Search PubMed⌕ Search

Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 307 records · Page 17Linked to original sources
PubMed1996

Metabolic intermediates in lactic acidosis: compounds, samples and interpretation.

A number of acquired conditions including infections, severe catabolic states, tissue anoxia, severe dehydration and poisoning can give rise to hyperlactacidaemia. All these causes should be ruled out before considering inborn errors of metabolism. Carefully collected samples are necessary if artefacts that result in spuriously increased lactate/pyruvate (L/P) and 3-hydroxybutyrate/acetoacetate (B/A) ratios are to be avoided. When properly performed, 24-h studies of L/P and B/A ratios provide a useful tool in making a diagnosis. A few metabolic profiles when present are specific or highly suggestive of a given disorder. When the L/P ratio is normal or low, pyruvate dehydrogenase (PDH) deficiency is highly probable whatever the lactate concentration, which is often only moderately elevated after meal, may be. When the L/P ratio is very high in association with post-prandial hyperketonaemia and in contrast to a normal or low B/A ratio, pyruvate carboxylase (PC) deficiency and alpha-ketoglutarate dehydrogenase (KGDH) deficiency are the most likely diagnoses. The distinction between the two disorders relies upon amino acid and organic acid profiles (glutamate and alpha-ketoglutarate accumulations in KGDH deficiency and hyperammonaemia and hypercitrullinaemia in PC deficiency). When both L/P and B/A ratios are elevated and associated with significant post-prandial hyperketonaemia, respiratory-chain disorders should first be suspected. All other profiles, especially a high L/P ratio without hyperketonaemia, are compatible with respiratory-chain disorders but are not specific; all acquired anoxic conditions should also be ruled out. Clearly, the clinical utility of these profiles needs to be interpreted cautiously in very ill patients in relation to the cardiocirculatory condition and to therapy. Finally, a normal profile, even after stress and loading, does not rule out an inborn error of lactate/pyruvate oxidation.

Acidosis, Lactic↗
PubMed1996

Clinical presentation of mitochondrial disorders in childhood.

Respiratory-chain deficiencies have long been regarded as neuromuscular diseases. In fact, oxidative phosphorylation, i.e. adenosine triphosphate (ATP) synthesis by the respiratory chain, does not occur only in the neuromuscular system. Indeed, a number of non-neuromuscular organs and tissues are dependent upon mitochondrial energy supply. For this reason, a respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, owing to the twofold genetic origin of respiratory enzymes (nuclear DNA and mitochondrial DNA, mtDNA). In recent years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in childhood. Among 100 patients with respiratory-chain deficiencies identified in our centre, 56% presented with a non-neuromuscular symptom and 44% were referred for a neuromuscular problem. It appears that the diagnosis of a respiratory-chain deficiency is difficult initially when only one symptom is present. In contrast, this diagnosis is easier to consider when two seemingly unrelated symptoms are observed.

Child↗
PubMed1996

Abnormal cholesterol biosynthesis in the Smith-Lemli-Opitz and the lethal acrodysgenital syndromes.

UNLABELLED: The Smith-Lemli-Opitz syndrome (SLO) is an autosomal recessive disorder characterized by dysmorphic facial features with abnormal limbs and genitalia. Two forms have been recognized based on clinical course and severity: the classical SLO (type I) and the lethal acrodysgenital syndrome (type II). Type I SLO has been recently ascribed to a defect in cholesterol synthesis. Taking advantage of a series of seven patients including five type I and two type II SLO, we describe micrognathia, severe microcephaly, major ante and post natal growth retardation and feeding difficulties as consistent features in the disease. In addition, we give support to the presence of abnormal cholesterol levels in the lethal acrodysgenital syndrome but find no correlation between plasma sterol levels and the clinical severity of the disease. CONCLUSION: The identification of the same biochemical defect in both types of Smith-Lemli-Opitz Syndrome suggests that despite major discrepancies in clinical course and severity, type I and type II SLo are probably allelic disorders.

Child↗
PubMed1996

Clinical presentations and laboratory investigations in respiratory chain deficiency.

Respiratory chain deficiencies have long been regarded as neuromuscular diseases. In fact, oxidative phosphorylation, i.e., ATP synthesis by the respiratory chain not only occurs in the neuromuscular system, indeed, a number of non-neuromuscular organs and tissues are dependent upon mitochondrial energy supply. For this reason, a respiratory chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age with any mode of inheritance, due to the twofold genetic origin of respiratory enzymes (nuclear DNA and mitochondrial DNA).

Child, Preschool↗
PubMed1996

Most cases of medium-chain acyl-CoA dehydrogenase deficiency escape detection in France.

DNA from 414 French blood donors from the Paris area was assessed for the A985G mutation responsible for most cases of autosomal recessive medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. The mutant gene frequency averaged 1/140, predicting a frequency of mutant homozygotes of 1/19 000. Discrepancy between the numbers of expected (42 per year) and recorded cases of MCAD (6 per year) suggests that most MCAD-deficient patients escape detection in France.

Acyl-CoA Dehydrogenase↗
PubMed1996

Evidence of genetic heterogeneity of Leber's congenital amaurosis (LCA) and mapping of LCA1 to chromosome 17p13.

Leber's congenital amaurosis (LCA) is an autosomal recessive disease responsible for congenital blindness. It is the earliest and most severe inherited retinal dystrophy in human and its genetic heterogeneity has long been recognised. We have recently reported on the first localisation of a disease gene (LCA1) to the short arm of chromosome 17 by homozygosity mapping in five families of North African origin. Here, we refine the genetic mapping of LCA1 to chromosome 17p13 between loci D17S938 and D17S1353 and provide strong support for the genetic heterogeneity of this condition (maximum likelihood for heterogeneity, 17.20 in InL; heterogeneity versus homogeneity, P = 0.0002, heterogeneity versus no linkage, P < 0.0001)

Blindness↗
PubMed1996

Possible genetic heterogeneity in the Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3-p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Zmax = 4.78 at [symbol: see text] = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval.

