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Biomedical subjects

J-M Saudubray

Publications and source records attributed to J-M Saudubray.

9 recordsLinked to original sources
PubMed2006

Dihydropteridine reductase deficiency: levodopa's long-term effectiveness without dyskinesia.

We report an adult patient lacking endogenous synthesis of monoamines (dopamine, serotonin, and catecholamines) due to a severe dihydropteridine reductase (DHPR) deficiency. With levodopa and 5-hydroxytryptophan (5HTP) supplementation, the patient exhibited moderate mental retardation, acute episodes of parkinsonism, and episodes of depression. Despite the use of levodopa from age 3 months, he exhibited no dyskinesia or dopaminergic cell loss as suggested by normal PET imaging of the dopamine transporter.

5-Hydroxytryptophan↗
PubMed2006

[Status of lysosomal diseases amongst metabolic diseases].

Lysosomal diseases belong to the group of diseases which disturb the synthesis, catabolism or processing of complex molecules. These are the most common metabolic diseases, as they account for about one-third of all known metabolic diseases. They can be expressed as early as the intra-uterine stage of life, or appear after birth at any age, including during adulthood. They develop gradually, evolve independently of any intercurrent catabolic event and are independent of diet. Although they have long been associated with an inevitably fatal outcome, several can now be treated effectively, either by enzyme replacement therapy which increases catabolism of the overloaded substance thanks to an input of the deficient enzyme, or by drugs which reduce the synthesis of the overloaded substance.

Adult↗
PubMed2005

[Congenital hyperinsulinism in newborn and infant].

Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias requiring aggressive treatment to prevent severe and irreversible brain damage. Several classifications of HI can be attempted, based on: 1) the onset of hypoglycemia in the neonatal period or later in infancy; 2) the histological lesion: focal or diffuse; 3) the genetic transmission: sporadic, recessive, or less frequently dominant. The most common underlying mechanism of HI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The 2 subunits of the K(+)(ATP) channel are encoded by either the sulfonylurea receptor gene (SUR1 or ABCC8) or the inward-rectifying potassium channel gene (KIR6.2. or KCNJ11), both located in the 11p15.1 region. Focal CHI has been shown to result from a paternally inherited mutation on the SUR1 or KIR6.2 gene and loss of the maternal 11p15 allele restricted to the pancreatic lesion. Diffuse HI, frequently due to mutations of the SUR1 or KIR6.2 genes of autosomal recessive inheritance is genetically heterogeneous. The distinction between the focal and the diffuse HI is very important, because the treatments are different. To distinguish between focal and diffuse HI, transhepatic catheterisation with pancreatic venous sampling was the reference technique, but will likely be replaced by [(18)F] Fluoro-L-Dopa PET scan, which is easier to perform. In absence of response to the medical treatment (diazoxide) a limited pancreatectomy permits to cure focal HI, while a diffuse HI requires a subtotal pancreatectomy with high risk of subsequent diabetes mellitus.

ATP-Binding Cassette Transporters↗
PubMed2005

Dominantly inherited hyperinsulinaemic hypoglycaemia.

