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Biomedical subjects

Jan Smeitink

Publications and source records attributed to Jan Smeitink.

At least 19 recordsLinked to original sources
PubMed2007

Anesthesia-related morbidity and mortality after surgery for muscle biopsy in children with mitochondrial defects.

BACKGROUND: Children with mitochondrial defects (MD) may have an increased risk for cardiorespiratory and neurological complications from anesthesia. The aim of this study was to determine the incidence of perioperative complications and adverse events in children with MD. METHODS: We performed a retrospective review of the anesthesia, surgical and medical records of 155 children up to 10 years who underwent a diagnostic surgical muscle biopsy for suspected mitochondrial and muscle disorders between 1999 and 2003. The data of the 122 patients where a definite MD diagnosis was found were analyzed. Anesthesia was conducted according to the discretion of the attending staff. In children with MD the activity of the different complexes of the oxidative phosphorylation system was measured. RESULTS: From the preoperative assessment, signs of encephalopathy were most frequent (n = 93), followed by muscle weakness (n = 32), lactic acidosis (n = 15), cardiomyopathy and/or conduction defects (n = 10) and chronic respiratory problems (n = 7). The mean age of the children with MD was 32.4 months (SD = 26.9). The mean duration of anesthesia was 36.0 min (SD = 12.6) and the mean length of stay in the recovery room was 33.0 min (SD = 24.0). There were no major changes in heart rate or blood pressure which required pharmacological intervention during anesthesia or postanesthesia care unit (PACU) stay. A short episode of SpO2 <80% with airway obstruction occurred once in the PACU. Biochemical analysis in the children with a MD showed an isolated deficiency of one of the five protein complexes of oxidative phosphorylation in 42 children, a combination of complex deficiencies in 41 and no definite localization in 39 children. CONCLUSION: With standard preoperative assessment, monitoring and anesthesia management, there were no major peroperative and postoperative anesthesia-related complications in children undergoing surgical muscle biopsy with a MD diagnosis.

Anesthesia↗
PubMed2006

Dietary intervention and oxidative phosphorylation capacity.

Secondary deterioration of mitochondrial function has been reported in patients with anorexia and cancer-related malnutrition. Inadequate nutrition, failure to thrive and feeding problems are also common symptoms in children with primary oxidative phosphorylation defects. As a standard intervention protocol we advise an age-appropriate diet and energy intake in our patients diagnosed with a mitochondrial dysfunction. By comparing the results of the first and the second samples from a group of children who underwent repeated muscle biopsies, we observed biochemical improvement in the mitochondrial function in 7 out of 10 patients following dietary advice and intervention. We suggest evaluating the nutritional state by interpretation of the skeletal muscle biochemistry in patients with a suspected oxidative phosphorylation defect. Since an insufficient dietary intake could play a role in secondary mitochondrial dysfunction, nutritional intervention should be performed prior to the biopsy. On the other hand, our data suggest that optimizing the nutritional and energy intake might also improve the utilization of the residual mitochondrial energy-generating capacity in patients with primary oxidative phosphorylation defects.

Adenosine Triphosphate↗
PubMed2006

Normal serum alanine concentration differentiates transient neonatal lactic acidemia from an inborn error of energy metabolism.

BACKGROUND: Elevated blood lactate levels are common in the critically ill neonate; however, sometimes they are difficult to interpret. Persistent or recurrent lactic acidemia might point to an inborn error of metabolism, like disturbances of the oxidative phosphorylation. Chronic lactic acidemia results in increased serum alanine levels. Serum alanine levels in newborns with transient lactic acidemia have not yet been studied. OBJECTIVE: We designed a pilot study to evaluate the use of serum alanine levels as an additional metabolic marker to differentiate the transient effect of circulatory failure from a possible mitochondrial dysfunction. METHODS: We prospectively evaluated 10 newborns with transient lactic acidemia after mild dysoxia, and 10 newborns with recurrent lactic acidemia consecutively diagnosed with a disorder in oxidative phosphorylation. RESULTS: No significant serum alanine level elevation was found in transient lactic acidemia. Increased serum alanine was a sensitive marker in mitochondrial dysfunction. CONCLUSIONS: We propose to measure the serum alanine level in hypotonic newborns with lactic acidemia to facilitate the decision making in further diagnostics and management.

Alanine↗
PubMed2006

Clinical and biochemical characteristics in patients with a high mutant load of the mitochondrial T8993G/C mutations.

