ENPP1 – autosomal recessive inherited pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is a connective tissue disorder characterized by progressive fragmentation and ectopic calcification of elastic fibers, typically caused by biallelic mutations in the ABCC6 gene. However, pathogenic variants in the ectonucleotide pyrophosphatase/phosphodiesterase 1 gene (ENPP1) have been identified in patients presenting with classic PXE, establishing ENPP1 as a second autosomal recessive genetic cause of PXE (MONDO:0009925).

Genetic evidence includes a single 2-year-old patient with generalized arterial calcification of infancy who presented with PXE skin lesions and was found to harbor a homozygous missense variant c.1538A>G (p.Tyr513Cys) in ENPP1 (one proband) (PMID:22229486). In a retrospective cohort of 92 generalized arterial calcification of infancy probands, three children with biallelic ENPP1 mutations developed angioid streaks and skin plaques consistent with PXE in later childhood (three probands) (PMID:22209248). More recently, two unrelated adults with classic PXE were shown to carry biallelic ENPP1 variants by clinical registry analysis (two probands) (PMID:35482848). Altogether, six unrelated probands across six families demonstrate a consistent autosomal recessive inheritance pattern and clinical concordance.

The variant spectrum in PXE includes missense changes predicted to abolish or reduce enzyme activity. The recurrent homozygous variant c.1538A>G (p.Tyr513Cys) impairs pyrophosphatase function and localizes normally to the plasma membrane, consistent with loss-of-function (PMID:27467858). Additional private ENPP1 alleles have been reported in PXE patients, underscoring allelic heterogeneity.

Inheritance is strictly autosomal recessive, with biallelic ENPP1 variants required for disease expression. No clear reports of segregation beyond the index cases are available, and affected relatives have not been documented in these PXE cohorts.

Functional studies confirm that ENPP1 generates inorganic pyrophosphate (PPi), a potent inhibitor of tissue mineralization. In vitro assays show that pathogenic ENPP1 missense mutants abolish PPi generation, leading to ectopic calcification. In Enpp1-deficient mice, treatment with recombinant ENPP1-Fc (INZ-701) restores circulating PPi, prevents pathological calcification, and rescues bone architecture, demonstrating mechanistic concordance and therapeutic potential (PMID:33900645).

Integration of genetic and functional data supports a Strong clinical validity classification for ENPP1-associated PXE. Biallelic loss-of-function variants in ENPP1 cause classic PXE through haploinsufficiency of PPi generation. Recognition of ENPP1 as a PXE gene informs molecular diagnosis, enables enzyme-replacement strategies, and expands the spectrum of ectopic calcification disorders. Key take-home: ENPP1 testing should be included in genetic work-up for PXE, given its direct impact on diagnosis and emerging therapies.

References

• The British journal of dermatology | 2012 | Cutaneous features of pseudoxanthoma elasticum in a patient with generalized arterial calcification of infancy due to a homozygous missense mutation in the ENPP1 gene. PMID:22229486
• American journal of human genetics | 2012 | Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. PMID:22209248
• 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
• Human mutation | 2016 | Effects of Different Variants in the ENPP1 Gene on the Functional Properties of Ectonucleotide Pyrophosphatase/Phosphodiesterase Family Member 1. PMID:27467858
• 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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