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Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 361 records · Page 20Linked to original sources
PubMed1995

Spectrum of mitochondrial DNA rearrangements in the Pearson marrow-pancreas syndrome.

The Pearson marrow-pancreas syndrome (MIM 557000) is a disorder involving the hematopoietic system and the exocrine pancreas in early infancy. We have previously shown that this disease results from a defect of oxidative phosphorylation associated with deletions of the mitochondrial DNA. We present here a series of 21 cases (including 15 unreported patients) with Pearson syndrome and describe mitochondrial DNA deletions as consistent features in this syndrome. Nine patients presented the same 4.9 kb deletion, while other patients presented different deletions ranging in size from 9 to 14 kb between tRNACyst and the D-loop. Direct repeats (4-13 bp) were consistently present in the wild-type mtDNA at the boundaries of the deletions. Deletion-dimers, deletion-multimers or duplications were observed in association with deletions. Duplications were identified both in patients who died of their Pearson syndrome and in the ones who survived and developed Kearns-Sayre syndrome, suggesting that no correlation could be made between the clinical severity and the type, size or location of the rearrangements.

Base Sequence↗
PubMed1995

Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease.

Hirschsprung disease (HSCR) is a common congenital malformation (1 in 5,000 live births) due to the absence of autonomic ganglia in the terminal hindgut, and resulting in intestinal obstruction in neonates. Recently, a dominant gene for familial HSCR has been mapped to chromosome sub-band 10q11.2 and the disease has been ascribed to mutations in a tyrosine kinase receptor gene mapping to this region, the RET proto-oncogene. Studying the 20 exons of the RET gene by a combination of denaturating gradient gel electrophoresis and single strand conformation polymorphism in a large series of HSCR patients (45 sporadic cases and 35 familial forms), we found mutations of the RET gene in 50% of familial HSCR, regardless of the length of the aganglionic segment. The mean penetrance of the mutant allele in familial HSCR was significantly higher in males (72%) than in females (51%). Most interestingly, mutations at the RET locus accounted for at least 1/3 of sporadic HSCR in our series. These mutations were scattered along the length of the gene. Finally, among the mutations identified in sporadic cases (16/45), seven proved to be de novo mutations suggesting that new mutations at the RET locus significantly contribute to sporadic HSCR. Taken together, the low penetrance of the mutant gene, the lack of genotype-phenotype correlation, the sex-dependent effect of RET mutations and the variable clinical expression of the disease support the existence of one or more modifier genes in familial HSCR.

Base Sequence↗
PubMed1995

No evidence of genetic heterogeneity in dominant optic atrophy.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease causing a variable reduction of visual acuity with an insidious onset in the first six years of life. It is associated with a central scotoma and an acquired blue-yellow dyschromatopsia. A gene for dominant optic atrophy (OPA1) has recently been mapped to chromosome 3q in three large Danish pedigrees. Here, we confirm the mapping of OPA1 to chromosome 3q28-qter by showing close linkage of the disease locus to three recently reported microsatellite DNA markers in the interval defined by loci D3S1314 and D3S1265 in four French families (Zmax = 5.13 at theta = 0 for probe AFM 308yf1 at locus D3S1601). Multipoint analysis supports the mapping of the disease gene to the genetic interval defined by loci D3S1314 and D3S1265. The present study provides three new markers closely linked to the disease gene for future genetic studies in OPA.

Chromosome Mapping↗
PubMed1995

Exclusion of RET and Pax 3 loci in Waardenburg-Hirschsprung disease.

The RET and the Pax 3 genes have recently been shown to account for autosomal dominant Hirschsprung's disease (HSCR) and Waardenburg syndrome type 1 (WS1) respectively, which led us to consider them as candidate genes in the WS/HSCR association. Linkage analyses performed in a consanguineous WS/HSCR family support the view that neither the RET locus nor the Pax 3 locus are involved in the disease phenotype. Hence, at least one further locus altering neural crest cell development is responsible for the pleiotropic features observed in the WS/HSCR association.

Consanguinity↗
PubMed1995

Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness.

The A 3243 G mutation of the mitochondrial tRNA(Leu) gene was found to segregate with maternally inherited diabetes mellitus, sensorineural deafness, hypertrophic cardiomyopathy, or renal failure in a large pedigree of 35 affected members in four generations. Presenting symptoms almost consistently involved deafness and recurrent attacks of migraine-like headaches, but the clinical course of the disease varied within and across generations. The A 3243 G mutation has been previously reported in association with the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome (MELAS) and with diabetes mellitus and deafness. To our knowledge, however, hypertrophic cardiomyopathy is not a common feature in people with the A 3243 G mutation and renal failure has not been hitherto reported in association with this mutation. The present observation gives additional support to the variable clinical expression of mtDNA mutations in humans.