We retrospectively analyzed the clinical, histological, and biochemical data of 11 children, five of which carried the maternally-inherited mitochondrial T8993C and six carrying the T8993G point mutations in the ATP synthase 6 gene. The percentage of heteroplasmy was 95% or higher in muscle and in blood. All patients had an early clinical presentation with muscle hypotonia, severe extrapyramidal dysfunction and Leigh disease demonstrated by the cranial MRI. A slower clinical progression and more frequent sensory-neuronal involvement were noted in the patients carrying the T8993C mutation in a high mutation load in muscle and blood. No histological abnormality was found. In 9 out of 11 patients a decreased ATP production was detected, and complex V activity was deficient in all children. The activities of the respiratory enzyme complexes II and IV were normal, whereas an associated combined complex I and III deficiency were present in two patients. No obvious difference was found between the biochemical parameters of the two patient groups harboring different mutations in the same gene. No correlation was found between the degree of complex V enzyme deficiency and the severity of the phenotype. We confirmed an impaired assembly/stability of complex V in our patients. This is the first report of decreased activity and impaired assembly/stability of complex V in patients with T8993C mutations measured in muscle tissue.

Adenosine Triphosphate↗
PubMed2006

Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells.

The role of MT (metallothionein) gene expression was investigated in rotenone-treated HeLa cells to induce a deficiency of NADH:ubiquinone oxidoreductase (complex I). Complex I deficiency leads to a diversity of cellular consequences, including production of ROS (reactive oxygen species) and apoptosis. HeLa cells were titrated with rotenone, resulting in dose-dependent decrease in complex I activity and elevated ROS production at activities lower than 33%. Expression of MT2A (MT isoform 2A), but not MT1A or MT1B RNA, was significantly inducible by rotenone (up to 7-fold), t-BHP (t-butyl hydroperoxide; 5-fold) and CdCl2 (50-fold), but not ZnCl2. Myxothiazol treatment did not elevate either ROS or MT2A levels, which supports a ROS-related mechanism for rotenone-induced MT2A expression. To evaluate the role of MT2A expression, MT2A and MT1B were overexpressed in HeLa cells and treated with rotenone. Compared with control and MT1B-overexpressing cells, ROS production was significantly lower and cell viability higher in MT2A-overexpressing HeLa cells when ROS production was enhanced by treatment with t-BHP. Mitochondrial membrane potential was noticeably less reduced in both MT-overexpressing cell lines. MT2A overexpression in rotenone-treated cells also significantly reduced or delayed apoptosis induction, as measured by caspase 3/7 activity and cytosolic nucleosome enrichment. We conclude that MT2A offers significant protection against the main death-causing consequences of rotenone-induced complex I deficiency in HeLa cells. Our results are in support of the protective role against oxidative stress ascribed to MTs and provide evidence that MT2A expression may be a beneficial downstream adaptive response in complex I-deficient cells.

Adenosine Triphosphate↗
PubMed2006

Mitochondrial dysfunction in Brooks-Wisniewski-Brown syndrome.

Brooks, Wisniewski, and Brown described a familial presentation of severe developmental retardation, speech delay, static encephalopathy with atrophic hydrocephalus, microcephaly, progressive spastic diplegia, a characteristic facial appearance, optic atrophy, and growth retardation associated with hypoplastic corpus callosum in one of the patients. The authors postulated a distinct X-linked mental retardation syndrome. Later on a similar phenotype was observed in three male siblings with an early lethal outcome. Here we describe three patients with several overlapping features and a progressive neurological picture presenting with a significantly compromised mitochondrial oxidative phosphorylation measured in a fresh muscle biopsy. Neurological deterioration is a commonly observed feature in mitochondrial disorders. Based on the unique combination of the clinical symptoms, we suggest that our patients have the Brooks-Wisniewski-Brown syndrome.

Abnormalities, Multiple↗
PubMed2005

Defective protein glycosylation in patients with cutis laxa syndrome.

Congenital cutis laxa is a genetically heterogeneous condition presenting with loose and redundant skin folds, decreased elasticity of the skin, connective tissue involvement and a highly variable spectrum of associated features. The most common forms are inherited in an autosomal recessive or dominant fashion. Fibulin 5 and elastin mutations were detected in a limited number of patients, but in most cases the etiology is not known. Based on a previous observation of an abnormal transferrin isoelectric focusing pattern in a patient with cutis laxa indicating an N-glycosylation defect, we performed a screening for disorders of protein glycosylation in unrelated children with cutis laxa syndrome, including a recently developed test for defective O-glycosylation. Here, we describe five patients from consanguineous marriages with a cutis laxa syndrome with skeletal and joint involvement, developmental delay and neurological findings. Three of these five children have an inborn error of glycan biosynthesis affecting the synthesis of both N- and O-linked glycans. Two patients had normal glycosylation patterns. All known causes of secondary glycosylation disorders were excluded in the children. No mutations were found in the FBLN5 gene. In conclusion, we have identified a new combined glycosylation defect with a distinct clinical phenotype. Our results suggest that a combined defect of glycosylation might be a causative factor in congenital cutis laxa. This is the first report where abnormal N- and O-linked glycosylation is implicated in the etiology of cutis laxa syndrome.

