Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey.

Background: Adenine phosphoribosyltransferase deficiency is an inborn error of metabolism that can cause kidney disease from crystalline nephropathy or kidney stones.

Methods: We present three cases from a single centre with varied presentations to illustrate how increasing awareness led to better patient identification. We then undertook a cross-sectional survey of all the patients identified from the Purine Research Laboratory in the UK since 1974.

The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic.

Background: Thioguanine nucleotides (TGNs) are the active product of thiopurine metabolism. Levels have been correlated with effective clinical response. Nonetheless, the value of TGN monitoring in clinical practice is debated.

HPRT deficiency: identification of twenty-four novel variants including an unusual deep intronic mutation.

Hypoxanthine phosphoribosyltranferase (HPRT) deficiency is an X-linked disorder of purine salvage that ranges phenotypically from hyperuricaemia to Lesch-Nyhan Syndrome. Molecular testing is necessary to identify female carriers within families as a prelude to prenatal diagnosis. During the period 1999-2010 the Purine Research Laboratory studied 106 patients from 68 different families.

Purine nucleoside phosphorylase deficiency: a mutation update.

Purine nucleoside phosphorylase (PNPase) deficiency is an autosomal recessive disorder affecting purine degradation and salvage pathways. Clinically, patients typically present with severe immunodeficiency, neurological dysfunction, and autoimmunity. Biochemically, PNPase deficiency may be suspected in the presence of hypouricemia.

An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency.

Molybdenum cofactor deficiency (MOCOD) is a rare inherited metabolic disorder resulting in the combined deficiency of aldehyde oxidase (AO, EC 1.2.3.

The genetic basis of the interaction between pyrimidine 5' nucleotidase I deficiency and hemoglobin E.

We have previously described a family in which the interaction between pyrimidine 5' nucleotidase I (P5N-I) deficiency and hemoglobin E resulted in severe haemolytic anaemia. In this study we explored the genetic basis of the severe clinical phenotype and look for evidence of the interaction between these conditions. A P5N-I gene mutation (IVS8 + 1-2delGT) was found in the family, confirming that the severe phenotype results from the interaction between two genetic diseases.

Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase).

Adverse drug reactions to azathioprine (AZA), the pro-drug of 6-mercaptopurine (6-MP), occur in 15% to 28% of patients and the majority are not explained by thiopurine methyltransferase (TPMT) deficiency. Inosine triphosphate pyrophosphatase (ITPase) deficiency results in the benign accumulation of the inosine nucleotide ITP. 6-MP is activated through a 6-thio-IMP intermediate and, in ITPase deficient patients, potentially toxic 6-thio-ITP is predicted to accumulate.

Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians.

Objective: Polymorphisms in the TPMT gene open reading frame (ORF) are associated with reduced TPMT activity. Variable number tandem repeats (VNTR*3 to VNTR*9) in the promoter region of the gene consisting of combinations of Type A, B and C repeat units, may modulate TPMT activity. Here we present the allele frequencies of genetic modifiers of TPMT activity in a British Asian population, as well as the concordance between intermediate TPMT activity and ORF and VNTR genotypes in a predominantly Caucasian population.

Genetic basis of hemolytic anemia caused by pyrimidine 5' nucleotidase deficiency.

Pyrimidine 5' nucleotidase (P5'N-1) deficiency is an autosomal recessive condition causing hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. It is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Recently, a protein with P5'N-1 activity was analyzed and a provisional complementary DNA (cDNA) sequence published.