A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3.

Does increasing blood pH stimulate protein synthesis in dialysis patients?

BACKGROUND: Although the mechanism of muscle wasting in end-stage renal disease is not fully understood, there is increasing evidence that acidosis induces muscle protein degradation and could therefore contribute to the loss of muscle protein stores of patients on hemodialysis, a prototypical state of chronic metabolic acidosis (CMA). Because body protein mass is controlled by the balance between synthesis and degradation, protein loss can occur as result of either increased breakdown, impaired synthesis, or both. Correction of acidosis may therefore help to maintain muscle mass and improve the health of patients with CMA. We evaluated whether alkalizing patients on hemodialysis might have a positive effect on protein synthesis and on nutritional parameters. METHODS: Eight chronic hemodialysis patients were treated daily with oral sodium bicarbonate (NaHCO(3)) supplementation for 10-14 days, yielding a pre-dialytic plasma bicarbonate concentration of 28.6 +/-1.6 mmol/l. The fractional synthesis rates (FSR) of muscle protein and albumin were obtained by the L-[(2)H(5)ring]phenylalanine flooding technique. RESULTS: Oral NaHCO(3 )supplementation induced a significant increase in serum bicarbonate (21.5 +/- 3.4 vs. 28.6 +/- 1.6 mmol/l; p = 0.018) and blood pH (7.41 vs. 7.46; p = 0.041). The FSR of muscle protein and the FSR of albumin did not change significantly (muscle protein: 2.1 +/- 0.2 vs. 2.0 +/- 0.5% per day, p = 0.39; albumin: 8.3 +/- 2.2 vs. 8.6 +/- 2.5% per day, p = 0.31). Plasma concentrations of insulin-like growth factor 1 decreased significantly (33.4 +/- 21.3 vs. 25.4 +/- 12.3 nmol/l; p = 0.028), whereas thyroid-stimulating hormone, free thyroxin and free triiodothyronine did not change significantly and nutritional parameters showed no improvement. CONCLUSION: In contrast to other findings, raising the blood pH of dialysis patients was not associated with a positive effect on albumin and muscle protein synthesis, or nutritional and endocrinal parameters.

Disseminated varicella infection in adult renal allograft recipients: four cases and a review of the literature.

Disseminated varicella-zoster (VZV) infection is a rare complication after renal allotransplantation in adults. We report four patients, among them one with combined VZV and cytomegalovirus infection. The main complications were hepatitis, pneumonitis, and disseminated intravascular coagulation. A review of the literature from 1981 to 2000 revealed 34 additional cases of disseminated varicella infection in adult renal allograft recipients with an overall mortality of 34%. Among these patients 82% suffered from primary varicella, 18% had a reactivation. High-dose acyclovir therapy combined with reduction of immunosuppression lead to reduction of mortality from 53% before 1990 to 22% after 1990. No immunosuppressive drug is significantly associated with a higher risk of disseminated VZV infection. Immunization against VZV in adults is still a matter of controversy. Whereas passive immunization is performed only for prophylactic but not therapeutic purpose, active immunization is routinely performed in children and may also be recommended for adults before renal transplantation.