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Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy

Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy
Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy
Background: generalized arterial calcification of infancy has been reported to be frequently 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 generalized arterial calcification of infancy.
Methods and Results: we performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients 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 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients 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 (50%) patients 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 generalized arterial calcification of infancy in {approx}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 seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment
genetics, mortality, pediatrics, prognosis, survival
1942-325X
133-140
Rutsch, Frank
3a21d2ad-5144-41d0-8925-4e544d7cd54b
Boyer, Petra
b62c4dec-50bc-49c2-8dde-3d0bc7ad17da
Nitschke, Yvonne
2b061287-f7d9-45a3-bebe-cb7c341e106a
Ruf, Nico
2b721d3f-cc8d-4af9-bf79-8b74e89f3f25
Lorenz-Depierieux, Bettina
835210d6-de61-46ad-b78a-7ed752d3fefd
Wittkampf, Tanja
83493ae8-5f04-412e-ba14-0471e5f0bc7c
Weissen-Plenz, Gabriele
d427dada-68dd-46ba-8bd9-033e903fc686
Fischer, Rudolf-josef
47475958-ba69-4026-a47f-f5c59bf0a61f
Mughal, Zulf
289613cc-a78b-4335-9221-f19419eaa32e
Gregory, John W.
745ba9d8-0ece-488e-8c3f-6d6f9b8bf99d
Davies, Justin H.
9f18fcad-f488-4c72-ac23-c154995443a9
Loirat, Chantal
3ccd69cf-a799-40da-b7e8-ce579af493f7
Strom, Tim M.
32d73304-316c-4a44-a7fc-7a527cf602fc
Schnabel, Dirk
597a096a-e2c7-4e4a-be2d-c14c97924d1a
Nurnberg, Peter
d8320d5a-1bf6-4b0a-baee-edf2de29fa7e
Terkeltaub, Robert
8d2f9b58-5a52-4504-afbd-9fcbce7a6ab4
GACI Study Group
Rutsch, Frank
3a21d2ad-5144-41d0-8925-4e544d7cd54b
Boyer, Petra
b62c4dec-50bc-49c2-8dde-3d0bc7ad17da
Nitschke, Yvonne
2b061287-f7d9-45a3-bebe-cb7c341e106a
Ruf, Nico
2b721d3f-cc8d-4af9-bf79-8b74e89f3f25
Lorenz-Depierieux, Bettina
835210d6-de61-46ad-b78a-7ed752d3fefd
Wittkampf, Tanja
83493ae8-5f04-412e-ba14-0471e5f0bc7c
Weissen-Plenz, Gabriele
d427dada-68dd-46ba-8bd9-033e903fc686
Fischer, Rudolf-josef
47475958-ba69-4026-a47f-f5c59bf0a61f
Mughal, Zulf
289613cc-a78b-4335-9221-f19419eaa32e
Gregory, John W.
745ba9d8-0ece-488e-8c3f-6d6f9b8bf99d
Davies, Justin H.
9f18fcad-f488-4c72-ac23-c154995443a9
Loirat, Chantal
3ccd69cf-a799-40da-b7e8-ce579af493f7
Strom, Tim M.
32d73304-316c-4a44-a7fc-7a527cf602fc
Schnabel, Dirk
597a096a-e2c7-4e4a-be2d-c14c97924d1a
Nurnberg, Peter
d8320d5a-1bf6-4b0a-baee-edf2de29fa7e
Terkeltaub, Robert
8d2f9b58-5a52-4504-afbd-9fcbce7a6ab4

Rutsch, Frank, Boyer, Petra, Nitschke, Yvonne, Ruf, Nico, Lorenz-Depierieux, Bettina, Wittkampf, Tanja, Weissen-Plenz, Gabriele, Fischer, Rudolf-josef, Mughal, Zulf, Gregory, John W., Davies, Justin H., Loirat, Chantal, Strom, Tim M., Schnabel, Dirk, Nurnberg, Peter and Terkeltaub, Robert , GACI Study Group (2008) Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circulation: Cardiovascular Genetics, 1 (2), 133-140. (doi:10.1161/CIRCGENETICS.108.797704).

Record type: Article

Abstract

Background: generalized arterial calcification of infancy has been reported to be frequently 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 generalized arterial calcification of infancy.
Methods and Results: we performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients 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 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients 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 (50%) patients 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 generalized arterial calcification of infancy in {approx}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 seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment

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Published date: December 2008
Keywords: genetics, mortality, pediatrics, prognosis, survival

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Local EPrints ID: 72459
URI: http://eprints.soton.ac.uk/id/eprint/72459
ISSN: 1942-325X
PURE UUID: ef79016b-0169-42a4-926f-ea6205b0d3b2

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Date deposited: 15 Feb 2010
Last modified: 13 Mar 2024 21:30

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Contributors

Author: Frank Rutsch
Author: Petra Boyer
Author: Yvonne Nitschke
Author: Nico Ruf
Author: Bettina Lorenz-Depierieux
Author: Tanja Wittkampf
Author: Gabriele Weissen-Plenz
Author: Rudolf-josef Fischer
Author: Zulf Mughal
Author: John W. Gregory
Author: Chantal Loirat
Author: Tim M. Strom
Author: Dirk Schnabel
Author: Peter Nurnberg
Author: Robert Terkeltaub
Corporate Author: GACI Study Group

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