Publications by authors named "Manuela Grazina"

37 Publications

Identification of a novel mutation in MEF2C gene in an atypical patient with frontotemporal lobar degeneration.

Neurol Sci 2021 May 17. Epub 2021 May 17.

Faculty of Medicine, University of Coimbra, Pólo III - Subunit I, Azinhaga de Sta. Comba Celas PT, 3000-548, Coimbra, Portugal.

The MEF2C gene encodes a transcription factor known to play a crucial role in molecular pathways affecting neuronal development. MEF2C mutations were described as a genetic cause of developmental disease (MRD20), and several reports sustain its involvement in dementia-related conditions, such as Alzheimer's disease and amyotrophic lateral sclerosis. These pathologies and frontotemporal degeneration (FTLD) are thought to share common physiopathological pathways. In this exploratory study, we searched for alterations in the DNA sequence of exons and boundaries, including 5'- and 3'-untranslated regions (5'UTR, 3'UTR), of MEF2C gene in 11 patients with clinical phenotypes related with MRD20 or FTLD. We identified a heterozygous deletion of 13 nucleotides in the 5'UTR region of a 69 years old FTLD patient. This alteration was absent in 200 healthy controls, suggesting a contribution to this patient's disease phenotype. In silico analysis of the mutated sequence indicated changes in mRNA secondary structure and stability, thus potentially affecting MEF2C protein levels. Furthermore, in vitro functional analysis of this mutation revealed that the presence of this deletion abolished the transcriptional activity of the gene in human embryonic cells and rat brain neurons, probably by modifying MEF2C expression. Altogether, our results provide evidence for the involvement of MEF2C in FTLD manifesting with seizures.
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http://dx.doi.org/10.1007/s10072-021-05269-0DOI Listing
May 2021

MPV17 Mutations Are Associated With a Quiescent Energetic Metabolic Profile.

Front Cell Neurosci 2021 17;15:641264. Epub 2021 Mar 17.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.

Mutations in the MPV17 gene are associated with hepatocerebral form of mitochondrial depletion syndrome. The mechanisms through which MPV17 mutations cause respiratory chain dysfunction and mtDNA depletion is still unclear. The MPV17 gene encodes an inner membrane mitochondrial protein that was recently described to function as a non-selective channel. Although its exact function is unknown, it is thought to be important in the maintenance of mitochondrial membrane potential (ΔΨm). To obtain more information about the role of MPV17 in human disease, we investigated the effect of MPV17 knockdown and of selected known MPV17 mutations associated with MPV17 disease . We used different approaches in order to evaluate the cellular consequences of MPV17 deficiency. We found that lower levels of MPV17 were associated with impaired mitochondrial respiration and with a quiescent energetic metabolic profile. All the mutations studied destabilized the protein, resulting in reduced protein levels. We also demonstrated that different mutations caused different cellular abnormalities, including increased ROS production, decreased oxygen consumption, loss of ΔΨm, and mislocalization of MPV17 protein. Our study provides novel insight into the molecular effects of MPV17 mutations and opens novel possibilities for testing therapeutic strategies for a devastating group of disorders.
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http://dx.doi.org/10.3389/fncel.2021.641264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011494PMC
March 2021

MYOC Gene Sequencing Analysis in Primary Open-Angle Glaucoma Patients from the Centre Region of Portugal.

Acta Med Port 2020 Dec 3. Epub 2020 Dec 3.

Institute for Clinical and Biomedical Research (iCBR). Faculty of Medicine. University of Coimbra. Coimbra. Portugal.

Introduction: Primary open-angle glaucoma is the most frequent subtype of glaucoma. Relatives of primary open-angle glaucoma patients have an increased risk of developing the disease, suggesting a genetic predisposition to the disease. MYOC was the first primary open-angle glaucoma-causing gene identified. This study aimed to identify sequence variations in the MYOC gene that may be responsible for the phenotype in a group of primary open-angle glaucoma patients from the Centre Region of Portugal.

Material And Methods: The three coding exons and the proximal splicing junctions of the MYOC gene were studied using a PCR sequencing approach in a group of 99 primary open-angle glaucoma patients.

Results: The sequencing analysis enabled the identification of 20 variants, including four in the promoter region, seven in the introns and nine in exons one and three, of which four were missense variants.

Discussion: Initially, all four missense sequence variations identified were considered candidates to glaucoma causing disease mutations. However, after literature review, only variant c.1334C>T (Ala445Val) remained as likely responsible for mild late-onset normal tension glaucoma.

Conclusion: This is the first study performed in a group of primary open-angle glaucoma patients from the Centre Region of Portugal, contributing to the identification of one genetic variant in the MYOC gene and reinforcing the hypothesis that normal tension glaucoma could be also due to MYOC gene mutations.
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http://dx.doi.org/10.20344/amp.14922DOI Listing
December 2020

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

Clin Pharmacol Ther 2020 01 7;107(1):257-268. Epub 2019 Oct 7.

RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics, Badajoz, Extremadura, Spain.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.
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http://dx.doi.org/10.1002/cpt.1598DOI Listing
January 2020

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

OMICS 2018 09 11;22(9):575-588. Epub 2018 Sep 11.

