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R W Watts

Publications and source records attributed to R W Watts.

At least 19 recordsLinked to original sources
PubMed1992

Alanine glyoxylate aminotransferase deficiency: biochemical and molecular genetic lessons from the study of a human disease.

The decision to treat a patient with primary hyperoxaluria type 1 (PHI) by combined liver and kidney transplantation, the former to correct the metabolic lesion which was then thought to be deficiency of cytoplasmic 2-oxoglutarate:glyoxylate carboligase, and the latter to replace the organ which is destroyed, provided an opportunity to investigate the disease by modern biochemical methods. It was shown that 2-oxoglutarate:glyoxylate carboligase (the first decarboxylating component of 2-oxoglutarate dehydrogenase) is entirely mitochondrial so that deficiency of a cytoplasmic form of this enzyme could not be the cause of PHI. The deficient enzyme proved to be hepatic peroxisomal alanine:glyoxylate aminotransferase (AGT). The disease can be diagnosed enzymologically on percutaneous liver biopsies and this is possible for the fetus in utero. There are four types of genetically determined heterogeneity in PHI:(1) responsiveness and non-responsiveness to pharmacological doses of pyridoxine, in terms of an effect on the rate of oxalate production; (2) the presence or absence of residual catalytic AGT activity; (3) CRM+ and CRM-variants; (4) locational variation by virtue of which the enzyme (AGT) is mitochondrial and not peroxisomal. About one third of patients with PHI have residual AGT activity and at least a large proportion of these have mitochondrial and not peroxisomal AGT. The molecular features which guide peroxisomal and mitochondrial enzymes from their sites of synthesis into the appropriate organelle are reviewed and the possibilities for genetic variation in the relevant parts of the AGT molecule are discussed. The gene directing the synthesis of AGT has been cloned and sequenced, as has the AGT cDNA from a patient with mitochondrial AGT. Three point mutations causing amino acid substitution in the predicted AGT protein sequence have been identified: proline----leucine at residue 11, glycine----arginine at residue 170 and isoleucine----methionine at residue 340. The present evidence based on screening PHI patients and control subjects suggest that the substitution at residue 11, which cosegregates with that at residue 340, generates an amphiphilic alpha-helix which resembles mitochondrial targeting sequences but that misrouting of all the newly synthesized AGT into mitochondria requires the substitution at residue 170 which may act by impeding the entry of the enzyme into peroxisomes. The recognition of enzyme locational heterogeneity in PHI due to mutations affecting leader sequences should encourage a search for similar metabolic lesions in other inborn errors of metabolism affecting peroxisomal and/or mitochondrial enzymes.

Alanine Transaminase↗
PubMed1992

Obstetric epidural services in rural South Australia.

A survey of sixty South Australian country hospitals found that 35 units had more than 25 deliveries per year (total deliveries 4,247, which is 21.5% of total live births in South Australia during 1989). Twenty-five of these units had an epidural service (71%) and the overall epidural rate was 16.7%, 9.5% provided by general practitioner anaesthetists and 7.2% by specialists. General practitioner anaesthetists were involved more in the medium-sized units (50-200 deliveries per year), whereas specialists provided more services in the larger regional units and the small units as visitors. The epidural rate varied between 6-20% depending on the size of the unit. Most country regions in South Australia have reasonable access to an epidural service. The more geographically isolated areas are being serviced by general practitioner anaesthetists.

Analgesia, Epidural↗
PubMed1992

A five-year prospective analysis of the efficacy, safety and morbidity of epidural anaesthesia performed by a general practitioner anaesthetist in an isolated rural hospital.

During a five-year period, 324 epidurals were performed by a general practitioner anaesthetist in an isolated rural hospital. Of these 160 were for obstetric purposes, 72% in primagravida patients, the majority in early and established labour (median cervical dilatation of 3.0 cm). The median epidural insertion time was seven minutes: 80% were free of all complications, there were no dural taps and there was a failure rate of 2%. The median visual analogue pain score (VAPS) was 8.3 prior to insertion and at peak of epidural blockade it was reduced to 0.5. Ten per cent of patients had unblocked segments, half of these were corrected and 90% of patients had even blocks. Despite higher pain scores in the 6-10 cm cervical dilatation group, epidural analgesia was just as effective when compared to the 0.5 cm group. Seventy-seven percent of women interviewed the day after delivery were fully satisfied with the epidural: 19% said it was considerable help, 2% some help and 2% said no help at all. During epidural caesarean section (n = 72), 75% of patients were comfortable, 17% had some discomfort and 7% required general or spinal anaesthesia. The incidence of hypotension (systolic blood pressure less than 90 mmHg), was 24.6% with a median ephedrine dose of 10 mg; however, with a greater than 20% drop in systolic blood pressure, the dose of ephedrine required to maintain blood pressure increased in a log-dose fashion. For women who received epidurals in labour, the caesarean section rate was 25%, instrumental vaginal delivery 34% and spontaneous vaginal delivery 41%. There were no adverse neonatal outcomes.

