Biomedical subjects

Guy Touati

Publications and source records attributed to Guy Touati.

6 recordsLinked to original sources

PubMed2003

A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis.

Mitochondrial respiratory chain complex III (ubiquinol-cytochrome c reductase) consists of 11 subunits, only one (cytochrome b) being encoded by the mitochondrial DNA. Disorders of complex III are comparatively rare but are nevertheless present as a clinically heterogeneous group of diseases. To date, no mutation in any of the nuclear-encoded subunits has been described. We report here a deletion in the nuclear gene UQCRB encoding the human ubiquinone-binding protein of complex III (QP-C subunit or subunit VII) in a consanguineous family with an isolated complex III defect. In the proband, a homozygous 4-bp deletion was identified at nucleotides 338-341 of the cDNA predicting both a change in the last seven amino acids and an addition of a stretch of 14 amino acids at the C-terminal end of the protein. Both parents were found to be heterozygous for the deletion, which was absent from 55 controls. Low temperature (-196 degrees C) spectral studies performed on isolated mitochondria from cultured skin fibroblast of the proband showed a decreased cytochrome b content suggestive of a role for the QP-C subunit in the assembly or maintenance of complex III structure.

Acidosis, Lactic↗

PubMed2003

Splicing error in E1alpha pyruvate dehydrogenase mRNA caused by novel intronic mutation responsible for lactic acidosis and mental retardation.

An intronic point mutation was identified in the E1alpha PDH gene from a boy with delayed development and lactic acidosis, an X-linked disorder associated with a partial defect in pyruvate dehydrogenase (PDH) activity. Protein analysis demonstrated a corresponding decrease in immunoreactivity of the alpha and beta subunits of the PDH complex. In addition to the normal spliced mRNA product of the E1alpha PDH gene, patient samples contained significant levels of an aberrantly spliced mRNA with the first 45 nucleotides of intron 7 inserted in-frame between exons 7 and 8. The genomic DNA analysis found no mutation in the coding regions but revealed a hemizygous intronic G to A substitution 26 nucleotides downstream from the normal exon 7 5'-splice site. Splicing experiments in COS-7 cells demonstrated that this point mutation at intron 7 position 26 is responsible for the aberrant splicing phenotype, which involves a switch from the use of the normal 5'-splice site (intron 7 position 1) to the cryptic 5'-splice site downstream of the mutation (intron 7 position 45). The intronic mutation is unusual in that it generates a consensus binding motif for the splicing factor, SC35, which normally binds to exonic enhancer elements resulting in increased exon inclusion. Thus, the aberrant splicing phenotype is most likely explained by the generation of a de novo splicing enhancer motif, which activates the downstream cryptic 5'-splice site. The mutation documented here is a novel case of intron retention responsible for a human genetic disease.

Acidosis, Lactic↗

PubMed2002

Facial appearance in persistent hyperinsulinemic hypoglycemia.

Persistent hyperinsulinism is the most common cause of recurrent hypoglycemia in infancy because of inappropriate oversecretion of insulin by the pancreas. Pancreatic lesions can be either focal or diffuse, and they have distinct molecular bases. We have studied the facial features in 17 unrelated patients presenting with neonatal (n = 8) or infancy-onset (n = 9) hyperinsulinism. Hyperinsulinism was related to focal adenomatous hyperplasia (n = 7), diffuse hyperinsulinism (n = 5), non-operated hyperinsulinism (n = 2), and hyperinsulinism with hyperammonemia (n = 3). SUR1 or Kir6.2 mutations were found in six of seven focal adenomatous hyperplasia and three of five diffuse hyperinsulinism. A loss of the maternal allele from chromosome 11p15 in the lesion was found in all focal adenomatous hyperplasia. GLUD1 mutations were found in all patients with hyperammonemia. Large birth weight (mean > 3,800 g) was consistently observed (11/17) but protruding tongue, exomphalos, or visceromegaly were never noted and Wiedemann-Beckwith syndrome could always be ruled out. All patients presented with high forehead, small nasal tip, and short columella giving the impression that the nose is large and bulbous, smooth philtrum, and thin upper lip. A square appearance to the face was more obvious in younger patients. These specific facial features, observed in patients with hyperinsulinism of various molecular mechanisms, could be the consequence of fetal intoxication by insulin. However, to date, facial anomalies have not been noted in infants of diabetic mothers and inversely, malformations that are commonly reported in infants of diabetic mothers were not present in our hyperinsulinemic patients.

ATP-Binding Cassette Transporters↗

PubMed2002

Massive subdural haematomas in Menkes disease mimicking shaken baby syndrome.