1 RIBEF Ibero-American Network of Pharmacogenetics and Pharmacogenomics , Badajoz, Spain .

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.
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http://dx.doi.org/10.1089/omi.2018.0114DOI Listing
September 2018

CYP2D6 Pharmacogenetics Testing and Post-Cesarean Section Pain Scores-a Preliminary Study.

Pain Med 2019 02;20(2):359-368

CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal.

Objective: Prospective observational study to analyze CYP2D6 pharmacogenetics in 55 Portuguese adult parturients undergoing elective cesarean section and to investigate the association between CYP2D6 alleles and pain score.

Methods: DNA was extracted from peripheral blood by standard methods. Genetic analysis included allelic discrimination (CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, and *41) and copy number determination with TaqMan probes by real-time polymerase chain reaction (PCR). Allele duplications were confirmed (long PCR and PCR-restriction fragment length polymorphism). Theoretical metabolic profiles prediction was based on genetic data and activity scores. Association was investigated between genotypes and predicted phenotypes with pain scores. Statistical analysis was performed by using a χ2 test, and significance was set at P < 0.05.

Results: The percentage of poor, intermediate, extensive, and ultrarapid metabolizers found were 9%, 38%, 46%, and 7%, respectively. The results reveal a positive association between alleles *4, *10, and pain.

Conclusions: A positive association was found between predicted reduced or null activity of CYP2D6 and increased pain. It can be hypothesized that if CYP2D6 activity is reduced, tyramine metabolism will decrease, resulting in reduced formation of endogenous dopamine. Consequently, activation of the signal transduction pathways that controls pain and analgesic effect may be reduced, leading to an increase in pain. Therefore, we would recommend CYP2D6 genotyping to anticipate the needs for analgesia, which will help to adjust opioid dose and maximize clinical efficacy while reducing side effects.
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http://dx.doi.org/10.1093/pm/pny033DOI Listing
February 2019

Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant.

Neuromuscul Disord 2018 04 23;28(4):350-360. Epub 2017 Nov 23.

FMUC - Faculty of Medicine, University of Coimbra, Coimbra, Portugal; CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal. Electronic address:

Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the "common deletion" in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNA variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The "common mtDNA deletion" is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNA variant cannot be fully excluded.
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http://dx.doi.org/10.1016/j.nmd.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952895PMC
April 2018

Glutaminemia prognostic significance in critical surgical patients - An analysis of plasma aminogram profile.

Nutr Hosp 2017 Jul 28;34(4):799-807. Epub 2017 Jul 28.

"A" Surgical Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background: Glutamine depletion is common in the critically-ill patients. Glutaminemia lower than 420 μmol/l has been considered as an independent predictive factor of mortality, but the indications for exogenous glutamine supplementation remain controversial. This study intends to determine the glutaminemia profile in critical surgical patients and to investigate its correlation with the severity indexes and the prognosis.

Methods: A prospective study of 28 adult critical surgical patients was performed. Plasma amino acid concentrations were quantified, by ion exchange chromatography, at the moment of admission and at the first and third days, and compared with those of 11 reference healthy individuals. Severity indexes and parameters of prognosis were registered.

Results: In critical surgical patients, mean glutaminemia at admission was lower than that of control individuals (385.1 ± 123.1 versus515 ± 57.9 μmol/l, p = 0.002) and decreased until the third day (p = 0.042). Prevalence of severe hypoglutaminemia (< 420 μmol/l) at admission was 64.3%. Baseline glutaminemia correlated with the Simplified Acute Physiology Score II (SAPS II score) (Pearson's correlation coefficient r = -39.4%, p = 0.042), and it was lower in cases of erythrocytes transfusion (339.9 ± 78.8 versus 454.9 ± 148.8 μmol/l, p = 0.013). Glutaminemia at the third day correlated with the duration of invasive ventilation support (r = -65%, p = 0 .012) and ICU stay (r = -66.5%, p = 0.009). Glutaminemia below 320 μmol/l, observed in 25% of the patients, was associated with higher in-hospital mortality (42.9 versus19%, statistically not significant [n.s.]) and lower actuarial survival (212.1 ± 77.9 versus 262.3 ± 32.4 days, n.s.).

Conclusions: Those results underscore the relevance of hypoglutaminemia as an adverse predictive factor in the critical surgical patients. Determination of glutaminemia may contribute to a better definition of the indications for glutamine supplementation.
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http://dx.doi.org/10.20960/nh.817DOI Listing
July 2017

mtDNA copy number associated with age of onset in familial amyloid polyneuropathy.

J Neurol Neurosurg Psychiatry 2018 03 10;89(3):300-304. Epub 2017 Oct 10.

Centre for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics (LGB), Universidade de Coimbra, Coimbra, Portugal.

Background: Transthyretin-related familial amyloid polyneuropathy (TTR-FAP Val30Met) shows a wide variation in age-at-onset (AO) between generations and genders, as in Portuguese families, where women display a later onset and a larger anticipation (>10 years). Mitochondrial DNA (mtDNA) copy number was assessed to clarify whether it has a modifier effect on AO variability in Portuguese patients.

Methods: The mtDNA copy number of 262 samples (175 Val30Met carriers and 87 controls (proven Val30Val)) was quantified by quantitative real-time PCR. Statistical analysis was performed using IBM SPSS V.23 software.

