Search PubMed⌕ Search

Biomedical subjects

A Munnich

Publications and source records attributed to A Munnich.

At least 91 records · Page 5Linked to original sources
PubMed2001

Orthotopic liver transplantation for mitochondrial respiratory chain disorders: a study of 5 children.

BACKGROUND: Liver involvement in mitochondrial respiratory chain disorders (MRCD) frequently ends in liver failure and death. Because of the high risk of extrahepatic, particularly neuromuscular, manifestations of the disease, the indication of orthotopic liver transplantation (OLT) in these patients remains controversial. We report on 5 such children in whom OLT was carried out, in an attempt to help clarify the matter. PATIENTS: Patients 1 and 2 presented with fulminant liver failure at ages 7 and 6 months respectively. Emergency liver transplantation was performed before etiological investigations were completed. Retrospective examination of the explanted livers showed defects in complexes I, III and IV. In patient 1, severe neurological deterioration occurred 2 months after OLT with fatal outcome 9 months later. Patient 2 is alive 22 months after OLT with moderate motor impairment. Patients 3, 4 and 5 presented with progressive liver failure before 6 months of age. Surgical liver biopsies displayed a 50% defect in complex IV (patient 3), a defect in complexes I, IV (patient 4) and in complexes I, III, IV (patient 5). Because there was no clinical extrahepatic involvement on investigations, OLT was carried out in these patients. Patient 3 died of multiple organ failure soon after OLT, patients 4 and 5 are alive respectively 21 months and 12 months after OLT with normal neurological examination. CONCLUSION: OLT may be a valid therapeutic option in infants with delayed liver cell failure due to MRCD, only after performing in emergency a thorough inves tigation to exclude clinically significant extrahepatic, especially neuromuscular, involvement.

Child↗
PubMed2001

Mutations in the basic domain and the loop-helix II junction of TWIST abolish DNA binding in Saethre-Chotzen syndrome.

Saethre-Chotzen syndrome is an autosomal dominant skull disorder resulting from premature fusion of coronal sutures (craniosynostosis). It is caused by mutations in the TWIST gene encoding a basic Helix-Loop-Helix transcription factor. Here we report on the identification of a novel mutation affecting a highly conserved residue of the basic domain. Unlike nonsense and missense mutations lying within helices, this mutation does not affect protein stability or heterodimerisation of TWIST with its partner E12. However, it does abolish TWIST binding capacity to a target E-box as efficiently as two missense mutations in the loop-helix II junction. By contrast, elongation of the loop through a 7 amino acid insertion appears not to hamper binding to the DNA target. We conclude that loss of TWIST protein function in Saethre-Chotzen patients can occur at three different levels, namely protein stability, dimerisation, and DNA binding and that the loop-helix II junction is essential for effective protein-DNA interaction.

Acrocephalosyndactylia↗
PubMed2001

Expression study of genes involved in iron metabolism in human tissues.

Iron is required in all organisms for crucial functions, as a number of proteins need iron for activity. Mutations of the genes encoding proteins involved in iron uptake, transport, and utilization result in various human disorders or animal models with very different clinical presentations and organ involvement. However, little is known concerning the expression of iron metabolism genes in various human tissues and their eventual concerted regulation. We therefore examined the expression levels of various genes involved in iron uptake, reduction, and storage, in Fe-S protein biogenesis, in mitochondrial electron transport chain, plus the two SOD genes, in human adult tissues by Northern blot analysis. We observed that most of these genes were ubiquitously expressed, but that their transcript showed strongly different levels in the various tissues investigated denoting different mechanisms for iron utilization in various organs. However, surprisingly, no correlation could be made between expression pattern of these genes and the clinical presentation resulting in their mutations.

Animals↗
PubMed2001

Mazabraud syndrome in two patients: clinical overlap with McCune-Albright syndrome.

Mazabraud syndrome is a rare sporadic disorder, mainly characterized by bone fibrous dysplasia and intramuscular myxomas. We report here two new cases of Mazabraud syndrome. One of our patients (Patient 1) also had café-au-lait spots and multinodular goiter suggestive of McCune-Albright syndrome. We review the 37 previously reported cases with Mazabraud syndrome and discuss the 6/37 patients with criteria of Mazabraud and McCune-Albright syndromes. Based on the clinical overlap between the two syndromes, we tested the GNAS1 gene in blood leukocytes and skin fibroblasts of Patient 1, but found no evidence of an activating mutation in the GNAS1 gene.

Abnormalities, Multiple↗
PubMed2001

Temporal bone anomaly proposed as a major criteria for diagnosis of CHARGE syndrome.

The acronym CHARGE defines a non-random clustering of congenital malformations of unknown origin. Classical diagnostic criteria include: 1) one major feature namely coloboma/microphthalmia or choanal atresia, and 2) four of the six features designated in the CHARGE acronym. Interestingly, all CHARGE patients hitherto reported had partial or complete semicircular canal hypoplasia on temporal bone CT-scan. We report on semicircular canal agenesis/hypoplasia in three patients with three to four features of the CHARGE syndrome and neither coloboma nor choanal atresia and we propose to include temporal bone malformations as a major criteria for diagnosis of CHARGE syndrome.

