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Biomedical subjects

A Rötig

Publications and source records attributed to A Rötig.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy.

Cytochrome c oxidase (COX) catalyzes both electron transfer from cytochrome c to molecular oxygen and the concomitant vectorial proton pumping across the inner mitochondrial membrane. Studying a large family with multiple cases of neonatal ketoacidotic comas and isolated COX deficiency, we have mapped the disease locus to chromosome 17p13.1, in a region encompassing two candidate genes involved in COX assembly-namely, SCO1 and COX10. Mutation screening revealed compound heterozygosity for SCO1 gene mutations in the patients. The mutated allele, inherited from the father, harbored a 2-bp frameshift deletion (DeltaGA; nt 363-364) resulting in both a premature stop codon and a highly unstable mRNA. The maternally inherited mutation (C520T) changed a highly conserved proline into a leucine in the protein (P174L). This proline, adjacent to the CxxxC copper-binding domain of SCO1, is likely to play a crucial role in the tridimentional structure of the domain. Interestingly, the clinical presentation of SCO1-deficient patients markedly differs from that of patients harboring mutations in other COX assembly and/or maturation genes.

Age of Onset↗
PubMed2000

Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency.

BACKGROUND: The respiratory-chain deficiencies are a broad group of largely untreatable diseases. Among them, coenzyme Q10 (ubiquinone) deficiency constitutes a subclass that deserves early and accurate diagnosis. METHODS: We assessed respiratory-chain function in two siblings with severe encephalomyopathy and renal failure. We used high-performance liquid chromatography analyses, combined with radiolabelling experiments, to quantify cellular coenzyme Q10 content. Clinical follow-up and detailed biochemical investigations of respiratory chain activity were carried out over the 3 years of oral quinone administration. FINDINGS: Deficiency of coenzyme Q10-dependent respiratory-chain activities was identified in muscle biopsy, circulating lymphocytes, and cultured skin fibroblasts. Undetectable coenzyme Q10 and results of radiolabelling experiments in cultured fibroblasts supported the diagnosis of widespread coenzyme Q10 deficiency. Stimulation of respiration and fibroblast enzyme activities by exogenous quinones in vitro prompted us to treat the patients with oral ubidecarenone (5 mg/kg daily), which resulted in a substantial improvement of their condition over 3 years of therapy. INTERPRETATION: Particular attention should be paid to multiple quinone-responsive respiratory-chain enzyme deficiency because this rare disorder can be successfully treated by oral ubidecarenone.

Administration, Oral↗
PubMed2000

A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency.

Cytochrome c oxidase (COX) defects are found in a clinically and genetically heterogeneous group of mitochondrial disorders. To date, mutations in only two nuclear genes causing COX deficiency have been described. We report here a genetic linkage study of a consanguineous family with an isolated COX defect and subsequent identification of a mutation in a third nuclear gene causing a deficiency of the enzyme. A genome-wide search for homozygosity allowed us to map the disease gene to chromosome 17p13.1-q11.1 (Z (max)= 2.46; theta = 0.00 at the locus D17S799). This region encompasses two genes, SCO1 and COX10, encoding proteins involved in COX assembly. Mutation analysis followed by a complementation study in yeast permitted us to ascribe the COX deficiency to a homozygous missense mutation in the COX10 gene. This gene encodes heme A:farnesyltransferase, which catalyzes the first step in the conversion of protoheme to the heme A prosthetic groups of the enzyme. All three nuclear genes now linked to isolated COX deficiency are involved in the maturation and assembly of COX, emphasizing the major role of such genes in COX pathology.

Abnormalities, Multiple↗
PubMed2000

Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency.

