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Biomedical subjects

J V Leonard

Publications and source records attributed to J V Leonard.

At least 37 records · Page 2Linked to original sources
PubMed2001

The management of organic acidaemias: the role of transplantation.

This workshop addressed the issue of treatment in propionic acidaemia (PA) and methylmalonic acidaemia (MMA) and in particular the outcome of conventional management compared with organ transplantation. Although it appears that with medical treatment the mortality for early-onset disease has improved, long-term outcome remains poor. However, liver and liver/kidney transplantation is associated with a high perioperative mortality and long-term complications. It offers only a partial cure. The indications for transplantation remain unclear. It is recommended that a register of PA and MMA patients should be established.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Plasma glutamine and ammonia concentrations in ornithine carbamoyltransferase deficiency and citrullinaemia.

A retrospective review of the plasma ammonia and glutamine concentrations during the long-term management of 7 patients with ornithine carbamoyltransferase (OCT) deficiency and three with citrullinaemia is presented. The relationship between the plasma concentrations of ammonia and glutamine is not a simple linear one and there are significant differences between the two disorders. Patients with citrullinaemia tend to have higher plasma ammonia concentrations for a given plasma glutamine concentration compared to those with OCT deficiency. The possible reasons for these differences and the implications for management are discussed.

Adolescent↗
PubMed2001

Outcome of tyrosinaemia type III.

Tyrosinaemia type III is a rare disorder caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the catabolic pathway of tyrosine. The majority of the nine previously reported patients have presented with neurological symptoms after the neonatal period, while others detected by neonatal screening have been asymptomatic. All have had normal liver and renal function and none has skin or eye abnormalities. A further four patients with tyrosinaemia type III are described. It is not clear whether a strict low tyrosine diet alters the natural history of tyrosinaemia type III, although there remains a suspicion that treatment may be important, at least in infancy.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed2001

Immunological phenotyping of fibroblast cultures from patients with a mitochondrial respiratory chain deficit.

Conventional approaches to the diagnosis of mitochondrial respiratory chain diseases, using enzyme assays and histochemistry, are laborious and give limited information concerning the genetic basis of a deficiency. We have evaluated the diagnostic value of 12 monoclonal antibodies to subunits of the four respiratory chain enzyme complexes and F(1)F(0)-ATP synthase. Antibodies were used in immunological studies with skin fibroblast cultures derived from patients with diverse mitochondrial diseases, including patients in which the disease was caused by a nuclear genetic defect and patients known to harbor a heteroplasmic mutation in a mitochondrial tRNA gene. Immunoblotting experiments permitted the identification of specific enzyme assembly deficits and immunocytochemical studies provided clues regarding the genetic origin of the disease. The immunological findings were in agreement with the biochemical and genetic data of the patients. Our study demonstrates that characterization of the fibroblast cultures with the monoclonal antibodies provides a convenient technique to complement biochemical assays and histochemistry in the diagnosis of mitochondrial respiratory chain disorders.

Adult↗
PubMed2001

The nutritional management of urea cycle disorders.

Diet is one of the mainstays of the treatment of patients with urea cycle disorders. The protein intake should be adjusted to take account of the inborn error and its severity and the patient's age, growth rate, and individual preferences. Currently, the widely used standards for protein intake are probably more generous than necessary, particularly for those with the more severe variants. Most patients, except those with arginase deficiency, will need supplements of arginine, but the value of other supplements including citrate and carnitine is unclear. Any patient on a low-protein diet should be monitored clinically and with appropriate laboratory tests. All should have an emergency (crisis) regimen to prevent decompensation during periods of metabolic stress.

Amino Acid Metabolism, Inborn Errors↗
PubMed2001

Feeding difficulties in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Feeding difficulties are common in long chain 3-hydroxyacyl-CoA dehydrogenase deficiency in early childhood and are not associated with developmental disability, metabolic abnormalities, or the overnight feeding regimen. They are an inherent part of the phenotype and it is important to recognise them because of the distress and disruption they cause.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2001

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients.

