inosinic-acid and Purine-Pyrimidine-Metabolism--Inborn-Errors

Purines are essential molecules that are components of vital biomolecules, such as nucleic acids, coenzymes, signaling molecules, as well as energy transfer molecules. The de novo biosynthesis pathway starts from phosphoribosylpyrophosphate (PRPP) and eventually leads to the synthesis of inosine monophosphate (IMP) by means of 10 sequential steps catalyzed by six different enzymes, three of which are bi-or tri-functional in nature. IMP is then converted into guanosine monophosphate (GMP) or adenosine monophosphate (AMP), which are further phosphorylated into nucleoside di- or tri-phosphates, such as GDP, GTP, ADP and ATP. This review provides an overview of inborn errors of metabolism pertaining to purine synthesis in humans, including either phosphoribosylpyrophosphate synthetase (PRS) overactivity or deficiency, as well as adenylosuccinate lyase (ADSL), 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), and adenylosuccinate synthetase (ADSS) deficiencies. ITPase deficiency is being described as well. The clinical spectrum of these disorders is broad, including neurological impairment, such as psychomotor retardation, epilepsy, hypotonia, or microcephaly; sensory involvement, such as deafness and visual disturbances; multiple malformations, as well as muscle presentations or consequences of hyperuricemia, such as gouty arthritis or kidney stones. Clinical signs are often nonspecific and, thus, overlooked. It is to be hoped that this is likely to be gradually overcome by using sensitive biochemical investigations and next-generation sequencing technologies.

Topics: Adenylosuccinate Lyase; Autistic Disorder; Humans; Inosine Monophosphate; Purine-Pyrimidine Metabolism, Inborn Errors; Purines

Topics: Amidophosphoribosyltransferase; Chemical Phenomena; Chemistry; Glucosephosphate Dehydrogenase Deficiency; Glutathione Reductase; Gout; Humans; Inosine Monophosphate; Lesch-Nyhan Syndrome; Phosphoribosyl Pyrophosphate; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Uric Acid; Xanthine Oxidase; Xanthines; Xeroderma Pigmentosum

We report a 20-year-old man with gigantism syndrome, hypertrophic cardiomyopathy, muscle weakness, exercise intolerance, and severe psychomotor retardation since childhood. Histochemical and biochemical analysis of skeletal muscle biopsy revealed myoadenylate deaminase deficiency; molecular genetic analysis confirmed the diagnosis of primary (inherited) myoadenylate deaminase deficiency. Plasma, urine, and muscle carnitine concentrations were reduced. L-Carnitine treatment led to gradual improvement in exercise tolerance and cognitive performance; plasma and tissue carnitine levels returned to normal, and echocardiographic evidence of left ventricular hypertrophy disappeared. The combination of inherited myoadenylate deaminase deficiency, gigantism syndrome and carnitine deficiency has not previously been described.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; AMP Deaminase; Biopsy; Cardiomyopathy, Hypertrophic; Carnitine; Diagnosis, Differential; Gigantism; Humans; Inosine Monophosphate; Male; Muscle, Skeletal; Phenotype; Purine-Pyrimidine Metabolism, Inborn Errors

The specific activities of the three enzymes of the inosinate branchpoint are independently regulated when lymphoblasts are grown under various tissue culture conditions. In comparison to rapidly dividing cells, lymphoblasts at high cell density with no cellular division have decreased activity of the enzymes which commit inosinate to adenylate or guanylate, while cytoplasmic 5'-nucleotidase is relatively preserved. A linear relationship between inosinate dehydrogenase activity and growth rate (r = 0.92) exists in lymphoblasts with slowed growth rates. In contrast, in dividing cells adenylosuccinate synthetase and 5'-nucleotidase do not vary with growth rate. Adenylosuccinate synthetase and inosinate dehydrogenase activities appear to be related to the presence or rate of cellular division, as opposed to the presence or degree of neoplastic transformation. Lymphoblast lines with alterations of specific purine metabolic enzymes have characteristic alteration of the inosinate utilizing enzymes. Deficiencies of purine nucleoside phosphorylase or hypoxanthine phosphoribosyltransferase, abnormalities which render the cell unable to salvage purine effectively, are associated with depressed inosinate dehydrogenase activity. Insertion of the hypoxanthine phosphoribosyltransferase gene into hypoxanthine phosphoribosyltransferase-deficient cells normalizes inosinate dehydrogenase activity, while a hypoxanthine phosphoribosyltransferase-deficient mutant selected from a hypoxanthine phosphoribosyltransferase-containing line has depressed inosinate dehydrogenase activity. In contrast, overactivity of phosphoribosylpyrophosphate synthetase, with enhanced excretion of purines due to excessive production, is associated with elevated inosinate dehydrogenase activity. Inosinate dehydrogenase appears to be regulated according to the availability of purine nucleotides. Patients who overproduce uric acid and potentially have undescribed purine metabolic defects are now being screened for abnormalities in the inosinate branchpoint enzymes.

Topics: 5'-Nucleotidase; Adenylosuccinate Synthase; Cell Count; Cell Division; Cell Line; Humans; IMP Dehydrogenase; Inosine Monophosphate; Inosine Nucleotides; Lymphocytes; Mutation; Nucleotidases; Purine-Pyrimidine Metabolism, Inborn Errors

Clinical and enzymatic studies on two brothers with severe deficiencies of erythrocyte hypoxanthineguanine phosphoribosyltransferase (HGPRTase) are described, and are compared with similar studies of a classical case of the Lesch-Nyhan syndrome from another family. The two brothers have no neurological abnormalities, only traces of erythrocyte HGPRTase, erythrocyte adenine phosphoribosyltransferase activities approaching the high levels found in the Lesch-Nyhan patient, and similarly raised plasma and urinary concentrations of uric acid. Despite these strong biochemical similarities between the three patients, there were wide differences in the clinical case histories. In both families the enzyme deficiency appeared to be inherited as an X-linked character through asymptomatic carrier females. The relationship of HGPRTase deficiencies to the Lesch-Nyhan syndrome is discussed. Some observations relating to techniques are reported. Cellulose acetate has been found to give much better separations of labelled reaction products in low-level phosphoribosyltransferase assays than filter paper, when used as a supporting medium for electrophoresis. The analysis of hair follicles gives indications of individuals heterozygous for the enzyme deficiency, but the proportion of enzyme-deficient follicles was very small, and the test needs support from studies of other cell types. Using haemolysates, there were signs of a slow indirect conversion of hypoxanthine to inosinic acid, via inosine. Inosine appears to be labelled by a ribosyl-transfer reaction.

Topics: Adenine Phosphoribosyltransferase; Adolescent; Child; Child, Preschool; Diagnosis, Differential; Electrophoresis, Cellulose Acetate; Erythrocytes; Genetic Linkage; Hair; Heterozygote; Humans; Hypoxanthine Phosphoribosyltransferase; Hypoxanthines; Inosine Monophosphate; Lesch-Nyhan Syndrome; Male; Pedigree; Purine-Pyrimidine Metabolism, Inborn Errors; Sex Chromosomes; Uric Acid