Adenine↗
PubMed1995

Filippi syndrome: a new case with skeletal abnormalities.

We report on a 9 year old girl, born to consanguineous parents, with major microcephaly, cutaneous syndactyly of the toes, and moderate mental retardation with marked speech involvement. In addition, moderate dysmorphic features and skeletal abnormalities were noted. This multiple congenital anomalies/mental retardation pattern very much resembles that described by Filippi. This observation confirms that this syndrome is a distinct, probably autosomal recessive entity.

Abnormalities, Multiple↗
PubMed1995

Unusual association of juvenile macular dystrophy with congenital hypotrichosis: occurrence in two siblings suggesting autosomal recessive inheritance.

A familial association between juvenile macular dystrophy and congenital hypotrichosis is described in two siblings aged 25 and 23 years. We put forward arguments for locating the retinal alteration at the level of the retinal pigment epithelium and suggest that the hair disorder could be a Marie-Unna type hypotrichosis. This association is transmitted as an autosomal recessive condition.

Adult↗
PubMed1995

[Gene localisation in 12q12 in Holt-Oram atrio-digital syndrome].

The Holt-Oram syndrome, first described in 1960, consists of non-cyanotic congenital heart disease, usually an atrial septal defect, arrhythmias and malformations of the upper limbs affecting the radial segment. The transmission of the syndrome is autosomal dominant with almost complete penetrance. The authors report the localisation of a genetic abnormality of the Holt-Oram syndrome on the long arm of chromosome 12 (12q21-q3) by analysis of linkage in 9 multiplex families (Zmax = 8.19 at locus D12S354). Multipoint analysis showed a genetic interval of 7 centimorgans containing a gene of the Holt-Oram syndrome between loci D12S84 and D12S79 (multipoint lod score, 10 g base 10 = 8.96). In situ hybridization of artificial yeast chromosomes containing the surrounding markers showed that a gene of the Holt-Oram syndrome is located in 12q23-q24. The genetic heterogeneity was demonstrated in 3 families of the Holt-Oram syndrome with polydactyly or without cardiac disease (homog-test: chi 2 = 13.28; p = 0.0001). The localisation of a gene of the Holt-Oram syndrome is, to the authors' knowledge, the first chromosomal localisation of a cardiac malformation with septal defects in man. The identification of this gene should open wide perspectives for genetic research of cardiac morphogenesis and clarify the molecular mechanisms which govern cardiac septation during embryogenesis.

Chromosome Mapping↗
PubMed1995

A gene for late-onset fundus flavimaculatus with macular dystrophy maps to chromosome 1p13.

Fundus flavimaculatus with macular dystrophy is an autosomal recessive disease responsible for a progressive loss of visual acuity in adulthood, with pigmentary changes of the macula, perimacular flecks, and atrophy of the retinal pigmentary epithelium. Since this condition shares several clinical features with Stargardt disease, which has been mapped to chromosome 1p21-p13, we tested the disease for linkage to chromosome 1p. We report here the mapping of the disease locus to chromosome 1p13-p21, in the genetic interval defined by loci D1S435 and D1S415, in four multiplex families (maximum lod score 4.79 at recombination fraction 0 for probe AFM217zb2 at locus D1S435). Thus, despite differences in the age at onset, clinical course, and severity, fundus flavimaculatus with macular dystrophy and Stargardt disease are probably allelic disorders. This result supports the view that allelic mutations produce a continuum of macular dystrophies, with onset in early childhood to late adulthood.

Alleles↗
PubMed1995

Mitochondrial respiratory chain defect: a new etiology for neonatal cholestasis and early liver insufficiency.

Two siblings presented with neonatal cholestasis and early liver insufficiency. The older was admitted for end-stage cirrhosis with severe hypoglycemia and had long-term successful liver transplant at the age of 15 months. The second child presented a similar neonatal history of cholestasis, hypoglycemia, hyperlactacidemia, liver insufficiency and progressive cirrhosis. Extensive work-up excluded all known causes of neonatal cholestasis. Gluconeogenesis was found normal following alanine and fructose infusion. Repeated hypoglycemia with early post-prandial hyperlactacidemia led us to investigate the mitochondrial respiratory chain enzyme activities. Selective defects of complexes I, III and IV, coded by mitochondrial DNA, were detected in liver tissue of this patient and on preserved frozen tissue from his sibling, whilst normal activities were found in liver tissue samples from control patients with end-stage liver diseases. No extrahepatic manifestations were found. We conclude that liver deficiency of mitochondrial respiratory chain enzymes may cause liver disease in neonates, associated with hypoglycemia and post-prandial hyperlactacidemia. The disease is cured by liver transplantation.