Hereditary deficiency of mitochondrial HMG-CoA synthase (mHS, OMIM 600234) is a poorly defined, treatable, probably underdiagnosed condition that can cause episodes of severe hypoketotic hypoglycemia. We present clinical follow-up and molecular analysis of the two known mHS-deficient patients. The diagnosis of mHS deficiency is challenging because the symptoms and metabolite pattern are not specific. Moreover, enzyme analysis is technically difficult and requires sampling of an expressing organ such as liver. The patients, now aged 16 and 6 y, have normal development and have had no further decompensations since diagnosis. Patient 1 is homozygous for a phenylalanine-to-leucine substitution at codon 174 (F174L). Interestingly, although the F174 residue is conserved in vertebrate mHS and cytoplasmic HS isozymes, a Leu residue is predicted in the corresponding position of HS-like sequences from Caenorhabditis elegans, Arabidopsis thaliana, and Brassica juncea. Bacterial expression of human F174L-mHS produces a low level of mHS polypeptide with no detectable activity. Similarly, in purified cytoplasmic HS, which in contrast to purified human mHS is stable and can be studied in detail, the corresponding F-->L substitution causes a 10,000-fold decrease in V(max) and a 5-fold reduction in thermal stability. Patient 2 is a genetic compound of a premature termination mutation, R424X, and an as-yet uncharacterized mutant allele that is distinguishable by intragenic single nucleotide polymorphisms that we describe. Molecular studies of mHS are useful in patients with a suggestive clinical presentation.

Adolescent↗
PubMed2000

The effects of l-alanine supplementation in late-onset glycogen storage disease type II.

Myopathy in glycogen storage disease type II (GSD-II) is slowly progressive. Five subjects with the late-onset form of GSD-II (age range, 15 to 47 years) and seven healthy control subjects (age range, 28 to 55 years) were studied. Following alanine supplementation, resting energy expenditure decreased in patients with GSD-II (p < 0.05) compared to values seen in control subjects. Leucine flux decreased (p < 0.004), as did leucine oxidation, to levels lower than those observed in control subjects (p < 0.001). l-Alanine reduces protein turnover and catabolism in GSD-II.

Adolescent↗
PubMed2000

Inborn errors of metabolism around time of birth.

Inborn errors of metabolism commonly present around the time of birth. Although most affected babies are born healthy and subsequently deteriorate, some disorders may present at (or shortly after) birth and a few may be detected by antenatal ultrosonography. In many cases, it is important that the diagnosis is made quickly and a strategy to identify those at high risk is proposed. Treatment should not be delayed for a definitive diagnosis.

Humans↗
PubMed2000

Mitochondrial respiratory chain disorders II: neurodegenerative disorders and nuclear gene defects.

The first part of this review (Lancet 2000; 355: 299) covered primary disorders of mitochondrial DNA (mtDNA). This section will cover nuclear-encoded defects of the oxidative phosphorylation (OXPHOS) system, including mtDNA mutations that are secondary to nuclear gene mutations and nuclear gene defects responsible for secondary OXPHOS deficiency (panel). The latter group of diseases are predominantly neurodegenerative. The mitochondrion's role in apoptosis and its contribution to the pathogenesis of neurodegenerative diseases are also covered.

Animals↗
PubMed2000

Mitochondrial respiratory chain disorders I: mitochondrial DNA defects.

Mitochondria have a pivotal role in cell metabolism, being the major site of ATP production via oxidative phosphorylation (OXPHOS); they have a critical role in apoptotic cell death; and they also contribute to human genetics since mitochondria have a functional genome separate from that of nuclear DNA. Defects of mitochondrial metabolism are associated with a wide spectrum of disease. An Important part of this spectrum is caused by mutations of mitochondrial DNA (mtDNA). These class I OXPHOS diseases are covered in part I of this two-part review. Dysfunction of mitochondrial OXPHOS has also emerged as an important component of a range of predominantly neurodegenerative diseases in which the mitochondrial abnormality is most probably secondary. These class II OXPHOS diseases are due to mutations of genes not encoding OXPHOS subunits or are caused by exogenous or endogenous OXPHOS toxins. Class II mitochondrial diseases and the mitochondrion's role in apoptosis are covered in part II (Lancet 2000; 355: 389-94).

DNA, Mitochondrial↗
PubMed2000

Phenylalanine supplementation improves the phenylalanine profile in tyrosinaemia.

Tyrosinaemia types I and II are caused by enzyme deficiencies in the tyrosine catabolism pathway. Successful treatment is possible with the novel enzyme inhibitor NTBC in tyrosinaemia type I and with dietary tyrosine and phenylalanine restriction in both conditions. This is achieved with a low natural protein intake and a supplementary amino acid formula that is phenylalanine- and tyrosine-free. Patients on this regimen had been noted, periodically, to have very low plasma phenylalanine concentrations (<20 micromol/L). The tyrosine and phenylalanine profiles in six patients were measured. Five of the six patients had very low concentrations of phenylalanine during the later half of the day. The response to phenylalanine supplementation was assessed and supplementing the diet with phenylalanine 30-40 mg/kg per day resulted in normal concentrations throughout the day. Possible complications of hypophenylalaninaemia and potential preventive treatment strategies are discussed. Further studies are needed to investigate the longer-term clinical and biochemical consequences of phenylalanine supplementation.