Genetic counselling and prenatal diagnosis are major issues of mitochondrial respiratory chain deficiency, especially as these conditions are largely untreatable. In the absence of known mitochondrial or nuclear gene mutations, measurement of respiratory chain enzyme activities represents the only possibility to prevent recurrence of the disease in affected families. We carried out enzymatic prenatal diagnosis in 21 pregnancies from 10 unrelated couples using uncultured choriocytes and/or amniocytes. Twelve babies were born and are healthy, seven pregnancies were discontinued early on because of an enzyme deficiency detected prenatally. In two cases, a fetus which appeared normal after early and/or late prenatal diagnosis, turned out to be affected. We conclude that a deficient enzyme activity is indicative of recurrence, but a normal result at 10 weeks of gestation does not give conclusive evidence as to the outcome of the pregnancy. We therefore suggest the following procedure: (1) a choriocentesis or an amniocentesis in early pregnancy when the proband expresses the disease in cultured skin fibroblasts; (2) a second amniocentesis at 28 weeks' gestation should be offered to avoid false negative results due to a possible late expression of the disease, in combination with: (3) a careful and repeated ultrasound survey for detection of growth failure in the third trimester; (4) prenatal diagnosis should not be performed in case of late onset clinical symptoms in the proband; and (5) parents should be aware of the possibility of false negative results. Prenatal diagnosis should not be proposed for a complex I deficiency as this enzyme activity cannot be accurately measured in fetal cells.

Adult↗
PubMed2000

Screening human EST database for identification of candidate genes in respiratory chain deficiency.

Disorders of mitochondrial oxidative phosphorylation (OXPHOS) are now recognized as major causes of human metabolic diseases and several mutations of mitochondrial and nuclear genes encoding respiratory chain components have been reported. Interestingly, mutations of nuclear genes involved in mitochondrial respiratory chain assembly, protein trafficking, and iron metabolism are also known to alter oxidative phosphorylation. While several hundred of these genes have been described in yeast, only a few nuclear genes have been hitherto identified in humans. Yeast gene databases present therefore an invaluable tool for identification of human homologues that should be regarded as candidate genes in OXPHOS diseases. In an attempt to identify the human counterparts of yeast genes, we developed a systematic comparison of yeast protein sequences to the GenBank dbEST database. Starting from 340 yeast protein sequences as templates, we searched the human dbEST counterparts using the BLAST similarity searching program and identified 102 groups of human EST likely to represent orthologues of yeast genes because of significant homology. This collection of human genes possibly related to mitochondrial OXPHOS may help identify nuclear genes responsible of mitochondrial disorders.

Algorithms↗
PubMed2000

Compound heterozygous mutations in the flavoprotein gene of the respiratory chain complex II in a patient with Leigh syndrome.

Succinate dehydrogenase (SDH) deficiency represents a minor cause of Leigh syndrome (LS). Noticeably, the first mutation in a nuclear-encoded respiratory chain component, a mutation in the 5p15 copy of the flavoprotein (Fp) subunit gene of the SDH, was reported 4 years ago in two siblings with LS and SDH deficiency. We now report a new patient with LS and SDH deficiency. Because two copies of the Fp gene are present in the human genome, we first determined the complete structure of these two copies. This allowed us to identify a 1 bp deletion creating a frameshift in the 3q29 copy, confirming that this second copy was a pseudogene. We also sequenced the promoter region of the 5p 15 gene and, in addition, screened for mutations in the patient. Sequencing of the Fp SDH cDNA in the patient only allowed us to identify a heterozygous C to T transition, changing an alanine to a valine in one allele. This transition was found to be heterozygous in the patient's father but was absent from 150 controls. Transfection of the corresponding mutant cDNA into human Fp-deficient cells failed to restore normal SDH activity, confirming the deleterious effect of this mutation. The second allele, inherited from the mother, carried an A to C substitution changing the methionine translation initiation codon to a leucine. This mutant transcript represented only 10% of total Fp transcript suggesting instability of this transcript. So far, profound deficiencies in complex II activity resulting from mutations in the Fp gene of the SDH present only as LS, a striking observation in view of the ubiquitous expression of this typical housekeeping gene in humans.

Base Sequence↗
PubMed2000

Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency.

Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.

Adolescent↗
PubMed2000

Inherited palmoplantar keratoderma and sensorineural deafness associated with A7445G point mutation in the mitochondrial genome.

