Recurrent Myoglobinuria Due to Muscle Carnitine Palmityl Transferase Deficiency

Reza, Michael J.; Kar, Nirmal C.; Pearson, Carl M.; Kark, Ruth

doi:10.7326/0003-4819-88-5-610

Cited by 43 publications

(12 citation statements)

References 13 publications

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“…"^,^^ Indirect evidence that the liver may also be involved was derived from fasting experiments showing delayed or decreased formation of ketone bodies. 5,8,25,98,104 Decreased CPT activity (26% of the lowest control value) has been documented in a liver biopsy from the patient of Bertorini et al*…”

Section: Disorders Of Lipid Metabolismmentioning

confidence: 97%

Disorders of lipid metabolism in muscle

1980

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At rest and during sustained exercise, lipids are the main source of energy for muscle. Free fatty acids become available to muscle from plasma free fatty acids and triglycerides, and from intracellular triglycride lipid droplets. Transport of long-chain fatty acyl groups into the mitochondria requires esterification and de-esterification with carnitine by the "twin" enzymes carnitine palmityltransferase (CPT) I and II, bound to the outer and inner faces of the inner mitochondrial membrane. Carnitine deficiency occurs in two clinical syndromes. (1) In the myopathic form, there is weakness; muscle biopsy shows excessive accumulation of lipid droplets; and the carnitine concentration is markedly decreased in muscle but normal in plasma. (2) In the systemic form, there are weakness and recurrent episodes of hepatic encephalopathy; muscle biopsy shows lipid storage; and the carnitine concentration is decreased in muscle, liver, and plasma. The etiology of carnitine deficiency is not known in either the myopathic or the systemic form, but administration of carnitine or corticosteroids has been beneficial in some patients. "Secondary" carnitine deficiency may occur in patients with malnutrition, liver disease, chronic hemodialysis, and, possibly, mitochondrial disorders. CPT deficiency causes recurrent myoglobinuria, usually precipitated by prolonged exercise or fasting. Muscle biopsy may be normal or show varying degrees of lipid storage. Genetic transmission is probably autosomal recessive, but the great male predominance (20/21) remains unexplained. In many cases, lipid storage myopathy is not accompanied by carnitine or CPT deficiency, and the biochemical error remains to be identified.

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Section: Disorders Of Lipid Metabolismmentioning

confidence: 97%

Disorders of lipid metabolism in muscle

1980

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“…Other precipitants may include, but are not limited to, infection, fasting, cold, increased fat intake, emotional distress, and certain drugs (Kelly et al, 1989;Kottlors et al, 2001;Reza et al, 1978;Wallace et al, 2001). The clinical features of the adult form have occasionally been reported to occur in childhood, as in the case of a 6-year-old girl who presented with acute muscle weakness, pain, and inability to walk.…”

Section: Clinical and Metabolic Features Of Cpt II Deficiencymentioning

confidence: 99%

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

Sigauke

Rakheja

Kitson

et al. 2003

Laboratory Investigation

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SUMMARY:Congenital deficiency of carnitine palmitoyltransferase (CPT) II has been known for at least 30 years now, and its phenotypic variability remains fascinating. Three distinct clinical entities have been described, the adult, the infantile, and the perinatal, all with an autosomal recessive inheritance pattern. The adult CPT II clinical phenotype is somewhat benign and requires additional external triggers such as high-intensity exercise before the predominantly myopathic symptoms are elicited. The perinatal and infantile forms involve multiple organ systems. The perinatal disease is the most severe form and is invariably fatal. The introduction of mass spectrometry to analyze blood acylcarnitine profiles has revolutionized the diagnosis of fatty acid oxidation disorders including CPT II deficiency. Its use in expanded neonatal screening programs has made presymptomatic diagnosis a reality. An increasing number of mutations are being identified in the CPT II gene with a distinct genotype-phenotype correlation in most cases. However, clinical variability in some patients suggests additional genetic or environmental modifiers. Herein, we present a new case of lethal perinatal CPT II deficiency with a rare missense mutation, R296Q (907GϾA) associated with a previously described 25-bp deletion on the second allele. We review the clinical features, the diagnostic protocol including expanded neonatal screening, the treatment, and the biochemical and molecular basis of CPT II deficiency. (Lab Invest 2003, 83:1543-1554.T he carnitine palmitoyltransferase (CPT) enzyme system, in association with acyl-coenzyme A (CoA) synthetase and the carnitine-acylcarnitine translocase (CACT), plays an important role in the transfer of long chain fatty acids (LCFA) from the cytosolic compartment to the mitochondrial matrix, where ␤-oxidation occurs (Bieber, 1988). Two genetically distinct mitochondrial membrane-bound enzymes make up the CPT system. CPT I is located on the inner aspect of the outer mitochondrial membrane. This enzyme is physiologically inhibited by the high levels of malonyl-CoA that occur postprandially and thus regulates the entry of LCFA into the mitochondria (McGarry and Brown, 1997). CPT II, which is not inhibited by malonyl-CoA, is situated on the inner aspect of the inner mitochondrial membrane (Murthy and Pande, 1987).CPT II deficiency was first reported by DiMauro and DiMauro (1973) in adults with exercise-induced rhabdomyolysis. It is an autosomal recessive disorder (Angelini et al, 1981;Meola et al, 1987) and is now regarded as one of the most common inherited disorders of lipid metabolism . Isolated presentation in two successive generations has been reported, indicating a possible dominant inheritance (Mongini et al, 1991). Partial CPT II deficiency with an autosomal dominant inheritance pattern has also been reported (Ionasescu et al, 1980). The molecular basis for this presentation was not elucidated.To date, three distinct CPT II-deficient phenotypes have been described in the literature, for wh...

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“…Hypotheses include lack of enzymatically active protein, partial enzyme deficiency and abnormally regulated enzyme [62]. In previous studies, CPT activities in muscles of patients with CPT II deficiency are reported to be undetectable [30,63,64], reduced [62][63][64][65][66][67][68] or normal [69].…”

Section: Molecular Genetic Aspectsmentioning

confidence: 99%

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

Joshi

Zierz

2020

Molecules

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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.

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Recurrent Myoglobinuria Due to Muscle Carnitine Palmityl Transferase Deficiency

Cited by 43 publications

References 13 publications

Disorders of lipid metabolism in muscle

Disorders of lipid metabolism in muscle

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

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

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