Results: This study shows that Val30Met carriers have a significantly higher (p<0.001) mean mtDNA copy number than controls. Furthermore, the highest mtDNA copy number mean was observed in early-onset patients (AO <40 years). Importantly, early-onset offspring showed a significant increase (p=0.002) in the mtDNA copy number, when compared with their late AO parents.

Conclusions: The present findings suggest, for the first time, that mtDNA copy number may be associated with earlier events and may therefore be further explored as a potential biomarker for follow-up of TTR-FAP Val30Met carriers.
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http://dx.doi.org/10.1136/jnnp-2017-316657DOI Listing
March 2018

Response to "In silico prediction is insufficient to assess pathogenicity of mtDNA variants".

Eur J Med Genet 2018 01 12;61(1):46-47. Epub 2017 Aug 12.

Faculty of Medicine, University of Coimbra, PA 3000-354, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra - Laboratory of Biochemical Genetics, Portugal. Electronic address:

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http://dx.doi.org/10.1016/j.ejmg.2017.08.008DOI Listing
January 2018

Intestinal dysfunction in the critical trauma patients - An early and frequent event.

Nutr Hosp 2017 Mar 30;34(2):284-289. Epub 2017 Mar 30.

"A" Surgical Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background: Small-bowel dysfunction exerts a relevant prognostic impact in the critically ill patients. Citrullinemia has been used in the evaluation of the intestinal function and it is considered an objective parameter of the functional enterocyte mass. Present study proposes to determine the intestinal dysfunction prevalence and the citrullinemia kinetic profile in severe trauma patients and to investigate its correlation with severity indicators and clinical outcome.

Methods: A prospective study including 23 critical trauma patients was performed. Aminoacidemias were quantified, by ion exchange chromatography, at the admission and at the first and third days. Severity and outcome parameters were registered.

Results: In severe trauma patients, severe hypocitrullinemia (< 20 μmol/L) prevalence at admission was high (69.6%) and mean citrullinemia was low (19.5 ± 11.1 μmol/L). Baseline citrullinemia was inversely and significantly correlated with shock index (r = -55.1%, p = 0.008) and extent of invasive ventilation support (r = -42.7%, p = 0.042). Citrullinemia < 13.7 μmol/L at admission, observed in 17.4% of patients, was associated with higher shock index (1.27 ± 0.10 versus 0.75 ± 0.18, p = 0.0001) and longer duration of invasive ventilation support (20.3 ± 7 versus 11.2 ± 7.1 days, p = 0.029) and intensive care unit stay (22 ± 5.9 versus 12.2 ± 8.8 days, p = 0.048). A citrullinemia decrease in the first day after admittance superior to 12.7% constituted a significant predictive factor of in-hospital mortality (75 versus 14.3%, p = 0.044; odds ratio = 7.8; accuracy = 65.2%; specificity = 92.3%; negative predictive value = 85.7%] and lower actuarial survival (69.8 ± 41.6 versus 278.1 ± 37.4 days, p = 0.034).

Conclusions: Those results confirm the high prevalence and the prognostic relevance of hypocitrullinemia, considered a biomarker of enterocyte dysfunction, in severe trauma patients.
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http://dx.doi.org/10.20960/nh.788DOI Listing
March 2017

Genotyping CYP2D6 by three different methods: advantages and disadvantages.

Drug Metab Pers Ther 2017 03;32(1):33-37

Background: CYP2D6 belongs to P450 superfamily, and is responsible for the metabolism of 25% of the drugs used clinically. Genetic variability of CYP2D6 affects individual drug or toxic response leading to differences in the drug outcome or toxicity mediating adverse drug effects. The different variant alleles are associated with increased, decreased, or abolished enzyme hydroxylation functions. The CYP2D6*10 (rs1065852, c.100C>T) allele is associated with reduced function and is one of the most studied alleles.

Methods: The aim of this study was to perform three different methods (PCR-RFLP, TaqMan® Drug Metabolism Genotyping Assays, and Sanger Sequencing) for genotyping alteration c.100C>T, rs1065852 in a group of 24 Portuguese subjects (15 females and 9 males, mean age 70±9 years) and compare the results.

Results: We found 16 samples homozygous for *1 allele and 8 heterozygous for *10 allele.

Conclusions: The three methods provide concordant results suggesting that any of these techniques is a reliable and sensitive method for genotyping CYP2D6. However, we would recommend the use of TaqMan® Drug Metabolism Assays, given the advantages concerning time spending, straightforwardness, reliability, and accuracy.
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http://dx.doi.org/10.1515/dmpt-2016-0035DOI Listing
March 2017

In silico analysis for predicting pathogenicity of five unclassified mitochondrial DNA mutations associated with mitochondrial cytopathies' phenotypes.

Eur J Med Genet 2017 Mar 24;60(3):172-177. Epub 2016 Dec 24.