We report a French pedigree with members having an inherited combination of non-epidermolytic palmoplantar keratoderma (NEPPK) and sensorineural deafness. The penetrance of both features was incomplete. Additional ectodermal defects were absent. The expression of numerous epidermal proteins (keratins, fillagrin, cornified envelope proteins, intercellular junction proteins including connexin 26, and loricrin) defined with immunolabelling was normal in the proband. The combination was shown to be associated with the A7445G point mutation in the mitochondrial genome (mtDNA). This mutation is responsible for a subtype of NEPPK which is so far the only mtDNA mutation-associated keratoderma.

Adolescent↗
PubMed1999

Two sibs with myoclonic epilepsy, congenital deafness, macular dystrophy, and psychiatric disorders.

We present a family with four children born to second-cousin parents. Two of the children had myoclonic epilepsy, congenital deafness, a dystrophic pattern of the macular pigment epithelium, incomplete right bundle branch block, and psychiatric disorders appearing after fever episodes. Results of all laboratory investigations including mitochondrial DNA analysis were normal. Despite the fact that this condition resembles one reported by Latham and Munro in 1937, it is possible that we might be reporting on a new autosomal recessive syndrome.

Adult↗
PubMed1999

Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues.

BACKGROUND: Zidovudine is commonly administered during pregnancy to prevent mother-to-child HIV-1 transmission. We investigated mitochondrial toxic effects in children exposed to zidovudine in utero and after birth. METHODS: We analysed observations of a trial of tolerance of combined zidovudine and lamivudine and preliminary results of a continuing retrospective analysis of clinical and biological symptoms of mitochondrial dysfunction in children born to HIV-1-infected women in France. Mitochondrial dysfunction was studied by spectrophotometry and polarography of respiratory-chain complexes in various tissues. FINDINGS: Eight children had mitochondrial dysfunction. Five, of whom two died, presented with delayed neurological symptoms and three were symptom-free but had severe biological or neurological abnormalities. Four of these children had been exposed to combined zidovudine and lamivudine, and four to zidovudine alone. No child was infected with HIV-1. All children had abnormally low absolute or relative activities of respiratory-chain complexes I, IV, or both months or years after the end of antiretroviral treatment. No mutation currently associated with constitutional disease was detected in any patient. INTERPRETATION: Our findings support the hypothesis of a link between mitochondrial dysfunction and the perinatal administration of prophylactic nucleoside analogues. Current recommendations for zidovudine monotherapy should however be maintained. Further assessment of the toxic effects of these drugs is required.

Acidosis, Lactic↗
PubMed1999

Biochemical, genetic and immunoblot analyses of 17 patients with an isolated cytochrome c oxidase deficiency.

Mitochondrial respiratory chain defects involving cytochrome c oxidase (COX) are found in a clinically heterogeneous group of diseases, yet the molecular basis of these disorders have been determined in only a limited number of cases. Here, we report the clinical, biochemical and molecular findings in 17 patients who all had isolated COX deficiency and expressed the defect in cultured skin fibroblasts. Immunoblot analysis of mitochondrial fractions with nine subunit specific monoclonal antibodies revealed that in most patients, including in a patient with a novel mutation in the SURF1 gene, steady-state levels of all investigated COX subunits were decreased. Distinct subunit expression patterns were found, however, in different patients. The severity of the enzymatic defect matched the decrease in immunoreactive material in these patients, suggesting that the remnant enzyme activity reflects the amount of remaining holo-enzyme. Four patients presented with a clear defect of COX activity but had near normal levels of COX subunits. An increased affinity for cytochrome c was observed in one of these patients. Our findings indicate a genetic heterogeneity of COX deficiencies and are suggestive of a prominent involvement of nuclear genes acting on the assembly and maintenance of cytochrome c oxidase.

Antibodies, Monoclonal↗
PubMed1999

Effect of idebenone on cardiomyopathy in Friedreich's ataxia: a preliminary study.