Child↗
PubMed2000

Resting energy expenditure in disorders of propionate metabolism.

OBJECTIVES: During intercurrent illness children with methylmalonic acidemia were found to have increased resting energy expenditure (REE). We measured REE in children with disorders of propionate metabolism (methylmalonic and propionic acidemia) when they were well and compared the values with those predicted by the Schofield equation. STUDY DESIGN: Prospective study in tertiary care facility. REE was measured with open-circuit indirect calorimetry under standardized conditions. Predicted REE values were calculated with the Schofield equation. Fourteen subjects with propionic acidemia (n = 3) and methylmalonic acidemia (n = 11) were studied. RESULTS: The median REE was 690 kcal/d (range 186 to 1687 kcal/d), which is significantly reduced, representing 80% +/- 18% of that predicted by the Schofield height and weight equation (P <.01). REE was significantly lower in female compared with male patients for unknown reasons. There were no differences with age or neurologic state. REE was not further reduced in those with chronic renal failure. CONCLUSION: REE in patients with disorders of propionate metabolism is reduced when they are well.

Amino Acid Metabolism, Inborn Errors↗
PubMed2000

Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European Study on Glycogen Storage Disease type I.

OBJECTIVE: To investigate the incidence, the severity, and the course of neutropenia, neutrophil dysfunction, and inflammatory bowel disease (IBD) in glycogen storage disease (GSD) type Ib. METHOD: As part of a collaborative European Study on GSD type I, a retrospective registry was established in 12 European countries that included all patients with GSD-I who were known at the centers and were born from 1960 to 1995. Of a total of 288 patients with GSD-I, 57 who had GSD-Ib form the basis of this study. RESULTS: Neutropenia (defined as an absolute neutrophil count <1 x 10(9)/L) was found in 54 patients. In 64% of the patients neutropenia was documented before the age of 1 year, but in 18% of the patients neutropenia was first noted between the ages of 6 and 9 years. Neutropenia was persistent in 5 patients and intermittent without any clear cyclical course in 45. Neutrophil function was investigated in 18 patients with neutropenia and was abnormal in all. Perioral infections were reported in 37 patients, perianal infections in 27 patients, and protracted diarrhea in 23 patients. Findings on colonoscopy and radiologic studies in 10 of 20 patients suspected to have IBD were abnormal in all. All patients with IBD, perioral infections, and perianal infections had neutropenia. CONCLUSIONS: Intermittent severe neutropenia is frequently found in patients with GSD-Ib. The study also indicates that IBD in GSD-Ib is underdiagnosed; up to 77% of the patients studied had evidence of IBD, all of whom had neutropenia. IBD was not detected in those with normal neutrophil counts. These findings support the notion that neutropenia and/or neutrophil dysfunction in GSD-Ib and IBD are causally related.

Adolescent↗
PubMed2000

Cytochrome oxidase immunohistochemistry: clues for genetic mechanisms.

Cytochrome c oxidase (COX) is encoded by three mitochondrial and nine nuclear genes. COX deficiency is genetically heterogeneous but current diagnostic methods cannot easily distinguish between mitochondrial and nuclear defects. We hypothesized that there may be differential expression of COX subunits depending on the underlying mutation. COX subunit expression was investigated in five patients with known mtDNA mutations. Severe and selective reduction of mtDNA-encoded COX subunits I and II was consistently observed in all these patients and was restricted to COX-deficient fibres. Immunostaining of nuclear-encoded subunits COX IV and Va was normal, whilst subunit VIc, also nuclear-encoded, was decreased. Twelve of 36 additional patients with histochemically defined COX deficiency also had this pattern of staining, suggesting that they had mtDNA defects. Clinical features in this group were heterogeneous, including infantile encephalopathy, multisystem disease, cardiomyopathy and childhood-onset isolated myopathy. The remaining patients did not have the same pattern of immunostaining. Fourteen had reduced staining of all subunits, whilst 10 had normal staining of all subunits despite reduced enzyme activity. Patients with COX deficiency secondary to mtDNA mutations have a specific pattern of subunit loss, but the majority of children with COX deficiency do not have this pattern of subunit loss and are likely to have nuclear gene defects.

Adolescent↗