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Copyright of German International Journal of Modern Science / Deutsche Internationale Zeitschrift für Zeitgenössische Wissenschaft is the property of Artmedia24 and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease. Methods MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients. Results We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients’ skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities. Conclusions We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.

Mutations in mitochondrial DNA (mtDNA) may lead to a range of mitochondrial diseases that are related to the damage of the mitochondrial respiratory chain. These mitochondrial diseases are characterized by early onset, difficult-to-cure and maternal inheritance. Mutations at site 8 344 in the mitochondrial tRNA lysine gene can result in the reduced translation of the protein encoded by mtDNA and an inadequate energy supply, leading to myoclonic epilepsy associated with ragged red fiber (MERRF) syndrome, with severe myoclonic symptoms, seizures and ataxia. Another characteristic lesion is multiple symmetric lipomatosis (MSL) in the posterior neck and upper back. Among all of pathogenic mtDNA mutations, m.8344A>G mutations were accounted for about 4% . Nuclear gene modification and environmental factors may be involved in the pathogenesis of m.8344A>G mutation. At present, the specific treatment methods for MERRF are lacking. Preimplantation genetic diagnosis and mitochondrial transplantation based on assisted reproductive technology are expected to be new methods for the treatment of this kind of mitochondrial genetic diseases, but the safety and effectiveness still need to be further verified. [ABSTRACT FROM AUTHOR]

Background: Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNALys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease. Methods: MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients. Results: We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities. Conclusions: We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNALys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome. [ABSTRACT FROM AUTHOR]

Background: Given the etiologic heterogeneity of disease classification using clinical phenomenology, we employed contemporary criteria to classify variants associated with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome and to assess the strength of evidence of gene-disease associations. Standardized approaches are used to clarify the definition of MERRF, which is essential for patient diagnosis, patient classification, and clinical trial design.Methods: Systematic literature and database search with application of standardized assessment of gene-disease relationships using modified Smith criteria and of variants reported to be associated with MERRF using modified Yarham criteria.Results: Review of available evidence supports a gene-disease association for two MT-tRNAs and for POLG. Using modified Smith criteria, definitive evidence of a MERRF gene-disease association is identified for MT-TK. Strong gene-disease evidence is present for MT-TL1 and POLG. Functional assays that directly associate variants with oxidative phosphorylation impairment were critical to mtDNA variant classification. In silico analysis was of limited utility to the assessment of individual MT-tRNA variants. With the use of contemporary classification criteria, several mtDNA variants previously reported as pathogenic or possibly pathogenic are reclassified as neutral variants.Conclusions: MERRF is primarily an MT-TK disease, with pathogenic variants in this gene accounting for ~90% of MERRF patients. Although MERRF is phenotypically and genotypically heterogeneous, myoclonic epilepsy is the clinical feature that distinguishes MERRF from other categories of mitochondrial disorders. Given its low frequency in mitochondrial disorders, myoclonic epilepsy is not explained simply by an impairment of cellular energetics. Although MERRF phenocopies can occur in other genes, additional data are needed to establish a MERRF disease-gene association. This approach to MERRF emphasizes standardized classification rather than clinical phenomenology, thus improving patient diagnosis and clinical trial design. [ABSTRACT FROM AUTHOR]

Myoclonic epilepsy with ragged-red fibers (MERRF) is a maternally inherited mitochondrial neuromuscular disease. We previously reported a significant decrease of mRNA and protein levels of nuclear DNA-encoded carbonic anhydrase VIII (CA8) in MERRF cybrids harboring A8344G mutation in mitochondrial DNA (mtDNA). In this study, we established a reporter construct of luciferase gene-carrying hCA8 promoter containing several putative transcription factor-binding sites, including GC-box, AP-2 and TATA-binding element in the 5'flanking region of the hCA8 gene. Using a series of mutated hCA8 promoter constructs, we demonstrated that a proximal GC-box, recognized by Sp1 and other Sp family members, may be a key cis-element functioning at the promoter. Additionally, a significant increase of the hCA8 promoter activity was observed in the wild-type and mutant cybrids with over-expression of eGFP-Sp1, but no detectable increase in the CA8 protein expression. In contrast, over-expression of Flag-Sp1 and Flag-Sp4 significantly increased the hCA8 promoter activity as well as endogenous CA8 protein expression in neuron-like HEK-293 T cells. However, down-regulation of Sp1, but not Sp4, in 293 T cells revealed a significant reduction of CA8 expression, suggesting that Sp1 is a predominant transcription factor for regulation of CA8 activity. Furthermore, our data indicate that chromatin structure may be involved in the expression of hCA8 gene in MERRF cybrids. Taken together, these results suggest that Sp1 transactivates hCA8 gene through the proximal GC box element in the promoter region. The key modulator-responsive factor to the mtDNA mutation and how it may affect nuclear hCA8 gene transcription need further investigations. [ABSTRACT FROM AUTHOR]