BACKGROUND: Friedreich's ataxia is caused by a deficiency of frataxin, a protein involved in regulation of mitochondrial iron content. We have reported a combined deficiency of a Krebs-cycle enzyme, aconitase, and three mitochondrial respiratory-chain complexes in endomyocardial biopsy samples from patients with this disorder. All four enzymes share iron-sulphur cluster-containing proteins that are damaged by iron overload through generation of oxygen free radicals. We used an in-vitro system to elucidate the mechanism of iron-induced injury and to test the protective effects of various substances. On the basis of these results, we assessed the effect of idebenone (a free-radical scavenger) in three patients with Friedreich's ataxia. METHODS: Heart homogenates from patients with valvular stenosis were tested for respiratory-chain complex II activity, lipoperoxidation, and aconitase activity by spectrophotometric assays, in the presence of reduced iron (Fe2+), oxidised iron (Fe3+), desferrioxamine, ascorbic acid, and idebenone. The Friedreich's ataxia patients (aged 11 years, 19 years, and 21 years) underwent ultrasonographic heart measurements at baseline and after 4-9 months of idebenone (5 mg/kg daily). FINDINGS: Fe2+ (but not Fe3+) decreased complex II activity and increased lipoperoxidation in heart homogenate. Addition of ascorbate or desferrioxamine increased some of the iron-induced adverse effects. Idebenone protected against these effects. In the three patients, left-ventricular mass index decreased from baseline to 4-9 months of idebenone treatment (patient 1, 145 g to 114 g; patient 2, 215 g to 151 g; patient 3, 408 g to 279 g). INTERPRETATION: Our in-vitro data suggest that both iron chelators and antioxidant drugs that may reduce iron are potentially harmful in patients with Friedreich's ataxia. Conversely, our preliminary findings in patients suggest that idebenone protects heart muscle from iron-induced injury.

Adult↗
PubMed1999

The neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G) triggers muscle ATPase deficiency and hypocitrullinaemia.

UNLABELLED: Based on the study of three unrelated families, we report what we believe to be the first in vivo evidence of muscle ATPase deficiency in individuals carrying the neurogenic weakness, ataxia and retinitis pigmentosa (NARP) syndrome mtDNA mutation (T8993G). Since plasma citrulline was consistently low in 4/5 patients, we suggest that the NARP mutation caused complex V deficiency in the small intestine as well, thus reducing the availability of mitochondrial ATP required for citrulline synthesis. CONCLUSION: We suggest giving consideration to hypocitrullinaemia as a hallmark of the neurogenic weakness, ataxia and retinitis pigmentosa syndrome mutation and more generally of impaired oxidative phosphorylation in the small intestine in vivo.

Adenosine Triphosphatases↗
PubMed1999

A mitochondrial cytochrome b mutation but no mutations of nuclearly encoded subunits in ubiquinol cytochrome c reductase (complex III) deficiency.

Ubiquinol cytochrome c reductase (complex III) deficiency represents a clinically heterogeneous group of mitochondrial respiratory chain disorders that can theoretically be subject to either a nuclear or a mitochondrial mode of inheritance. In an attempt to elucidate the molecular bases of the disease, we first determined the nucleotide sequence of three unknown subunits (9.5 kDa, 7.2 kDa, 6.4 kDa) by cyberscreening of human expressed sequence tag data bases and sequenced the 11 cDNA subunits encoding complex III in five patients with isolated complex III deficiency. No mutation in the nuclearly encoded complex III subunits was observed, but a mutation in the cd2 helix of the mitochondrial (mt) cytochrome b gene was found to alter the conformation of the bc1 complex in one patient with severe hypertrophic cardiomyopathy. The present study is highly relevant to genetic counseling as the absence of mtDNA mutations in all but one patient in our series strongly supports autosomal rather than maternal inheritance in the majority of patients with complex III deficiency.

Amino Acid Sequence↗
PubMed1999

Unusual presentation of Kearns-Sayre syndrome in early childhood.

Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he developed short stature, pigmentary retinopathy, progressive external ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can have the unusual presenting signs described above.

Adolescent↗