Anesthesia Department, Hospital↗
PubMed1991

Low arylsulphatase A activity and choreoathetotic syndrome in three siblings: differentiation of pseudodeficiency from metachromatic leukodystrophy.

We report on a family with a sibship of three children for whom the diagnosis of "an unusual form of metachromatic leukodystrophy (MLD)" had been suggested earlier. The patients had choreiform movements and dystonic posturing accompanied by dysarthria since childhood. The availability of the polymerase chain reaction enabled us to show that the three siblings have a pseudodeficiency genotype (ASAp/ASAp). There was no abnormal sulphatiduria, and we propose that the neurological disease and low arylsulphatase A activity are unrelated to one another in this family. A diagnosis of MLD carries very serious implications, and we recommend that gene amplification by polymerase chain reaction and hybridization with allele-specific oligonucleotide probes should be used to corroborate the diagnosis, especially when there is no abnormal sulphatiduria and when metachromatic material cannot be demonstrated in a sural nerve biopsy.

Adolescent↗
PubMed1991

Combined liver-kidney and isolated liver transplantations for primary hyperoxaluria type 1: the European experience. The European Study Group on Transplantation in Hyperoxaluria Type 1.

The data provided by 14 European centres concerning 22 combined liver-kidney and two isolated liver grafts performed in primary hyperoxaluria type 1 (PH1) were discussed at a workshop which drew the following main conclusions: 1. In end-stage renal failure due to PH1 1-year kidney graft survival rate is far better after combined liver-kidney transplantation than after kidney transplantation alone. This may be due to enhanced renal graft tolerance induced by the simultaneously grafted liver, in addition to the reduced risk of oxalate-induced damage to the kidney graft because the oxalate overproduction has been corrected. 2. Prolonged dialysis using conventional regimes gives rise to extensive systemic oxalosis, especially oxalate osteopathy, which leads to long-lasting excretion of large amounts of oxalate even after oxalate synthesis has been normalised by liver-kidney transplantation, with the risk of jeopardising the success of the kidney graft. In addition, oxalate arteriopathy may endanger the recipient's life. 3. Patients whose GFR is in the range of 25-60 ml/min per 1.73 m2 should be followed up closely, with sequential assessments based on the rate of loss of overall renal function and the plasma and urine oxalate values. An isolated liver transplantation should be considered once the disease has been shown to be following an aggressive course. If this strategy is not followed, planning for an elective liver-kidney graft should begin when GFR decreases to about 25 ml/min per 1.73 m2 and the operation should be as soon as possible. 4. As orthotopic liver transplantation involves the removal of the recipient's biochemically defective but otherwise normal liver, the diagnosis of PH1 should be unequivocally established in every case by the measurement of alanine: glyoxylate aminotransferase enzyme activity in a preoperative liver biopsy.

Adolescent↗
PubMed1991

[Which transplantation strategies in primary hyperoxaluria type 1?].

The following main conclusions concerning the transplantation strategies to be adopted in primary hyperoxaluria type 1 (PH1) were drawn from the data collected from 22 patients who received combined liver-kidney grafts and 2 patients who received isolated liver grafts in Europe from June 1984 to March 1990. In end-stage renal failure due to PH1 liver-kidney transplantation yields better results than conventional renal transplantation. An isolated liver graft should be planned in patients with GFR between 25 and 60 ml/min/1.73 m2 whereas a combined liver-kidney graft is to be recommended as soon as the GFR falls below 25 ml/min/1.73 m2. Such patients should not be maintained on dialysis for more than a few months since they would unavoidably develop oxalosis with the risk of disabling lesions in the skeleton and cardiovascular system. Besides, oxalosis would be regularly followed by long-standing hyperoxaluria, with the risk of damage to the kidney graft, despite the correction of the enzyme deficit brought up by the liver graft.

Glomerular Filtration Rate↗
PubMed1991

Treatment of type 1 Gaucher's disease affecting bone with aminohydroxypropylidene bisphosphonate (pamidronate).