Faculty of Medicine, University of Coimbra, PA 3000-354, Portugal; Center for Neuroscience and Cell Biology, University of Coimbra - Laboratory of Biochemical Genetics, Portugal. Electronic address:

Mitochondrial DNA (mtDNA) mutations have been assigned as a major cause of genetic disease. When a novel sequence variation is found, it is necessary to evaluate its functional impact, usually requiring functional molecular studies. Given the fact that this approach is difficult to put in practice in a routine basis, it is possible to take advantage of the in silico tools available and predict protein/RNA structure changes and therefore pathogenicity. Here, we describe the characterization of five undescribed mtDNA variants, upon detection of 23 unclassified alterations at Laboratory of Biochemical Genetics, from 2004 to 2014. Those five sequence variations are located in protein-coding genes, in five patients with a diverse range of mitochondrial respiratory chain disease phenotypes including encephalopathy, optic neuropathy, developmental delay, deafness and epilepsy. According to the prediction established by in silico analysis using tools to predict structure and function changes (ClustalW2, PolyPhen-2, SIFT, MutationAssessor, PredictProtein, Provean, I-TASSER, Haplogrep), from the 23 variants analyzed, the five described are potentially pathogenic. This approach is inexpensive and compatible with a rapid first line response to clinical demanding, contributing to a more rationale genetic diagnosis concerning novel mutations and to clarify the mtDNA involvement in these pathologies.
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http://dx.doi.org/10.1016/j.ejmg.2016.12.009DOI Listing
March 2017

Identification of a novel deletion in SURF1 gene: Heterogeneity in Leigh syndrome with COX deficiency.

Mitochondrion 2016 Nov 15;31:84-88. Epub 2016 Oct 15.

CNC - Center for Neuroscience and Cell Biology, Biochemical Genetics Laboratory, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Leigh syndrome (LS) is a rare, progressive neurodegenerative mitochondrial disorder of infancy. It is a genetically heterogeneous disease. The mutations in SURF1 gene are the most frequently known cause. Here two cases of LS likely caused by SURF1 gene variants are reported: a 39-year-old male patient with a novel homozygous deletion (c.-11_13del), and a case of a 6-year-old boy with the same deletion and a nonsense mutation (c.868dupT), both in heterozygosity. Blue native PAGE showed absence of assembled complex IV. This is the first report of a variant that may abolish the SURF1 gene initiation codon in two LS patients.
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http://dx.doi.org/10.1016/j.mito.2016.10.004DOI Listing
November 2016

Argininemia and plasma arginine bioavailability - predictive factors of mortality in the severe trauma patients?

Nutr Metab (Lond) 2016 31;13(1):60. Epub 2016 Aug 31.

"A" Surgical Department, Hospitais da Universidade de Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Prof. Mota Pinto, 3000-075 Coimbra, Portugal ; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Background: Arginine is an amino acid determinant in the metabolic, immune and reparative responses to severe trauma. The present study aims to determine argininemia and plasma arginine bioavailability (PAB) in critical trauma patients and to analyze its correlation with prognosis.

Methods: A prospective study of 23 critical trauma patients was undertaken. Aminoacidemias were determined, by ion exchange chromatography, at admission and in the first and third days and compared with those of 11 healthy individuals. PAB was calculated. Severity indexes and outcome parameters were recorded.

Results: Values of argininemia, citrullinemia and ornithinemia at the admission were significantly lower than those of the controls (arginine: 41.2 ± 20.6 versus 56.1 ± 11.9 μmol/L, P = 0.034). Hipoargininemia (<60 μmol/L) prevalence was 82.6 %. Mean PAB was 62.4 ± 25.6 %. Argininemia < 26 μmol/L constituted a significant predictive factor of in-hospital mortality [n = 4 (17.4 %); 75 versus 15.8 %, P = 0.04; odds ratio = 4.7; accuracy = 87 %] and lower actuarial survival (63.5 ± 43.9 versus 256.1 ± 33.3 days, P = 0.031). PAB <42 % [n = 6 (26.1 %)] was associated with higher lactacidemia levels (P = 0.033), higher in-hospital mortality (66.7 versus 11.8 %, P = 0.021; odds ratio = 5.7, accuracy = 82.6 %) and lower actuarial survival (87.2 ± 37.5 versus 261.4 ± 34.7 days, n.s.). Probability of in-hospital mortality was inversely and significantly related with PAB [61.8 ± 8.8 % (95 % CI 50.8-72.7) when PAB <41 % and 2.8 ± 1.9 % (95 % CI 1.9-8.3) when PAB > 81 %, P = 0.0001]. Charlson's index ≥1, APACHE II ≥19.5, SOFA ≥7.5, and glutaminemia < 320 μmol/L were also predictive factors of actuarial survival.

Conclusions: Those results confirm the high prevalence of arginine depletion in severe trauma patients and the relevance of argininemia and PAB as predictive factors of mortality in this context.
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http://dx.doi.org/10.1186/s12986-016-0118-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006376PMC
September 2016

Lethal Neonatal LTBL Associated with Biallelic EARS2 Variants: Case Report and Review of the Reported Neuroradiological Features.

JIMD Rep 2017 30;33:61-68. Epub 2016 Aug 30.

