Posts Categorized: Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION



A novel mechanism for mitochondrial toxicity of valproic acid

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Luís PB et al (2013) Valproyl-CoA inhibits the activity of ATP- and GTP-dependent succinate:CoA ligases. J Inherit Metab Dis. 2013 Oct 24. [Epub ahead of print]   Luis et al propose a new mechanism for valproic acid-induced mitochondrial dysfunction, particularly in patients with deficiencies of the mtDNA replication machinery. Succinate:CoA ligase (SUCL), also known as […]



FARS2

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I have been seeing a patient for several  years who carried a clinical diagnosis of a mitochondrial disorder based on chronic lactic acidosis, brain abnormalities and other organ involvement. However,  a molecular diagnosis was elusive despite mtDNA sequencing and various gene panels. I therefore recently sent whole exome sequencing on this patient, and he was […]



Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

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Multiple-system atrophy (MSA) is an adult-onset neurodegenerative disease encompassing various combinations of parkinsonism, autonomic dysfunction, cerebellar ataxia and pyramidal dysfunction. As the neuropathologic diagnosis of MSA requires the finding of cytoplasmic aggregates of alpha-synuclein in oligodendroglia, it is classed among the alpha-synucleinopathies, alongside Parkinson disease and Lewy-body dementia. The disease is generally considered sporadic, though […]



Hepatic disease in fatty acid oxidation defects

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A recently published study reports the range of phenotypes of a large number (187) of French patients with fatty acid beta-oxidation defects (FAODs). The study highlights that the liver is the main organ involved at diagnosis regardless of age at diagnosis, classical phenotype (i.e. cardiac, hepatic, or muscular), or enzyme deficiency. Hepatic symptoms were present in 89% of patients […]



SCAD deficiency: biochemical variant or clinically relevant IEM?

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With the expansion of newborn screening in the past decade, biochemical variants are being uncovered without a clear understanding of their clinical significance. One such disorder is Short-chain acyl-CoA dehydrogenase (SCAD) deficiency, which causes an inability to process the shortest chain fatty acids. While early descriptions of this biochemical abnormality imply this is a disorder of […]



Phenylbutyrate for therapy of pyruvate dehydrogenase deficiency

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My apologies for posting my own work published this month in Science Translational Medicine. The data presented in this paper highlight the potential of phenylbutyrate for therapy of pyruvate dehydrogenase complex (PDHC) deficiency, the most common genetic disorder leading to lactic acidosis, and systemic lactic acidosis. PDHC activity is regulated by phosphorylation of the E1-alpha subunit by pyruvate […]



Mitochondrial Cardiomyopathy

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Mitochondrial disease caused by mutations in mitochondrial DNA (mtDNA) can manifest in very different ways. If only an isolated organ is apparently affected, mtDNA defects might not be considered in the differential diagnosis. Giordano et al (Hum Pathol 2013 Jan 17) described three cases of isolated hypertrophic cardiomyopathy caused by homoplasmic mutations in the MTTI gene coding for mitochondrial isoleucine tRNA. […]



FGF21, a mitochondrial disease biomarker, extends lifespan in mice

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Measurement of Fibroblast growth factor 21 (FGF21) concentrations are raised in serum of mice and humans with mitochondrial respiratory chain deficiencies and has been proposed by Suomalainen et al. (http://www.ncbi.nlm.nih.gov/pubmed/21820356) as a first-line diagnostic test for mitochondrial disorders to reduce the need for muscle biopsy. FGF21 is a hormone secreted by the liver during fasting […]



Targeted aCGH for mitochondrial and metabolic disorders

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Targeted aCGH can be useful in the diagnosis of mitochondrial and metabolic disorders. Wang et al. have developed a custom designed oligonucleotide aCGH platform targeting the entire mitochondrial genome and a set of nuclear genes involving mitochondrial and metabolic disorders. This technology can be used to evaluate large deletions, particularly as a complementary diagnostic test […]