Two patients with Type 1 (adult) Gaucher's disease and major skeletal involvement with multiple fractures have been treated with the second generation bisphosphonate pamidronate for extensive periods. There was evidence of an immediate reduction in bone resorption, with increased calcium absorption (delayed in Patient 1), improved calcium balance and maintained or improved bone density indices in the axial and peripheral skeleton. There was no evidence of immediate relapse on treatment cessation. No toxic effects of pamidronate treatment were identified and subjective skeletal pain diminished in both patients. Histomorphometry of transiliac bone biopsies obtained before the start of treatment, after double in vivo tetracycline labelling, represents one of the earliest reports of the quantitative findings in iliac bone invaded by Gaucher cells.

Adult↗
PubMed1991

Combined hepatic and renal transplantation in primary hyperoxaluria type I: clinical report of nine cases.

PURPOSE AND PATIENTS AND METHODS: The purpose of this article is to report the experience of three centers with combined hepatic and renal transplantation for pyridoxine-resistant primary hyperoxaluria type I (alanine:glyoxylate aminotransferase [EC 2.6.1.44] deficiency), with particular emphasis on the selection criteria and timing of the operation. Nine patients with this inherited disease were treated by combined hepatic and renal transplantation. The former replaces the enzyme-deficient organ while the latter replaces the functionally affected organ. RESULTS: One patient with gross systemic oxalosis died in the immediate postoperative period and another died 8 weeks postoperatively of a generalized cytomegalovirus infection, having shown evidence of biochemical correction. One patient with particularly severe osteodystrophy at the time of the operation died 14 months postoperatively from renal failure due to progressive calcium oxalate nephrocalcinosis involving the transplanted kidney, plus thromboembolic disease. He also had very extensive systemic oxalosis. An additional patient with severe osteodystrophy died 9 months postoperatively. One patient developed hyper-rejection of the kidney and died later of gastrointestinal hemorrhage. The four long-term survivors (22 to 38 months) have remained asymptomatic from the standpoint of their renal disease, with resolution of any manifestations of systemic oxalosis that they may have had. They are either employed or continuing their education. CONCLUSIONS: A prolonged period of end-stage renal failure treated by dialysis regimens that are suitable for non-hyperoxaluric renal failure and extensive systemic oxalosis, particularly oxalotic osteodystrophy, are poor prognostic features. We propose that hepatic transplantation should be considered as definitive treatment before end-stage renal failure develops. This should be supplemented by renal transplantation with vigorous pre- and perioperative hemodialysis to deplete the body stores of oxalate. Although some authorities would reserve hepatic transplantation for patients in whom renal transplantation has failed, we suggest that combined liver and kidney transplantation is appropriate in patients who have never had a renal graft. Furthermore, the time has come to consider hepatic transplantation before any irreversible renal damage has occurred in these patients.

Adolescent↗
PubMed1991

Identification of 17 independent mutations responsible for human hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency.

Complete hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency causes the Lesch-Nyhan syndrome, an X-linked, purine metabolism disorder manifested by hyperuricemia, hyperuricaciduria, and neurologic dysfunction. Partial HPRT deficiency causes hyperuricemia and gout. One requirement for understanding the molecular basis of HPRT deficiency is the determination of which amino acids in this salvage enzyme are necessary for structural or catalytic competence. In this study we have used the PCR coupled with direct sequencing to determine the nucleotide and subsequent amino acid changes in 22 subjects representing 17 unrelated kindreds from the United Kingdom. These mutations were confirmed by using either RNase mapping or Southern analyses. In addition, experiments were done to determine enzyme activity and electrophoretic mobility, and predictive paradigms were used to study the impact of these amino acid substitutions on secondary structure.

Chromosome Deletion↗
PubMed1990

Purine synthesis de novo and salvage in hypoxanthine phosphoribosyltransferase-deficient mice.

Extreme degrees of hypoxanthine phosphoribosyltransferase (HPRT) deficiency in man are associated with gross sex-linked neurological dysfunction, gout and urinary stones (the Lesch-Nyhan or 'complete HPRT-deficiency' syndrome). The less severe degrees of enzyme deficiency (sex-linked recessive gout and/or urolithiasis or the 'partial HPRT-deficiency' syndrome) may be associated with minor neurological manifestations. Whole body purine synthesis de novo is accelerated in both these groups of patients. A strain of mice with an experimentally produced mutation at the HPRT locus showed some residual 'apparent HPRT activity' in brain, liver, testicular, splenic, kidney and ovarian tissues but not in erythrocyte haemolysates. The mutation removes exons 1 and 2 of the coding region of the gene together with the promotor and about 10 kb of upstream sequence from the gene. It is therefore possible that the observed 'apparent HPRT activity' in these mice is due to the operation of an alternative metabolic pathway. Purine synthesis de novo was markedly accelerated in their brain, testicular, splenic and kidney tissues. It was not accelerated in the liver tissue of male mice hemizygous for the mutation and the degree of acceleration in the female homozygotes only just reached statistical significance at the p = 0.02 level. This observation casts doubt on the importance of modulations in the rate of hepatic purine synthesis de novo as a mechanism for maintaining a steady supply of purines for translocation to other organs.