doi: 10.3969/j.issn.1672-6731.2014.03.020

Objective Mitochondrial myopathy (MM) is a relatively rare type of mitochondrial disorder characterized by predominant skeletal muscle involvement. Both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) mutations have been reported as the genetic causes of this disease. Here, we described the clinical and genetic features of a cohort of patients with MM. Methods We conducted a retrospective, single center study enrolling 22 patients with clinically and myopathologically diagnosed MM. The clinical records and results of laboratory examinations were collected and analyzed. The follow-up was conducted by telephone interview in 12 patients. Muscle biopsy and gene analysis was performed in all patients. MtDNA mutation load was quantified in all available tissues. Results Muscle biopsy revealed ragged red fibers and/or cytochrome c oxidase deficient fibers in all patients. Mitochondrial DNA analysis identified pathogenic mutations in 11 patients, including four previously reported mutations (mt-tRNA Leu(UUR) m.3243A > G in five patients, mt-tRNA Lys m.8344A > G in four patients, mt-tRNA Leu(UUR) m.3302A > G in one patient, and mt-tRNA Leu(UUR) m.3250T > C in one patient) and a novel possible pathogenic variant ( MTND1 m.3437G > A) in one patient. The mtDNA mutation load was consistently higher in muscles than in blood. In the remaining 10 patients, there was no pathogenic mutation found either by the Sanger sequencing of entire mitochondrial genome or by the targeted next-generation sequencing which included 238 nuclear genes related to mitochondrial diseases. Clinically, the onset age of these 22 MM patients ranged from 1 to 51 years (mean = 21.1 ± 14.3 years), and the disease duration was between 3 and 44 years (mean = 14.1 ± 9.4 years). Proximal limb weakness with or without exercise intolerance was present in 21 patients, and one patient showed only exercise intolerance. Out of these 22 patients, dysphagia/dysarthria, neck flexor muscle weakness, dyspnea, cardiomyopathy and exercise induced myalgia were observed in five, two, four, one and four patients, respectively. Neither central nervous system manifestation nor brain MRI abnormality was present in these patients. Notably, three of the four patients carrying the m.8344A > G mutation presented with dysarthria. The follow-up of 12 patients revealed symptom improvements in four cases, stable conditions in two cases, and worsened conditions in five cases. The case with the m.3302A > G mutation died of respiratory failure. Conclusions Mitochondrial tRNA genes, as hotspots for mutations, accounted for 50% of MM in this cohort of patients. Patients associated with the m.8344A > G mutation were prone to laryngopharyngeal muscle involvement. The prognosis in our patients is relatively benign except one patient with the m.3302A > G mutation. [ABSTRACT FROM AUTHOR]

Objective To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro , have a distinct clinical presentation and outcome. Methods Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board ( IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. Results Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography ( EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. Significance Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

For the first time, the possibility of maintaining an intact human mitochondrial genome in a heterologous system in the mitochondria of yeast Yarrowia lipolytica is shown. A method for introducing directional changes into the structure of the mitochondrial human genome replicating in Y. lipolytica by an artificially induced ability of yeast mitochondria for homologous recombination is proposed. A method of introducing and using phenotypic selection markers for the presence or absence of defects in genes tRNA-Lys and tRNA-Leu of the mitochondrial genome is developed. The proposed system can be used to correct harmful mutations of the human mitochondrial genome associated with mitochondrial diseases and for preparative amplification of intact mitochondrial DNA with an adjusted sequence in yeast cells. The applicability of the new system for the correction of mutations in the genes of Lys- and Leu-specific tRNAs of the human mitochondrial genome associated with serious and widespread human mitochondrial diseases such as myoclonic epilepsy with lactic acidosis (MELAS) and myoclonic epilepsy with ragged-red fibers (MERRF) is shown. [ABSTRACT FROM AUTHOR]

Background and purpose Peripheral neuropathy in mitochondrial diseases ( MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients. Methods To investigate the involvement of the peripheral nervous system in MDs extensive electrophysiological studies were performed in 109 patients with morphological, biochemical and genetic diagnosis of MD [12 A3243G progressive external ophthalmoplegia ( PEO)/mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes ( MELAS), 16 myoclonic epilepsy with ragged-red fibres ( MERRF), four mitochondrial neurogastrointestinal encephalomyopathy ( MNGIE), 67 PEO with single or multiple deletions of mitochondrial DNA, 10 others]. Results A neuropathy was found in 49 patients (45%). The incidence was very high in MNGIE (100%), MELAS (92%) and MERRF (69%), whilst 28% of PEO patients had evidence of peripheral involvement. The most frequent abnormality was a sensory axonal neuropathy found in 32/49 patients (65%). A sensory-motor axonal neuropathy was instead detected in 16% of the patients and sensory-motor axonal demyelinating neuropathy in 16%. Finally one Leigh patient had a motor axonal neuropathy. It is interesting to note that the great majority had preserved tendon reflexes and no sensory disturbances. Conclusions In conclusion, peripheral involvement in MD is frequent even if often mild or asymptomatic. The correct identification and characterization of peripheral neuropathy through electrophysiological studies represents another tile in the challenge of MD diagnosis. [ABSTRACT FROM AUTHOR]

The myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial encephalomyopathic disease caused due to the lack of hypermodified nucleoside 5-taurinomethyl-2-thiouridine at 'wobble' 34th position in the anticodon loop of human mitochondrial tRNA. Understanding the structural significance of τmsU might be helpful to get more information about the MERRF disease in detail at the atomic level. Hence, conformational preferences of hypermodified nucleoside 5-taurinomethyl-2-thiouridine 5′-monophosphate, 'p-τmsU,' have been studied using semiempirical quantum chemical RM1 method. Full geometry optimization using ab initio molecular orbital HF-SCF (6-31G**) and DFT (B3LYP/6-31G**) methods has also been used to compare the salient features. The RM1 preferred most stable conformation of 'p-τmsU' has been stabilized by hydrogen bonding interactions between O(11a)...HN(8), O1P...HN(8), O1P...HC(10), O4′...HC(6), S(2)...HC1′ O5′...HC(6), and O(4)...HC(7). Another conformational study of 5-taurinomethyl-2-thiouridine side chain in the presence of anticodon loop bases of human mitochondrial tRNA showed similar conformation as found in RM1 preferred most stable conformation of 'p-τmsU.' The glycosyl torsion angle of τmsU retains 'anti' conformation. Similarly, MD simulation results are also found in accordance with RM1 preferred stable structure. The solvent-accessible surface area calculations revealed surface accessibility of τmsU in human mt tRNA anticodon loop. The MEPs calculations of codon-anticodon models of τmsU:G and τmsU:A showed unique potential tunnels between the hydrogen bond donor and acceptor atoms. These results might be useful to understand the exact role of τmsU to recognize AAG/AAA codons and to design new strategies to prevent mitochondrial disease, MERRF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Vietnamese patients (106) tentatively diagnosed with encephalomyopathy were screened for the presence of 15 common point mutations in mitochondria using PCR-RFLP. The screened mutations include A3243G, T3271C and T3291C for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS); A8344G and T8356C for Myoclonus Epilepsy and Rag-Red Fibers (MERRF); G11778A, G3460A and T14484C for Leber's Hereditary Optic Neuropathy (LHON); T8993G/C and T9176G for Leigh syndrome; A1555G for deafness syndrome; G4298A, T10010C, T14728C and T14709C for neuromuscular syndrome. As a result, 6 cases of A3243G (5.7%) and 2 cases of T14727C (3.9%) were found. The 6 cases of A3243G mutation were heteroplasmic at different levels (4.23–80.85%). The T14727C change was discovered for the first time in the MTTE gene encoding for tRNAGluand showed homoplasmy. The T14727C change was probably a mutation because it was further confirmed as vertically inherited from the mother and not the result of isolated polymorphism. [ABSTRACT FROM AUTHOR]

The objective of the study was to better characterize the clinical phenotype associated with the A8344G 'MERRF' mutation of mitochondrial DNA. Fifteen mutated patients were extensively investigated. The frequency of main clinical features was: exercise intolerance and/or muscle weakness 67 %, respiratory involvement 67 %, lactic acidosis 67 %, cardiac abnormalities 53 %, peripheral neuropathy 47 %, myoclonus 40 %, epilepsy 40 %, ataxia 13 %. A restrictive respiratory insufficiency requiring ventilatory support was observed in about half of our patients. One patient developed a severe and rapidly progressive cardiomyopathy requiring cardioverter-defibrillator implantation. Five patients died of overwhelming, intractable lactic acidosis. Serial muscle MRIs identified a consistent pattern of muscle involvement and progression. Cardiac MRI showed non-ischemic late gadolinium enhancement in the left ventricle inferolateral part as early sign of myocardial involvement. Brain spectroscopy demonstrated increased peak of choline and reduction of N-acetylaspartate. Lactate was never detected in brain areas, while it could be documented in ventricles. We confirm that muscle involvement is the most frequent clinical feature associated with A8443G mutation. In contrast with previous reports, however, about half of our patients did not develop signs of CNS involvement even in later stages of the disease. The difference may be related to the infrequent investigation of A8344G mutation in 'pure' mitochondrial myo-cardiomyopathy, representing a bias and a possible cause of syndrome's underestimation. Our study highlights the importance of lactic acidosis and respiratory muscle insufficiency as critical prognostic factors. Muscle and cardiac MRI and brain spectroscopy may be useful tools in diagnosis and follow-up of MERRF. [ABSTRACT FROM AUTHOR]

The article describes the case of a 45-year-old patient suffering from genetically confirmed progressive myoclonic epilepsy who experienced a severe recurrence of seizures following a delay of surgical stimulator replacement.

