Pyridoxine challenge reflects pediatric hypophosphatasia severity and thereby examines tissue-nonspecific alkaline phosphatase's role in vitamin B metabolism.

Alkaline phosphatase (ALP) is detected in most human tissues. However, ALP activity is routinely assayed using high concentrations of artificial colorimetric substrates in phosphate-free laboratory buffers at lethal pH. Hypophosphatasia (HPP) is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of the ALPL gene that encodes the ALP isoenzyme expressed in bone, liver, kidney, and elsewhere and is therefore designated "tissue-nonspecific" ALP (TNSALP).

Hypophosphatasia: Vitamin B status of affected children and adults.

Hypophosphatasia (HPP) is the heritable dento-osseous disease caused by loss-of-function mutation(s) of the gene ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphomonoester phosphohydrolase expressed in healthy people especially in the skeleton, liver, kidneys, and developing teeth. In HPP, diminished TNSALP activity leads to extracellular accumulation of its natural substrates including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B (B).

Vitamin B deficiency with normal plasma levels of pyridoxal 5'-phosphate in perinatal hypophosphatasia.

Pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B (B), is elevated in the plasma of individuals with hypophosphatasia (HPP). HPP is the inborn-error-of-metabolism caused by loss-of-function mutation(s) of ALPL, the gene that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). PLP accumulates extracellularly in HPP because it is a natural substrate of this cell-surface phosphomonoester phosphohydrolase.

Hypophosphatasia: Biochemical hallmarks validate the expanded pediatric clinical nosology.

Hypophosphatasia (HPP) is the inborn-error-of-metabolism due to loss-of-function mutation(s) of the ALPL (TNSALP) gene that encodes the tissue non-specific isoenzyme of alkaline phosphatase (TNSALP). TNSALP represents a family of cell-surface phosphohydrolases differing by post-translational modification that is expressed especially in the skeleton, liver, kidney, and developing teeth. Thus, the natural substrates of TNSALP accumulate extracellularly in HPP including inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B.

Vitamin B-6 Metabolism and Interactions with TNAP.

Two observations stimulated the interest in vitamin B-6 and alkaline phosphatase in brain: the marked increase in plasma pyridoxal phosphate and the occurrence of pyridoxine responsive seizures in hypophosphatasia. The increase in plasma pyridoxal phosphate indicates the importance of tissue non-specific alkaline phosphatase (TNAP) in transferring vitamin B-6 into the tissues. Vitamin B-6 is involved in the biosynthesis of most of the neurotransmitters.

Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients.

Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations.

"Atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia.

We report a 55-year-old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for "osteoporosis." Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began.

Hypophosphatasia: nonlethal disease despite skeletal presentation in utero (17 new cases and literature review).

Hypophosphatasia (HPP) is caused by deactivating mutation(s) within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Patients manifest rickets or osteomalacia and dental disease ranging from absence of skeletal mineralization in utero to only loss of adult dentition. Until recently, HPP skeletal disease in utero was thought to always predict a lethal outcome.

Enhancement of calcium/vitamin d supplement efficacy by administering concomitantly three key nutrients essential to bone collagen matrix for the treatment of osteopenia in middle-aged women: a one-year follow-up.

Two vitamins and proline (CB(6)Pro), three nutrients essential for bone collagen, were used in combination to a 1000 mg calcium/250 IU vitamin D (Ca/D) daily supplement to treat osteopenia as a preventive measure against osteoporosis later in life. Middle-aged women not using estrogen were screened for osteopenia using the WHO criteria and divided into three groups (n = 20 each): 1) placebo healthy controls with normal bone mineral density (BMD); 2) control Ca/D-treated osteopenic patients; and 3) Ca/D + CB(6)Pro-treated osteopenic patients. The three groups were comparable at baseline except for BMD.

Chronic recurrent multifocal osteomyelitis mimicked in childhood hypophosphatasia.

Hypophosphatasia (HPP) is the inborn error of metabolism characterized by low serum alkaline phosphatase (ALP) activity caused by inactivating mutations within TNSALP, the gene that encodes the "tissue-nonspecific" isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate, a TNSALP substrate, inhibits hydroxyapatite crystal growth leading to rickets or osteomalacia. Chronic recurrent multifocal osteomyelitis (CRMO) is the pediatric syndrome of periarticular pain and radiographic changes resembling infectious osteomyelitis but without lesional pathogens.

Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement.

Context: Hypophosphatasia (HPP) is a heritable metabolic disorder of the skeleton that includes variable expressivity conditioned by gene dosage effect and the variety of mutations in the tissue nonspecific alkaline phosphatase (TNSALP) gene. Patient age when skeletal problems first manifest generally predicts the clinical course, with perinatal HPP causing bone disease in utero with postnatal lethality.