Abnormalities, Multiple↗
PubMed2001

Allelic and nonallelic heterogeneity in dyschondrosteosis (Leri-Weill syndrome).

Dyschondrosteosis (DCS) is an autosomal dominant form of mesomelic dysplasia that has been recently ascribed to large-scale deletions and nonsense mutations of the SHOX gene on the pseudoautosomal region of chromosome X and Y [Belin et al., 1998: Nat Genet 19:67-69; Shears et al., 1998: Nat Genet 19:70-73]. Here, we report the molecular analysis of a total of 23 DCS families including 16 previously reported pedigrees [Belin et al., 1998: Nat Genet 19:67-69; Huber et al., 2001: J Med Genet 38:281-284] and 7 novel DCS families. Linkage analyses in 21 of 23 families were consistent with linkage to the pseudoautosomal region. However, in 2 of 23 families, linkage studies excluded SHOX as the disease-causing gene, suggesting that this condition is genetically heterogeneous.

Alleles↗
PubMed2001

Clinical spectrum and diagnosis of mitochondrial disorders.

Respiratory chain deficiencies have long been regarded as neuromuscular diseases mostly originating from mutations in the mitochondrial DNA. Actually, oxidative phosphorylation, i.e., adenosine triphosphate (ATP) synthesis-coupled electron transfer from substrate to oxygen through the respiratory chain, does not only occur in the neuromuscular system. 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 dual genetic origin of respiratory chain enzymes (nuclear DNA and mitochondrial DNA). In recent years, it has become increasingly clear that genetic defects of oxidative phosphorylation account for a large variety of clinical symptoms in both childhood and adulthood. Diagnosis of a respiratory chain deficiency is difficult initially when only one symptom is present, and easier when additional, seemingly unrelated, symptoms are observed. The clinical heterogeneity is echoed by the genetic heterogeneity illustrated by the increasing number of nuclear genes that have been shown to be involved in these diseases. In the absence of clear-cut genotype-phenotype correlations and in front of the large number of possibly involved genes, biochemical analyses are still the cornerstone of the diagnosis of this condition.

Adult↗
PubMed2001

Prenatal diagnosis of respiratory chain deficiency by direct mutation screening.

Respiratory chain deficiency (RCD) is responsible for a clinically heterogeneous group of early-onset untreatable disorders. Enzymological prenatal diagnosis (PD) can only be offered to a fraction of families. Moreover, due to the two-fold genetic origin of the respiratory chain (nuclear and mitochondrial DNA) and owing to the large number of nuclear genes involved in the respiratory chain assembly, maintenance and functioning, the identification of the disease causing gene in a given family remains challenging. Here, we report on PD of RCD by direct screening of NDUFV1, SDH-Fp, SCO1 and SURF1 mutations in five unrelated families with complex I, II and IV deficiency, respectively. The identification of the disease-causing gene in a given family with RCD is a major issue to provide both adequate genetic counselling and early, reliable PD.

Electron Transport↗
PubMed2001

Denaturing high-performance liquid chromatography (DHPLC)-based prenatal diagnosis for tuberous sclerosis.

Tuberous sclerosis (TSC) is a frequent autosomal-dominant condition (affecting 1 in 6000 individuals) caused by various mutations in either the hamartin (TSC1) or the tuberin gene (TSC2). This allelic and non-allelic heterogeneity makes genetic counseling and prenatal diagnosis difficult, especially as a significant proportion of TSC cases are due to de novo mutations. For this reason the identification of the disease causing mutation is mandatory for accurate counseling, yet current mutation detection methods such as single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) are labor intensive with limited detection efficiency. Denaturing high-performance liquid chromatography (DHPLC) is a high-throughput, semi-automated mutation detection system with a reported mutation detection rate close to 100% for PCR fragments of up to 800 bp. We used a recently described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC. The fetus was found not to have inherited the deleterious mutation and the DHPLC diagnosis was confirmed by haplotype analysis. This represents the first DHPLC-based prenatal diagnosis of a genetic disease.

Chorionic Villi↗
PubMed2001

Partial maternal heterodisomy of chromosome 17q25 in a case of severe mental retardation.

We report a segmental maternal uniparental heterodisomy of chromosome 17 (mat UPD17) in a 3-year-old boy presenting with hyperactivity, major instability, mental retardation and facial dysmorphism. Since conventional and high resolution karyotypes were normal, this patient was tested for cryptic telomeric rearrangements by using the recently developed fluorescent genotyping-based technology. The mat UPD17 segment extended for a small 11-cM region of the distal chromosome 17q. Trisomy 17 in circulating lymphocytes and skin fibroblasts was excluded. Our finding emphasizes the potential use of fluorescent genotyping to detect uniparental disomies and suggests that chromosome 17q25 should contain one or several imprinted genes of particular importance for brain development.