Adenine Phosphoribosyltransferase↗
PubMed1990

Protein metabolism in phenylketonuria and Lesch-Nyhan syndrome.

Animal and in vitro studies have implicated decreased protein synthesis in the pathogenesis of tissue damage in phenylketonuria (PKU) and of growth failure in Lesch-Nyhan syndrome. Protein turnover was measured in vivo in ten young adult subjects with classical PKU, two subjects with hyperphenylalaninemia, and three children with Lesch-Nyhan syndrome using techniques based on continuous infusions of [13C]leucine and, in Lesch-Nyhan subjects, [2H5]phenylalanine. The PKU subjects had various degrees of dietary phenylalanine restriction and plasma phenylalanine levels at the time of study ranged from 450-1540 mumol/L (mean 1106). Plasma phenylalanine in the two hyperphenylalaninemic subjects was 533 and 402 mumol/L. Rates of protein synthesis in all PKU subjects (mean 3.71 g/kg/24 h, range 2.68-5.10, [13C]leucine as tracer) were in a range similar to or above control values (mean 2.97, range 2.78-3.22, n = 6), as were rates of protein catabolism (PKU mean 4.23 g/kg/24 h, range 3.15-5.45; controls 3.64, 3.50-3.91). Protein turnover values in hyperphenylalaninemia were also similar to those in controls. With [13C]leucine as tracer, both mean protein synthesis and catabolism values in Lesch-Nyhan subjects (mean 4.80 and 5.64 g/kg/24 h, respectively) were higher than values in control children matched for protein intake (synthesis 4.32 +/- 0.74 (SD) and catabolism 4.85 +/- 0.57 (g/kg/24 h, n = 5). Similar results were obtained in Lesch-Nyhan subjects using [2H5]phenylalanine as tracer. These results suggest that protein turnover is not decreased in either PKU or Lesch-Nyhan syndrome. This conclusion is inconsistent with the hypothesis that tissue damage in PKU results from impaired protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Factors governing urinary tract stone disease.

Urinary stone formation depends on the degree of saturation of the urine with respect to potential stone-forming substances. Urine contains a range of electrolytes which ionise to different and variable degrees and which interact with one another in ways which influence their solubilities. These ionisations are themselves influenced by the pH of the urine which is another variable factor. Urinary organic molecules, which may or may not ionise and which may bear surface charges, also influence the solubility of the low molecular weight stone-constituents. Some other substances in the urine, such as glycosaminoglycans, can modify the ability of inorganic micro-crystals to aggregate and form stones. Environmental factors, other urinary tract pathology and genetic influences all predispose to urolithiasis, but many cases lack either an identifiable specific cause or the presence of recognisable risk factors. In the risk factor model of calcium stone formation there are pre-renal risk factors which lead to urinary risk factors and hence to the chemical risk factors of supersaturation and decreased ability to inhibit crystallisation. There are, in addition to these general factors which may act synergistically to produce urinary stones, several specific single enzyme defects which alter the urinary composition in such a way as to produce stones of a highly characteristic composition.

Humans↗
PubMed1989

Perspectives in the assessment and management of patients with primary hyperoxaluria type I.

In normal adults the urinary excretion of oxalate rarely exceeds 0.5 mmol/24 hours-1 despite dietary and seasonal fluctuations of intake and absorption. Hyperoxaluria may be encountered in a number of disease states because of increased absorption of dietary oxalate or derangements of metabolism (Table 1). More unusually, hyperoxaluria may arise from one of three inborn errors of metabolism, i.e., the primary hyperoxalurias. The most common, primary hyperoxaluria type I (PHI), is recessively inherited; it will be discussed in detail in this paper. Primary hyperoxaluria type II, caused by a deficiency of D-glycerate dehydrogenase (EC 1.1.1.29), has a similar clinical pattern of disease, but has been described in only a very few families. More recently, another idiopathic form of hyperoxaluria has been defined (type III). It is likely that this form results from a primary defect in oxalate absorption in the absence of any morphologically or functionally definable intestinal disease; a satisfactory response to dietary restriction of oxalate, along with the use of thiazide diuretics, has been described.

Humans↗