Searchable abstracts of presentations at key conferences on calcified tissues
Bone Abstracts (2019) 7 P64 | DOI: 10.1530/boneabs.7.P64

ICCBH2019 Poster Presentations (1) (226 abstracts)

Missense mutations in ENPP1 result in osteoporosis in patients and is recapitulated in the ENPP1 loss of function murine model

Demetrios Braddock 1 , Ralf Oheim 2 , Kristin Zimmerman 1 , Dillon Kavanagh 1 , Mark Horowitz 3 & Thomas Carpenter 4

1Department of Pathology, Yale University Medical School, New Haven, CT, USA; 2Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3Department of Orthopædics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA; 4Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.

Biallelic ENPP1 deficiency in humans induces hypophosphatemic rickets in children characterized by increased circulating FGF23 levels and renal phosphate wasting (‘Autosomal Recessive Hypophosphatemic Rickets Type 2’, or ARHR2), but osteopenia or osteoporosis has not been described in adults. Here, we describe three adult male patients (ages 43, 59, and 62) suffering from early-onset osteoporosis who presented to the Institute of Osteology and Biomechanics at the University Hospital Hamburg, Germany. Two patients suffered from fractures in their thoracic spine and one a radial fracture. All patients exhibited elevated FGF23 levels and hypophosphatemia. DXA scans of hip demonstrated T-scores below −2.5 and HRpQCT demonstrated significantly reduced trabecular and cortical thickness of the tibia and radius. Next generation sequencing revealed that all 3 patients had heterozygous missense mutations in ENPP1: Y471C (1412A>G) (2 patients) and H777R (2330A>G) (1 patient). Enpp1asj/asj mice, a model of Enpp1 deficiency, were studied to understand the bone pathophysiology underlying this condition. Similar to what was observed in patients, 10 week-old male Enpp1asj/asj mice exhibited elevations in plasma FGF23 (350% of WT), hypophosphatemia (77% of WT), and osteopenia with reduced trabecular bone (trabecular BV/TV was 62% WT) and reduced cortical thickness (78% of WT). Other mineralization parameters in 10 week Enpp1asj/asj mice were as observed in ARHR2 – osteoid width was increased 130% of WT and mineralization lag time (MLT) was 214% of WT. Osteopenia progressed in 23 week-old male Enpp1asj/asj mice – BV/TV was 40% of WT, bone formation rate/bone surface area was 33% of WT, and mineral apposition rate (MAR) was 41% of WT. In conclusion, murine models of Enpp1 deficiency recapitulate the osteomalacia present in ARHR2 children and the osteoporosis present in adults with heterozygous ENPP1 mutations, and can therefore be used to model human bone mineralization disorders associated with ENPP1 deficiency. Our findings further suggest that parents of ARHR2 children may be at risk for early onset osteoporosis.

Disclosure: D.T.B. is an inventor of patents owned by Yale University, which describe therapeutics to treat ENPP1 deficiency. D.T.B is an equity holder and receives research and consulting support from Inozyme Pharma, Inc.

Volume 7

9th International Conference on Children's Bone Health


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