Mutation and biochemical analysis in carnitine palmitoyltransferase type II (CPT II) deficiency

Abstract

Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10-60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41 degrees C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88% of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42-60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.

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

“…Our findings revealed impaired kinetic stability of human CPT II by the common p.Ser113Leu mutation at increased temperatures [62]. The observation was consistent with the lower heat resistance of the mutated enzyme in cultured fibroblasts [72]. These results show that CPT II is extremely thermoliable and abnormally inhibited.…”

Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: Postmortem diagnosis of fatty acid oxidation disorders

“…The substitution in Case 5 was ACADS -P55L (c.164C > T), in Case 6 was CPT2 -F383Y (c.1148T > A), in Case 14 was ACADS -V84M (c.259G > A) and in Case 7 was SLC22A5 -D487N (c.1459G > A). Because the substitution of CPT2 -F383Y has also been shown to cause decreases in the CPT II activity and been reported in a CPT II deficiency patient [8], [19], [20], [21], [31], even in the heterozygous F383Y mutation state [21], [32], [33], the heterozygous CPT2 -F383Y mutation could be a cause of sudden death. While the postmortem acylcarnitine analysis in our current case did not suggest any CPT II deficiency, it is possible that Case 6 might have been affected by the mutation.…”

Laryngeal Spasm Mimicking Asthma and Vitamin D Deficiency

“…The clinical presentations of CPT-2 deficiency are manifolds, according to the age of onset and the tissue distribution of the symptoms. Muscular involvement is the most common manifestation3 with recurrent attacks of myalgias and muscle stiffness or weakness, occasionally associated with myoglobinuria. In heterozygous subjects, as the case under discussion, clinical symptoms are mild, consisting only in slight muscle fatigability, but may be worsened by other coexisting factors, either genetic (concurrent partial deficiency in other muscle enzymes) or acquired 4.…”