Summary
In this report, the syndrome of carnitine deficiency, its biochemistry, diagnosis, and treatment are discussed. We describe two families where carnitine deficiency was believed to cause cardiomyopathies in children. Three of five children died in one family but the fourth child could be treated successfully.
Carnitine (Car) is a quarternary ammonium compound, synthesized in the body from the amino acids lysin and methion and plays an important role in fatty acid metabolism. It is required as a carrier for the transport of long-chain-acyl-CoA esters from the cytoplasm into mitochondria. Lack of Car, therefore, results in impairment of mitochondrial fatty acid oxidation and cytoplasmic accumulation of lipids. This particularly affects the myocardium, which normally depends largely on fatty acid oxidation. There are different clinical syndromes of Car deficiency, depending on the underlying biochemical defect. Systematic Car deficiency is due to a defect in the biosynthesis of Car and was found in a familiy where four of five siblings developed a cardiomyopathy and three children died suddenly before the age of 3 years. At the autopsy, cardiomyopathy was confirmed in all three cases. The autopsy of the fifth child revealed lipid accumulation and abnormal mitochondria in cardiac and skeletal muscle together with extremely low Car levels in the plasma (4.5 mM; normal 50±10 nM), skeletal muscle (30.9 nmol/g; normal 5,000 nmol/g), and heart (56.8 nmol/g; normal 2,000 nmol/g). The surviving fourth child with cardiomyopathy and heart insufficiency (NYHA III) had also dramatically decreased plasma (4.8 mM) and muscle (30.9 nmol/g) Car levels. Oral substitution of L-Car caused dramatic clinical improvement. Plasma and muscle Car levels increased and muscle histology improved.
We conclude that Car deficiency may cause cardiomyopathies in children. These cardiomyopathies are characterized by lipid accumulation and are very sensitive to Car treatment. We suggest that in all familiar cardiomyopathies of unknown etiology, especially when lipid accumulation is present, plasma Car levels should be measured and, if necessary, a substitution with L-Car should be started.
Zusammenfassung
In diesem Bericht werden 2 Familien vorgestellt, in denen kindlicher Carnitin-Mangel zu Kardiomyopathien führte, die in einem Fall erfolgreich behandelt werden konnten. Symptomatik, Diagnose und Therapie des Carnitin-Mangels werden gemeinsam mit seinen biochemischen Grundlagen diskutiert.
Carnitin (CAR), eine 4wertige Ammoniumverbindung, die im Körper aus den Aminosäuren Lysin und Methinonin synthetisiert wird, spielt eine wichtige Rolle in der Fettsäureoxidation. CAR dient als Carrier für den Transport langkettiger Fettsäure-CoA-Ester aus dem Cytoplasma in die Mitochondrien. Daher führt Car-Mangel zu Störungen der mitochondrialen Fettsäureoxidation und der Akkumulation von Lipiden im Cytoplasma. Besonders betroffen ist das Herz, das zur Deckung seines Energiebedarfs in großem Umfang von der Fettsäure-Oxidation abhängig ist.
CAR-Mangel kann, je nach dem zugrundeliegenden biochemischen Defekt, in verschiedenen Formen auftreten. Systemischer CAR-Mangel wurde in einer Familie entdeckt, in der 4 von 5 Kindern Kardiomyopathien entwickelten und 3 Kinder vor dem Alter von 3 Jahren plötzlich verstarben. Bei der Autopsie wurde die klinische Diagnose einer Kardiomyopathie in allen Fällen bestätigt. Bei der Autopsie des 5, und jüngsten Kindes wurden außerdem Lipidakkumulation und abnorme Mitochondrien im Herz- und Skelettmuskel nachgewiesen, zusammen mit extrem niedrigen CAR-Spiegeln im Plasma (4,5 mM; normal 50±10 mM), im Skelettmuskel (30,9 nmol/g; normal 5000 nmol/g) und Myokard (56,8 nmol/g; normal 2000 nmol/g). Das überlebende 4. Kind hatte ebenfalls eine schwere congestive Kardiomyopathie und Herzinsuffizienz (NYHA III). Plasma (4,8 mM)-, und Muskel (30,9 nmol/g)-CAR-Spiegel waren extrem niedrig. Durch orale Substitutionstherapie mit L-CAR konnte eine dramatische klinische Besserung erreicht werden. Plasma- und Muskel-CAR-Spiegel stiegen, und die Muskelhistologie besserte sich.
Wir schließen aus diesem Verlauf, daß es das Krankheitsbild einer kindlichen Kardiomyopathie, die durch Carnitin-Mangel hervorgerufen wird, gibt. Diese Kardiomyopathie ist durch Lipidakkumulation gekennzeichnet und spricht gut auf CAR-Substitution an. Wir glauben, daß bei allen familiär auftretenden Kardiomyopathien unklarer Genese, besonders wenn Lipidakkumulation nachgewiesen ist, der Plasma-Carnitin-Spiegel gemessen und nötigenfalls eine Substitutionstherapie mit L-Carnitin eingeleitet werden sollte.
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Regitz, V., Hodach, R.J. & Shug, A.L. Carnitin-Mangel: Eine behandelbare Ursache kindlicher Kardiomyopathien. Klin Wochenschr 60, 393–400 (1982). https://doi.org/10.1007/BF01735930
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DOI: https://doi.org/10.1007/BF01735930