Alternative, noninvasive tissues for quantitative screening of mutant mitochondrial DNA

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Linkage disequilibrium and linkage analysis of the glucose-6-phosphatase gene

Recent studies have indicated that the four most common mutations account for 78% of mutant alleles in the glucose-6-phosphatase (G6Pase) gene. A significant fraction of mutant alleles remain unidentified. Thus, informative polymorphic markers are necessary for linkage analysis in carrier testing and prenatal diagnosis in families where mutations can not be identified. The common mutations appear to be ethnic-specific, suggesting that the individual mutations may have a common founder. With the recent discovery of the nucleotide 1176 polymorphism, we have studied whether these mutations are in linkage disequilibrium with the polymorphism. The results of polymerase chain reaction/allele-specific oligonucleotide analysis show that nucleotide 1176 C is in linkage disequilibrium with mutations R83 C and R83H, and with the splicing mutation 727G→T. The 1176 T polymorphism is in linkage disequilibrium with 459insTA. A GT repeat polymorphism has also been found. However, its heterozygosity is low. The 1176 nucleotide polymorphic marker can be used in carrier and prenatal diagnosis of GSD1a families that have unidentified mutations and are informative for this marker.link_to_subscribed_fulltex

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) triggered by valproate therapy

We report in this study a patient who developed repeated convulsions as a result of valproate therapy. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) was subsequently diagnosed and a nucleotide 3243 A→G mutation was detected in the mitochondrial DNA. This mutation predisposes the patient to the detrimental effects of valproate on oxidative phosphorylation. Conclusion: We support the suggestion of Ponchaut et al. [14] that valproate should not be given to patients suspected of having mitochondrial diseases. In addition, for patients whose seizures worsen with valproate therapy, an inborn error of mitochondrial metabolism should be suspected. The underlying mitochondrial DNA defects should be sought for family screening and genetic counselling.link_to_subscribed_fulltex

A novel DraI polymorphism in the 3' untranslated region of human glucose-6-phosphatase gene: Useful for carrier detection and prenatal diagnosis of glycogen storage disease type 1a

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De novo mutation in the mitochondrial tRNALeu(UUR) gene (A3243G) with rapid segregation resulting in MELAS in the offspring

A 14-year-old Chinese boy with a normal perinatal and early developmental history presented at 5 years of age with migraine, intractable epilepsy, ataxia, supraventricular tachycardia, paralytic ileus and progressive mental deterioration. Computerized tomography revealed multiple cerebral infarcts in the parieto-occipital region without basal ganglial calcification. Magnetic resonance imaging showed increased signal intensity in T2 weighted images in the same regions. A cerebral digital subtraction angiogram was normal. Venous lactate, pyruvate, lactate to pyruvate ratio and cerebrospinal fluid lactate were elevated. Muscle biopsy did not reveal any ragged red fibres; dinucleotide-tetrazolium reductase activity was normal. Mitochondrial DNA analysis detected an adenine to guanine mutation at nucleotide position 3243 of tRNALeu(UUR). All four tissues analysed demonstrated heteroplasmy: leucocyte 56%, hair follicle 70%; buccal cell 64%; muscle 54%. The mother and brother of the proband, both asymptomatic, were also found to have a heteroplasmic A3243G mutation in the leucocytes, hair follicle and buccal cells. Other members of the maternal lineage, including the maternal grandmother, did not have the mutation. This report describes a patient with mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, who presented with multisystem involvement. The absence of ragged red fibres in muscle biopsy did not preclude the diagnosis. Mutational analysis of mitochodrial DNA conveniently confirmed the diagnosis of the disorder. A de novo mutaton is demonstrated in this family.link_to_subscribed_fulltex

POLG mutation presenting with late-onset jerky torticollis

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