Biomedical subjects

Linda De Meirleir

Publications and source records attributed to Linda De Meirleir.

12 recordsLinked to original sources

PubMed2006

A new family with the mitochondrial tRNAGLU gene mutation m.14709T>C presenting with hydrops fetalis.

BACKGROUND: In the heterogeneous group of mitochondrial disorders, patients with the same genotype can show different phenotypes and the same phenotype can be caused by different genotypes. We describe a family with the m.14709T>C mutation and a clinical presentation of hydrops fetalis, in contrast to previous reports in which patients presented with myopathy and/or diabetes mellitus. AIM: To identify a mutation in the mtDNA of a family with a heterogeneous clinical presentation. METHODS: Both biochemical and molecular analyses were performed. RESULTS: Biochemical results showed a decreased complex I and IV activity in muscle tissue of the patients. A mosaic-staining pattern for complex I in the patients' fibroblasts was revealed using immunocytochemistry. Molecular analyses identified the m.14709T>C mutation in the mitochondrial encoded tRNA(Glu) gene. CONCLUSION: We report 2 siblings with the m.14709T>C mutation in the mitochondrial tRNA(Glu) gene. The first patient showed hydrops fetalis, a new presentation within the clinical spectrum of this mutation, and the other a known presentation namely mild myopathy.

Croatia↗

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↗

PubMed2006

A novel mitochondrial transfer RNA(Asn) mutation causing multiorgan failure.

BACKGROUND: Mitochondrial cytopathies are a heterogeneous group of disorders with a broad spectrum of clinical symptoms. OBJECTIVE: To characterize a novel mutation in the transfer RNA(Asn) (m.5728A>G) identified in a 13-year-old boy with multiorgan failure. DESIGN: Biochemical and immunocytochemical studies were performed in combination with transmitochondrial cybrid analysis. SETTING: A university hospital. Molecular and biochemical analyses were performed in collaboration between 2 other university hospitals. PATIENT: Thirteen-year-old boy with multiorgan failure. RESULTS: In the patient's muscle tissue and cultured skin fibroblasts, a combined deficiency of complexes I and IV was found, using spectrophotometric analysis and activity staining in the gel following blue native polyacrylamide gel electrophoresis. An identical biochemical profile was seen in transmitochondrial cybrids carrying more than 55% mutant mitochondrial DNA. CONCLUSION: These data suggest that the m.5728A>G transition is a pathogenic mutation and is the cause of the respiratory chain dysfunction in the propositus.

Adolescent↗

PubMed2005

Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV.

Congenital insensitivity to pain with anhidrosis or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is the first human genetic disorder implicated in the neurotrophin signal transduction pathway. HSAN IV is characterized by absence of reaction to noxious stimuli, recurrent episodes of fever, anhidrosis, self-mutilating behavior and often mental retardation. Mutations in the neurotrophic tyrosine kinase, receptor, type 1 (NTRK1) are associated with this disorder. Here we report four homozygous mutations, two frameshift (p.Gln626fsX6 and p.Gly181fsX58), one missense (p.Arg761Trp) and one splice site (c.359+5G>T) mutation in four HSAN IV patients. The splice site mutation caused skipping of exons 2 and 3 in patient's mRNA resulting in an in-frame deletion of the second leucine-rich motif. NTRK1 mutations are only rarely reported in the European population. This report extends the spectrum of NTRK1 mutations observed in patients diagnosed with HSAN IV.

Case-Control Studies↗

PubMed2005

Steroids in intractable childhood epilepsy: clinical experience and review of the literature.

Steroids and adrenocorticotrophic hormone (ACTH) have been used for the treatment of infantile spasms for several years. However, the use of steroids in the treatment of epilepsy beyond infantile spasms has been limited to only a few studies. We report the experience with steroids in 32 children with intractable epilepsy, not including West syndrome. In 47% there was a decrease in seizure frequency, 25% became seizure free, 11% had a seizure reduction of >50% and 11% had a seizure reduction of <50%. Our study confirms the conclusions of few previous reports of effective adjunctive steroid treatment for children with intractable epilepsy. The possible side effects, however, especially during prolonged therapy remain an important concern.

Administration, Oral↗

PubMed2004

A family with pyruvate dehydrogenase complex deficiency due to a novel C>T substitution at nucleotide position 407 in exon 4 of the X-linked Epsilon1alpha gene.

