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David R Thorburn - One of the best experts on this subject based on the ideXlab platform.

  • recent advances in the genetics of Mitochondrial encephalopathies
    Current Neurology and Neuroscience Reports, 2010
    Co-Authors: Elena J Tucker, Alison G Compton, David R Thorburn
    Abstract:

    Mitochondrial Encephalopathy, the most common neurometabolic disorder, may be caused by mutations in approximately 100 different genes and may present with various symptoms, such as seizures, ataxia, myopathy, cognitive impairment, blindness, and stroke. Fewer than 50% of patients with Mitochondrial Encephalopathy receive a molecular diagnosis, primarily because of the large degree of clinical and genetic heterogeneity among patients and the limited knowledge of the genes involved in Mitochondrial function. Here we review the most recent discoveries of genes associated with Mitochondrial disease with variable neuropathology. All these genes have been identified via homozygosity mapping or linkage analysis; however, advances in sequencing technology indicate that the future of genetic diagnosis and disease gene discovery likely lies in high-throughput sequencing.

Robert W Taylor - One of the best experts on this subject based on the ideXlab platform.

  • A patient with typical clinical features of Mitochondrial Encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report.
    Journal of medical case reports, 2009
    Co-Authors: Khaled K Abu-amero, Saeed Bohlega, Ali Hellani, Hesham M. Aldhalaan, Robert W Taylor
    Abstract:

    There are currently 23 missense point mutations and one 4 basepair deletion spanning different Mitochondrial genes associated with Mitochondrial Encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The spectrum of Mitochondrial DNA mutations in Arab patients with MELAS is largely unknown. A standard clinical examination was carried out on a 34-year-old Saudi woman showing clinical features of MELAS. Fresh frozen muscle tissue was subjected to enzyme histochemical analysis. DNA was extracted from her leukocytes and muscle tissue, and the full Mitochondrial genome was screened for base substitution mutations and deletions. Additionally, we screened the polymerase gamma-1 nuclear gene for mutations. The patient was negative for the most common m.3243 A>G MELAS mutation. Sequencing the full Mitochondrial genome did not reveal any known or potentially pathogenic sequence changes. The polymerase gamma-1 gene was also free from mutations. The clinical picture described here typically fits that observed in patients with MELAS or Mitochondrial stroke-like events, but mutations in recognized genes (Mitochondrial DNA and polymerase gamma-1 gene) were absent. We report the case of a patient with typical clinical features of MELAS, but without an obvious genetic cause.

  • A patient with typical clinical features of Mitochondrial Encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report
    Journal of Medical Case Reports, 2009
    Co-Authors: Khaled K Abu-amero, Hesham Al-dhalaan, Saeed Bohlega, Ali Hellani, Robert W Taylor
    Abstract:

    Introduction There are currently 23 missense point mutations and one 4 basepair deletion spanning different Mitochondrial genes associated with Mitochondrial Encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The spectrum of Mitochondrial DNA mutations in Arab patients with MELAS is largely unknown. Case presentation A standard clinical examination was carried out on a 34-year-old Saudi woman showing clinical features of MELAS. Fresh frozen muscle tissue was subjected to enzyme histochemical analysis. DNA was extracted from her leukocytes and muscle tissue, and the full Mitochondrial genome was screened for base substitution mutations and deletions. Additionally, we screened the polymerase gamma-1 nuclear gene for mutations. The patient was negative for the most common m.3243 A>G MELAS mutation. Sequencing the full Mitochondrial genome did not reveal any known or potentially pathogenic sequence changes. The polymerase gamma-1 gene was also free from mutations. Conclusion The clinical picture described here typically fits that observed in patients with MELAS or Mitochondrial stroke-like events, but mutations in recognized genes (Mitochondrial DNA and polymerase gamma-1 gene) were absent. We report the case of a patient with typical clinical features of MELAS, but without an obvious genetic cause.

  • guanidinoacetate methyltransferase deficiency masquerading as a Mitochondrial Encephalopathy
    Journal of Inherited Metabolic Disease, 2007
    Co-Authors: A A M Morris, Richard Appleton, B Power, D M Isherwood, L J Abernethy, Robert W Taylor, D M Turnbull, N M Verhoeven, Gajja S Salomons, C Jakobs
    Abstract:

    Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 ± 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 ± 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in Mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.

Elena J Tucker - One of the best experts on this subject based on the ideXlab platform.

  • recent advances in the genetics of Mitochondrial encephalopathies
    Current Neurology and Neuroscience Reports, 2010
    Co-Authors: Elena J Tucker, Alison G Compton, David R Thorburn
    Abstract:

    Mitochondrial Encephalopathy, the most common neurometabolic disorder, may be caused by mutations in approximately 100 different genes and may present with various symptoms, such as seizures, ataxia, myopathy, cognitive impairment, blindness, and stroke. Fewer than 50% of patients with Mitochondrial Encephalopathy receive a molecular diagnosis, primarily because of the large degree of clinical and genetic heterogeneity among patients and the limited knowledge of the genes involved in Mitochondrial function. Here we review the most recent discoveries of genes associated with Mitochondrial disease with variable neuropathology. All these genes have been identified via homozygosity mapping or linkage analysis; however, advances in sequencing technology indicate that the future of genetic diagnosis and disease gene discovery likely lies in high-throughput sequencing.

Josef Finsterer - One of the best experts on this subject based on the ideXlab platform.

Laurence A Bindoff - One of the best experts on this subject based on the ideXlab platform.

  • acute Mitochondrial Encephalopathy reflects neuronal energy failure irrespective of which genome the genetic defect affects
    Brain, 2012
    Co-Authors: Charalampos Tzoulis, Laurence A Bindoff
    Abstract:

    Mitochondrial dysfunction and disease may arise as a result of mutations in either the Mitochondrial genome itself or nuclear encoded genes involved in Mitochondrial homeostasis and function. Irrespective of which genome is affected, Mitochondrial encephalopathies share clinical and biochemical features suggesting common pathophysiological pathways. Two common paradigms of Mitochondrial Encephalopathy are Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes caused by maternally transmitted mutations of Mitochondrial DNA and Mitochondrial spinocerebellar ataxia and epilepsy caused by recessively inherited mutations of the nuclear-encoded DNA polymerase gamma, which replicates and repairs the Mitochondrial genome. We studied and compared the disease mechanisms involved in these two syndromes. Despite having different genetic origins, their pathophysiological pathways converge on one critical event, damage to the respiratory chain leading to insufficient energy to maintain cellular homeostasis. In the central nervous system, this appears to cause selective neuronal damage leading to the development of lesions that mimic ischaemic damage, but which lack evidence of decreased tissue perfusion. Although these stroke-like lesions may expand or regress dynamically, the critical factor that dictates prognosis is the presence of epilepsy. Epileptic seizures increase the energy requirements of the metabolically already compromised neurons establishing a vicious cycle resulting in worsening energy failure and neuronal death. We believe that it is this cycle of events that determines outcome and which provides us with a mechanistic structure to understand the pathophysiology of acute Mitochondrial encephalopathies and plan future treatments.