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Objective: The objective of this study is to clarify the usefulness of parental alkaline phosphatase (ALP) for prenatal diagnosis of hypophosphatasia (HPP)., Methods: Maternal (m) and paternal (p) ALP values were measured in 77 cases from a multicenter cohort (fetal skeletal dysplasia forum in Japan) of cases with short limbs on ultrasonography during pregnancy. After birth, X-rays, cord blood ALP, and gene analysis were evaluated to achieve an exact diagnosis. The screening usefulness of ALP was examined retrospectively., Results: Seventeen cases were eventually diagnosed as HPP and 60 as not HPP; the overall mean m-ALP and p-ALP (standard deviation) values were 133.4 (53) versus 197 (69) IU/L and 149.6 (71.8) versus 231 (61.4) IU/L (p < 0.001). Receiver operating characteristic curve analysis showed that the optimal m-ALP and p-ALP cutoff values were 123 and 165 IU/L, respectively. Presence of at least one of the m-ALP or p-ALP values abnormally low had a sensitivity, specificity, and positive predictive values of 82% (14/17), 93%, and 78%, respectively, for the diagnosis of HPP., Conclusion: Parental ALP measurement might be an auxiliary tool to hone in the prenatal diagnosis of fetal HPP. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Background: Inactivating mutations in tissue-nonspecific alkaline phosphatase (TNAP) cause hypophosphatasia (HPP), which is commonly characterized by decreased bone mineralization. Infants and mice with HPP can also develop craniosynostosis and craniofacial shape abnormalities, although the mechanism by which TNAP deficiency causes these craniofacial defects is not yet known. Manifestations of HPP are heterogeneous in severity, and evidence from the literature suggests that much of this variability is mutation dependent. Here, we performed a comprehensive analysis of craniosynostosis and craniofacial shape variation in the Alpl(-/-) mouse model of murine HPP as an initial step toward better understanding penetrance of the HPP craniofacial phenotype., Results: Despite similar deficiencies in alkaline phosphatase, Alpl(-/-) mice develop craniosynostosis and a brachycephalic/acrocephalic craniofacial shape of variable penetrance. Only those Alpl(-/-) mice with a severe bone hypomineralization defect develop craniosynostosis and an abnormal craniofacial shape., Conclusions: These results indicate that variability of the HPP phenotype is not entirely dependent upon the type of genetic mutation and level of residual alkaline phosphatase activity. Additionally, despite a severity continuum of the bone hypomineralization phenotype, craniofacial skeletal shape abnormalities and craniosynostosis occur only in the context of severely diminished bone mineralization in the Alpl(-/-) mouse model of HPP., (© 2015 Wiley Periodicals, Inc.)

We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephalopathy resulting in death. Both had increased levels of urinary vanillactate, indicating functional deficiency of aromatic amino acid decarboxylase, a pyridoxal-5-phosphate (PLP)-dependent enzyme required for dopamine and serotonin biosynthesis. Clinical findings and results of subsequent metabolic investigations were consistent with secondary pyridoxine-deficient encephalopathy. These patients highlight the importance of tissue non-specific alkaline phosphatase in the neuronal PLP-dependent metabolism of neurotransmitters. In addition, the disturbance of PLP metabolism appears to underlie the predominant neurological presentation in our patients. We recommend the measurement of serum alkaline phosphatase (ALP) during the assessment of perinatal seizures.

Objective: We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP., Method: The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP., Results: Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series., Conclusion: The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.

Objectives: Hypophosphatasia is a rare heritable inborn error of metabolism characterized by a liver/bone/kidney alkaline phosphatase defective bone mineralization due to mutations in the tissue-non-specific alkaline phosphatase (TNS-ALP) gene. To date 128 mutations are described in the TNS-ALP gene located on the short arm of chromosome 1. The clinical presentation of hypophosphatasia is variable ranging from early onset lethal short-limb dwarfism to a late-onset presentation with fractures in childhood or adulthood., Methods: We report a pregnancy with a positive maternal serum triple test screening and a post-mortem pathological and molecular diagnosis of perinatal lethal hypophosphatasia., Results: Two heterogeneous missense mutations in the TNS-ALP gene were found, of which one was not previously described., Conclusion: This case report adds to the list of fetal malformations found after positive maternal serum triple test screening and reports a previously undescribed mutation in the TNS-ALP gene responsible for hypophosphatasia., (Copyright 2004 John Wiley and Sons, Ltd.)

Objectives: Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and deficiency of tissue nonspecific alkaline phosphatase (TNSALP) activity. This disorder is caused by various mutations in the TNSALP gene. We report here hypophosphatasia in two siblings, both of them severely affected by the perinatal (lethal) type., Methods: We diagnosed the first infant by clinical and radiologic manifestations, and laboratory findings. Laboratory findings were characterized by deficiency of serum alkaline phosphatase. Both parents and the second infant were then analyzed by molecular techniques., Results: The radiograph of the first infant showed severe hypomineralization of the skeleton. Molecular analysis of the second infant showed that this condition was caused by a homozygous single T nucleotide deletion at cDNA number 1559 (1559delT). Both parents were heterozygous carriers for this mutation, although they were not consanguineous., Conclusion: This mutation has been frequently found in Japanese hypophosphatasia patients, but this is the first observation of a homozygous deletion. This report shows that homozygosity for the 1559delT mutation of the TNSALP gene results in a severe lethal phenotype., (Copyright 2003 John Wiley & Sons, Ltd.)

