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Biomedical subjects

D Rabier

Publications and source records attributed to D Rabier.

At least 37 records · Page 2Linked to original sources
PubMed1999

Liver transplantation in urea cycle disorders.

We report here our experience in the long-term management of 28 patients with citrullinaemia, 13 patients with carbamoyl phosphate synthase deficiency and 15 patients with argininosuccinic aciduria. In addition, we report a national French survey of 119 patients with ornithine transcarbamylase (OTC) deficiency enzymatically characterized in our laboratory. We also include in this report four personal patients (two with OTC and two with citrullinaemia) who were liver transplanted, and one OTC patient from the National French survey. Although this retrospective series is not really representative of the modern treatment combining low protein diet and arginine, sodium benzoate and sodium phenylbutyrate, it is obvious that the long-term outcome of all urea cycle disorders remains very guarded. We highlight the severity of the neonatal forms of such disorders, and mostly for OTC-deficient males. According to this evidence, our policy is not to treat such severely affected patients in the neonatal period who die anyway spontaneously within 2 to 3 days. At the present time, we only have three patients with neonatal citrullinaemia, aged 1, 6 and 10 years respectively, who are still doing well. One of them has been successfully liver transplanted at 5 years. Another transplanted patient died in the post-surgical phase. We emphasize the unexpected severity of argininosuccinic aciduria in which there is no one patient doing well. This is a rather surprising finding as this disorder is easy to manage and rarely presents with recurrent attacks of hyperammonaemia when it is treated by arginine supplementation. This consideration would suggest to extend the indication of orthotopic liver transplantation in this disorder. Finally, the most difficult indication is in the late onset symptomatic female OTC group. In this last group, despite a significant residual activity due to heterozygote status, even with a variable lyonisation, only seven girls are still mentally and neurologically normal. Interestingly, three of these seven were liver-transplanted before the constitution of irreversible neurological damage. These three girls and their family declare their well-being, their feeling to be cured and enjoy their normal life.

Amino Acid Metabolism, Inborn Errors↗
PubMed1999

Liver transplantation in propionic acidaemia.

Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8-12 g/day for the first 3 years of life, and then slowly increased to 15-20 g/day by the age of 6-8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very effective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40-50 g/day) and still on carnitine supplementation. Interestingly, another patient who filled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was finally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is difficult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modified or not.

Adolescent↗
PubMed1999

The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia.

UNLABELLED: Based on the study of three unrelated families, we report what we believe to be the first in vivo evidence of muscle ATPase deficiency in individuals carrying the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G). Since plasma citrulline was consistently low in 4/5 patients, we suggest that the NARP mutation caused complex V deficiency in the small intestine as well, thus reducing the availability of mitochondrial ATP required for citrulline synthesis. CONCLUSION: We suggest giving consideration to hypocitrullinaemia as a hallmark of the neurogenic weakness, ataxia and retinitis pigmentosa syndrome mutation and more generally of impaired oxidative phosphorylation in the small intestine in vivo.

Adenosine Triphosphatases↗
PubMed1999

D-2-hydroxyglutaric aciduria: further clinical delineation.

It has recently been recognized that D-2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical and neuroimaging findings of the severe phenotype were homogeneous among the patients, the findings in the mild phenotype were much more variable, leaving the clinical picture poorly defined. We were able to collect the clinical, biochemical and neuroimaging data on an additional 8 patients with D-2-hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With the new information, it becomes clear that the mild phenotype shares the essential characteristics of the severe phenotype. The most frequent findings, regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, are episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most consistent MRI finding is enlargement of the lateral ventricles, occipital more than frontal. Regardless of the clinical phenotype, early MRI shows in addition subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white-matter abnormalities. Two patients had vascular abnormalities, but it is as yet unclear whether these are related to D-2-hydroxyglutaric aciduria or are incidental findings.

Brain↗
PubMed1999

Defects in activation and transport of fatty acids.

The oxidation of long-chain fatty acids in mitochondria plays an important role in energy production, especially in skeletal muscle, heart and liver. Long-chain fatty acids, activated to their CoA esters in the cytosol, are shuttled across the barrier of the inner mitochondrial membrane by the carnitine cycle. This pathway includes four steps, mediated by a plasma membrane carnitine transporter, two carnitine palmitoyltransferases (CPT I and CPT II) and a carnitine-acylcarnitine translocase. Defects in activation and uptake of fatty acids affect these four steps: CPT II deficiency leads to either exercise-induced rhabdomyolysis in adults or hepatocardiomuscular symptoms in neonates and children. The three other disorders of the carnitine cycle have an early onset. Hepatic CPT I deficiency is characterized by recurrent episodes of Reye-like syndrome, whereas severe muscular and cardiac signs are associated with episodes of fasting hypoglycaemia in defects of carnitine transport and translocase. Convenient metabolic investigations for reaching the diagnosis of carnitine cycle disorders are determination of plasma free and total carnitine concentrations, determination of plasma acylcarnitine profile by tandem mass spectrometry and in vitro fatty acid oxidation studies, particularly in fresh lymphocytes. Application of the tools of molecular biology has greatly aided the understanding of the carnitine palmitoyltransferase enzyme system and confirmed the existence of different related genetic diseases. Mutation analysis of CPT II defects has given some clues for correlation of genotype and phenotype. The first molecular analyses of hepatic CPT I and translocase deficiencies were recently reported.