Abstract: The m.8344A>G mutation in the mt-tRNALys gene, first described in myoclonic epilepsy and ragged red fibers (MERRF), accounts for approximately 80% of mutations in individuals with MERRF syndrome. Although originally described in families with a classical syndrome of myoclonus, ataxia, epilepsy and ragged red fibers in muscle biopsy, the m.8344A>G mutation is increasingly recognised to exhibit marked phenotypic heterogeneity. This paper describes the clinical, morphological and laboratory features of an unusual phenotype in a patient harboring the m.8344A>G ‘MERRF’ mutation. We present the case of a middle-aged woman with distal weakness since childhood who also had ptosis and facial weakness and who developed mid-life respiratory insufficiency necessitating non-invasive nocturnal ventilator support. Neurophysiological and acetylcholine receptor antibody analyses excluded myasthenia gravis whilst molecular genetic testing excluded myotonic dystrophy, prompting a diagnostic needle muscle biopsy. Mitochondrial histochemical abnormalities including subsarcolemmal mitochondrial accumulation (ragged-red fibers) and in excess of 90% COX-deficient fibers, was seen leading to sequencing of the mitochondrial genome in muscle. This identified the m.8344A>G mutation commonly associated with the MERRF phenotype. This case extends the evolving phenotypic spectrum of the m.8344A>G mutation and emphasizes that it may cause indolent distal weakness with respiratory insufficiency, with marked histochemical defects in muscle. Our findings support consideration of screening of this gene in cases of indolent myopathy resembling distal limb-girdle muscular dystrophy in which screening of the common genes prove negative. [Copyright &y& Elsevier]

We report the case of a 19-year-old Chinese female harboring the m.3291T>C mutation in the MT-TL1 gene encoding the mitochondrial transfer RNA for leucine. She presented with a complex phenotype characterized by progressive cerebellar ataxia, frequent myoclonus seizures, recurrent stroke-like episodes, migraine-like headaches with nausea and vomiting, and elevated resting lactate blood level. It is known that the myoclonus epilepsy with ragged-red fibers (MERRF) is characterized by cerebellar ataxia and myoclonus epilepsy, while that the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by recurrent stroke-like episodes, migraine-like headaches, and elevated resting lactate blood level. So the patient's clinical manifestations suggest the presence of a MERRF/MELAS overlap syndrome. Muscle biopsy of the patient showed the presence of numerous scattered ragged-red fibers, some cytochrome c oxidase-deficient fibers, and several strongly succinate dehygrogenase-reactive vessels, suggestive of a mitochondrial disorder. Direct sequencing of the complete mitochondrial genome of the proband revealed no mutations other than the T-to-C transition at nucleotide position 3291. Restriction fragment length polymorphism analysis of the proband and her family revealed maternal inheritance of the mutation in a heteroplasmic manner. The analysis of aerobic respiration and glycolysis demonstrated that the fibroblasts from the patient had mitochondrial dysfunction. Our results suggest that the m.3291T>C is pathogenic. This study is the first to describe the m.3291T>C mutation in association with the MERRF/MELAS overlap syndrome. [ABSTRACT FROM AUTHOR]

Copyright of Medizinische Genetik is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background aims. The feasibility of delivering mitochondria using the cell-penetrating peptide Pep-1 for the treatment of MERRF (myoclonic epilepsy with ragged red fibers) syndrome, which is caused by point mutations in the transfer RNA genes of mitochondrial DNA, is examined further using cellular models derived from patients with MERRF syndrome. Methods. Homogenesis of mitochondria (wild-type mitochondria) isolated from normal donor cells with about 83.5% preserved activity were delivered into MERRF fibroblasts by Pep-1 conjugation (Pep-1-Mito). Results. Delivered doses of 52.5 (tg and 105 μg Pep-1-Mito had better delivered efficiency and mitochondrial biogenesis after 15 days of treatment. The recovery of mitochondrial function in deficient cells receiving 3 days of treatment with peptide-mediated mitochondrial delivery was comprehensively demonstrated by restoration of oxidative phosphorylation subunits (complex I, III and IV), mitochondrial membrane potential, adenosine triphosphate synthesis and reduction of reactive oxygen species production. The benefits of enhanced mitochondrial regulation depended on the function of foreign mitochondria and not the existence of mitochondrial DNA and can be maintained for at least 21 days with dramatically elongated mitochondrial morphology. In contrast to delivery of wild-type mitochondria, the specific regulation of Pep-1-Mito during MERRF syndrome progression in cells treated with mutant mitochondria was reflected by the opposite performance, with increase in reactive oxygen species production and matrix metalloproteinase activity. Conclusions. The present study further illustrates the feasibility of mitochondrial intervention therapy using the novel approach of peptide-mediated mitochondrial delivery and the benefit resulting from mitochondria-organelle manipulation. [ABSTRACT FROM AUTHOR]

