Myopathy in Cystinosis

August 11, 2006

 

Progress Report: Mitchondrial Dysfunction in Cystinosis Myopathy

Principal Investigator: Doris A. Trauner M.D.

 

 

Aims of the study:

The specific aims are to determine whether the myopathy associated with nephropathic cystinosis is the result of mitochondrial dysfunction with resultant deficiency in respiratory transport chain function in adolescents and adults with cystinosis, and to determine if a treatment regimen that provides additional co-factors for these enzymes will improve the strength and prevent deterioration in muscle strength.

 

Progress to date:

  1. Enrollment

Eleven patients (age range 16-43 years) have been enrolled in the study to date. One was unable to continue because of his prior participation in a study of cardiac function. He has subsequently died of cardiac complications of his disease. Of the remaining 10, all have completed the 6 month visit and nine of the ten have completed the 12-month visit. The one participant who did not complete the 12 month data point had been placed on additional medications by his physician that interfered with our ability to interpret the results of our data. All patients were randomized to treatment with a “mitochondrial cocktail” or placebo for the first 6 months, and then offered open-label treatment with the vitamin-cofactor combination if they wished.

 

Results of study to date

We are still in the process of entering the data into the database and have not as yet broken the code for treatment. Preliminary qualitative data analyses reveal the following:

 

    1. Strength: of the 10 participants, 4 had clinical evidence of muscle weakness on neurological examination. The weakness was mild to moderate in 3 and severe in one. One had shoulder girdle weakness, one mild leg weakness, one mild hand weakness, and one severe upper greater than lower extremity weakness. Grip strength testing at baseline was weaker than expected for age and gender in 5 of the 10 participants. At the 6 month follow-up, 2 of the four with initial weakness had improvement in strength on muscle strength testing, but no change in grip strength. One person who had initially had normal strength on clinical exam was thought to have slight hand weakness at 6 months. At 12 months, the subject with the most severe weakness had improved to mild to moderate weakness. Four additional subjects had mild to moderate weakness, including 2 who had normal exams previously. One person with an initial finding of mild leg weakness no longer exhibited that at 12 months. No individual had worsening of lower extremity strength over the 12 months, and weakness appeared to be confined to the upper extremities when present at all.
    2. Muscle pathology: Seven of the 10 individuals had abnormal results on muscle biopsy. The most common findings were muscle atrophy, fiber type disproportion, ring fibers, and filamentous bodies. Two had increase red granular staining and an increase in lipid droplets, findings suggestive of mitochondrial disorders. Biopsy findings did not always correlate with clinical examination or patient report of strength. Interestingly, no cystine crystals were found in muscle tissue.
    3. Muscle biochemistry: Muscle carnitine levels were normal in all 10 patients. Plasma carnitine levels were normal as well. Mitochondrial respiratory chain activity for Complex I, II, III and IV was normal in all patients.
  1. Plans

We plan to break the treatment code and discuss the longitudinal results to determine whether there was any relationship between treatment and improvement. All data will be analyzed and manuscripts prepared within the next 6 months.