Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy.

The clinical features, complications, and pharmacokinetics of intentional acute valproic acid (VPA) overdoses are described. Alteration in fatty acid metabolism is evaluated and therapy-induced changes are discussed. Central nervous system features were the predominant clinical manifestations (6/6), followed by respiratory failure (5/6) and multiorgan failure (2/6).

Wolfram syndrome: structural and functional analyses of mutant and wild-type wolframin, the WFS1 gene product.

Mutations of the WFS1 gene are responsible for Wolfram syndrome, a rare, recessive disorder characterized by early-onset, non-autoimmune diabetes mellitus, optic atrophy and further neurological and endocrinological abnormalities. The WFS1 gene encodes wolframin, a putative multispanning membrane glycoprotein of the endoplasmic reticulum. The function of wolframin is completely unknown.

Screening for carnitine palmitoyltransferase II deficiency by tandem mass spectrometry.

Mitochondrial carnitine palmitoyltransferase II (CPT II) deficiency is the most common inherited disorder of lipid metabolism in adults. Currently the routine diagnosis is based on the determination of CPT enzyme activity in muscle tissue. We have analysed the tandem mass spectra of serum acylcarnitines of nine CPT II-deficient patients.

The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space.

Mohr-Tranebjaerg syndrome is a progressive, neurodegenerative disorder caused by loss-of-function mutations in the DDP1/TIMM8A gene. DDP1 belongs to a family of evolutionary conserved proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. They mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane.

Tandem mass spectrometric assay for the determination of carnitine palmitoyltransferase II activity in muscle tissue.

Carnitine palmitoyltransferase II (CPT-II) mediates the import of long-chain fatty acids into the mitochondrial matrix for subsequent beta-oxidation. Defects of CPT-II manifest as a severe neonatal hepatocardiomuscular form or as a mild muscular phenotype in early infancy or adolescence. CPT-II deficiency is diagnosed by the determination of enzyme activity in tissues involving the time-dependent conversion of radiolabeled CPT-II substrates (isotope-exchange assays) or the formation of chromogenic reaction products.

Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy.

Objective: To report three unrelated infants with a distinctive phenotype of Leigh-like syndrome, neurogenic muscular atrophy, and hypertrophic obstructive cardiomyopathy. The patients all had a homozygous missense mutation in SCO2.

Background: SCO2 encodes a mitochondrial inner membrane protein, thought to function as a copper transporter to cytochrome c oxidase (COX), the terminal enzyme of the respiratory chain.

"Adult" form of muscular carnitine palmitoyltransferase II deficiency: manifestation in a 2-year-old child.

Unlabelled: We describe a 6-year-old girl admitted with acute muscular weakness and pain which made her unable to walk. Her parents reported a 4-year history of similar episodes which occurred once or twice a year and always resolved spontaneously. Laboratory investigations showed elevated serum creatine kinase which peaked at day 2 of the attack with 18,600 U/l.

Frequency of mitochondrial transfer RNA mutations and deletions in 225 patients presenting with respiratory chain deficiencies.

Objective: To evaluate the frequency of pathogenic mtDNA transfer RNA mutations and deletions in biochemically demonstrable respiratory chain (RC) deficiencies in paediatric and adult patients.

Methods: We screened for deletions and sequenced mitochondrial transfer RNA genes in skeletal muscle DNA from 225 index patients with clinical symptoms suggestive of a mitochondrial disorder and with biochemically demonstrable RC deficiency in skeletal muscle.

Results: We found pathogenic mitochondrial DNA mutations in 29% of the patients.

Role of the deafness dystonia peptide 1 (DDP1) in import of human Tim23 into the inner membrane of mitochondria.

Tim8 and Tim13 of yeast belong to a family of evolutionary conserved zinc finger proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. Mutations in DDP1 (deafness dystonia peptide 1), the human homolog of Tim8, are associated with the Mohr-Tranebjaerg syndrome, a progressive neurodegenerative disorder. We show that DDP1 acts with human Tim13 in a complex in the intermembrane space.

