Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results

Abstract

Six individuals with Ullrich congenital muscular dystrophy (UCMD) and mutations in the genes-encoding collagen VI, aging 5–9, received 3–5 mg/kg of cyclosporine A (CsA) daily for 1 to 3.2 years. The primary outcome measure was the muscle strength evaluated with a myometer and expressed as megalimbs. The megalimbs score showed significant improvement (P = 0.01) in 5 of the 6 patients. Motor function did not change. Respiratory function deteriorated in all. CsA treatment corrected mitochondrial dysfunction, increased muscle regeneration, and decreased the number of apoptotic nuclei. Results from this study demonstrate that long-term treatment with CsA ameliorates performance in the limbs, but not in the respiratory muscles of UCMD patients, and that it is well tolerated. These results suggest considering a trial of CsA or nonimmunosuppressive cyclosporins, that retains the PTP-desensitizing properties of CsA, as early as possible in UCMD patients when diaphragm is less compromised.

Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies

“…Based on the literature and our findings, we recommend that repeated goniometry measures in clinical trials be limited to joint measurements with reliable bony landmarks [13,20–22,40]. In fact, a limitation of the study was that goniometry was reproducible only in certain joints over 2 years (hip extension, knee extension, elbow extension), and inconsistent measurements as evidenced by large standard deviations were found in other joints (shoulder abduction, hip flexion, ankle dorsiflexion, cervical flexion).…”

Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies

“…Accordingly, an excessive ROS formation would mimic a condition of intramitochondrial Ca 2+ overload where PTP opening is observed also in the presence of CypD inhibition or deletion [45,46]. This hypothesis might also contribute to explain why treatment of MD patients with CsA displayed partial efficacy, with correction of mitochondrial alterations and reduced cell death in the limbs, but not in respiratory muscles [47].…”

Prevention of Recurrent Episodes of Rhabdomyolysis With Tacrolimus in a Transplant Recipient With Myopathy

“…In addition, there was a correction of the mitochondrial dysfunction, increased muscle regeneration, and a decreased number of apoptotic nuclei. 5 Our patient refused a muscle biopsy, and therefore we do not have a definitive diagnosis of the form of myopathy that resulted in his propensity to experience recurrent severe rhabdomyolysis. However, based on his clinical course and laboratory data after transplantation, we hypothesize that tacrolimus, a CNI, had a protective or stabilizing effect on his myocytes that reduced the tendency for rhabdomyolysis.…”

“…In murine and human studies of limb-girdle muscle dystrophy, Ullrich congenital muscular dystrophy (UCMD), and other collagen VI myopathies, the inhibition of calcineurin has resulted in an amelioration of symptoms, muscle degeneration, and histopathology. 5,[23][24][25] It is believed that the presence of mitochondrial dysfunction in UCMD results in spontaneous apoptosis and muscle wasting, and this increased apoptosis could be inhibited by the administration of cyclosporine A. 23,24 In a mouse model of limb-girdle muscular dystrophy, genetic deletion of a lox P-targeted calcineurin B1 substantially reduced skeletal muscle degeneration and histopathology, whereas increased calcineurin expression increased muscle fiber loss.…”

“…Calcineurin has a significant role in structure and function of myocytes, and calcineurin inhibitors (CNIs) have a therapeutic role in certain myopathies. 4,5 We describe a case of a patient who received a kidney transplant for CKD resulting from recurrent severe episodes of rhabdomyolysis. In the posttransplant period, the maintenance of tacrolimus trough above a specific target level appeared to confer protection from further episodes of rhabdomyolysis.…”