We describe a patient diagnosed with lethal perinatal hypophosphatasia with a unique clinical presentation of convulsions that responded to vitamin B6. Genomic DNA sequence analysis of the tissue-nonspecific alkaline phosphatase (TNSALP) gene revealed two missense mutations: a G-to-A transition resulting in a Glu to Lys at codon 274 (E274K), and a G-to-C transversion resulting in a Gly to Arg at codon 309 (G309R). The first mutation was maternally transmitted and was previously characterized as a moderate one, whereas the latter was paternally transmitted and has not been previously reported. Phenotype/genotype correlation indicates that G309R is a deleterious mutation that can lead to seizures and a lethal outcome, as was demonstrated in our patient.

Prenatal diagnosis of severe hypophosphatasia by mutation analysis of the tissue non-specific alkaline phosphatase (TNSALP) gene is reliable and mostly informative. However, alkaline phosphatase (ALP) assay of CVS may be a useful complementary and independent method, especially when a mutation is unidentified and DNA from the index case is unavailable, rendering impossible the use of DNA polymorphisms as genetic markers of the disease. We report here mutation analysis of the TNSALP gene and ALP assay in nine cases of prenatal diagnosis of severe hypophosphatasia. The results showed a good correlation between ALP assay and DNA analysis in all but one case, which suggested that in at least some cases low values of ALP may correspond to affected fetuses as well as to heterozygotes., (Copyright 1999 John Wiley & Sons, Ltd.)

We report the inactivation, via homologous recombination, of two of the three active mouse alkaline phosphatase genes, i.e., embryonic (EAP) and tissue nonspecific (TNAP). Whereas expression of the EAP isozyme was abolished in all tissues that express EAP developmentally (such as the preimplantation embryo, thymus, and testis), the EAP knock-out mice show no obvious phenotypic abnormalities. They reproduce normally and give birth to live offspring, indicating the nonessential role of EAP during embryonic development. Mice deficient in the TNAP gene mimic a severe form of hypophosphatasia. These TNAP-/- mice are growth impaired, develop epileptic seizures and apnea, and die before weaning. Examination of the tissues indicates abnormal bone mineralization and morphological changes in the osteoblasts, aberrant development of the lumbar nerve roots, disturbances in intestinal physiology, increased apoptosis in the thymus, and abnormal spleens. Our results indicate that, in the mouse, TNAP appears not to be essential for the initial events leading to bone mineral deposition but that TNAP seems to play a role in the maintenance of this process after birth. The other phenotypic manifestations may be a consequence of the lack of TNAP in the developing neural tube between stages E8.5 and E13.5 of embryogenesis. We hypothesize that the autonomic nervous system is compromised in these TNAP-/- mice.

We obtained a prenatal molecular diagnosis during the first trimester in a Japanese woman whose first child (the proband) had been a compound heterozygote for infantile hypophosphatasia. We examined chorionic villus DNA samples obtained at 10 weeks of gestation for the base substitutions detected in the proband DNA using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) and PCR-allele-specific oligonucleotide (ASO) analysis. The genotype of the fetus was the same as that of the proband. The same mobility shift patterns of single strand conformation polymorphism (SSCP) bands were observed in the fetus and the proband. This molecular approach to prenatal diagnosis appears to be more accurate than the enzymatic method and also more accurate and more rapid than the conventional RFLP method.

We successfully assessed a fetus at risk for lethal infantile hypophosphatasia using amniocyte DNA and allele-specific oligonucleotide (ASO) probes for two missense mutations in the tissue-non-specific alkaline phosphatase isoenzyme (TNSALP) gene. The nucleotide changes had been discovered in a sister who died at 8 months of age from this inborn error of metabolism. The mother was known to carry the 747 (cDNA) G-->A transition, whereas her husband and 5-year-old daughter, who were also healthy, carried the 1309 A-->T transversion. Amniocytes, obtained at 16 weeks' gestation, provided genomic DNA for polymerase chain reaction (PCR) amplification of the appropriate TNSALP gene exons. ASO hybridization revealed absence of the 747A mutation and presence of the 1309T base changes in the fetus, indicating a carrier for hypophosphatasia. At 8 months of age, the offspring was in excellent health and without any radiological evidence of skeletal disease. His serum ALP activity and plasma pyridoxal 5'-phosphate level were decreased and increased, respectively, at levels consistent with the prenatal assessment. The ASO studies were confirmed postnatally using peripheral blood leukocyte DNA. This is the first application of direct mutational analysis to assess a fetus at risk for hypophosphatasia.

We measured plasma levels of pyridoxal-5'-phosphate (PLP), a cofactor form of vitamin B6 and apparent natural substrate for alkaline phosphatase (ALP), in carriers and in non-carriers of the severe perinatal and infantile forms of hypophosphatasia, both before and after an oral load of pyridoxine (i.e. 1/3 mg/kg body weight). The assignment of carrier status was determined by serum ALP activity, level of serum inorganic phosphate, and if necessary urinary phosphoethanolamine excretion. Plasma PLP levels were significantly increased in the carriers both before and especially after B6 loading.

Congenital hypophosphatasia is an autosomal recessive disorder, which usually has a fatal outcome during the neonatal period. This report presents the prenatal diagnosis of hypophosphatasia at 16 weeks of gestation. The characteristic ultrasonic findings in this abnormality demonstrate the superiority of ultrasound as compared with radiography.