Apolipoproteins C↗
PubMed2004

Human mitochondrial complex I assembles through the combination of evolutionary conserved modules: a framework to interpret complex I deficiencies.

With 46 subunits, human mitochondrial complex I is the largest enzyme of the oxidative phosphorylation system. We have studied the assembly of complex I in cultured human cells. This will provide essential information about the nature of complex I deficiencies and will enhance our understanding of mitochondrial disease mechanisms. We have found that 143B206 rho zero cells, not containing mitochondrial DNA, are still able to form complex I subcomplexes. To further address the nature of these subcomplexes, we depleted 143B osteosarcoma cells of complex I by inhibiting mitochondrial protein translation with doxycycline. After removing this drug, complex I formation resumes and assembly intermediates were observed by two-dimensional blue native electrophoresis. Analysis of the observed subcomplexes indicates that assembly of human complex I is a semi-sequential process in which different preassembled subcomplexes are joined to form a fully assembled complex. The membrane part of the complex is formed in distinct steps. The B17 subunit is part of a subcomplex to which ND1, ND6 and PSST are subsequently added. This is bound to a hydrophilic subcomplex containing the 30 and 49 kDa subunits, to which a subcomplex including the 39 kDa subunit is incorporated, and later on the 18 and 24 kDa subunits. At a later stage more subunits, including the 15 kDa, are added and holo-complex I is formed. Our results suggest that human complex I assembly resembles that of Neurospora crassa, in which a membrane arm is formed and assembled to a preformed peripheral arm, and support ideas about modular evolution.

DNA, Mitochondrial↗
PubMed2004

Congenital hypertrophic cardiomyopathy, cataract, mitochondrial myopathy and defective oxidative phosphorylation in two siblings with Sengers-like syndrome.

UNLABELLED: We describe two siblings with a Sengers-like syndrome, who presented with congenital hypertrophic cardiomyopathy, infantile cataract, mitochondrial myopathy, lactic acidosis and normal mental development. A mitochondrial adenine nucleotide translocator 1 (ANT1) defect was detected since the ANT1 protein was not detectable by immmunoblotting in muscle samples of the patients. Additionally to these features of classical Sengers syndrome (OMIM 212350), we found that the mitochondrial oxidative phosphorylation, measured by biochemical analysis, was severely compromised in skeletal muscle in both children. Biochemical and morphological analysis of the fibroblasts revealed normal results. The association of significantly decreased pyruvate oxidation rates, deficient energy production and decreased multiple mitochondrial enzyme-complex activities in the muscle samples of our patients is a new finding which differs from previous results in patients with Sengers syndrome. CONCLUSION: we recommend a muscle biopsy and the biochemical analysis of the oxidative phosphorylation system in patients with muscle hypotonia, cardiomyopathy and congenital or infantile cataract.

Acidosis, Lactic↗
PubMed2004

Complex I assembly: a puzzling problem.

PURPOSE OF REVIEW: Disturbances in the mitochondrial oxidative phosphorylation pathway most often lead to devastating disorders with a fatal outcome. Of these, complex I deficiency is the most frequently encountered. Recent characterization of the mitochondrial and nuclear DNA-encoded complex I subunits has allowed mutational analysis and reliable prenatal diagnosis. Nevertheless, complex-I-deficient patients without a mutation in any of the known subunits remain. It is assumed that these patients harbour defects in proteins involved in the assembly of this largest member of the oxidative phosphorylation complexes. This review describes current understanding of complex I assembly, new developments and future perspectives. RECENT FINDINGS: The first model of human complex I assembly has been proposed recently. New insights into supercomplex assembly and stability may help to explain combined deficiencies. Recent functional characterization of some of the 32 accessory subunits of the complex may link these subunits to complex I biogenesis and activity regulation. SUMMARY: Research on complex I assembly is increasing rapidly. However, comparison between theoretical and experimental models of complex I assembly is still problematic. The growing understanding of complex I assembly at the subunit and supercomplex level will clarify the picture in the future. The elucidation of complex I assembly, by combining patient data with new experimental methods, will facilitate the diagnosis of (and possibly therapy for) many uncharacterized mitochondrial disorders.

Animals↗
PubMed2003

Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.

