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McKelvie P.,St. Vincents Hospital Melbourne | Marotta R.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Thorburn D.R.,Murdoch Childrens Research Institute | Chin J.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | And 3 more authors.
Neuromuscular Disorders | Year: 2012

This 54. year old woman presented with symptoms of sensory ataxic neuropathy, with cerebellar features. She developed further weakness, visual disturbances with diplopia, dysarthria and dysphasia. After her death at 66. years, she was found to have compound heterozygous mutations of POLG1 gene in muscle, and Southern blot showed low levels of multiple deletions of mitochondrial DNA. Neuropathological examination showed profound dorsal column and dorsal spinocerebellar tract degeneration, degeneration of dorsal root ganglia and Clarke's nucleus in spinal cord and severe predominantly sensory peripheral neuropathy. The brain showed severe neuronal loss and gliosis in substantia nigra, medial posterior thalamus and head of caudate. Excess numbers of COX-negative fibres and " ragged-red" fibres were found in five skeletal muscles sampled. © 2011 Elsevier B.V. Source


McKelvie P.,St. Vincents Hospital Melbourne | Infeld B.,Epworth Richmond Hospital | Marotta R.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Chin J.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2012

We report an illustrative case of a 74-year-old man who, in the absence of intercurrent illness, presented with rapid cognitive decline. MRI showed bilateral, symmetrical, high T2-weighted signal in the anterior basal ganglia and medial thalami, extending to the periaqueductal grey matter, basal ganglia and basal frontal lobes. A 18F-fluorodeoxyglucose-positron emission tomography scan showed widespread reduction of metabolism in the cortex of the frontal, temporal and parietal lobes, posterior cingulate gyrus, precuneus and caudate nuclei, with sparing of the sensorimotor cortex, thalami and lentiform nuclei. A mild vitamin B12 deficiency was found and despite normal thiamine levels, intravenous (IV) thiamine and vitamin B therapy was commenced, with a short course of IV methylprednisolone and tetracycline. Repeat neuropsychological assessment four weeks following treatment revealed increased alertness and interactiveness but significant cognitive decline persisted. Unexpectedly, the patient suffered a transmural anterior myocardial infarction six weeks after presentation and died within 24 hours. An a autopsy showed: global reduction in cytochrome oxidase (COX) activity in all skeletal muscles examined; bilateral, symmetrical, hypervascular, focally necrotizing lesions in the substantia nigra, periaqueductal grey matter, superior colliculi, medial thalami anteriorly and posteriorly, as well as in the putamena but the mammillary bodies were not affected. Biochemical analysis of fresh muscle confirmed selective deficiency of complex IV of the oxidative phosphorylation chain. A diagnosis of late-adult onset Leigh syndrome was made. Multiple genetic studies failed to identify the specific underlying mutation. The relevant literature is reviewed. © 2011 Elsevier Ltd. All rights reserved. Source


Marotta R.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Chin J.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Kirby D.M.,Murdoch Childrens Research Institute | Chiotis M.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2011

A high number of cytochrome c oxidase (COX)-negative muscle fibres (approximately 45%) without ragged red fibres was found in a 27-year-old male patient with a single unprovoked episode of severe rhabdomyolysis. There was no family history of neuromuscular disorder and sequencing revealed a novel COX III single base pair deletion (MT-CO3{NC-012920.1}:m.[9559delC]). The deletion creates a frame shift and downstream termination codon affecting the last 136 amino acids (MT-CO3{YP-003024032.1}:p.[Pro118GlnfsX124]). The heteroplasmic mutation load in muscle was approximately 58% and single COX-negative fibres harboured significantly greater levels of mutant mitochondrial DNA than COX-positive fibres. © 2010 Elsevier Ltd. All rights reserved. Source


Chin J.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Marotta R.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Chiotis M.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Allan E.H.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory | Collins S.J.,St Vincents Melbourne Neuromuscular Diagnostic Laboratory
Mitochondrion | Year: 2014

The nucleotide change A to G at position m.3243 in the mitochondrial tRNA leucine (UUR) gene (MT-TL1) is the most common point mutation reported in association with the Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) syndrome. Since the original description of this disorder, factors including random mitochondrial segregation and consequent variable tissue heteroplasmy are recognised to contribute to a much broader phenotypic spectrum associated with the MT-TL1 m.3243A. >. G mutation, often rendering the process of making a diagnosis complex. Reliance on clinicians' referral patterns means that for most molecular diagnostic laboratories, their positive identification rates for the common pathogenic mitochondrial DNA (mtDNA) mutations, including MT-TL1 m.3243A. >. G, is often relatively low compared to those reported in clinically targeted research studies. Herein, we report our results of consecutive prospective screening of 745 patients with a clinically suspected mitochondrial syndrome encompassing features associated with MT-TL1 m.3243A. >. G mutation. © Elsevier B.V. and Mitochondria Research Society. Source

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