Conclusion

CPT II deficiency is a clinically as well as biochemically heterogeneous disease. Phe-notypic expression ranges from mild myalgia without myoglobinuria to severe exercise-induced attacks leading eventually to renal failure and death. Obviously it is rare disease, but might be immensely underdiagnosed, considering that: (i) the investigation of a muscle biopsy specimen is necessary to establish the diagnosis and (ii) expression of potentially mild phenotypes.

As more and more patients get investigated it shows that the marked clinical heterogeneity corresponds to a as marked genetic heterogeneity. Due to small numbers and only limited information on the clinical status of the patients it is difficult to draw strict phenotype/genotype correlations. A further problem is the different test methods used by different groups. Using the isotope forward assay all our patients had an overall CPT activity of 100%, but showed a different pattern after inhibition by malonyl-CoA and Triton X-100 as controls.

The range of residual CPT II activity in our patient sample was from 1.8% to 20%. The patient with the lethal infantile form who lead to the identification of the R631C mutation showed CPT II activity of 6.6%. Unaffected parents, which are heterozygous for disease causing mutations, obviously have 50% enzyme activity. In a very interesting experiment Bonnefont et al. compared the metabolic consequences of a lethal-infantile associated mutation (Y628S) with the common adult-onset S113L mutation, whereby they demonstrated a similar residual activity of CPT II between 10% and 15% of control mean values after expression in transfected COS-cells.27 Both the adult and infantile cases hitherto studied have been shown to be associated with a decreased amount of steady-

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state CPT II protein. ' ' ' All together these data do not suggest any threshold effect to be responsible for the two distinct clinical features of this disease, even bearing in mind that comparison of the data is difficult due to the different test methods used.

In summary, to date there is neither a plausible concept of how different mutations in the same gene cause such disparate clinical symptomatology of the disease on one hand (lethal-neonatal versus adult-onset) nor how such different residual activities of this enzyme lead to comparably similar phenotypes (adult-onset muscular) on the other hand. A variable degree of reduction of CPT activity, variable posttranslational modifications of the enzyme in different tissues, a disturbance of regulatory properties of the CPT system or a variable efficiency of further distal components of the p-oxidationmachin-ery by an pathologically altered enzyme might determine the difference in clinical severity of the different forms of CPT II deficiency.

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