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

Mitochondrial translation defects are important causes of early onset mitochondrial disease. Although the biochemical (combined respiratory chain deficiency) signature and neuroimaging are usually distinctive, they are not diagnostic as the genetic origin of mitochondrial translation defects is heterogeneous. We report a female child, born at term to non-consanguineous parents, who exhibited global hypotonia, failure to thrive, persistent and progressive hyperlactacidaemia with lactic acidosis, liver dysfunction and encephalopathy and died at the age of 5 months. Brain MRI revealed hypogenesis of the corpus callosum, T2 signal abnormalities in the medulla oblongata, pons, midbrain, thalami, cerebellar white matter, and a lactate peak on MRS. Muscle histochemistry showed cytochrome c oxidase (COX)-deficient and ragged-red fibres, while muscle biochemical studies showed decreased activities of mitochondrial respiratory chain complexes I and IV. Whole exome sequencing (WES) identified biallelic EARS2 (NM_001083614) variants, a previously reported start-loss (c.1>G, p.Met1?) variant and a novel missense (c.184A>T, p.Ile62Phe) variant. Patient fibroblasts and muscle homogenate displayed markedly decreased EARS2 protein levels, although decreased steady-state levels of complex I (NDUFB8) and complex IV (MT-CO1 and MT-CO2) subunits were only observed in muscle. Pathogenic variants in EARS2, encoding mitochondrial glutamyl-tRNA synthetase (mtGluR), are associated with Leukoencephalopathy involving the Thalamus and Brainstem with high Lactate (LTBL), a mitochondrial disorder characterised by a distinctive brain MRI pattern and a biphasic clinical course. We further outline the unique phenotypic spectrum of LTBL and review the neuroradiological features reported in all patients documented in the literature.
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http://dx.doi.org/10.1007/8904_2016_581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413444PMC
August 2016

Secondary coenzyme Q10 deficiencies in oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders.

Mitochondrion 2016 09 30;30:51-8. Epub 2016 Jun 30.

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Spain.

We evaluated the coenzyme Q₁₀ (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n=72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.
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http://dx.doi.org/10.1016/j.mito.2016.06.007DOI Listing
September 2016

Genetic Variation of MT-ND Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation.

Neurodegener Dis 2015 3;15(2):70-80. Epub 2015 Apr 3.

CNC - Center for Neuroscience and Cell Biology, Laboratory of Biochemical Genetics, University of Coimbra, Coimbra, Portugal.

Background: Frontotemporal lobar degeneration (FTLD) is the second most common early-onset dementia. Over the last few decades, a growing number of evidence suggests mitochondrial involvement in neurodegeneration, namely modifications of mitochondrial DNA (mtDNA) contributing to energy impairment.

Objective: To sequence the 7 mitochondrially encoded complex I (MT-ND) genes in 70 FTLD patients and investigate mitochondrial respiratory chain (MRC) complex I activity.

Methods: A sample of 70 patients was studied (39 females and 31 males; age range: 38-82 years, mean ± SD: 63 ± 11 years) with a probable diagnosis of FTLD. Total DNA was extracted from peripheral blood, and sequencing analysis of 7 MT-NDn (1, 2, 3, 4L, 4, 5, 6) genes was performed. Variants identified were submitted to in silico study. Spectrophotometric evaluation of MRC activity in lymphocytes was performed, and results were compared with age-matched controls.

Results: A total of 358 (161 different) alterations were found in 92.9% of patients. According to in silico analysis of nonsynonymous variants, only 5 variations are possibly or probably damaging. Complex I activity is significantly decreased in patients.

Conclusion: To our knowledge, this is the first report of the complete sequence of the MT-ND genes in FTLD patients and correlation with MRC activity. The high number of mtDNA variations identified and a significant decrease in complex I activity suggest a possible involvement of mtDNA alterations in FTLD. Although the majority of these alterations are not primarily pathogenic, an interaction with other mutations may occur, leading to the disease, worsening its expression or influencing age of onset.
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http://dx.doi.org/10.1159/000380766DOI Listing
January 2016

Metabolic effects of hypoxia in colorectal cancer by 13C NMR isotopomer analysis.

Biomed Res Int 2014 1;2014:759791. Epub 2014 Jul 1.

Biophysics Unit, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal ; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3001-301 Coimbra, Portugal.

(13)C NMR isotopomer analysis was used to characterize intermediary metabolism in three colorectal cancer cell lines (WiDr, LS1034, and C2BBe1) and determine the "metabolic remodeling" that occurs under hypoxia. Under normoxia, the three colorectal cancer cell lines present high rates of lactate production and can be seen as "Warburg" like cancer cells independently of substrate availability, since such profile was dominant at both high and low glucose media contents. The LS1034 was the less glycolytic of the three cell lines and was the most affected by the event of hypoxia, raising abruptly glucose consumption and lactate production. The other two colorectal cell lines, WiDr and C2BBe1, adapted better to hypoxia and were able to maintain their oxidative fluxes even at the very low levels of oxygen. These differential metabolic behaviors of the three colorectal cell lines show how important an adequate knowledge of the "metabolic remodeling" that follows a given cancer treatment is towards the correct (re)design of therapeutic strategies against cancer.
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http://dx.doi.org/10.1155/2014/759791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4100400PMC
March 2015

Characterization of CYP2D6 genotypes and metabolic profiles in the Portuguese population: pharmacogenetic implications.

Per Med 2013 Sep;10(7):709-718

CNC - Center for Neuroscience & Cell Biology, University of Coimbra, Portugal.

