Genetic and enzymatic analysis for two Japanese patients with idiopathic infantile arterial calcification

Abstract

Idiopathic infantile arterial calcification (IIAC) is a life-threatening disorder in young infants. Cardiovascular symptoms are usually apparent within the first month of life. The symptoms are caused by calcification of large and medium-sized arteries, including the aorta, coronary arteries, and renal arteries. Most of the patients die by 6 months of age because of heart failure. Recently, homozygous or compound heterozygous mutations for the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene were reported as causative for the disorder. ENPP1 regulates extracellular inorganic pyrophosphate (PPi), a major inhibiter of extracellular matrix calcification. Two Japanese patients with IIAC were studied. One, from first-cousin parents, showed a typical clinical course. The onset in the second patient was late. Both of the patients were clinically compatible for IIAC; arterial calcification was shown, and hypertension was prominent. We sequenced all the exons and exon-intron boundaries of the gene and measured nucleotide pyrophosphohydrolase (NPPH) activity of ENPP1. Homozygous Arg730Stop was detected in the typical IIAC patient. The mutation was a novel nonsense mutation and not detected in 60 healthy controls. His NPPH activity was 4% of normal. On the other hand, the late-onset patient was not shown to have any mutations. NPPH activity in this patient was 70% of normal. We confirmed that ENPP1 was also responsible for the Japanese patient with IIAC. The atypical late-onset phenotype may not be associated with ENPP1 abnormalities. IIAC is considered to be a clinically and genetically heterogeneous disorder.