Background: Myoclonic epilepsy with ragged-red fibers (MERRF) is a type of mitochondrial encephalomyopathy, clinical experience with the antiepileptic treatment for myoclonus in MERRF is still limited. Myoclonus appears to be intractable, and some antiepileptic drugs may change the blood lactate level. Objective: In this study, we report on two patients, a girl and her mother, both with MERRF in a Chinese family. We aimed to study their myoclonus attack, response to AEDs and blood lactate level. Methods: The diagnosis was based on muscle biopsies and a genetic test. We recorded their myoclonus and detected alterations of blood lactate when the patients received antiepileptic drugs. Results: The patients displayed substantial differences in their responses to antiepileptic drugs. The mother exhibited a good response to valproic acid, although valproic acid is not recommended for mitochondrial disease; however, her daughter was refractory to many antiepileptic drugs until she received a combination treatment of levetiracetam and topiramate. We did not find valproic acid, levetiracetam or topiramate affected the blood lactate levels. Conclusion: These findings imply that not all MERRF patients are resistant to antiepileptic drugs, and for those who are intractable, combination treatment involving levetiracetam and topiramate may be effective for treating myoclonus in MERRF and does not worsen lactic acidosis. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) mutations are associated with a large number of neuromuscular diseases. Myoclonus epilepsy with ragged-red fibers (MERRF) syndrome is a mitochondrial disease inherited through the maternal lineage. The most common mutation in MERRF syndrome, the A8344G mutation of mtDNA, is associated with severe defects in mitochondrial protein synthesis, which impair the assembly and function of the respiratory chain. We have previously shown that there is a decreased level of heat shock protein 27 (HSP27) in lymphoblastoid cells derived from a MERRF patient and in cytoplasmic hybrids (cybrids) harboring the A8344G mutation of mtDNA. In the present study, we found a dramatic decrease in the level of phosphorylated HSP27 (p-HSP27) in the mutant cybrids. Even though the steady-state level of p-HSP27 was reduced in the mutant cybrids, normal phosphorylation and dephosphorylation were observed upon exposure to stress, indicating normal kinase and phosphatase activities. To explore the roles that p-HSP27 may play, transfection experiments with HSP27 mutants, in which three specific serines were replaced with alanine or aspartic acid, showed that the phosphomimicking HSP27 desensitized mutant cybrids to apoptotic stress induced by staurosporine (STS). After heat shock stress, p-HSP27 was found to enter the nucleus immediately, and with a prolonged interval of recovery, p-HSP27 returned to the cytoplasm in wild-type cybrids but not in mutant cybrids. The translocation of p-HSP27 was correlated with cell viability, as shown by the increased number of apoptotic cells after p-HSP27 returned to the cytoplasm. In summary, our results demonstrate that p-HSP27 provides significant protection when cells are exposed to different stresses in the cell model of MERRF syndrome. Therapeutic agents targeting anomalous HSP27 phosphorylation might represent a potential treatment for mitochondrial diseases. [ABSTRACT FROM AUTHOR]

Myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are established phenotypes of mitochondrial encephalopathies. Nearly all patients affected by MERRF harbour a mutation in the mitochondrial tRNA gene. We report a 13-year-old patient who presented with the classical phenotype of MERRF but was found with the typical mutation of MELAS. The patient presented with myoclonic epilepsy beginning at 10 years of age, a muscle biopsy with ragged red fibres and some COX negative fibres and progressive bilateral MRI hyperintensitivities in the basal ganglia constituting MERRF syndrome but lacked clinical characteristics of MELAS. In particular, stroke-like episodes or lactic acidosis were not present. None of the tRNA mutations described in MERRF were found. However, further analyses showed the tRNA mutation m.3243A>G usually found in MELAS to be responsible for the condition in this patient. This report highlights the broad phenotypic variability of mitochondrial encephalopathies with juvenile onset. It shows that m.3243A>G mutations can cause classical MERRF and emphasises the significance of comprehensive genetic studies if mitochondrial disease is suspected clinically. [ABSTRACT FROM AUTHOR]

Abstract: We report that the energy metabolism shifts to anaerobic glycolysis as an adaptive response to oxidative stress in the primary cultures of skin fibroblasts from patients with MERRF syndrome. In order to unravel the molecular mechanism involved in the alteration of energy metabolism under oxidative stress, we treated normal human skin fibroblasts (CCD-966SK cells) with sub-lethal doses of H2O2. The results showed that several glycolytic enzymes including hexokinase type II (HK II), lactate dehydrogenase (LDH) and glucose transporter 1 (GLUT1) were up-regulated in H2O2-treated normal skin fibroblasts. In addition, the glycolytic flux of skin fibroblasts was increased by H2O2 in a dose-dependent manner through the activation of AMP-activated protein kinase (AMPK) and phosphorylation of its downstream target, phosphofructokinase 2 (PFK2). Moreover, we found that the AMPK-mediated increase of glycolytic flux by H2O2 was accompanied by an increase of intracellular NADPH content. By treatment of the cells with glycolysis inhibitors, an AMPK inhibitor or genetic knockdown of AMPK, respectively, the H2O2-induced increase of NADPH was abrogated leading to the overproduction of intracellular ROS and cell death. Significantly, we showed that phosphorylation levels of AMPK and glycolysis were up-regulated to confer an advantage of survival for MERRF skin fibroblasts. Taken together, our findings suggest that the increased production of NADPH by AMPK-mediated increase of the glycolytic flux contributes to the adaptation of MERRF skin fibroblasts and H2O2-treated normal skin fibroblasts to oxidative stress. [Copyright &y& Elsevier]

