pyrophosphate and Syndrome

Pathologic soft tissue calcification can occur in both genetic and acquired clinical conditions, causing significant morbidity and mortality. Although the pathomechanisms of pathologic calcification are poorly understood, major progress has been made in recent years in defining the underlying genetic defects in Mendelian disorders of ectopic calcification. This review presents an overview of the pathophysiology of five monogenic disorders of pathologic calcification: pseudoxanthoma elasticum, generalized arterial calcification of infancy, arterial calcification due to deficiency of CD73, ankylosis, and progeria. These hereditary disorders, caused by mutations in genes encoding ATP binding cassette subfamily C member 6, ectonucleotide pyrophosphatase/phosphodiesterase 1, CD73, progressive ankylosis protein, and lamin A/C proteins, respectively, are inorganic pyrophosphate (PPi) deficiency syndromes with reduced circulating levels of PPi, the principal physiologic inhibitor of calcium hydroxyapatite deposition in soft connective tissues. In addition to genetic diseases, PPi deficiency has been encountered in acquired clinical conditions accompanied by pathologic calcification. Because specific and effective treatments are lacking for pathologic calcification, the unifying finding of PPi deficiency suggests that PPi-targeted therapies may be beneficial to counteract pathologic soft tissue calcification in both genetic and acquired diseases.

Topics: Ankylosis; Calcinosis; Choristoma; Diphosphates; Humans; Pseudoxanthoma Elasticum; Syndrome; Vascular Calcification

Varying combinations of acute inflammatory and/or chronic degenerative arthritis have been found to be associated with crystals of calcium pyrophosphate dihydrate (CPPD) and/or basic calcium phosphates (BCPs). Since the arthropathies associated with CPPDs and/or BCPs occur in older individuals, while diagnosis and treatment for monosodium urate monohydrate crystal deposition disease (gout) have become extremely precise and effective, joint problems associated with calcium crystals have become more common than those associated with monosodium urate monohydrate crystals. The classification, pathogenesis, clinical manifestations, and treatment of CPPD and BCP crystal deposition are discussed.

Topics: Aged; Anti-Inflammatory Agents; Arthritis; Calcium Phosphates; Calcium Pyrophosphate; Colchicine; Crystallization; Diphosphates; Female; Humans; Hyperplasia; Inflammation; Joint Diseases; Methods; Peptide Hydrolases; Radiography; Shoulder Joint; Syndrome; Synovial Membrane

Pyrophosphatases (PPases) catalyze the hydrolysis of inorganic pyrophosphate generated in several cellular enzymatic reactions. A novel human pyrophosphatase cDNA encoding a 334-amino-acid protein approximately 60% identical to the previously identified human cytosolic PPase was cloned and characterized. The novel enzyme, named PPase-2, was enzymatically active and catalyzed hydrolysis of pyrophosphate at a rate similar to that of the previously identified PPase-1. A functional mitochondrial import signal sequence was identified in the N-terminus of PPase-2, which targeted the enzyme to the mitochondrial matrix. The human pyrophosphatase 2 gene (PPase-2) was mapped to chromosome 4q25 and the 1.4-kb mRNA was ubiquitously expressed in human tissues, with highest levels in muscle, liver, and kidney. The yeast homologue of the mitochondrial PPase-2 is required for mitochondrial DNA maintenance and yeast cells lacking the enzyme exhibit mitochondrial DNA depletion. We sequenced the PPA2 gene in 13 patients with mitochondrial DNA depletion syndromes (MDS) of unknown cause to determine if mutations in the PPA2 gene of these patients were associated with this disease. No pathogenic mutations were identified in the PPA2 gene of these patients and we found no evidence that PPA2 gene mutations are a common cause of MDS in humans.

Topics: Amino Acid Sequence; Blotting, Northern; Calcium Chloride; Cell Line, Tumor; Chromosome Mapping; Chromosomes, Human, Pair 4; Cloning, Molecular; Diphosphates; DNA, Complementary; Female; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins; HeLa Cells; Humans; Hydrolysis; Inorganic Pyrophosphatase; Isoenzymes; Mitochondrial Myopathies; Mitochondrial Proteins; Molecular Sequence Data; Protein Sorting Signals; Pyrophosphatases; Recombinant Fusion Proteins; RNA, Messenger; RNA, Small Interfering; Sequence Alignment; Sequence Analysis, DNA; Sequence Homology, Amino Acid; Syndrome; Transfection

Synovial fluid (SF) inorganic pyrophosphate (PPi) concentration is elevated in calcium pyrophosphate dihydrate (CPPD) crystal deposition arthropathy. Since CPPD and basic calcium phosphate (BCP) crystals often are present in the same joints, we determined [PPi] and activity of the PPi-generating enzyme, nucleotide pyrophosphohydrolase (NPPH), in SF from the joints of patients with various arthropathies, including those with BCP crystals. We found elevated SF [PPi] in joints with BCP crystals, as well as in joints with CPPD crystals. The presence of BCP crystals in synovial fluids was also predictive of elevated NPPH activity.

Topics: Calcium Phosphates; Crystallization; Diphosphates; Humans; Joint Diseases; Osmolar Concentration; Osteoarthritis; Preservation, Biological; Pyrophosphatases; Shoulder Joint; Syndrome; Synovial Fluid

The thesis of primariness of the disease and of its osseous tissue manifestations is discussed on the grounds of the results from a complex study on 3 patients. The periosteal ossifying hyperplasia and disturbances in the osseous tissue structure develop with no other organ symptomatics and in the absence of any changes in the available laboratory and immunological indices. The macromorphological X-ray characteristic corresponds to the radionuclide tests of the study with 99MTc-pertechnetate, 99MTc-pyrophosphate and 99MTc-sulfocolloid, informing about abnormal vascularization index, growth of bone-marrow tissue and intensified joint-tissue anabolism.

Topics: Adult; Arthrography; Diphosphates; Humans; Joints; Middle Aged; Osteoarthropathy, Primary Hypertrophic; Radionuclide Imaging; Sodium Pertechnetate Tc 99m; Syndrome; Technetium; Technetium Tc 99m Pyrophosphate; Technetium Tc 99m Sulfur Colloid

Topics: Adult; Bone and Bones; Diphosphates; Humans; Male; Osteoarthropathy, Primary Hypertrophic; Radionuclide Imaging; Skin Diseases; Syndrome; Technetium; Technetium Tc 99m Pyrophosphate

Topics: Calcium Pyrophosphate; Chondrocalcinosis; Diagnosis, Differential; Diphosphates; Humans; Radiography; Syndrome

Topics: Adult; Arthritis; Arthroplasty; Calcium Phosphates; Chondrocalcinosis; Chronic Disease; Diphosphates; Female; Humans; Knee; Middle Aged; Radiography; Syndrome; Synovial Fluid

Topics: Acute Disease; Age Factors; Aged; Calcium; Chondrocalcinosis; Diagnosis, Differential; Diphosphates; Female; Hospitals; Humans; Knee Joint; Male; Middle Aged; Postoperative Care; Postoperative Complications; Sex Factors; Syndrome; Synovitis