UNLABELLED: A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indicating that the mRNA coming from the IVS9+1G>A mutant allele is not stable. CONCLUSION: as opposed to the non-neurological phenotype of patients with a homozygous G229C mutation, this patient developed Leigh syndrome. Dihydrolipoamide dehydrogenase and pyruvate dehydrogenase complex activities in muscle were 29% and 14% of the lowest control values, respectively. Pyruvate dehydrogenase complex activity in fibroblasts was normal, however, indicating that the biochemical examination of defects in energy metabolism should be performed in a more energy demanding tissue.

Child, Preschool↗
PubMed2003

Application of a ketogenic diet in children with autistic behavior: pilot study.

A pilot prospective follow-up study of the role of the ketogenic diet was carried out on 30 children, aged between 4 and 10 years, with autistic behavior. The diet was applied for 6 months, with continuous administration for 4 weeks, interrupted by 2-week diet-free intervals. Seven patients could not tolerate the diet, whereas five other patients adhered to the diet for 1 to 2 months and then discontinued it. Of the remaining group who adhered to the diet, 18 of 30 children (60%), improvement was recorded in several parameters and in accordance with the Childhood Autism Rating Scale. Significant improvement (> 12 units of the Childhood Autism Rating Scale) was recorded in two patients (pre-Scale: 35.00 +/- 1.41[mean +/- SD]), average improvement (> 8-12 units) in eight patients (pre-Scale: 41.88 +/- 3.14[mean +/- SD]), and minor improvement (2-8 units) in eight patients (pre-Scale: 45.25 +/- 2.76 [mean +/- SD]). Although these data are very preliminary, there is some evidence that the ketogenic diet may be used in autistic behavior as an additional or alternative therapy.

Autistic Disorder↗
PubMed2002

CIA30 complex I assembly factor: a candidate for human complex I deficiency?

The human mitochondrial NADH:ubiquinone oxidoreductase (complex I), the first complex of the oxidative phosphorylation system, is composed of at least 42 subunits. Little is known about the assembly process of these subunits into the mature complex. Recently, two proteins in Neurospora crassa have been found to be involved in the assembly of complex I. These proteins are not constituent parts of the mature complex but are associated with smaller intermediate complexes of the assembly process and have a chaperone-like function. We have characterized the human homologue of one of these two complex I intermediate associated proteins, named CIA30, and show that expression of the human CIA30 protein is ubiquitous with a slightly higher expression in various heart tissues, kidney, lung and liver. As deletion of the Neurospora crassa CIA genes results in severe disruption of the assembly process, human CIA30 can be considered as a candidate gene related to complex I deficiency. Thirteen patients with an isolated complex I deficiency, but who were ruled out for mutations in the 35 nuclear genes of the complex and mtDNA, were subjected to mutational analysis of the gene coding for the human CIA30 protein. Four new single nucleotide polymorphisms (SNPs) were detected but no functional mutation was found.

Amino Acid Sequence↗
PubMed2002

Septo-optic dysplasia associated with a new mitochondrial cytochrome b mutation.

We report on a 25-year-old patient with isolated mitochondrial complex III deficiency and a new heteroplasmic mutation (T14849C) in the cytochrome b gene. He suffered from septo-optic dysplasia, retinitis pigmentosa, exercise intolerance, hypertrophic cardiomyopathy, and rhabdomyolysis. A HESX1 mutation was excluded as a cause of his septo-optic dysplasia. Low alpha-tocopherol concentrations in his muscles and an elevated urinary leukotriene E(4) excretion indicate increased production of reactive oxygen species.

Adult↗
PubMed2002

Succinate in dystrophic white matter: a proton magnetic resonance spectroscopy finding characteristic for complex II deficiency.

A deficiency of succinate dehydrogenase is a rare cause of mitochondrial encephalomyopathy. Three patients, 2 sisters and 1 boy from an unrelated family, presented with symptoms and magnetic resonance imaging signs of leukoencephalopathy. Localized proton magnetic resonance spectroscopy indicated a prominent singlet at 2.40ppm in cerebral and cerebellar white matter not present in gray matter or basal ganglia. The signal was also elevated in cerebrospinal fluid and could be identified as originating from the two equivalent methylene groups of succinate. Subsequently, an isolated deficiency of complex II (succinate:ubiquinone oxidoreductase) was demonstrated in 2 patients in muscle and fibroblasts. One of the sisters died at the age of 18 months. Postmortem examination showed the neuropathological characteristics of Leigh syndrome. Her younger sister, now 12 months old, is also severely affected; the boy, now 6 years old, follows a milder, fluctuating clinical course. Magnetic resonance spectroscopy provides a characteristic pattern in succinate dehydrogenase deficiency.

Brain↗