Aim: CYP2D6 codes for a protein that is vastly involved in the metabolism of various substances. This gene is highly polymorphic, which influences the enzymatic activity and contributes to the huge variability in the enzyme hydroxylation capacity. Different metabolic profiles determine the processing of xenobiotics and endobiotics, thereby influencing disease risk, therapeutic efficacy and side effects, or toxicity of xenobiotics. The aim of this work was to characterize CYP2D6 polymorphisms and predict metabolic profiles in the Portuguese population.

Subjects & Methods: The study comprised 300 Portuguese unrelated healthy adult volunteers. Genetic analysis included allelic discrimination and copy number determination with TaqMan probes by real-time PCR and allele duplications of CYP2D6*1, CYP2D6*2, CYP2D6*4 and CYP2D6*10 were confirmed by long PCR and PCR-RFLP.

Results: The percentages of poor and ultrarapid metabolizers found in this Portuguese population were 6.3 and 4.7%, respectively.

Discussion & Conclusion: Compared with other studies, such as in Spaniards, the allelic frequencies observed were similar, with some exceptions, such as for CYP2D6*10, which is higher in the Portuguese population, and for CYP2D6*6 and duplication of *1 and *2, appearing in lower frequencies in the present study. These results allow the determination of the frequency of the most relevant CYP2D6 polymorphisms and the prediction of the enzyme metabolic activity, being of much importance for the CYP2D6 pharmacogenetics approach in the Portuguese population. The data presented here are significant for the study of genetic variability influencing CYP2D6 activity, to improve the effectiveness and safety of xenobiotics exposure, also can be used as a tool in clinical practice for the development of individualized pharmacotherapy.
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http://dx.doi.org/10.2217/pme.13.56DOI Listing
September 2013

Citrullinemia stimulation test in the evaluation of the intestinal function.

Nutr Hosp 2013 Jan-Feb;28(1):202-10

Coimbra University Medical School and IIIrd Surgical, Department of Coimbra University Hospitals, Coimbra, Portugal.

Background: Citrullinemia is been reported as a quantitative parameter of the enterocyte mass and function.

Aim: The objective of this research is to analyse the value of fasting and stimulated citrullinemias in the intestinal function evaluation.

Methods: A case-control study was undertaken, including 11 patients with short bowel syndrome, 13 patients submitted to malabsorptive bariatric surgery and 11 healthy controls. Plasma levels of amino acids were determined, before and after a stimulation test with oral Lglutamine, by ion exchange chromatography.

Results: Citrullinemia was inferior in short bowel patients (28,6 ± 11,3 versus 35,5 ± 11 in operated obese versus 32,2 ± 6,6 μmol/L in controls; n.s.) and lower than 25,5 μmol/L in 54,5% of them (versus 16,7%; p = 0,041; accuracy = 74%; odds ratio = 3, 95%CI 1,2-7,6). ΔCitrullinemia80 (relative variation of citrullinemia at the 80th minute of test) was lower in short bowel patients; its diagnostic accuracy was similar to baseline citrullinemia and also not significant. ΔCitrullinemia80 revealed a high predictive capacity of a short bowel inferior or equal to 50 cm (auR.O.C. = 82,3%; 95%CI 61,7-102,8; p = 0,038).

Conclusions: In short bowel syndrome context, citrullinemia stimulation test with oral L-glutamine is feasible and it may improve the predictive capacity of severity. Further investigation is required to determine its clinical relevance and applicability.
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http://dx.doi.org/10.3305/nh.2013.28.1.6243DOI Listing
March 2014

Long term cortical plasticity in visual retinotopic areas in humans with silent retinal ganglion cell loss.

Neuroimage 2013 Nov 16;81:222-230. Epub 2013 May 16.

Visual Neuroscience Laboratory, IBILI, Faculty of Medicine, University of Coimbra, Portugal. Electronic address:

Visual cortical plasticity induced by overt retinal lesions (scotomas) has remained a controversial phenomenon. Here we studied cortical plasticity in a silent model of retinal ganglion cell loss, documented by in vivo optical biopsy using coherence tomography. The cortical impact of non-scotomatous subtle retinal ganglion cell functional and structural loss was investigated in carriers of the mitochondrial DNA 11778G>A mutation causing Leber's hereditary optic neuropathy. We used magnetic resonance imaging (MRI) to measure cortical thickness and fMRI to define retinotopic cortical visual areas V1, V2 and V3 in silent carriers and matched control groups. Repeated Measures analysis of variance revealed a surprising increase in cortical thickness in the younger carrier group (below 21 years of age). This effect dominated in extrastriate cortex, and notably V2. This form of structural plasticity suggests enhanced plastic developmental mechanisms in extrastriate retinotopic regions close to V1 and not receiving direct retinocortical input.
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http://dx.doi.org/10.1016/j.neuroimage.2013.05.032DOI Listing
November 2013

Coenzyme Q₁₀ deficiency in mitochondrial DNA depletion syndromes.

Mitochondrion 2013 Jul 11;13(4):337-41. Epub 2013 Apr 11.

Clinical Chemistry, Pathology and Neurology Departments, Hospital Sant Joan de Déu, Barcelona, Spain.

