pyrophosphate and Metabolic-Diseases

Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.

Topics: Animals; Choroidal Neovascularization; Diphosphates; Humans; Metabolic Diseases; Peripheral Arterial Disease; Pseudoxanthoma Elasticum; Skin

Topics: Androgens; Bone Diseases; Diphosphates; Estrogens; Fluorides; Heparin; Humans; Hyperparathyroidism; Metabolic Diseases; Organophosphonates; Osteitis Deformans; Osteomalacia; Osteoporosis; Parathyroid Hormone; Phosphates; Plicamycin

Topics: Adrenal Cortex Hormones; Aged; Aging; Bone and Bones; Bone Diseases; Bone Resorption; Calcium; Diphosphates; Female; Humans; Hyperparathyroidism; Hypoparathyroidism; Menopause; Metabolic Diseases; Osteogenesis; Osteomalacia; Osteoporosis; Space Flight

Several underlying metabolic abnormalities may be present in patients with recurrent calcium calculus disease (RCCD). The aim of this study was to determine the prevalence of deficiencies of 2 well-known potent inhibitors of crystal formation and growth, citrate and pyrophosphate, in the various metabolic subgroups and as single defects. In 107 patients with RCCD, urinary citrate was significantly decreased in all metabolic subgroups with 49% of patients having hypocitraturia (2.53 +/- 1.19 mmol/24 h) versus controls (3.44 +/- 0.96 mmol/24 h; p less than 0.001). Reduced pyrophosphate:creatinine ratios were present in all the patient subgroups, and 48% of all patients had reduced ratios (1.68 +/- 1.68 vs. 3.10 +/- 2.66 in controls; p less than 0.01). There was no correlation between citrate and pyrophosphate concentration. Isolated hypocitraturia was found in 11.2%, reduced pyrophosphate:creatinine ratios as the single defect in 11.2% and a combination of both in 12.1% of patients. Thus inhibitor defects play an important role in patients with RCCD and frequently occur as isolated biochemical defects.

Topics: Adolescent; Adult; Aged; Calcium; Citrates; Citric Acid; Diphosphates; Female; Humans; Kidney Calculi; Male; Metabolic Diseases; Middle Aged; Prevalence; Recurrence; Urine

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATP-binding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6(-/-) mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver. Why absence of this factor results in PXE has remained a mystery. Here we report that medium from HEK293 cells overexpressing either human or rat ABCC6 potently inhibits mineralization in vitro, whereas medium from HEK293 control cells does not. Untargeted metabolomics revealed that cells expressing ABCC6 excrete large amounts of nucleoside triphosphates, even though ABCC6 itself does not transport nucleoside triphosphates. Extracellularly, ectonucleotidases hydrolyze the excreted nucleoside triphosphates to nucleoside monophosphates and inorganic pyrophosphate (PPi), a strong inhibitor of mineralization that plays a pivotal role in several mineralization disorders similar to PXE. The in vivo relevance of our data are demonstrated in Abcc6(-/-) mice, which had plasma PPi levels <40% of those found in WT mice. This study provides insight into how ABCC6 affects PXE. Our data indicate that the factor that normally prevents PXE is PPi, which is provided to the circulation in the form of nucleoside triphosphates via an as-yet unidentified but ABCC6-dependent mechanism.

Topics: Animals; Dinucleoside Phosphates; Diphosphates; DNA Primers; DNA, Complementary; HEK293 Cells; Humans; Metabolic Diseases; Metabolomics; Mice; Mice, Knockout; Multidrug Resistance-Associated Proteins; Mutagenesis, Site-Directed; Mutation; Pseudoxanthoma Elasticum; Rats

Inorganic pyrophosphate (PPi) levels were estimated by radiometric assay in urine and in synovial fluid (SF) from asymptomatic, nonarthritic knees of patients with untreated metabolic disease and normal controls. SF PPi was significantly elevated in patients with hyperparathyroidism (mean +/- SEM 19 +/- 3 microM; n = 9), hemochromatosis (23 +/- 5 microM; n = 6), and hypomagnesemia (27 +/- 0.1 microM; n = 2) compared with normal subjects (10 +/- 0.5 microM, n = 50), and was low in patients with hypothyroidism (4.2 +/- 2.3 microM; n = 11) (P less than 0.05 all comparisons). Urinary PPi was elevated only in those with hypophosphatasia. Local elevation of ionic PPi may be relevant to the mechanism of crystal formation in metabolic diseases predisposing to calcium pyrophosphate dihydrate (CPPD) crystal deposition. The finding of low SF PPi levels in patients with hypothyroidism further questions the association between this condition and CPPD.

Topics: Adult; Aged; Aged, 80 and over; Calcium Pyrophosphate; Creatinine; Crystallization; Diphosphates; Endocrine System Diseases; Female; Hemochromatosis; Humans; Hyperparathyroidism; Hypophosphatasia; Hypothyroidism; Magnesium Deficiency; Male; Metabolic Diseases; Middle Aged; Synovial Fluid

A 61-year-old man had a tophus on the third finger of his right hand. There was no history of arthritis, no laboratory abnormality, and no chondrocalcinosis. Crystalline material from the tophus was identified as calcium pyrophosphate dihydrate by x-ray diffraction.

Topics: Calcium Pyrophosphate; Chondrocalcinosis; Diphosphates; Fingers; Humans; Male; Metabolic Diseases; Middle Aged; X-Ray Diffraction

The pseudogout syndrome is usually associated with radiographic evidence of articular cartilage calcification. Eight patients who had joints containing calcium pyrophosphate dihydrate crystals were studied. Extensive radiographic evaluation was obtained in seven patients and a limited evaluation in the other. None had evidence of chondrocalcinosis. Six had distinctive radiographic abnormalities of the wrists consisting of radiocarpal joint space narrowing and sclerosis, and subchondral cystic degeneration of the carpal bones. We conclude that calcium pyrophosphate dihydrate deposition disease and pseudogout can occur without radiographic evidence of chondrocalcinosis and that the diagnosis can be suggested by characteristic radiographic abnormalities of the wrists.

Topics: Adult; Aged; Calcium Phosphates; Chondrocalcinosis; Diphosphates; Humans; Joint Diseases; Male; Metabolic Diseases; Middle Aged; Radiography; Wrist Joint

Type I hyperoxaluria results from reduced activity of alpha-ketoglutarate: glyoxylate carboligase, which is necessary for the synergistic decarboxylation of glyoxylate and alpha-ketoglutarate to alpha-hydroxy-beta-keto-adipate. Since thiamine pyrophosphate is a cofactor in the reaction, thiamine deficiency might be expected to result in tissue oxalosis. However, there was no significant increase in the incidence of renal oxalosis in 15 patients with Wernicke's encephalopathy at necropsy compared with controls. It is possible that hyperoxaluria was present in these thiamine-deficient patients but at a urine concentration below that necessary for calcium oxalate deposition. It is also possible that the severity of the thiamine deficit required for hyperoxaluria exceeds that for the neuronal and cardiac manifestations.

Topics: Acute Kidney Injury; Adipates; Adult; Carboxy-Lyases; Diphosphates; Glyoxylates; Humans; Ketoglutaric Acids; Kidney Diseases; Metabolic Diseases; Middle Aged; Oxalates; Thiamine; Thiamine Deficiency; Wernicke Encephalopathy