Abstract: Mutations in the mitochondrial DNA can lead to the development of mitochondrial diseases such as Myoclonic Epilepsy with Ragged Red Fibers (MERRF) or Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS). We first show that human 143B-derived cybrid cells harboring either the A8344G (MERRF) or the A3243G (MELAS) mutation, are more prone to undergo apoptosis then their wild-type counterpart, when challenged with various apoptotic inducers such as staurosporine, etoposide and TRAIL. In addition, investigating the mechanisms underlying A8344G cybrid cells hypersensitivity to staurosporine-induced cell death, we found that staurosporine treatment activates caspases independently of cytochrome c release in both wild-type and mutated cells. Caspases are activated, at least partly, through the activation of calcium-dependent calpain proteases, a pathway that is more strongly activated in mutated cybrid cells than in wild-type cells exposed to staurosporine. These results suggest that calcium homeostasis perturbation induced by mitochondrial dysfunction could predispose cells to apoptosis, a process that could take part into the progressive cell degeneration observed in MERRF syndrome, and more generally in mitochondrial diseases. [Copyright &y& Elsevier]

A cohort of Malaysian patients with clinico-pathological diagnosis of three specifi c mitochondrial encephalomyopathy syndromes comprising of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy with ragged-red fibers (MERRF) and Leigh syndrome were studied to determine the frequency of their common mitochondrial DNA mutations. The 'hot-spot' point mutations for MELAS, MERRF and Leigh syndrome were screened. In the absence of common point mutations, screening of large-scale deletions as well as sequencing of tRNALeu and tRNALys genes were performed. Of 22 patients studied, nine m.3243A>G mutations, four m.8344A>G mutations, one m.8993T>G mutation and one deletion were identified (65% detection rate). While the m.3243A>G mutation was closely associated with MELAS, the m.8344A>G was more heterogenous, being seen in one MERFF, two isolated mitochondrial myopathies and one Leigh syndrome patient. Screening for m.8993T>G in Leigh syndrome has a low yield as unsurprisingly Leigh syndrome has considerable genetic heterogeneity. [ABSTRACT FROM AUTHOR]

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Human patients with myoclonic epilepsy with ragged-red fibers (MERRF) suffer from regionalized pathology caused by a mutation in the mitochondrial DNA (m.8344A→G). In MERRF-syndrome brain and skeletal muscles are predominantly affected, despite mtDNA being present in any tissue. In the past such tissue-specificity could not be explained by varying mtDNA mutation loads. In search for a region-specific pathology in human individuals we determined the mtDNA/nDNA ratios along with themutation loads in 43 different post mortem tissue samples of a 16-year-old female MERRF patient and in four previously healthy victims of motor vehicle accidents. In brain and muscle we further determined the quantity of mitochondrial proteins (COX subunits II and IV), transcription factors (NRF1 and TFAM), and VDAC1 (Porin) as amarker for themitochondrial mass. In the patient the mutation loads varied merely between 89-100%. However, mtDNA copy numbers were increased 3-7 fold in predominantly affected brain areas (e.g. hippocampus, cortex and putamen) and in skeletal muscle. Similar increases were absent in unaffected tissues (e.g. heart, lung, kidney, liver, and gastrointestinal organs). SuchmtDNA copy number increase was not paralleled by an augmentation of mitochondrial mass in some investigated tissues, predominantly in the most affected tissue regions of the brain. We thus conclude that "futile" stimulation of mtDNA replication per se or a secondary failure to increase the mitochondrial mass may contribute to the regionalized pathology seen in MERRF-syndrome. [ABSTRACT FROM AUTHOR]

Abstract: We developed a DNA biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy associated with ragged-red fibers (MERRF). A set of probes sharing a given allele-specific sequence with a single base substitution near the middle of the sequence was covalently immobilized. Cy5-labeled DNA targets were amplified from sample DNAs containing 31 potential MELAS and/or MERRF mutations by a multiplex PCR method. Detection parameters for the DNA biochip-based assay were accordingly optimized. Seven clinically confirmed patients with MELAS, 5 patients with MERRF, 1 suspected MERRF case and 25 healthy controls were tested using the DNA biochip. For discriminating of homoplasmic and heteroplasmic point mutations in mtDNA, a diagnostic factor based on the ratio between the hybridization signals from the reference and test targets with each probe was used. The results showed that all the cases with MELAS had a causal heteroplasmic A3243G tRNALeu(UUR) mutation. In the MERRF patients, four cases were found to be a homoplasmic A8344G tRNALys mutation and one case was a heteroplasmic T8356C tRNALys mutation. None of the healthy controls carried the potential mutations. The results of the DNA biochip were completely consistent with those by DNA sequencing. Thus, the DNA biochip would potentially become a valuable tool in clinical specific screening of the mtDNA point mutations associated with MELAS and/or MERRF syndrome. [Copyright &y& Elsevier]

Myoclonic epilepsy associated with ragged red fibers (MERRF) syndrome is one of the major mitochondrial encephalomyopathies, with the involvement of various organs, which could be caused by mitochondrial A8344G DNA mutation. Monostotic fibrous dysplasia of bone, an asymptomatic developmental disorder, was reported to result from c-fos overexpression in osteogenic cells. Mitochondrial A8344G mutation has been shown to increase c-fos expression in a MERRF cybrid cell line. The authors describe a boy aged 10 years and 2 months with MERRF syndrome and A8344G mutation. Visual disturbance developed and deteriorated rapidly 5 months after the diagnosis of MERRF. A brain magnetic resonance imaging revealed optic nerve compression by sphenoid fibrous dysplasia, which was confirmed by histology. Fibrous dysplasia has never been mentioned in MERRF patients in the literature. This rare association may be because of underestimation, or it could be a coincidence. Care should be taken to explore the skeletal system in MERRF patients with focal symptoms. [ABSTRACT FROM AUTHOR]