We evaluated coenzyme Q₁₀ (CoQ) levels in patients studied under suspicion of mitochondrial DNA depletion syndromes (MDS) (n=39). CoQ levels were quantified by HPLC, and the percentage of mtDNA depletion by quantitative real-time PCR. A high percentage of MDS patients presented with CoQ deficiency as compared to other mitochondrial patients (Mann-Whitney-U test: p=0.001). Our findings suggest that MDS are frequently associated with CoQ deficiency, as a possible secondary consequence of disease pathophysiology. Assessment of muscle CoQ status seems advisable in MDS patients since the possibility of CoQ supplementation may then be considered as a candidate therapy.
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http://dx.doi.org/10.1016/j.mito.2013.04.001DOI Listing
July 2013

Antenatal manifestations of mitochondrial disorders.

J Inherit Metab Dis 2013 Sep 30;36(5):805-11. Epub 2013 Jan 30.

Obstetric Unit, University Hospital of Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Mitochondrial respiratory chain diseases are a heterogeneous group of pathologies caused by genetic alterations affecting mitochondrial energy production. Theoretically, this deficiency may lead to any symptoms, in any organ or tissue, at any age even before birth. The aim of our study was to identify the frequency and characterize antenatal manifestations identifying possible associations between mitochondrial disease and more specific and earlier manifestation. We retrospectively review the files of 44 paediatric subjects with genetic and biochemical alterations of respiratory chain identified in the first decade of life and compare data with a control group (n = 88). Our results show that maternal age was similar in both groups. The female gender was predominant in patients group. Gestational age at delivery was similar in both groups. Concerning birth weight, it was significantly lower (p = 0.001) in patients (2899.9 ± 538.3 vs. 3246.6 ± 460.2 g). Fifteen pregnancies of the patients group were considered abnormal. Our findings show that intrauterine growth restriction was the most frequent antenatal feature observed. Neonatal morbidity was significantly higher (fivefold) in patients (p < 0.001). The clinical findings are independent of the molecular defect type. Our results are preliminary and more studies are needed, in order to learn more about mitochondrial physiology and activity in embryological development for the assessment of mitochondrial disease progress in fetal life. However, the present work is a significant contribution, given the scarcity of information in this field.
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http://dx.doi.org/10.1007/s10545-012-9567-xDOI Listing
September 2013

Mitochondrial metabolism in Parkinson's disease impairs quality control autophagy by hampering microtubule-dependent traffic.

Hum Mol Genet 2012 Nov 27;21(21):4680-702. Epub 2012 Jul 27.

CNC – Center for Neuroscience and Cell Biology, Institute of Biology, University of Coimbra, Coimbra, Portugal.

Abnormal presence of autophagic vacuoles is evident in brains of patients with Parkinson's disease (PD), in contrast to the rare detection of autophagosomes in a normal brain. However, the actual cause and pathological significance of these observations remain unknown. Here, we demonstrate a role for mitochondrial metabolism in the regulation of the autophagy-lysosomal pathway in ex vivo and in vitro models of PD. We show that transferring mitochondria from PD patients into cells previously depleted of mitochondrial DNA is sufficient to reproduce the alterations in the autophagic system observed in PD patient brains. Although the initial steps of this pathway are not compromised, there is an increased accumulation of autophagosomes associated with a defective autophagic activity. We prove that this functional decline was originated from a deficient mobilization of autophagosomes from their site of formation toward lysosomes due to disruption in microtubule-dependent trafficking. This contributed directly to a decreased proteolytic flux of α-synuclein and other autophagic substrates. Our results lend strong support for a direct impact of mitochondria in autophagy as defective autophagic clearance ability secondary to impaired microtubule trafficking is driven by dysfunctional mitochondria. We uncover mitochondria and mitochondria-dependent intracellular traffic as main players in the regulation of autophagy in PD.
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http://dx.doi.org/10.1093/hmg/dds309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471400PMC
November 2012

Neonatal liver failure due to deoxyguanosine kinase deficiency.

BMJ Case Rep 2012 Apr 2;2012. Epub 2012 Apr 2.

Serviço de Medicina, Unidade de Gastrenterologia eHepatologia, Hospital Pediátrico de Coimbra, Coimbra, Portugal.

Deoxyguanosine kinase (dGK) deficiency, a rare severe cause of mitochondrial DNA (mtDNA) depletion, has two forms of presentation: hepatocerebral syndrome and isolated hepatic disease. The authors report three cases with neonatal liver failure due to dGK deficiency. Consanguinity was present in all patients. One patient had a brother who died with a probable diagnosis of neonatal haemochromatosis. All patients had progressive cholestatic liver failure, hypoglycaemia, hyperlactacidaemia, elevated ferritin levels and nystagmus, since first day of life. Liver tissue study revealed: cholestasis, iron deposits, microvesicular steatosis and fibrosis/cirrhosis. Only one patient was submitted to liver transplantation. The other two died, at 2 and 5 months of age. mtDNA quantification and DGUOK gene study should be considered in infants/neonates with acute liver failure and systematically performed in patients with hepatocerebral presentation. Differential diagnosis with neonatal haemochromatosis is needed. Liver transplantation might be a therapeutic option. Early diagnosis is important for genetic counselling.
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http://dx.doi.org/10.1136/bcr.12.2011.5317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3339167PMC
April 2012

Nonketotic hyperglycinemia: a cause of encephalopathy in children.

J Child Neurol 2013 Feb 24;28(2):251-4. Epub 2012 Apr 24.

Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Laboratório de Bioquímica Genética, Coimbra, Portugal.

