy (CMP) in whom metabolic investigations evidenced medium-chain-acyl-CoA dehydrogenase deficiency (MCADD), that is one of three types of inherited disorders of mitochondrial fatty-acid -oxidation. Long-chain and very long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficits are recognized as responsible of hypertrophic or, less frequently, dilated cardiomyopathy (CMP) in childhood. Otherwise, to our knowledge, no case of MCADD associated to dilated CMP has been reported in literature.

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Round Table Discussion

Annals of Nutrition and Metabolism ◽

10.1159/000448323 ◽

2016 ◽

Vol 68 (Suppl. 3) ◽

pp. 21-23

Author(s):

Susan Winter ◽

Neil R.M. Buist ◽

Nicola Longo ◽

Saro H. Armenian ◽

Gary Lopaschuk ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Dehydrogenase Deficiency ◽

Round Table ◽

Acid Oxidation ◽

Round Table Discussion ◽

Table Discussion ◽

Chain Acyl ◽

Acyl Coenzyme A ◽

Long Chain

The 1st International Carnitine Working Group concluded with a round table discussion addressing several areas of relevance. These included the design of future studies that could increase the amount of evidence-based data about the role of carnitine in the treatment of fatty acid oxidation defects, for which substantial controversy still exists. There was general consensus that future trials on the effect of carnitine in disorders of fatty acid oxidation should be randomized, double-blinded, multicentered and minimally include the following diagnoses: medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency, very long-chain acyl-CoA dehydrogenase deficiency, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and mitochondrial trifunctional protein deficiency. Another area that generated interest was trials of carnitine in cardiomyopathy and, especially, the use of biomarkers to identify patients at greater risk of cardiotoxicity following treatment with anthracyclines. The possibility that carnitine treatment may lead to improvements in autistic behaviors was also discussed, although the evidence is still not sufficient to make any firm conclusions in this regard. Preliminary data on carnitine levels in children and adolescents with primary hypertension, low birth weight and nephrotic syndrome was also presented. Lastly, the panelists stressed that there remains an objective need to harmonize the terminology used to describe carnitine deficiencies (e.g., primary, secondary and systemic deficiency).

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Rhabdomyolysis – Mikor vessük fel metabolikus myopathia lehetőségét? Esetismertetés és diagnosztikus algoritmus

Orvosi Hetilap ◽

10.1556/650.2017.30923 ◽

2017 ◽

Vol 158 (47) ◽

pp. 1873-1882

Author(s):

Ágnes Sebők ◽

Endre Pál ◽

Gergő Attila Molnár ◽

István Wittmann ◽

Judit Berenténé Bene ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Dehydrogenase Deficiency ◽

Acid Oxidation ◽

Fatty Acid Oxidation Disorders ◽

Metabolic Myopathies ◽

Chain Acyl ◽

Recurrent Rhabdomyolysis ◽

Acyl Coenzyme A ◽

Long Chain

Abstract: We report the case of a 46-year-old female patient with recurrent rhabdomyolysis. In the background of her metabolic myopathy an inherited metabolic disorder of the fatty acid oxidation, very long-chain acyl-coenzyme A-dehydrogenase deficiency was diagnosed. The diagnosis was based on abnormal acyl-carnitine- and urine organic-acid profile in addition to low residual enzyme activity, and was confirmed by genetic testing. After introduction of dietotherapy metabolic crisis necessitating hospital admission has not occurred neither have fixed myopathic changes developed. We present here the differential diagnosis of rhabdomyolysis and exertional muscle complaints, with the metabolic myopathies in focus. The main features of fatty acid oxidation disorders are highlighted, acute and chronic managements of very long-chain acyl-coenzyme A-dehydrogenase deficiency are discussed. Metabolic myopathies respond well to treatment, so good quality of life can be achieved. However, especially in fatty acid oxidation disorders, a metabolic crisis may develop quickly and can be fatal, albeit rarely. Some of these disorders can be identified by newborn screening, but occasionally the symptoms may manifest only in adulthood. With the presentation of this case we would like to point out that in the differential diagnosis of recurrent rhabdomyolysis inherited metabolic disorders should be considered regardless of the patient’s age. Orv Hetil. 2017; 158(46): 1873–1882.

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