Correspondence

Bezafibrate for an Inborn Mitochondrial Beta-Oxidation Defect

N Engl J Med 2009; 360:838-840February 19, 2009

Article

To the Editor:

Carnitine palmitoyltransferase II (CPT2) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid oxidation. The most common form of this disorder is characterized by muscle stiffness, myalgia, and exercise intolerance,1,2 and current dietary approaches often do not prevent attacks of rhabdomyolysis. We found that bezafibrate, a commonly used hypolipidemic drug,3 restored the capacity for normal fatty acid oxidation in muscle cells from patients with a mild form of CPT2 deficiency by stimulating the expression of the mutated gene.4

We evaluated the efficacy of bezafibrate as a treatment for the mild form of CPT2 deficiency in six adults; bezafibrate was administered for 6 months (at a dose of three 200-mg tablets per day). The primary end point was the level of fatty acid oxidation in skeletal muscle. Muscle-biopsy specimens were obtained before and after treatment, mitochondria were isolated, and mitochondrial respiration rates were measured in the presence of palmitoyl L-carnitine, the specific substrate of CPT2. Before treatment, the palmitoyl L-carnitine oxidation levels were markedly reduced (by 21 to 54% of the normal value), reductions that were consistent with CPT2 deficiency. After bezafibrate treatment, the values increased significantly in the six patients (by 60 to 284%, P=0.03) (Figure 1AFigure 1Bezafibrate Treatment in Six Patients with CPT2 Deficiency.). In addition, CPT2 messenger RNA in skeletal muscle increased in all the patients (by 20 to 93%, P=0.002) (Figure 1B), as did the CPT2 protein level (data not shown), findings that were consistent with the increased oxidation levels. In vitro analysis of myoblasts from the patients (Figure 1C) showed that the initial defect in fatty acid oxidation (49 to 75% of control values) was fully corrected after the cells had been exposed to bezafibrate (P=0.002). There were 3 to 24 episodes of rhabdomyolysis per patient over a 6-month period before treatment (mean [±SD] creatine kinase level, 10,900±3900 IU per liter) and 0 to 6 episodes per patient during treatment (mean creatine kinase level, 4700±1900 IU per liter).

The effects of bezafibrate on health, physical functioning, and quality of life were evaluated with the use of the 36-Item Short-Form General Health Survey, which was completed by each patient before and after treatment. The scores for each domain were calculated for each patient and then averaged (Figure 1D). Before treatment, scores in five of eight domains were below the population norms,5 most notably, the scores for “role-physical” and bodily pain — findings that were consistent with symptoms of CPT2 deficiency. After treatment, the scores for all domains reached the control ranges. The largest improvements were seen in the scores for “role-physical” (an increase by a factor of 2.5) and bodily pain (an increase by a factor of 2.0), indicating less limitation in physical activity and a clear decrease in muscular pain. No adverse effects were reported.

The results of this pilot trial show a therapeutic effect of bezafibrate, suggesting that further study of this agent for pharmacologic treatment of the mild form of CPT2 deficiency may be of interest.

Jean-Paul Bonnefont, M.D., Ph.D.
Jean Bastin, Ph.D.
Université Paris Descartes, 75015 Paris, France

Anthony Behin, M.D.
Assistance Publique–Hôpitaux de Paris Reference Center, for Rare Neuromuscular Disorders, 75013 Paris, France

Fatima Djouadi, Ph.D.
Université Paris Descartes, 75015 Paris, France
fatima.djouadi@inserm.fr

Supported by a grant (to Drs. Bonnefont, Bastin, and Djouadi) from the Association Française contre les Myopathies.

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