Abstract: The impact of point mutations in mitochondrial tRNA genes on the amount and stability of respiratory chain complexes and ATP synthase (OXPHOS) has been broadly characterized in cultured skin fibroblasts, skeletal muscle samples, and mitochondrial cybrids. However, less is known about how these mutations affect other tissues, especially the brain. We have compared OXPHOS protein deficiency patterns in skeletal muscle mitochondria of patients with Leigh (8363G>A), MERRF (8344A>G), and MELAS (3243A>G) syndromes. Both mutations that affect mt-tRNALys (8363G>A, 8344A>G) resulted in severe combined deficiency of complexes I and IV, compared to an isolated severe defect of complex I in the 3243A>G sample (mt-tRNALeu(UUR)). Furthermore, we compared obtained patterns with those found in the heart, frontal cortex, and liver of 8363G>A and 3243A>G patients. In the frontal cortex mitochondria of both patients, the patterns of OXPHOS deficiencies differed substantially from those observed in other tissues, and this difference was particularly striking for ATP synthase. Surprisingly, in the frontal cortex of the 3243A>G patient, whose ATP synthase level was below the detection limit, the assembly of complex IV, as inferred from 2D-PAGE immunoblotting, appeared to be hindered by some factor other than the availability of mtDNA-encoded subunits. [Copyright &y& Elsevier]

By using cDNA microarray and RT-PCR techniques, we investigated the genome-wide alteration of gene expression in skin fibroblasts from patients with myoclonic epilepsy and ragged-red fibers (MERRF) syndrome. By screening for the genes with altered levels of expression, we first discovered that matrix metalloproteinase 1 (MMP1) was highly induced in the primary culture of skin fibroblasts of a female patient in a four-generation family with MERRF syndrome. This phenomenon was confirmed in skin fibroblasts from three other MERRF patients harboring about 85% of mtDNA with A8344G mutation. A further study revealed that the expression of MMP1 could be further induced by treatment of the skin fibroblasts with 200 μM hydrogen peroxide (H2O2) and inhibited by 1 mM N-acetylcysteine. Moreover, the intracellular level of H2O2 in skin fibroblasts of the female MERRF patient was higher than those of the asymptomatic family members and age-matched healthy controls. These findings imply that the increase in the expression of MMP1 may represent one of the responses to the increased oxidative stress in the skin fibroblasts of MERRF patients. We suggest that in affected tissues the oxidative stress-elicited overexpression of MMP1, and probably other matrix metalloproteinases involved in cytoskeleton remodeling, may play an important role in the pathogenesis and progression of mitochondrial encephalomyopathies such as MERRF syndrome. [ABSTRACT FROM AUTHOR]

Background The mitochondrial DNA gene encoding subunit 5 of complex I (ND5) has turned out to be a hot spot for mutations associated with mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes (MELAS) and various overlap syndromes. Objective To describe a novel mutation in the ND5 gene in a young man man with an overlap syndrome of MELAS and myoclonus epilepsy with ragged-red fibers. Design Case report. Patient A 25-year-old man had recurrent strokes, seizures, and myoclonus. His mother also had multiple strokes. A muscle biopsy specimen showed no ragged-red fibers but several strongly succinate dehydrogenase–reactive blood vessels. Results Biochemical analysis showed isolated complex I deficiency and molecular analysis revealed a novel heteroplasmic mutation (G13042A) in the ND5 gene. Conclusions These data confirm that ND5 is a genetic hot spot for overlap syndromes, including MELAS and strokelike and myoclonus epilepsy with ragged-red fibers. [ABSTRACT FROM AUTHOR]

The mitochondrial myopathies consist of a heterogeneous group of disorders caused by structural and functional abnormalities in mitochondria leading to involvement of the nervous system and muscles as well as other organ systems. The peculiar genetic characteristics of mitochondrial DNA impart distinctive properties to these disorders. The pathophysiology is presented. The methods employed in making the correct diagnosis, the preoperative patient assessment and correction of metabolic dysfunctions and anaesthetic techniques used, are highlighted. The conditions are briefly reviewed and suggestions are made for the safe anaesthetic management of affected patients. [ABSTRACT FROM AUTHOR]