Adult↗
PubMed1999

Recognition and management of fatty acid oxidation defects: a series of 107 patients.

In a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty-eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near-miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB-MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long-chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long-term dietary therapy aims to prevent periods of fasting and restrict long-chain fatty acid intake with supplementation of medium-chain triglycerides. Despite these therapeutic measures, the long-term prognosis remains uncertain.

Disease Management↗
PubMed1999

Hair and skin disorders as signs of mitochondrial disease.

OBJECTIVE: To compare and explore the skin manifestations of mitochondrial disorders in 14 children with puzzling and unexpected cutaneous presentations. STUDY DESIGN: One hundred forty children with mitochondrial disorders who had been under observation in our hospital for the last 10 years, were carefully examined by the same physicians. Skin and hair characteristics were investigated by the same dermatologist. All the children developed an early unexplained association of symptoms. Metabolic screening for abnormal oxidative-reduction in plasma and mitochondrial enzyme investigations confirmed the diagnosis of oxidative phosphorylation disorders. RESULTS: Fourteen children with mitochondrial disorders (10% of the original cohort) developed specific hair and skin abnormalities. Their cutaneous manifestations were similar, and could be classified into four categories: hair abnormalities, rashes and pigmentation disorders, hypertrichosis, and acrocyanosis. In 3 cases, skin disorders constituted the puzzling and unexpected manifestations of mitochondrial disease. Respiratory chain deficiencies in the cultured skin fibroblasts of 3 patients and heteroplasmic mitochondrial DNA rearrangement in the skin fibroblasts of 1 patient indicated that mitochondrial disorders may be expressed in the skin. CONCLUSION: Hair abnormalities and pigmented skin eruptions might belong to the broad spectrum of presenting symptoms of mitochondrial disease. The association of these dermatologic lesions with unrelated disorders should lead physicians to consider a diagnosis of mitochondriopathy as early as possible.

Age of Onset↗
PubMed1998

Clinical approach to inherited peroxisomal disorders: a series of 27 patients.

To illustrate the clinical and biochemical heterogeneity of peroxisomal disorders, we report our experience with 27 patients seen personally between 1982 and 1997. Twenty patients presented with a phenotype corresponding either to Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease, 3 of whom had a peroxisomal disorder due to a single enzyme defect. One patient had a mild form of rhizomelic chondrodysplasia punctata, 1 had classic Refsum disease. Finally, 5 patients presented with clinical manifestations that were either unusually mild or completely atypical, and initially did not arouse suspicion of a peroxisomal disorder. They showed multiple defects of peroxisomal functions with one or several functions remaining intact, suggesting a peroxisome biogenesis disorder. The defect in peroxisome biogenesis was further characterized by variable expression in different tissues and/or individual cells in 5 patients. Studies restricted to fibroblasts failed to identify abnormalities in this group. We demonstrate that clinical manifestations of peroxisomal disorders may be very mild or completely atypical, and therefore, peroxisomal disorders should be considered in a variety of clinical settings. Furthermore, we suggest performing extensive peroxisomal investigations in every patient suspected of suffering from a peroxisomal disorder, even when the clinical presentation is typical.

Adult↗
PubMed1998

Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency, an autosomal recessive disorder of fatty-acid oxidation, presents as three distinct phenotypes (neonatal, infantile, and adult onset). In order to investigate the molecular basis of these three phenotypes, six patients with CPT II deficiency have been studied. All six unrelated patients in this study experienced the clinical symptoms of CPT II deficiency. Three patients had the neonatal form, one had the milder infantile form, and the remaining two had the adult-onset form with "muscular" symptoms only. Their diagnoses were based upon in vitro analysis of the mitochondrial beta-oxidation pathway in fibroblasts and standard enzyme assays. We devised a method to screen the entire coding sequence and flanking splice junction of the CPT II gene. A total of six different mutations have been identified, including four novel mutations. Among them, the previously reported common mutation, S113L, was only found in 3 of 12 variant alleles. Three of the six mutations have been identified in a few unrelated patients, while the remaining three have been found in single families. This study, as well as those by others, indicates genetic heterogeneity in this disease. In addition to tabulating the mutations, the correlation of mutant genotype to clinical phenotype is briefly discussed.

