Generalized Arterial Calcification of Infancy: Fatal Clinical Course Associated with a Novel Mutation in ENPP1

Galletti, Silvia; Nitschke, Yvonne; Malavolti, Anna Maria; Aquilano, Giulia; Faldella, Giacomo; Corvaglia, Luigi; Rutsch, Frank

doi:10.1007/8904_2011_11

Cited by 18 publications

(20 citation statements)

References 21 publications

(32 reference statements)

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“…8 A limited number of case studies have reported on attempts to treat patients with GACI with oral and intravenous bisphosphonates. [21][22][23][24][25] There is no consensus, however, about the efficacy of bisphosphonates on the ectopic mineralization in these disorders. Some studies report apparent improvement, in some cases there has been very little, if any, effect, and in others bisphosphonate treatment has been accompanied by severe side effects.…”

Section: Discussionmentioning

confidence: 99%

“…20 Because PPi is relatively unstable in circulation and has a short half-life, administration of bisphosphonates, which are non-hydrolyzable PPi analogs, have been used to treat these patients with ectopic mineralization, including newborns or infants with GACI type 1 with ENPP1 mutations. [21][22][23][24][25] Careful analysis of these studies suggests improvements in some cases, no change in others, and even development of serious side effects in some patients. At the same time, recent demonstration of reduced PPi level in PXE patients suggested that bisphosphonates might be useful to treat ectopic calcification in patients with PXE and GACI type 2 due to ABCC6 mutations.…”

Section: Introductionmentioning

confidence: 99%

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The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene

Sundberg

Levine

et al. 2015

Cell Cycle

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Abbreviations: PXE, pseudoxanthoma elasticum; GACI, generalized arterial calcification of infancy; ETD, etidronate disodium;AST, alendronate sodium trihydrate; KO, knock-out; WT, wild-type.Pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI) are heritable ectopic mineralization disorders. Most cases of PXE and many cases of GACI harbor mutations in the ABCC6 gene. There is no effective treatment for these disorders. We explored the potential efficacy of bisphosphonates to prevent ectopic calcification caused by ABCC6 mutations by feeding Abcc6 ¡/¡ mice with diet containing etidronate disodium (ETD) or alendronate sodium trihydrate (AST) in quantities corresponding to 1x, 5x, or 12x of the doses used to treat osteoporosis in humans. The mice were placed on diet at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks by quantitation of the calcium deposits in the dermal sheath of vibrissae, a progressive biomarker of the mineralization, by computerized morphometry of histopathologic sections and by direct chemical assay of calcium. We found that ETD, but not AST, at the 12x dosage, significantly reduced mineralization, suggesting that selected bisphosphonates may be helpful for prevention of mineral deposits in PXE and GACI caused by mutations in the ABCC6 gene, when combined with careful monitoring of efficacy and potential side-effects.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene

Sundberg

Levine

et al. 2015

Cell Cycle

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“…Bisphosphonates were effective in reducing the progression of the disease in some children with generalized arterial calcification of infancy [60,61,62] but not in others [63]. Severe skeletal toxicity was observed in 1 patient [62].…”

Section: Bisphosphonate Use In Pediatric Patientsmentioning

confidence: 99%

The Use of Bisphosphonates in Pediatrics

Baroncelli

Bertelloni

2014

Horm Res Paediatr

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Bisphosphonates are widely used for the prevention and treatment of osteoporosis in adulthood. In the last years, bisphosphonates have been increasingly used in pediatric patients for the treatment of a growing number of disorders associated with osteoporosis, resistant hypercalcemia or heterotopic calcifications. The use of bisphosphonates in pediatric patients has been proven safe; however, the risk of potential severe consequences into adulthood should be kept in mind. Well-defined criteria for bisphosphonates treatment in pediatric patients are not specified, therefore an accurate selection of patients who could benefit from bisphosphonates is mandatory. A strict follow-up of pediatric patients receiving long-term bisphosphonate therapy is strongly recommended. The purpose of this mini review is to provide a summary of current knowledge on some main general aspects of the structure, mechanisms of action, pharmacokinetics, and bioavailability of bisphosphonates, and to focus on the latest advances of bisphosphonate treatment in pediatric patients. Particular attention has been paid to the common and potential adverse effects of bisphosphonate treatment, and some suggestions concerning the clinical approach and general measures for bisphosphonate treatment in pediatric patients are reported.

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“…It has been reported that treatment with EHDP improved the overall survival of patients with GACI by diminishing arterial calcification (Otero et al, 2013, Edouard et al, 2011, Galletti et al, 2011, Rutsch et al, 2008). Because the dose of EHDP required to inhibit bone resorption is near the one that impairs mineralization, EHDP could also serve as an inhibitor of mineralization in the bone and in the extra bone tissues (Fleisch, 2002).…”

Section: Introductionmentioning

confidence: 99%

Hypophosphatemic rickets developed after treatment with etidronate disodium in a patient with generalized arterial calcification in infancy

et al. 2015

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Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6–3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part.

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Generalized Arterial Calcification of Infancy: Fatal Clinical Course Associated with a Novel Mutation in ENPP1

Cited by 18 publications

References 21 publications

The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene

The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene

The Use of Bisphosphonates in Pediatrics

Hypophosphatemic rickets developed after treatment with etidronate disodium in a patient with generalized arterial calcification in infancy

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