Perinatal hypophosphatasia: Radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene

Abstract

We report on a postmortem diagnosis of perinatal lethal hypophosphatasia, an inborn error of metabolism characterized by a liver/bone/kidney alkaline phosphatase (ALP)-related defective bone mineralization due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Radiological and pathological studies identified a perinatal lethal hypophosphatasia showing a generalized bone mineralization defect including asymmetry of the cervical vertebral arches in a 22 +4 weeks' gestation fetus. Both parents revealed low serum ALP activities supporting the diagnosis. Sequencing analysis of the TNSALP gene showed two heterozygous mutations, 648+1A, a mutation affecting the donor splice site in exon 6, and N400S, a novel missense mutation in exon 11, located near the active site and very close to histidins 364 and 437, two crucial residues of the active site. Sequencing of exons 6 and 11 in the parents showed that 648+1A was from maternal origin and N400S from paternal origin. DNA-based prenatal testing in the subsequent pregnancy following a chorionic villous sampling performed at 10 weeks of gestation showed no mutation and a healthy infant was born at term.

Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia

“…As shown in Table 1, three patients with infantile hypophosphatasia (numbers 17,18,19) were also included in the current study. One of them (number 18) was the previously reported patient [17] and is still alive with characteristic skeletal changes, i.e.…”

“…In contrast, ten patients (numbers 7-16) were classified as the classical perinatal form; nine of them died and the remaining one is currently on mechanical ventilation with very low levels of TNSALP (<30 IU/l). Three patients (numbers [17][18][19] were diagnosed with infantile hypophosphatasia. All of these three patients were diagnosed before 6 months of age based on their severe bony hypomineralisation and hypercalcaemia.…”

“…The severity of the disease is generally well correlated with the onset of the disease, except for odontohypophosphatasia where only the teeth are affected. Patients with the perinatal form of hypophosphatasia almost always die around birth due to impaired development of the lungs and the severe hypomineralisation of their bones [19]. However, the classification of these subgroups is not definite and there is diversity in the phenotype creating a so-called spectrum.…”

Prevalence of c.1559delT in ALPL, a common mutation resulting in the perinatal (lethal) form of hypophosphatasia in Japanese and effects of the mutation on heterozygous carriers

“…10 Biochemical markers, serum ALP activity and urinary PEA levels fell within their normal ranges in the majority of the c.1559delT carriers examined in this paper, whereas heterozygous carriers of the severe forms in other ALPL mutations were reported to have reduced serum ALP activity and increased urinary PEA. [4][5][6][7][8] Some possible reasons why c.1559delT carriers display normal marker levels are as follows: the first is the protein properties caused by the different mutation positions. The c.1559delT mutation causes a frameshift downstream of codon L503, resulting in the elimination of the termination codon at 508 and the addition of 80 amino acids at the C-terminus.…”

“…They show no clinical symptoms, but have reduced serum ALP activity and increased urinary phosphoethanolamine (PEA). [4][5][6][7][8] ALPL is the only gene known to be associated with HPP. 1 More than 200 ALPL mutations have been described, accounting for most phenotype variabilities.…”