Acrocephalosyndactylia↗
PubMed1996

Retinitis punctata albescens associated with the Arg135Trp mutation in the rhodopsin gene.

PURPOSE: To screen for mutations in the rhodopsin, peripherin/RDS, and ROM1 genes in a family affected with retinitis punctata albescens. Because clinical heterogeneity was observed in this family, with some members affected with retinitis punctata albescens and one member affected with features typical of retinitis pigmentosa, we analyzed the apolipoprotein E gene to elucidate this unusual intrafamilial heterogeneity. METHODS: The coding sequences of these genes were analyzed with a combination of single-strand conformation polymorphism and direct sequence analysis. Haplotypes of the apolipoprotein E gene were analyzed by polymerase chain reaction and enzymatic digestion. RESULTS: The Arg135Trp mutation in the rhodopsin gene was observed in all affected members of this family, but no mutation was detected in the peripherin/RDS or ROM1 genes. The e4 allele of the apolipoprotein E gene apparently cosegregated with the albescens phenotype in this family. CONCLUSIONS: The albescent phenotype in retinal dystrophy appears to not be caused exclusively by a peripherin/RDS gene mutation, and we suggest that the apolipoprotein E gene may play a role in the albescent phenotype.

Adolescent↗
PubMed1996

Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).

Hirschsprung disease (HSCR) and Waardenburg sundrome (WS) are congenital malformations regarded as neurocristopathies since both disorders involve neural crest-derived cells. The WS-HSCR association (Shah-Waardenburg syndrome) is a rare autosomal recessive condition that occasionally has been ascribed to mutations of the endothelin-receptor B (EDNRB) gene. WS-HSCR mimicks the megacolon and white coat-spotting observed in Ednrb mouse mutants. Since mouse mutants for the EDNRB ligand, endothelin-3 (EDN3), displayed a similar phenotype, the EDN3 gene was regarded as an alternative candidate gene in WS-HSCR. Here, we report a homozygous substitution/deletion mutation of the EDN3 gene in a WS-HSCR patient. EDN3 thus becomes the third known gene (after RET and EDNRB) predisposing to HSCR, supporting the view that the endothelin-signaling pathways play a major role in the development of neural crests.

Amino Acid Sequence↗
PubMed1996

Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.

Drosophila Proteins↗
PubMed1996

Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis.

Leber's congenital amaurosis (LCA, MIM 204,000), the earliest and most severe form of inherited retinopathy, accounts for at least 5% of all inherited retinal dystrophies. This autosomal recessive condition is usually recognized at birth or during the first months of life in an infant with total blindness or greatly impaired vision, normal fundus and extinguished electroretinogram (ERG). Nystagmus (pendular type) and characteristic eye poking are frequently observed in the first months of life (digito-ocular sign of Franceschetti). Hypermetropia and keratoconus frequently develop in the course of the disease. The observation by Waardenburg of normal children born to affected parents supports the genetic heterogeneity of LCA. Until now, however, little was known about the pathophysiology of the disease, but LCA is usually regarded as the consequence of either impaired development of photoreceptors or extremely early degeneration of cells that have developed normally. We have recently mapped a gene for LCA to chromosome 17p13.1 (LCA1) by homozygosity mapping in consanguineous families of North African origin and provided evidence of genetic heterogeneity in our sample, as LCA1 accounted for 8/15 LCA families in our series. Here, we report two missense mutations (F589S) and two frameshift mutations (nt 460 del C, nt 693 del C) of the retinal guanylate cyclase (RETGC, GDB symbol GUC2D) gene in four unrelated LCA1 probands of North African ancestry and ascribe LCA1 to an impaired production of cGMP in the retina, with permanent closure of cGMP-gated cation channels.

Blindness↗
PubMed1996

Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease.

Hirschsprung disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Two susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene and the endothelin B receptor (EDNRB) gene. Hitherto however, homozygosity for EDNRB mutations accounted for the HSCR-Waardenburg syndrome (WS) association. Here, we report heterozygous EDNRB missense mutations (G57S, R319W and P383L) in isolated HSCR. These data might suggest that EDNRB mutations could be dosage sensitive: heterozygosity would predispose to isolated HSCR with incomplete penetrance, while homozygosity would result in more complex neurocristopathies associating HSCR and WS features. In addition, the present data give further support to the role of the endothelin-signalling pathway in the development of neural crest-derived enteric neurons.

Female↗
PubMed1996

Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1).

Thanatophoric dwarfism (TD) is a sporadic lethal skeletal dysplasia with micromelic shortening of the limbs, macrocephaly, platyspondyly and reduced thoracic cavity. In the most common subtype (TD1), femurs are curved, while in TD2, straight femurs are associated with cloverleaf skull. Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene were identified in both subtypes. While TD2 was accounted for by a single recurrent mutation in the tyrosine kinase 2 domain, TD1 resulted from either stop codon mutations or missense mutations in the extracellular domain of the gene. Here, we report the identification of FGFR3 mutations in 25/26 TD cases. Two novel missense mutations (Y373C and G370C) were detected in 8/26 and 1/26 TD1 cases respectively. Both mutations created cysteine residues in the juxta extramembrane domain of the receptor. Sixteen cases carried the previously reported R248C (9/26 cases), S249C (2/26 cases) or stop codon FGFR3 mutations (5/26 cases). Our results suggest that TD1 is a genetically homogeneous condition and give additional support to the view that newly created cysteine residues in the extracellular domain of the protein play a key role in the severity of the disease.

Base Sequence↗