Biomedical subjects
G Touati
Publications and source records attributed to G Touati.
Pseudo-metabolic presentation in a Duchenne muscular dystrophy symptomatic carrier with 'de novo' duplication of dystrophin gene.
We report a 6-year-old female patient presenting with a sudden and severe single episode of rhabdomyolysis in which screening for a metabolic disorder was negative. Four months after the episode a muscle biopsy was performed and showed a mild pattern of necrosis/regeneration. Upon immunofluorescence, a mosaic pattern of dystrophin deficiency was found, and in the dystrophin deficient muscle fibres, the four proteins of the sarcoglycan complex were also lacking. Genetic analysis showed a duplication of exons 3 to 17 on one X-chromosome of the proband, but not on the mother's X-chromosome. A clearly skewed X-inactivation (85% of the defective X being active) was found and is consistent with the patient being symptomatic. To our knowledge, a spontaneous rhabdomyolysis in a female Duchenne muscular dystrophy carrier has never been reported.
N219Y, a new frequent mutation among mut(degree) forms of methylmalonic acidemia in Caucasian patients.
Mutations in the MUT locus encoding for the methylmalonyl-CoA mutase (MCM) apoenzyme are responsible for the mut forms of methylmalonic acidemia (MMA). To date, 49 different mutations have been identified in mut MMA. Only two frequent mutations have been reported in the Japanese population and in African-Americans. Here we report a new missense mutation N219Y (731 A-->T) which we found in five unrelated families of French and Turkish descent. All the patients exhibited a severe mut(degree) phenotype and three of them were homozygotes for N219Y. Direct involvement of the mutation in the loss of enzyme activity was demonstrated by mutagenesis and transient expression study. Mapping of the mutation onto a three-dimensional model of human MCM constructed by homology with the Propionibacterium shermanii enzyme shows that it lies in a highly conserved secondary structure motif and might suggest impaired folding and/or poor stability compatible with the mut(degree) phenotype. Finally, a 1% N219Y carrier frequency was observed in a French anonymous control population. Thus, N219Y is the first frequent mut mutation to be reported in the Caucasian population.
Hyperinsulinism and hyperammonemia syndrome: report of twelve unrelated patients.
Hyperinsulinism and hyperammonemia syndrome has been reported as a cause of moderately severe hyperinsulinism with diffuse involvement of the pancreas. The disorder is caused by gain of function mutations in the GLUD1 gene, resulting in a decreased inhibitory effect of guanosine triphosphate on the glutamate dehydrogenase (GDH) enzyme. Twelve unrelated patients (six males, six females) with hyperinsulinism and hyperammonemia syndrome have been investigated. The phenotypes were clinically heterogeneous, with neonatal and infancy-onset hypoglycemia and variable responsiveness to medical (diazoxide) and dietary (leucine-restricted diet) treatment. Hyperammonemia (90-200 micromol/L, normal <50 micromol/L) was constant and not influenced by oral protein, by protein- and leucine-restricted diet, or by sodium benzoate or N-carbamylglutamate administration. The patients had mean basal GDH activity (18.3 +/- 0.9 nmol/min/mg protein) not different from controls (17.9 +/- 1.8 nmol/min/mg protein) in cultured lymphoblasts. The sensitivity of GDH activity to inhibition by guanosine triphosphate was reduced in all patient lymphoblast cultures (IC(50), or concentrations required for 50% inhibition of GDH activity, ranging from 140 to 580 nM, compared with control IC(50) value of 83 +/- 1.0 nmol/L). The allosteric effect of ADP was within the normal range. The activating effect of leucine on GDH activity varied among the patients, with a significant decrease of sensitivity that was correlated with the negative clinical response to a leucine-restricted diet in plasma glucose levels in four patients. Molecular studies were performed in 11 patients. Heterozygous mutations were localized in the antenna region (four patients in exon 11, two patients in exon 12) as well as in the guanosine triphosphate binding site (two patients in exon 6, two patients in exon 7) of the GLUD1 gene. No mutation has been found in one patient after sequencing the exons 5-13 of the gene.