Adult↗
PubMed1998

Defective peroxisome biogenesis with a neuromuscular disorder resembling Werdnig-Hoffmann disease.

OBJECTIVE: Characterization of the defect in a patient presenting a peripheral neuropathy with atypical features of distal motor involvement mimicking Werdnig-Hoffmann disease. PATIENT: Clinical signs included generalized hypotonia and floppiness, absence of stretch reflexes, muscle wasting, lack of head control and lingual fasciculations associated with unaffected facial muscles, and normal intellectual development. RESULTS: Normal muscle histology ruled out Werdnig-Hoffmann disease. Elevated plasma concentrations of very long-chain fatty acids and bile acid intermediates combined with normal plasmalogen levels in erythrocytes suggested defective peroxisomal beta-oxidation directly demonstrated by deficient pristanic acid and partially deficient C26:0 was present oxidation in cultured fibroblasts. Severely impaired pipecolic acid oxidation in liver and phytanic acid oxidation in fibroblasts was present. On light and electron microscopy of the liver tissue, rare peroxisomal membrane ghosts and trilamellar inclusions but absence of peroxisomes was noted. Immunoblot analysis revealed absence of peroxisomal beta-oxidation enzymes in liver tissue but normal results in fibroblasts. Remarkably, expression of the peroxisomal defect in fibroblasts was indicated by the finding of mainly cytoplasmatic catalase, as in liver. Preliminary studies excluded classification of this patient within the large PEX1 complementation group. CONCLUSIONS: The results suggest a novel peroxisome biogenesis disorder involving peroxisomal beta-oxidation as well as phytanic and pipecolic acid oxidation rather than an isolated defect of peroxisomal beta-oxidation. The association of a clinical picture mimicking Werdnig-Hoffmann disease with a novel peroxisomal disorder raises the question of whether investigation for peroxisomal function should be considered in every patient with an enigmatic spinal muscular atrophy-like syndrome.

Bile Acids and Salts↗
PubMed1997

[Variation of amino acids in relation to age in Down syndrome subjects].

BACKGROUND: A preliminary study of plasma and urinary amino acid concentration in Down's syndrome subjects had shown some impairments. PATIENTS AND METHODS: A comparative study of the variations of amino acid concentration with age in Down's syndrome subjects aged 0 to 60 years and in control subjects aged 0 to 94 years was made in order to determine whether these impairments could be explained by generalized premature aging, or by a specific gene dosage effect. RESULTS: Two major changes (P < 0.001) were found in Down's syndrome: a decrease in plasma concentration of serine at any age, which could be due to a dosage effect of cytathionine-beta-synthase, and an increase in plasma lysine concentration in patients above 10 year's old, probably due to premature aging. Other minor changes were also present in plasma and urine, also possibly explained by premature aging. CONCLUSIONS: Other studies are necessary to evaluate possible consequences of such changes in the amino acid profiles.

Adolescent↗
PubMed1997

Continuous venovenous haemodiafiltration in the acute phase of neonatal maple syrup urine disease.

Maple syrup urine disease results in accumulation of leucine and its metabolites, which may lead in the long term to neurological dysfunction. In acute neonatal crises, large amounts of leucine may be removed by continuous venovenous haemofiltration. This extracorporeal technique has its risks and hazards, which increase with duration of treatment. We report three neonates in life-threatening conditions due to maple syrup urine disease, treated for not more than 12 h with various continuous venovenous techniques: continuous haemofiltration, haemodiafiltration and haemodialysis. The efficiency of and tolerance to these techniques was evaluated. For all three patients, plasma leucine levels decreased dramatically from 2186, 3818 and 2536 mumol/L to 1131, 1275 and 488 mumol/L, respectively. Leucine clearance obtained was 4.28 ml/min in haemodiafiltration. Their patients' neurological status improved rapidly and they have a normal developmental quotient at 22 months, 13 months, and 11 months of age, respectively. Tolerance was good except for hypothermia and drop in haematocrit in all cases. Haemodiafiltration management was more cumbersome and time consuming because it required continual adjustment of the substitution fluid flow rate to precisely balance inflow and outflow rates. We recommend continuous venovenous haemodialysis as the therapy of choice. It might be anticipated that improvement of this technique, by increasing dialysate flow rate and blood flow rate, will allow leucine concentration to be decreased below 1000 mumol/L within 6-8 h, whatever the initial level.

Acute Disease↗
PubMed1997

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Adolescent↗