on December 9, 2008
Published online before print December 9, 2008, doi: 10.1161/CIRCGENETICS.108.797704
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Original Article |
Hypophosphatemia, Hyperphosphaturia and Bisphosphonate Treatment are Associated with Survival Beyond Infancy in Generalized Arterial Calcification of Infancy (GACI)
1 University Children's Hospital, Münster, Germany;
2 The Babraham Institute, Cambridge, United Kingdom;
3 Helmholtz Zentrum München and Technical University, Munich, Germany;
4 University Hospital, Münster, Germany;
5 Saint Mary's Hospital for Women & Children, Manchester, United Kingdom;
6 Cardiff University, Cardiff , United Kingdom;
7 Southampton University Hospital, Southampton, United Kingdom;
8 Hôpital Robert Debré, Paris, France;
9 Charité University Hospital, Berlin, Germany;
10 University of Cologne, Cologne, Germany;
11 University of California, San Diego, CA
12 E-mail: rutschf{at}mednet.uni-muenster.de
Background—Generalized arterial calcification of infancy (GACI) has been reported to frequently be lethal and the efficiency of any therapy, including bisphosphonates is unknown. A phosphate poor diet markedly increases survival of NPP1 null mice, a model of GACI.
Methods and Results—We performed a multi-center genetic study and retrospective observational analysis of 55 subjects affected by GACI to identify prognostic factors. Nineteen patients (34%) survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 patients (65 %) treated with bisphosphonates survived. Of 26 patients, who survived their first day of life and were not treated with bisphosphonates, only 8 patients (31 %) survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1 were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median: 30 days). Seven of the 14 patients (50%) without ENPP1 mutations died in infancy (median: 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen.
Conclusion—ENPP1 coding region mutations are associated with GACI in ~75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival appears to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment.
Key Words: genetics • mortality • pediatrics • prognosis • survival