Congenital hyperinsulinism (HI), the most important cause of hypoglycaemia in early infancy, is a heterogeneous disease with two types of histological lesions, focal and diffuse, with major consequences in terms of surgical approaches. In contrast to focal islet-cell hyperplasia, always sporadic to our knowledge, diffuse hyperinsulinism is a heterogeneous disorder involving several genes, various mechanisms of pathogenic mutations and different transmissions: (i) channelopathy involving the genes encoding the sulphonylurea receptor (SUR1) or the inward-rectifying potassium channel (Kir6.2) in recessively inherited HI or more rarely dominantly inherited HI; (ii) metabolic disorders implicating the short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) enzyme inrecessively inherited HI, the glucokinase gene (GK), the glutamate dehydrogenase gene (GLUD1) when hyperammonemia is associated, dominant exercise-induced HI with still-unknown mechanism, and more recently the human insulin receptor gene in dominantly inherited hyperinsulinism. Thus, dominant HI disorders always correspond to diffuse HI, where most hypoglycaemia occur in infancy, and are sensitive to medical treatment. Channel causes could be due to dominant negative mutation with one abnormality in channels composed of four Kir6.2 subunits and four SUR1 subunits, leading to a complete destruction of the channel structure or function, or due to haploinsufficiency with only one functional allele, leading to 50% of functional protein, which is not sufficient to obtain enough opened channels to maintain the membrane depolarized. Metabolic causes are due to a gain of function of enzyme activity (deregulated enzymes), except for physical exercise-induced hyperinsulinaemic hypoglycaemia, of still-unknown cause. Congenital hyperinsulinism (HI) is the most important cause of hypoglycaemia in early infancy (Aynsley-Green et al 2000; Cornblath et al 1990; Pagliara et al 1973; Thomas et al 1977). The inappropriate oversecretion of insulin is responsible for profound hypoglycaemia that requires aggressive treatment to prevent severe and irreversible brain damage (Volpe 1995). HI is a heterogeneous disease associated with several genes, various mechanisms of pathogenic mutations and different transmissions (Dunne et al 2004).

Exercise↗
PubMed2004

Trends in serum citrulline and acute rejection among recipients of small bowel transplants.

A test for detecting acute cellular rejection (ACR) of small intestinal transplants (ITx) would be a major advance. Small preliminary studies suggest that serum citrulline levels correlate with ACR. The results for a group of 26 isolated intestinal and multivisceral transplant recipients are summarized here. Serum citrulline concentrations were determined by ion exchange chromatography and compared to biopsy-based grade of ACR. Other factors considered included patient and donor age and sex, ischemia time, and serum creatinine. Straight-line fits were employed to describe how each patient's citrulline levels changed over time. Estimated times to achieve normal citrulline (>or=30 micromol/L) ranged from 1 to 730 days posttransplant for 21 patients demonstrating increasing citrulline levels over time. Using stepwise linear regression, patients' ranks for time required to achieve normal citrulline levels were the only independent predictors of both maximum ACR (P <.0001) and average ACR (P =.0059) after 14 days posttransplant. The rate and direction of change in citrulline over time may be an indicator of the risk of acute rejection. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies.

Adult↗
PubMedDate not supplied

Breast feeding in IMD.

Breast feeding has proven benefits for many infants with inherited metabolic disorders (IMDs) but, with the exception of phenylketonuria, there are few reports in other conditions. A questionnaire, completed by dietitians and clinicians from 27 IMD centres from 15 countries (caring for a total of over 8000 patients with IMDs on diet) identified breast feeding experience in IMD. Successful, demand breast feeding (in combination with an infant amino acid formula free of precursor amino acids) was reported in 17 infants with MSUD, 14 with tyrosinaemia type I, and 5 with homocystinuria. Eighty-nine per cent were still breast fed at 16 weeks. Fewer infants with organic acidaemias were demand breast fed (7 with propionic acidaemia; 6 with methylmalonic acidaemia and 13 with isovaleric acidaemia) (usually preceded by complementary feeds of a protein-free infant formula or infant amino acid formula free of precursor amino acids). Only 12 infants with urea cycle disorders were given demand breast feeds, but this was unsuccessful beyond 8 days in CPS deficiency. Further work is needed in developing guidelines for feeding and for clinical and biochemical monitoring for breast-fed infants with IMDs.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture.

In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

Clinical approach to treatable inborn metabolic diseases: an introduction.

In view of the major improvements in treatment, it has become increasingly important that in order for first-line physicians not to miss a treatable disorder they should be able initiate a simple method of clinical screening, particularly in the emergency room. We present a simplified classification of treatable inborn errors of metabolism in three groups. Group 1 includes inborn errors of intermediary metabolism that give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias. Clinical expression can be acute or systemic or can involve a specific organ, and can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes inborn errors of intermediary metabolism that affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and includes lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable inborn error in an emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms--general (failure to thrive), neurological, or specific for various organs or systems. These symptoms are summarized in four tables. In addition, an extensive list of medications used in the treatment of inborn errors is presented.

Humans↗