Neurologic outcomes of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.
OBJECTIVE: To evaluate the neurologic outcomes of neonates and infants suffering from persistent hyperinsulinemic hypoglycemia of infancy (PHHI). METHODS: The neurologic development of 90 PHHI patients was studied retrospectively. Sixty-three patients were treated surgically and 27 were treated medically. Fifty-four patients were neonates, of whom 8 were treated medically and 46 were operated on (19 for a focal adenomatous hyperplasia and 27 for diffuse hyperinsulinism). Thirty-six patients had infancy-onset hyperinsulinism, of whom 19 were treated medically and 17 underwent pancreatectomy (10 patients for a focal adenomatous hyperplasia and 7 for diffuse hyperinsulinism). RESULTS: Severe psychomotor retardation was found in 7 patients, 6 with neonatal-onset PHHI. Intermediate psychomotor disability existed in 12 patients; epilepsy existed in 16. Neonatal-onset was the main risk factor for severe retardation or epilepsy. Medically treated patients were less severely affected than those treated by surgery, and there was no difference between the diffuse and focal forms of hyperinsulinism. CONCLUSION: Neonatal hyperinsulinemic hypoglycemia is still a severe disease with an important risk to rapidly develop severe mental retardation and epilepsy.
[A rare cause of cardiomyopathy in childhood: propionic acidosis. Three case reports].
Dilated cardiomyopathy is a rare and unrecognised complication of propionic acidosis. It usually progresses to chronic cardiac failure with a poor prognosis. The authors report three cases of cardiomyopathy due to this condition. One of the children underwent liver transplantation which cured the cardiac complication.
[Dissection of the aorta complicated by aorto-pulmonary fistula].
The authors report the case of chronic dissection of the aorta presenting with congestive cardiac failure. The diagnosis was made for the first time by transoesophageal echocardiography which showed both the dissection of the aorta and its fistulalisation into the pulmonary artery. Aortography confirmed the diagnosis. The patient underwent surgery which consisted of suture of the fistula and replacement of the ascending aorta with a prosthetic tube. The outcome was favourable after 8 months follow-up.
Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biological improvement.
We report an attempt at dietetic therapy in two unrelated patients with isolated sulphite oxidase deficiency, with a mild clinical course and late onset of symptoms. In case 1, disease started at 15 months with an acute crisis of agitation, unexplained crying and restlessness following otitis. Case 2 was diagnosed at 10 months when she presented with slight motor delay and dislocation of lenses. In both cases, sulphite oxidase activity measured in fibroblasts was undetectable. Therapy consisted of a diet low in protein from natural foods (daily methionine intake 130-150 mg) and a synthetic amino acid mixture (50 g per day) without cystine and methionine (Xmet, Cys Maxamaid, SHS International Ltd). A comparison of clinical and biochemical parameters was made between the period before treatment and after 2 years of treatment. Restriction in protein and sulphur amino acids brought about a dramatic decrease of urinary thiosulphate and S-sulphocysteine. It also brought about a generalized hypoaminoacidaemia with a low plasma methionine and cystine in both patients. Furthermore, both patients grew normally with no signs of neurological deterioration, and there was evidence of progress in psychomotor development.
Genetic hypoglycaemia in infancy and childhood: pathophysiology and diagnosis.
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Effects on bone metabolism of one year recombinant human growth hormone administration to children with juvenile chronic arthritis undergoing chronic steroid therapy.
