Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease

Howell, Neil; Kubacka, Iwona; Smith, Richard J.H.; Frerman, Frank E.; Parks, Jason C.; Parker, W. Davis

doi:10.1212/wnl.46.1.219

Cited by 60 publications

(33 citation statements)

References 5 publications

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“…The mother of case IV reportedly was unambulatory because of a profound muscle weakness when she was alive, and so, it is assumed that the amount of mutant DNA should be big enough to inherit the disease to some of her siblings, according to the "bottle neck hypothesis" in mtDNA segregation (37,38). The A8344G MERRF mutation is located at the T C loop of the tRNA Lys gene, and different phenotypes have been reported as in A3243G MELAS mutation (39,40). The A8344G mutation in the tRNA Lys gene affects the translation of lysine, and thus, produce the defect in protein synthesis (ex.…”

Section: Discussionmentioning

confidence: 99%

Histochemical and Molecular Genetic Study of MELAS and MERRF in Korean Patients

et al. 2002

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Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) and myoclonic epilepsy and ragged-red fibers (MERRF) are rare disorders caused by point mutation of the tRNA gene of the mitochondrial genome. To understand the pathogenetic mechanism of MELAS and MERRF, we studied four patients. Serially sectioned frozen muscle specimens with a battery of histochemical stains were reviewed under light microscope and ultrastructural changes were observed under electron microscope. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed and the tRNA genes were sequenced to confirm mutations. In two patients with MELAS, strongly succinyl dehydrogenase positive blood vessels (SSVs) and many cytochrome oxidase (COX) positive ragged-red fibers (RRFs) were observed, and A3243G mutations were found from the muscle samples. In two patients with MERRF, neither SSV nor COX positive RRFs were seen and A8344G mutations were found from both muscle and blood samples. In the two MERRF families, the identical mutation was observed among family members. The failure to detect the mutation in blood samples of the MELAS suggests a low mutant load in blood cells. The histochemical methods including COX stain are useful for the confirmation and differentiation of mitochondrial diseases. Also, molecular biological study using muscle sample seems essential for the confirmation of the mtDNA mutation.

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Section: Discussionmentioning

confidence: 99%

Histochemical and Molecular Genetic Study of MELAS and MERRF in Korean Patients

et al. 2002

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“…The m.8344A[G mutation in MTTK was calculated to occur with a prevalence of 0.7/ 100,000 in a large population-based study in North East England [6] and accounts for approximately 80-90 % of MERRF cases [7]. In addition to MERRF, the m.8344A[G mutation has more rarely been associated with other clinical phenotypes, such as childhood-or adult-onset Leigh Syndrome [8][9][10][11] and myopathy, with or without lipomas [8,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Expanded phenotypic spectrum of the m.8344A>G “MERRF” mutation: data from the German mitoNET registry

et al. 2016

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The m.8344A>G mutation in the MTTK gene, which encodes the mitochondrial transfer RNA for lysine, is traditionally associated with myoclonic epilepsy and ragged-red fibres (MERRF), a multisystemic mitochondrial disease that is characterised by myoclonus, seizures, cerebellar ataxia, and mitochondrial myopathy with ragged-red fibres. We studied the clinical and paraclinical phenotype of 34 patients with the m.8344A>G mutation, mainly derived from the nationwide mitoREGISTER, the multicentric registry of the German network for mitochondrial disorders (mitoNET). Mean age at symptom onset was 24.5 years ±10.9 (6-48 years) with adult onset in 75 % of the patients. In our cohort, the canonical features seizures, myoclonus, cerebellar ataxia and ragged-red fibres that are traditionally associated with MERRF, occurred in only 61, 59, 70, and 63 % of the patients, respectively. In contrast, other features such as hearing impairment were even more frequently present (72 %). Other common features in our cohort were migraine (52 %), psychiatric disorders (54 %), respiratory dysfunction (45 %), gastrointestinal symptoms (38 %), dysarthria (36 %), and dysphagia (35 %). Brain MRI revealed cerebral and/or cerebellar atrophy in 43 % of our patients. There was no correlation between the heteroplasmy level in blood and age at onset or clinical phenotype. Our findings further broaden the clinical spectrum of the m.8344A>G mutation, document the large clinical variability between carriers of the same mutation, even within families and indicate an overlap of the phenotype with other mitochondrial DNA-associated syndromes.

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“…30, 31 Swerdlow and colleagues 32 have described a pedigree in which PD and complex I deficiency in cybrids were maternally inherited. Also, Howell and associates 33 described neurodegeneration with diverse features in a family with the nt 8344 mutation in tRNA Lys found usually in MERRF (myoclonus epilepsy and ragged-red fibers). No mtDNA mutations have been found in idiopathic PD, however, despite complete sequencing of the mitochondrial genome in patients.…”

Section: Discussionmentioning

confidence: 98%