Acidosis, Lactic↗
PubMed1994

[Hypertrophic cardiomyopathy caused by cytochrome-oxidase deficiency].

Mitochondrial cytopathies are due to genetic anomalies in the oxidative phosphorylation enzymes (excepting Krebs cycle, pyruvate and certain other mitochondrial enzymes). Recently discovered, these diseases have a characteristic heterogeneous clinical expression because of the ubiquitous nature of this intracellular organelle. We observed a case in a 16-year-old girl who had cytochrome C oxidase deficiency. The child was born to non-consanguinous parents and had a healthy brother. The first manifestation of the disease was a systolic murmur heard at the age of 4 years. Progressively, exertion dyspnoea, lipothymia with cyanose led to the first echocardiography at 8 years revealing non-obstructive cardiomyopathy. Functional inadaptation of cardiac performance worsened requiring various symptomatic treatments. At the age of 16, the symptomatology included lower limb fatigue and the diagnosis of a metabolic disease was entertained. Phosphorylase A and B activity and phosphokinase activity were normal. High lactic acid levels after exertion suggested a mitochondrial enzyme deficiency. The diagnosis of cytochrome C oxidase deficiency was confirmed by spectrophotometric and polarographic assay of mitochondria from a peripheral muscle biopsy. Treatment with riboflavin, ascorbic acid, factor P, menadione, carnitine and iron sulfate has currently provided some symptomatic improvement. In patients with unexplained cardiomyopathy, the diagnosis of mitochondrial cytopathy should be entertained if oxidoreduction potentials (lactate/pyruvate ratio) are perturbed. The diagnosis is confirmed by enzyme studies of fresh muscle mitochondria. Currently therapeutic prospects are at best very poor. Genetic counselling may be advisable.

Adolescent↗
PubMed1994

Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.

Achondroplasia, the most common cause of chondrodysplasia in man (1 in 15,000 live births), is a condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, suggesting that de novo mutations are of paternal origin. Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (10%). In contrast, homozygous achondroplasia is usually lethal in the neonatal period and affects 25% of the offspring of matings between heterozygous achondroplasia parents. The gene responsible for achondroplasia has been mapped to chromosome 4p16.3 (refs 7, 8); the genetic interval encompassing the disease gene contains a member of the fibroblast-growth-factor receptor (FGFR3) family which is expressed in articular chondrocytes. Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia. We show that the mutant genotype segregates with the disease in these families. Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.

Achondroplasia↗
PubMed1994

Apparent genetic homogeneity of the Treacher Collins-Franceschetti syndrome.

The Treacher Collins-Franceschetti syndrome (TCOF) or mandibulofacial dysostosis (MFD) is an autosomal dominant disorder characterized by craniofacial abnormalities and hearing loss. A refined genetic linkage map of the TCOF locus was established in 8 independent families, using 12 microsatellite DNA markers of the distal 5q. Positive lod score values were obtained for all markers with a maximum at the D5S413 locus (Zmax = 3.79 at theta = 0%). Multipoint linkage analysis and haplotype analysis supported the location of the gene between loci D5S434 and D5S412. These results are consistent with previous linkage analyses [Dixon et al.: Am J Hum Genet 49:17-22, 1991, Am J Hum Genet 52:907-914, 1993; Jabs et al.: Genomics 11:193-198, 1991, Genomics 18:7-13, 1993] and provide further evidence of genetic homogeneity in this syndrome.

Chromosomes, Human, Pair 5↗
PubMed1994

An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy.

We performed linkage analysis of 161 families with spinal muscular atrophy (SMA) in which affected individuals suffer from the intermediate or mild form of the disease (Types II or III). Markers for six loci encompassing the chromosome 5q11.2-q13.3 region were typed. The best map location for the disease locus was found to be between D5S6 and MAP1B. The corresponding 1 lod unit support intervals is confined to this interval and spans 0.5 cM. The data strongly support the hypothesis of linkage heterogeneity (likelihood ratio, 1.14 x 10(4)), with 5% of the families unlinked. Four families have a probability of less than 50% of segregating the SMA gene linked to the region 5q11.2-q13.3. A likelihood approach to test for linkage disequilibrium revealed no significant departure from Hardy-Weinberg equilibrium with any marker under study.

Alleles↗
PubMed1994

Mutations of the RET proto-oncogene in Hirschsprung's disease.

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons 2, 3, 5 and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

Base Sequence↗
PubMed1994

Genetic heterogeneity of Crigler-Najjar syndrome type I: a study of 14 cases.

Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients; Q357R); Turkey (one patient: S381R); italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.

Crigler-Najjar Syndrome↗