UNLABELLED: The pyruvate dehydrogenase complex (PDHc; McKusick 312170), localised in the mitochondrial matrix, is a multienzyme complex which converts pyruvate to acetyl-CoA. A deficiency of PDHc leads to inadequate removal of pyruvate and lactate resulting in lactic acidaemia and insufficient energy production. The major cause of PDHc deficiency is a defect in the E1alpha component. The gene of this component is localised to Xp22.1. We describe two brothers with a relatively mild clinical phenotype of PDHc deficiency. Onset of disease was associated with muscle weakness and swallowing difficulties in both. At follow-up, the older brother developed encephalopathic features consistent with Leigh syndrome. Lactate to pyruvate ratios were low, consistent with a PDHc deficiency which was confirmed by measurements of PDHc activity in thrombocytes. A 407C>T change in exon 4 of the E1alpha gene was found in both brothers and their mother. This substitution predicts a replacement of a conserved alanine at position 136 by valine. CONCLUSION: Due to the X-linked inheritance pattern combined with the overall results of clinical investigations, molecular genetic findings and a corresponding functional deficiency of the gene product we believe that this substitution in the pyruvate dehydrogenase E1alpha gene is a mutation leading to pyruvate dehydrogenase complex deficiency in this family.

Amino Acid Substitution↗

PubMed2004

Early onset Huntington disease: a neuronal degeneration syndrome.

UNLABELLED: Huntington disease (HD) is an autosomal dominant, lethal neurodegenerative disorder of the central nervous system, caused by an uncontrolled expansion of a CAG dynamic mutation in the coding region of the IT15gene. Although a majority of patients have a midlife onset of the disease, in a small number of patients the disease manifests before 20 years of age. In adults, HD is mainly characterised by involuntary movements, personality changes and dementia. By contrast, in children a dominant picture of bradykinesia, rigidity, dystonia and epileptic seizures is noticed. The earlier onset is often associated with a paternal transmission of the disease allele to the offspring. We report here a rather unusual infantile onset of the disease in a little girl who presented with a history of seizures and psychomotor regression starting at the age of 3 years. A progressive cortical-subcortical atrophy, progressive cerebellar atrophy and lesions in the basal ganglia were found on MRI. An important expansion, of 214 triplet numbers, of the CAG repeat size associated with HD, was observed. CONCLUSION: Juvenile Huntingdon disease should be considered in children suffering from a progressive neurodegenerative disease.

Atrophy↗

PubMed2004

Analysis of the mitochondrial encoded subunits of complex I in 20 patients with a complex I deficiency.

NADH-ubiquinone oxidoreductase or complex I deficiency is a frequently diagnosed enzyme defect of the oxidative phosphorylation (OXPHOS) system in humans. However, in many patients, with complex I deficiency and clinical symptoms suggestive of mitochondrial disease, often no genetic defect can be found after investigation of the most common mitochondrial DNA (mtDNA) mutations. In this study, 20 patients were selected with a biochemically documented complex I defect and no common mtDNA mutation. We used the Denaturing Gradient Gel Electrophoresis (DGGE) method with primers encompassing all mitochondrial encoded fragments, to search in a systematic manner for mutations in the mitochondrial genome of complex I. In our group of patients, we were able to detect a total of 96 nucleotide changes. We were not able to find any disease causing mutation in the mitochondrial encoded subunits of complex I. These results suggested that the complex I deficiency in this group of patients is most probably caused by a defect in one of the nuclear encoded structural genes of complex I, or in one of the genes involved in proper assembly of the enzyme.

Age of Onset↗

PubMed2003

Clinical and diagnostic characteristics of complex III deficiency due to mutations in the BCS1L gene.

We investigated two siblings of a Spanish family presenting with congenital lactic acidosis. They had severe failure to thrive, liver dysfunction, and renal tubulopathy. An isolated biochemical complex III deficiency was detected in liver. A search for mutations in the human bc1 synthesis like (BCS1L) gene was undertaken. Direct sequencing revealed a missense mutation R45C and a nonsense mutation R56X, both located in exon 1 of BCS1L. The missense mutation in combination with a loss of function of the second allele is responsible for the isolated complex III deficiency in this family.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2003

Identification of 16 novel mutations in the argininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients.

Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate-limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 patients mainly in Japan and the United States, and to date 34 different mutations have been described in 50 families worldwide. In the present study, we report ASS mutations detected in 35 additional CTLN1 families from 11 countries. By analyzing the entire coding sequence and the intron-exon boundaries of the ASS gene using RT-PCR and/or genomic DNA-PCR, we have identified 16 novel mutations (two different 1-bp deletions, a 67-bp insertion, and 13 missense) and have detected 12 known mutations. Altogether, 50 different mutations (seven deletion, three splice site, one duplication, two nonsense, and 37 missense) in 85 CTLN1 families were identified. On the basis of primary sequence comparisons with the crystal structure of E. coli ASS protein, it may be concluded that any of the 37 missense mutations found at 30 different positions led to structural and functional impairments of the human ASS protein. It has been found that three mutations are particularly frequent: IVS6-2A>G in 23 families (Japan: 20 and Korea: three), G390R in 18 families (Turkey: six, U.S.: five, Spain: three, Israel: one, Austria: one, Canada: one, and Bolivia: one), and R304W in 10 families (Japan: nine and Turkey: one). Most mutations of the ASS gene are "private" and are distributed throughout the gene, except for exons 5 and 12-14. It seems that the clinical course of the patients with truncated mutations or the G390R mutation is early-onset/severe. The phenotype of the patients with certain missense mutations (G362V or W179R) is more late-onset/mild. Eight patients with R86H, A118T, R265H, or K310R mutations were adult/late-onset and four of them showed severe symptoms during pregnancy or postpartum. However, it is still difficult to prove the genotype-phenotype correlation, because many patients were compound heterozygotes (with two different mutations), lived in different environments at the time of diagnosis, and/or had several treatment regimes or various knowledge of the disease.

Adolescent↗

PubMed2002

Study of pediatric brain development using magnetic resonance imaging of anisotropic diffusion.

The properties of water diffusion in human brain tissue can be characterized by diffusion tensors computed from diffusion weighted magnetic resonance images. Since these properties are strongly determined by the structural and geometrical characteristics of the tissue, the maturation process of white matter and gray matter tissue can be expected to be reflected in these images and derived tensor quantities. The purpose of this work was therefore to study the development of pediatric brain in terms of changes occurring in the observed diffusion behavior. Echo planar diffusion tensor imaging was performed on 22 (10 females and 12 males) full term newborn and infant patients, diagnosed in retrospect as neurologically healthy. The subjects were subdivided in three age categories. A number of quantities based on the diffusion images were calculated for each tissue type and age category, and the ability of these quantities to provide sensitive and consistent information about the tissue differences and evolution was evaluated. The results clearly illustrate that the rotationally invariant quantities (e.g., the highest diffusivity, anisotropy ratio and volume ratio) are superior to the rotationally variant ones (e.g., ADCs measured along the three axes of the magnet) often used in the clinic. On the basis of the anisotropy ratio and the volume ratio indices, a correlation between the white matter maturation and the evolution of the diffusion anisotropy could be established. The same quantities did not exhibit any age dependence for the gray matter tissues.

Anisotropy↗

PubMed2002

Defects of pyruvate metabolism and the Krebs cycle.

Seizures and metabolic disease are frequently associated, either indirectly as a consequence of the metabolically caused brain dysgenesis or directly by the metabolic derangement. This article describes defects in pyruvate metabolism (pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency) and Krebs cycle defects such as fumarase deficiency. Clinical characterizations and diagnostic strategies have been developed for each of these diseases. In contrast, very little is known about the specific epileptic features in these disorders. In females with a pyruvate dehydrogenase deficiency E1alpha owing to the mutation in the subunit E1alpha of the pyruvate dehydrogenase complex West's syndrome associated with large ventricles and corpus callosum agenesis on magnetic resonance imaging can be the main feature of the disease. In fumarase deficiency, prenatal brain dysgenesis is the most prominent feature of the disease. Diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid, analysis of amino acids in plasma and organic acids in urine, and neuroradiologic investigations. Further biochemical and molecular analysis leads to a definitive diagnosis and opens the way to adequate treatment, genetic counseling, and prenatal diagnosis.

Brain↗