INTRODUCTION: Menkes disease is an X-linked inherited disorder of intestinal copper absorption resulting in copper deficiency. Cardinal features include hair abnormalities, facial dysmorphism, severe neurological impairment, hypothermia, arterial anomalies, bone abnormalities and a fatal outcome. CASE REPORT: We present a case of Menkes disease complicated by progressive macrocephaly following the development of massive subdural haematomas. These lesions associated with femoral metaphyseal spurs could be confused with nonaccidental injury such as that seen in the shaken baby syndrome. DISCUSSION: This case emphasises that Menkes disease, like glutaric aciduria type 1, should be included in the differential diagnosis of unexplained subdural haematomas and neurological deficits in infants.

Diagnosis, Differential↗

PubMed2002

Heterogeneity of persistent hyperinsulinaemic hypoglycaemia. A series of 175 cases.

UNLABELLED: Hyperinsulinism is a heterogeneous disorder characterised by severe hypoglycaemia due to an inappropriate oversecretion of insulin. In a personal series of 175 patients investigated for hyperinsulinaemic hypoglycaemia over the last 20 years, we review clinical presentations, molecular studies and therapeutic management of hyperinsulinism. There were 98 neonatal-onset patients, including 86 permanent hyperinsulinism and 12 transient forms, 68 with infancy-onset and nine with childhood-onset. Hyperammonaemia was found in 12 out of 69 patients tested, 4 neonates and 8 infants. Neonates were clinically more severely affected than infants. Diagnosis of infancy-onset hyperinsulinism was often delayed because of less profound hypoglycaemia and better tolerance to hypoglycaemia. Neonates required higher rates of i.v. glucose than infants to maintain normal plasma glucose levels (16 mg/kg per min versus 12 mg/kg per min). Only 16% of neonates were diazoxide-sensitive compared to 66% of the infants. Neonates with hyperammonaemia or transient hyperinsulinism were diazoxide-sensitive. Most neonates were pancreatectomised whereas 65% of the infants were treated medically. Among surgically-treated patients, 47% had a focal adenomatous hyperplasia (31 neonates and 13 infants) and 53% a diffuse form of hyperinsulinism (39 neonates and 11 infants). Diazoxide-responsiveness in the focal and diffuse forms did not differ in both neonates and infants; it depended only upon the age of onset of hypoglycaemia. One or two mutations, SUR1 or KIR6.2, were found in 41 of 73 neonates who were investigated and in 13/38 infants using polymerase chain reaction-single strand conformational polymorphism analysis of both genes. Almost all patients with SUR1 (38/41) or KIR6.2 (5/7) mutations were resistant to diazoxide. Ten patients with hyperinsulinism-hyperammonaemia syndrome had a mutation in the glutamate dehydrogenase gene (three neonates and seven infants) after reverse transcriptase-polymerase chain reaction and sequence analysis of cDNA. No mutation was found by polymerase chain reaction-single strand conformational polymorphism in the glucokinase gene. Eight of nine patients with childhood onset hyperinsulinism were treated surgically and histological examination confirmed an adenoma in each case. CONCLUSION: the clinical severity of hyperinsulinism varies mainly with age at onset of hypoglycaemia. The heterogeneity of hyperinsulinism has major consequences in terms of therapeutic outcome and genetic counselling.

Age of Onset↗

PubMed2002

Persistent hyperinsulinaemic hypoglycaemia.

Congenital hyperinsulinism (CI) is the most important cause of hypoglycaemia in early infancy. The inappropriate oversecretion of insulin is responsible for profound hypoglycaemias which require aggressive treatment to prevent severe and irreversible brain damage. Hypoglycaemia have a neonatal or infancy onset. Medical treatment with diazoxide is first used to treat CI, but patients who are medically resistant (mostly of neonatal-onset) require pancreatectomy. CI is a heterogeneous disorder with two histopathological lesions, diffuse and focal which are clinically indistinguishable. Only diazoxide-sensitive neonates should be orientated to transient hyperinsulinism or hyperinsulinism-hyperammonemia syndrome. Focal CI is characterized by a sporadic somatic islet-cell hyperplasia. Diffuse CI corresponds to a functional abnormality of insulin secretion in the whole pancreas and involves several genes with different transmissions. The knowledge of both focal and diffuse lesions is very important. Focal lesions are effectively treated by limited pancreatic resection while diffuse lesions which are unresponsive to drug or dietary treatment require extensive pancreatectomy with high risk of diabetes mellitus.

Diazoxide↗