ENPP1 – Generalized Arterial Calcification of Infancy Type 1

Generalized Arterial Calcification of Infancy type 1 (GACI1) is a rare, autosomal recessive disorder characterized by early and diffuse calcification of large- and medium-sized arteries due to loss of extracellular pyrophosphate (PPi) inhibition. The condition is caused predominantly by biallelic pathogenic variants in ENPP1, which encodes ectonucleotide pyrophosphatase/phosphodiesterase 1, a key regulator of PPi homeostasis.

Autosomal recessive inheritance is supported by biallelic ENPP1 variants identified in 11 unrelated probands across six families (PMID:35482848, PMID:34199854). Parental carrier testing demonstrated complete segregation of pathogenic alleles without clinical manifestations among heterozygotes, confirming recessive transmission.

Case series have described a spectrum of missense and splice-site variants in GACI1 patients, including novel and recurrent alleles. A representative novel variant is c.1715T>C (p.Leu572Ser), identified in trans with the recurrent c.1412A>G (p.Tyr471Cys) in a 2021 case report (PMID:34199854). No founder effects have been reported, and population databases lack these alleles, supporting their rarity and pathogenicity.

Functional studies demonstrate that ENPP1 deficiency leads to VSMC calcification and neointimal hyperplasia in both cell culture and animal models. ENPP1-deficient mice (Enpp1−/−) develop accelerated neointimal lesions and robust arterial calcification upon injury (PMID:24530784). Patient-derived fibroblasts with splice-site variants show exon skipping, reduced enzyme activity, and increased calcification. Enzyme replacement with INZ-701 in Enpp1asj/asj mice restored PPi levels, prevented ectopic calcification, corrected bone defects, and improved survival (PMID:33900645).

These concordant genetic and experimental data delineate haploinsufficiency of ENPP1 as the mechanism underlying GACI1 and justify the development of targeted therapies. Early genetic testing of ENPP1 in infants presenting with arterial calcification enables prompt diagnosis and may inform enzyme replacement strategies.

Key Take-home: Biallelic ENPP1 variants definitively cause GACI1; genetic testing is essential for diagnosis and emerging enzyme replacement therapies hold clinical promise.

References

• Diagnostics (Basel, Switzerland) • 2021 • Generalized Arterial Calcification of Infancy Type 1 (GACI1): Identification of a Novel Pathogenic Variant (c.1715T>C (p.Leu572Ser)). PMID:34199854
• PLoS genetics • 2022 • ENPP1 variants in patients with GACI and PXE expand the clinical and genetic heterogeneity of heritable disorders of ectopic calcification. PMID:35482848
• Atherosclerosis • 2014 • Mono-allelic and bi-allelic ENPP1 deficiency promote post-injury neointimal hyperplasia associated with increased C/EBP homologous protein expression. PMID:24530784
• Journal of Bone and Mineral Research • 2021 • INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice. PMID:33900645

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