Detection of neonatal argininosuccinate lyase deficiency by serum tandem mass spectrometry.

Argininosuccinate lyase (ASL) deficiency (McKusick 207900) is an inborn error of the urea cycle. The leading symptom is progressive hyperammonaemia, which is a life-threatening condition, particularly in patients with a neonatal onset. Early diagnosis and treatment of the hyperammonaemia are necessary to improve survival and the long-term outcome of ASL-deficient patients.

Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency.

At least three proteins, COX17p, SCO1p, and its homologue SCO2p are thought to be involved in mitochondrial copper transport to cytochrome-c-oxidase (COX), the terminal enzyme of the respiratory chain. Recently, we and others have shown that mutations in SCO2 are associated with a lethal infantile hypertrophic cardiomyopathy (HCMP) with COX-deficiency. The majority of patients with a similar phenotype were, however, negative for SCO2 mutations, suggesting the other genes as candidates for this disorder.

Mutations in SCO2 are associated with a distinct form of hypertrophic cardiomyopathy and cytochrome c oxidase deficiency.

Mutations in SCO2, a cytochrome c oxidase (COX) assembly gene located on chromosome 22, have recently been reported in patients with fatal infantile cardio-encephalomyopathy and severe COX deficiency in heart and skeletal muscle. The Sco2 protein is thought to function as a copper chaperone. To investigate the extent to which mutations in SCO2 are responsible for this phenotype, a complete sequence analysis of the gene was performed on ten patients in nine families.

Novel mutations of mitochondrial complex I in pathologically proven Parkinson disease.

Complete sequence analysis of all mitochondrial complex I genes was performed in 22 cases of neuropathologically confirmed idiopathic Parkinson disease (PD). DNA from the substantia nigra was used as a template for polymerase chain reaction-based genomic sequencing. Seven novel mutations causing the exchange of amino acids were detected in subunit genes ND1 (3992 C/ T, 4024 A/G), ND4 (11253 T/C, 12084 C/T), ND5 (13711 G/A, 13768 T/C), and ND6 (14582 T/C).

Decreased aminoacylation of mutant tRNAs in MELAS but not in MERRF patients.

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs.

The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom.

The Mohr-Tranebjaerg syndrome (MTS), a neurodegenerative syndrome characterized by progressive sensorineural hearing loss, dystonia, mental retardation and blindness, is a mitochondrial disease caused by mutations in the deafness/dystonia peptide 1 (DDP1) gene. DDP1 shows similarity to the yeast proteins Tim9, Tim10 and Tim12, components of the mitochondrial import machinery for carrier proteins. Here, we show that DDP1 belongs to a large family of evolutionarily conserved proteins.

Mitochondrial disorders. A diagnostic challenge in clinical chemistry.

Mitochondria play a pivotal role in cellular metabolism and in energy production in particular. Defects in structure or function of mitochondria, mainly involving the oxidative phosphorylation (OXPHOS), mitochondrial biogenesis and other metabolic pathways, have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogeneity of mitochondrial diseases.

MITOP, the mitochondrial proteome database: 2000 update.

MITOP (http://www.mips.biochem.

Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.

Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases.

Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.

Systemic primary carnitine deficiency (CDSP, MIM 212140) is a disorder of fatty acid oxidation manifesting in acute metabolic decompensation or in progressive cardiomyopathy and muscle weakness. Mutations in the plasmalemmal organic cation/carnitine transporter OCTN2 were recently identified in CDSP patients of diverse ethnic backgrounds. We have performed OCTN2 mutation analysis in two unrelated German patients with primary carnitine deficiency and identified three molecular abnormalities.

Genetic and structural characterization of the human mitochondrial inner membrane translocase.

Translocation of nuclear-encoded mitochondrial preproteins is mediated by translocases in the outer and inner membranes. In the yeast Saccharomyces cerevisiae, translocation of preproteins into the matrix requires the membrane proteins Tim23, Tim17 and Tim44, which drive translocation in cooperation with mtHsp70 and its co-chaperone Mge1p. We have cloned and functionally analyzed the human homologues of Tim17, Tim23 and Tim44.