OBJECTIVE: To study the effects on bone metabolism of treatment with recombinant human growth hormone (rhGH) in children with juvenile chronic arthritis (JCA) who are undergoing treatment with glucocorticoids (GC) and have severe bone lesions. METHODS: We assessed the effects of rhGH treatment (1.4 U/kg/week) on bone metabolism markers and bone density measured during a one year treatment course in 14 patients with systemic forms of JCA undergoing longterm GC treatment. RESULT: All patients at inclusion showed severe bone demineralization (mean bone density: -3.7 standard deviation score for chronological age). Compared to pretreatment values, bone formation markers (blood levels of osteocalcin and C-terminal propeptide of type 1 procollagen) and bone resorption markers (urinary hydroxyproline, pyridinoline, and deoxypyridinoline levels) increased significantly during treatment and returned to pretreatment values after discontinuation of rhGH. We observed that plasma level of osteocalcin was the best predictive variable of growth response to rhGH treatment in these patients. CONCLUSION: The results reflect an increase in bone turnover in these patients. Despite these biochemical changes no improvement of bone density was observed during the one year treatment. Treatment of longer duration is necessary to evaluate the curative effects of GH.
Clinical features of 52 neonates with hyperinsulinism.
BACKGROUND: Neonatal hyperinsulinemic hypoglycemia is often resistant to medical therapy and is often treated with near-total pancreatectomy. However, the pancreatic lesions may be focal and treatable by partial pancreatic resection. METHODS: We studied 52 neonates with hyperinsulinism who were treated surgically. The type and location of the pancreatic lesions were determined by preoperative pancreatic catheterization and intraoperative histologic studies. Partial pancreatectomy was performed in infants with focal lesions, and near-total pancreatectomy was performed in those with diffuse lesions. The postoperative outcome was determined by measurements of plasma glucose and glycosylated hemoglobin and by oral glucose-tolerance tests. RESULTS: Thirty neonates had diffuse beta-cell hyperfunction, and 22 had focal adenomatous islet-cell hyperplasia. Among the latter, the lesions were in the head of the pancreas in nine, the isthmus in three, the body in eight, and the tail in two. The clinical manifestations were similar in both groups. The infants with focal lesions had no symptoms of hypoglycemia and had normal preprandial and postprandial plasma glucose and glycosylated hemoglobin values and normal results on oral glucose-tolerance tests after partial pancreatectomy (performed in 19 of 22 neonates). By contrast, after near-total pancreatectomy, 13 of the patients with diffuse lesions had persistent hypoglycemia, type 1 diabetes mellitus developed in 8, and hyperglycemia developed in another 7; overall, only 2 patients with diffuse lesions had normal plasma glucose concentrations in the first year after surgery. CONCLUSIONS: Among neonates with hyperinsulinism, about half may have focal islet-cell hyperplasia that can be treated with partial pancreatectomy. These neonates can be identified through pancreatic catheterization and intraoperative histologic studies.
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.
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.
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.
Growth hormone treatment of short stature and metabolic dysfunction in juvenile chronic arthritis.
Severe growth retardation and profoundly altered body composition are observed in children treated with glucocorticoids for systemic forms of juvenile chronic arthritis. The aim of this study was to assess the effects of 1 year of treatment with growth hormone (GH) on height velocity and body composition, and the potential effects of such treatment on glucose tolerance. Fourteen children receiving steroid therapy for juvenile chronic arthritis were treated with GH, 1.4 IU/kg/week (0.47 mg/kg/week), for 1 year and were then followed up for 1 year after cessation of treatment. Baseline GH secretion and plasma levels of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were at the lower limit of normal, but increased with GH treatment. During the year of GH treatment, mean height velocity increased from 1.9 to 5.4 cm/year (p < 0.001), mean lean body mass increased by 12% (p < 0.01) and mean fat mass fell by 20% (p < 0.01) compared with baseline. Decreased glucose tolerance and increased glycosylated haemoglobin levels were also observed. This may have been a result of insulin resistance, as indicated by induced hyperinsulinaemia. Following the 1-year GH treatment period, height velocity fell to pretreatment values, and the height SDS at the end of the second year was lower (p < 0.01) than before treatment. Weight and fat mass increased markedly after cessation of GH treatment. These results suggest that GH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease. Long-term controlled studies are needed to determine the risks and benefits of GH therapy in such patients.
Long-term treatment of persistent hyperinsulinaemic hypoglycaemia of infancy with diazoxide: a retrospective review of 77 cases and analysis of efficacy-predicting criteria.