Objective: Our objective was to identify TNSALP mutations and characterize the inheritance pattern of a family with clinically variable HPP with one child manifesting in utero with long bone deformity but showing spontaneous prenatal and postnatal improvement.

N-methylpyridoxamine: novel canine vitamin B6 urine metabolite.

Cation-exchange HPLC analysis of urine from dogs given large daily doses of pyridoxamine revealed an unidentified metabolite hypothesized to be N-methylpyridoxamine. Identity was established by N-methylpyridoxamine synthesis and HPLC comparison to the canine metabolite. Compound synthesis was confirmed by IR, NMR, UV-vis and emission spectroscopy.

Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts.

Background: Hypophosphatasia (HPP) is a rare, heritable, metabolic bone disease due to deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. The infantile form features severe rickets often causing death in the first year of life from respiratory complications. There is no established medical treatment.

Use of chlorite to improve HPLC detection of pyridoxal 5'-phosphate.

The sensitivity of fluorescent detection of the biologically active form of Vitamin B-6, pyridoxal 5'-phosphate (PLP), in biological samples has been improved approximately four-fold by adopting chlorite as a post-column derivatization reagent (instead of bisulfite) in high-performance liquid chromatography (HPLC) separation. Chlorite oxidizes PLP to the more fluorescent 4-pyridoxic acid 5'-phosphate, and avoids the toxicity and heating of the cyanide procedure. Detection of another major metabolite, 4-pyridoxic acid (4-PA), is not effected.

Roscovitine targets, protein kinases and pyridoxal kinase.

(R)-Roscovitine (CYC202) is often referred to as a "selective inhibitor of cyclin-dependent kinases." Besides its use as a biological tool in cell cycle, neuronal functions, and apoptosis studies, it is currently evaluated as a potential drug to treat cancers, neurodegenerative diseases, viral infections, and glomerulonephritis. We have investigated the selectivity of (R)-roscovitine using three different methods: 1) testing on a wide panel of purified kinases that, along with previously published data, now reaches 151 kinases; 2) identifying roscovitine-binding proteins from various tissue and cell types following their affinity chromatography purification on immobilized roscovitine; 3) investigating the effects of roscovitine on cells deprived of one of its targets, CDK2.

Marrow cell transplantation for infantile hypophosphatasia.

An 8-month-old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T-cell-depleted, haplo-identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor.

Cutaneous metabolism of vitamin B-6.

Vitamin B-6 is important for skin development and maintenance. We examined vitamin B-6 metabolism in human and mouse skin collected at different phases of the hair cycle; in hamster melanomas; in normal and immortalized human keratinocytes (HaCaT) and several human melanoma cell lines. Pyridoxamine 5'-phosphate content was higher in mouse and hamster than in human skin.

Vitamin B6 status of children with sickle cell disease.

Purpose: In vitro, vitamin B(6) has antisickling properties, but the effect of vitamin B status on the health of children with sickle cell disease-SS (SCD-SS) is not well described. The purpose of this study was to assess vitamin B(6) status of children with SCD-SS ages 3 to 20 years and determine its relationship to growth, dietary intake, and disease severity.

Patients And Methods: Vitamin B(6) status was assessed by serum pyridoxal 5-phosphate (PLP) concentration in subjects with SCD-SS and by urinary 4-pyridoxic acid (4-PA) concentration in other subjects with SCD-SS and healthy control children.

Vitamin B6 metabolism and homocysteine in end-stage renal disease and chronic renal insufficiency.

Homocysteine (tHcy) is a risk factor for atherosclerosis in patients with end-stage renal disease and chronic renal insufficiency (CRI). Vitamin B6 deficiency may result in high tHcy levels, especially after a methionine load (PML). Therefore, we evaluated vitamin B6 metabolism and tHcy (fasting and PML) levels in patients with CRI and those on hemodialysis (HD) therapy before and during high-dose sequential vitamin B6 and folic acid supplementation in male patients (27 patients, HD, 17 patients, CRI) and 19 age-matched healthy controls.

Elevated plasma 4-pyridoxic acid in renal insufficiency.

Background: Renal insufficiency is associated with altered vitamin B-6 metabolism. We have observed high concentrations of 4-pyridoxic acid, the major catabolite of vitamin B-6 metabolism, in plasma during renal insufficiency.

Objective: The objective was to evaluate the renal handling of 4-pyridoxic acid and the effects of renal dysfunction on vitamin B-6 metabolism.