Child, Preschool↗
PubMed2001

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.

Biopsy↗
PubMed2001

Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain.

NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.

Alleles↗
PubMed2001

Dramatic improvement in mitochondrial cardiomyopathy following treatment with idebenone.

Idebenone, a synthetic analogue of coenzyme Q10, has been shown to improve cardiac function in patients with Friedreich ataxia and a deficiency of respiratory chain complexes I-III. We describe a woman with severe combined right and left heart failure due to a mitochondrial cardiomyopathy. The patient underwent an endomyocardial biopsy as part of an evaluation for cardiac transplantation. It showed severely decreased respiratory complex activities dependent on CoQ, pointing to CoQ depletion. Following idebenone treatment there was a dramatic improvement in her clinical status with resolution of the heart failure.

Adult↗
PubMed2001

Impact of new mutations in the methylenetetrahydrofolate reductase gene assessed on biochemical phenotypes: a familial study.

Methylenetetrahydrofolate reductase (MTHFR) deficiency was identified in two out of four children born from nonconsanguineous parents. One of the affected children exhibited some clinical findings suggesting cystathionine beta-synthase deficiency; MTHFR activity was extremely reduced. In addition, hyperhomocysteinaemia, hypomethioninaemia, low total folate, especially methylfolate in red blood cells, and a reduced methylfolate/total folate ratio were found. Two mutations not yet reported, one on exon 1 of the gene changing an arginine to stop codon and one other on exon 9 changing an arginine to tryptophan were identified in both children in the compound heterozygous state associated with a common polymorphism, 1298A>C, also in the heterozygous state. The mother, homozygous for the mutation on exon 9 and for the polymorphism 1298A>C on exon 7, was clinically and biochemically normal, with normal folate status, mainly methylfolate levels in red blood cells, although MTHFR activity was moderately decreased. The father, heterozygous for the transition arginine to stop codon and for the common polymorphism 677C>T on exon 4, exhibited major biochemical abnormalities, hyperhomocysteinaemia and low methylfolate levels in red blood cells, but was clinically normal. The unaffected children had a biochemical pattern close to that of their mother and were heterozygous for the mutation on exon 9 and also for the two common polymorphisms, 677C>T and 1298A>C. In the affected children, some biochemical abnormalities, including folate status, especially methylfolate levels, were improved with treatment combining methyltetrahydrofolic acid, hydroxocobalamin, pyridoxine and betaine; however, homocysteine concentrations remained high and methionine concentrations were lowered. The father was treated with folic acid, which partially improved biochemical abnormalities. The impact of these mutations is discussed.

Adult↗
PubMed2001

Comparative genomic hybridisation in mentally retarded patients with dysmorphic features and a normal karyotype.

Segmental aneusomy for small chromosomal regions has been shown to be a common cause of mental retardation and multiple congenital anomalies. A screening method for such chromosome aberrations that are not detected using standard cytogenetic techniques is needed. Recent studies have focused on detection of subtle terminal chromosome aberrations using subtelomeric probes. This approach however excludes significant regions of the genome where submicroscopic rearrangements are also liable to occur. The aim of the present study was to evaluate the efficiency of comparative genomic hybridisation (CGH) for screening of submicroscopic chromosomal rearrangements. CGH was performed in a cohort of 17 patients (14 families) with mental retardation, dysmorphic features and a normal karyotype. Five subtle unbalanced rearrangements were identified in 7 patients. Subsequent FISH studies confirmed these results. Although no interstitial submicroscopic rearrangement was detected in this small series, the study emphasises the value of CGH as a screening approach to detect subtle chromosome rearrangements in mentally retarded patients with dysmorphic features and a normal karyotype.

Cytogenetic Analysis↗
PubMed2001

X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Adolescent↗
PubMed2001

A mutant mitochondrial respiratory chain assembly protein causes complex III deficiency in patients with tubulopathy, encephalopathy and liver failure.

Complex III (CIII; ubiquinol cytochrome c reductase of the mitochondrial respiratory chain) catalyzes electron transfer from succinate and nicotinamide adenine dinucleotide-linked dehydrogenases to cytochrome c. CIII is made up of 11 subunits, of which all but one (cytochrome b) are encoded by nuclear DNA. CIII deficiencies are rare and manifest heterogeneous clinical presentations. Although pathogenic mutations in the gene encoding mitochondrial cytochrome b have been described, mutations in the nuclear-DNA-encoded subunits have not been reported. Involvement of various genes has been indicated in assembly of yeast CIII (refs. 8-11). So far only one such gene, BCS1L, has been identified in human. BCS1L represents, therefore, an obvious candidate gene in CIII deficiency. Here, we report BCS1L mutations in six patients, from four unrelated families and presenting neonatal proximal tubulopathy, hepatic involvement and encephalopathy. Complementation study in yeast confirmed the deleterious effect of these mutations. Mutation of BCS1L would seem to be a frequent cause of CIII deficiency, as one-third of our patients have BCS1L mutations.

ATPases Associated with Diverse Cellular Activitie↗