UNLABELLED: Primary persistent hyperinsulinaemic hypoglycaemia of infancy is rare. Diazoxide treatment remains the mainstay of medical therapy in long-term management. We reviewed 77 cases of primary persistent hyperinsulinism in neonates and infants who were treated with diazoxide and studied criteria predictive of therapeutic efficacy. The only criterion identified was age at manifestation. All but 1 of the 31 neonatal cases were unresponsive to diazoxide. Responsiveness increased with age: 12 of 39 early-infantile cases, and all seven late-infantile cases were diazoxide-responsive. In responders, a diazoxide dose of 10-15 mg/kg per day was always effective, suggesting an "all or none" response. Diazoxide-resistant hyperinsulinism is characterized by its severity with higher plasma insulin levels. The analysis of 46 surgically treated patients showed that the efficacy of diazoxide is not related to the aetiology of the pancreatic lesions. In six cases, after many years of management, diazoxide treatment was stopped without recurrence of hypoglycaemia. CONCLUSION: Diazoxide is an efficient treatment in the long-term management of most persistent hyperinsulinaemic hypoglycaemia of infancy revealed in infants and children but is usually ineffective in neonatal forms. Drug efficacy does not correlate with anatomical lesions. Medical treatment can sometimes be stopped after many years of management without recurrence of disease manifestations.
[Persistent hyperinsulinemic hypoglycemia in the newborn and infants].
Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is the most frequent cause of hypoglycaemia in infancy. Clinical presentation is heterogeneous, with variable onset of hypoglycaemia and response to diazoxide, and presence of sporadic or familial forms. Underlying histopathological lesions can be focal or diffuse. Focal lesions are characterised by focal hyperplasia of pancreatic islet-like cells, whereas diffuse lesions implicate the whole pancreas. The distinction between the two forms is important because surgical treatment and genetic counselling are radically different. Focal lesions correspond to somatic defects which are totally cured by limited pancreatic resection, whereas diffuse lesions require a subtotal pancreatectomy exposing to high risk of diabetes mellitus. Diffuse lesions are due to functional abnormalities involving several genes and different transmission forms. Recessively inherited PHHI have been attributed to homozygote mutations for the beta-cell sulfonylurea receptor (SUR1) or the inward-rectifying potassium-channel (Kir6.2) genes. Dominantly inherited PHHI can implicate the glucokinase gene, particularly when PHHI is associated with diabetes, the glutamate dehydrogenase gene when hyperammonaemia is associated, or another locus.
Exploration of glucose homeostasis during fasting in growth hormone-deficient children.
In order to define more precisely the risk of hypoglycaemia in GH-deficient children and to clarify the role of growth hormone (GH) in glucose homeostasis, a 24-h fast was monitored in 10 GH-deficient children aged 1.1-6.5 y. Asymptomatic hypoglycaemia (blood glucose < or = 2.6 mmol/l) occurred in 9/10 children, 2 of whom prematurely interrupted the test. Blood glucose profile was not reproducible between children and had no correlation with age (p = 0.48). Gluconeogenesis was considered as non-altered as read from the normal plasma lactate and pyruvate concentrations throughout the test. Plasma ketone body concentrations increased during the test, but were lower than expected with respect to the decrease of blood glucose. This suggests insufficient ketogenesis which could exacerbate hypoglycaemia in GH-deficient children if brain glucose utilization were not alleviated by ketone body oxidization, as is normally the case. The positive glucose response after glucagon stimulation in 6/10 patients indicated normal hepatic glycogen content. However, these responses were unexpected following the prolonged fast and its concomitant hypoglycaemia, and would therefore tend to suggest a defect in glycogenolysis. These results confirm the tendency to hypoglycaemia, even after infancy, in GH-deficient children. These hypoglycaemias may occur by different types of malfunctioning, such as insufficient ketogenesis or a defect in glycogenolysis. These hypotheses require confirmation by a more systematic study of the metabolic and hormonal changes that occur during fasting in both GH-deficient and normal children.