Nonketotic hyperglycinemia is a rare metabolic disorder with severe, frequently fatal, neurologic manifestations. Reliable and accurate diagnosis depends on careful interpretation of laboratory findings. The clinical suspicion should lead to determination of glycine in plasma and cerebrospinal fluid. Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated movements. Clinical assessment should be reinforced by demonstration of elevated cerebrospinal fluid-to-plasma glycine ratio. Confirmatory diagnosis requires enzymatic and genetic investigation of glycine cleavage system. An early diagnosis, though not affecting clinical outcome, allows proper genetic counseling, with the possibility of prenatal diagnosis. We report 3 cases of nonketotic hyperglycinemia, 2 typical neonatal and 1 atypical, diagnosed in Pediatric Hospital of Coimbra, Portugal, and investigated at Laboratory of Biochemical Genetics in 2004 to 2010 (incidence 1:47 455; prevalence 1:782 951).
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http://dx.doi.org/10.1177/0883073812441063DOI Listing
February 2013

Mitochondrial DNA 8993T>G mutation in a child with ornithine transcarbamylase deficiency and leigh syndrome: an unexpected association.

J Child Neurol 2012 Aug 12;27(8):1059-61. Epub 2012 Jan 12.

Centro de Desenvolvimento Dr Luís Borges, Hospital Pediátrico de Coimbra, CHC, Coimbra, Portugal.

MC, female, is the third child of a nonconsanguineous Portuguese couple, born after an uneventful pregnancy and delivery. A positive family history of ornithine transcarbamylase deficiency, associated with the IVS8+1 G>A mutation in the ornithine transcarbamylase gene, prompted prenatal diagnosis with identification of the same mutation in the proband. During an episode of Klebsiella pneumoniae sepsis at 1.5 months of age, lactic acidosis and moderate hyperammonemia were noticed. After a short asymptomatic period, progressive neurologic symptoms, with normal ammonemia, persistent hyperlactacidemia, and typical lesions in brain computed tomography (CT) scan led to a diagnosis of Leigh syndrome. Mitochondrial respiratory chain complex V was reduced in the liver. The mtDNA 8993T>G mutation was identified in the liver, muscle, and blood (82%-87% heteroplasmy). She died at 6 months of age. This case represents a benign phenotype of ornithine transcarbamylase deficiency, associated with a severe mitochondrial respiratory chain disorder due to an mtDNA pathogenic mutation.
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http://dx.doi.org/10.1177/0883073811431015DOI Listing
August 2012

Mitochondrial respiratory chain: biochemical analysis and criterion for deficiency in diagnosis.

Methods Mol Biol 2012 ;837:73-91

Laboratory of Biochemical Genetics (CNC/UC), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

Spectrophotometric evaluation of mitochondrial respiratory chain (MRC) enzymatic complexes is the main approach to the biochemical investigation and diagnosis in oxidative phosphorylation disorders (also known as mitochondrial cytopathies). Regular dual beam spectrophotometers may be used, but we describe the protocols for double wavelength devices, allowing the analysis of complex activities from a small amount of tissue, with high sensitivity. An important concern is which tissue should be selected for analysis. Accordingly, we present the results obtained with different tissues and control values to be used. There are no standards available for the determinations and no interlaboratory quality control schemes are implemented. Additionally, different laboratories may use different protocols and comparison of results may be difficult. Currently, there is no consensus in literature for defining a criterion of an MRC deficiency to be used in biochemical diagnosis. There is statistical evidence that the most adequate criterion to define an MRC deficiency is below 40% of the mean control value normalized to citrate synthase activity.
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http://dx.doi.org/10.1007/978-1-61779-504-6_6DOI Listing
April 2012

Value of brain magnetic resonance imaging in mitochondrial respiratory chain disorders.

Pediatr Neurol 2010 Mar;42(3):196-200

Metabolic Diseases Unit, Luís Borges Center for Child Development, Pediatric Hospital of Coimbra-CHC EPE, Coimbra, Portugal.

Mitochondrial respiratory chain (MRC) disorders have variable clinical manifestations which are mainly neurologic. Diagnosis in children is more complex than in adults because the classic phenotype, ragged red fibers, and mtDNA mutations are rarely seen in children. Moreover, clinical manifestations of disease in developing brains are less explicit. Although not specific, neuroimaging may be contributory to the diagnosis of these disorders in pediatric patients. Brain magnetic resonance images were reviewed for 133 pediatric patients investigated for a MRC disorder at a single center over a period of 10 years (1997-2006), in an attempt to identify distinctive neuroimaging features of MRC defects. Patients fit into four groups, according to the Bernier criteria: definite (63 cases), probable (53 cases), possible (7 cases) and unlikely diagnosis (10 cases). Brain atrophy (41 cases), supratentorial white matter lesions (14 cases), basal ganglia involvement (9 cases), and delayed myelination (9 cases) were the most frequent anomalies in the definite group, and 8 patients presented Leigh syndrome. Neuroimaging findings of the 63 children in the definite group were compared with the remainder and with those in the possible and unlikely groups. There were no significant differences in brain images between the groups analyzed, and therefore no distinctive brain imaging features were identified specific for MRC disorders.
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http://dx.doi.org/10.1016/j.pediatrneurol.2009.09.010DOI Listing
March 2010
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