We developed a rapid and simple method to identify single-nucleotide polymorphisms (SNPs) in the human mitochondrial tRNA genes. This method is based on a universal, functionalized, self-assembled monolayer, XNA on Gold chip platform. A set of probes sharing a given allele-specific sequence with a single base substitution near the middle of the sequence was immobilized on chips and the chips were then hybridized with fluorescence-labeled reference targets produced by asymmetric polymerase chain reaction from patient DNA. The ratio of the hybridization signals from the reference and test targets with each probe was then calculated. A ratio of above 3 indicates the presence of a wild-type sequence and a ratio of below 0.3 indicates a mutant sequence. We tested the sensitivity of the chip for known mutations in tRNALeu(UUR) and tRNALys genes and found that it can also be used to discriminate multiple mutations and heteroplasmy, two typical features of human mitochondrial DNA. The XNA on Gold biochip method is a simple and rapid microarray method that can be used to test rapidly and reliably any SNP in the mitochondrial genome or elsewhere. It will be particularly useful for detecting SNPs associated with human diseases. [Copyright &y& Elsevier]

Myoclonic epilepsy with ragged-red fibers is a maternally inherited disease that is characterized by myoclonic epilepsy, cerebellar ataxia and progressive muscular weakness. The present study reports the case of a 25-year-old male who presented with paroxysmal left upper limb tics and weakness for two years. Neurological examination revealed intact cranial nerves, decreased deep tendon reflexes and decreased sensation of touch, pain and vibration. The gait of the patient was broad and he was unable to walk in a straight line. Local cortical atrophy was also observed in the left temporal-occipital cortex on a magnetic resonance imaging scan. The muscle biopsy revealed ragged-red fibers. Therefore, the present study hypothesized that imaging observations and follow-up examinations are important in patients with myoclonic epilepsy. [ABSTRACT FROM AUTHOR]

Investigates the association between myoclonus epilepsy with ragged-red fibers (MERRF)/mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) overlap syndrome and 3243 transfer RNA mutation of mitochondrial DNA. Characteristic of MERRF and MELAS; Degeneration of the dental nuclei; Use of gene analysis in verifying the syndrome.

Abstract Introduction Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic lipomatosis may be rarely observed. Case report The authors report 4 cases of MERRF syndrome associated with lipomatosis. In 3 patients, the diagnosis of MERRF syndrome was established on the basis of the clinical features of the lipomas and clinical interview revealing a personal or family history of lipomas and myopathy. Discussion In the presence of extensive spinal lipomatosis, the presence of other clinical signs of MERRF syndrome in the patient or the patient's family must be investigated. A diagnosis of MERRF syndrome can guide appropriate genetic counselling. [ABSTRACT FROM AUTHOR]

Abstract: We report a patient with myoclonic epilepsy who underwent muscle biopsy for suspected mitochondrial disease (myoclonic epilepsy with ragged-red fibers, MERRF). In spite of normal histochemical studies and of the absence of a severe COX deficiency, the molecular analysis showed the common MERRF mutation (A8344G) in the tRNALys gene on mitochondrial DNA. The case serves to illustrate the importance of pursuing the proposed mitochondrial genetic abnormality, even in patients with normal biopsy findings. [Copyright &y& Elsevier]

There are several specific considerations regarding anesthesia in patients with mitochondrial disease. We describe the successful administration of a combined general and epidural anesthesia with sevoflurane maintenance in a patient with myoclonic epilepsy with ragged red fibers (MERRF syndrome) scheduled for surgical treatment of bilateral clubfoot. [ABSTRACT FROM AUTHOR]

Background: Only five patients have previously been reported to harbor mutations in the MT-TT gene encoding mitochondrial tRNA threonine. The m.15923A > G mutation has been found in three severely affected children. One of these patients died within days after birth and two had a phenotype of myoclonic epilepsy with ragged red fibers (MERRF) in early childhood. We have now found the mutation in an adult patient with mild myopathy.Case Presentation: The patient is a 64-year-old Finnish man, who developed bilateral ptosis, diplopia and exercise intolerance in his fifties. Family history was unremarkable. Muscle histology showed cytochrome c-oxidase (COX) negative and ragged red fibres. The m.15923A > G mutation heteroplasmy was 33% in the skeletal muscle and 2% in buccal epithelial cells. The mutation was undetectable in the blood. Single-fibre analysis was performed and COX-negative fibres had a substantially higher heteroplasmy of 92%, than the normal fibres in which it was 43%.Conclusions: We report the fourth patient with m. 15923A > G and with a remarkably milder phenotype than the previous three patients. Our findings and recent biochemical studies suggest that the mutation m.15923A > G is a definite disease-causing mutation. Our results also suggest that heteroplasmy of the m.15923A > G mutation correlates with the severity of the phenotype. This study expands the catalog of the phenotypes caused by mutations in mtDNA. [ABSTRACT FROM AUTHOR]

Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases. [ABSTRACT FROM AUTHOR]

Summary: MERRF syndrome (myoclonic epilepsy with ragged-red fibres) is a mitochondrial encephalomyopathy characterised by a mixed seizure disorder and myoclonus. The condition is associated with multiple large cervical lipomas that often require surgical excision. Comprehensive clinical examination combined with pre-operative radiographic imaging is vital in such cases to help differentiate benign fatty masses from potential liposarcomas. We describe a case in which a lipoma-like liposarcoma was identified following excision of what was expected, on clinical and radiological grounds, to be a lipoma. This case highlights the potential for sarcomatous changes in suspicious lipomas, and the key role that imaging plays in differentiating benign from malignant. [Copyright &y& Elsevier]