Á. García

Mitochondrial DNA Haplogroups Do Not Play a Role in the Variable Phenotypic Presentation of the A3243G Mutation

Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in association with either MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes (ranging from diabetes and deafness to a mixture of chronic progressive external ophthalmoplegic symptoms and strokelike episodes) were studied by use of high-resolution restriction fragment length polymorphism analysis and control-region sequencing. A total of 34 different haplotypes were found, indicating that all instances of the A3243G mutation are probably due to independent mutational events. Haplotypes were distributed into 13 haplogroups whose frequencies were close to those of the general Spanish population. Moreover, there was no statistically significant difference in haplogroup distribution between patients with MELAS and those with disease phenotypes other than MELAS. Overall, these data indicate that the A3243G mutation harbors all the evolutionary features expected from a severely deleterious mtDNA mutation under strong negative selection, and they reveal that European mtDNA backgrounds do not play a substantial role in modulating the mutations phenotypic expression.

Two pathogenic mutations in the mitochondrial DNA tRNA Leu(UUR) gene (T3258C and A3280G) resulting in variable clinical phenotypes

We studied two patients with ragged-red fibers and combined defects of the mitochondrial respiratory chain in their muscle biopsy. One had mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and harbored a T3258C transition in the tRNA(Leu(UUR)) gene. The other showed myopathy plus cardiomyopathy and had an A3280G mutation in the same gene. Both mutations were heteroplasmic, abundant in muscle of the patients, less abundant in blood, and still less abundant in blood from their maternal relatives. In both patients, single muscle fiber analysis revealed greater abundance of mutant genomes in ragged-red fibers than in normal fibers, supporting the pathogenicity of both mutations.

A new mtDNA mutation in the tRNALeu(UUR) gene associated with ocular myopathy

We studied a patient with ptosis, ophthalmoparesis, and exercise intolerance who showed in her muscle biopsy ragged-red fibers and combined defects of the complexes I and IV of the mitochondrial respiratory chain. Molecular analysis revealed a T3273C transition in the mitochondrial DNA tRNA(Leu(UUR)) gene. The mutation was heteroplasmic and very abundant in muscle from the proposita, less abundant in her other tissues studied, and still less abundant in blood from her maternal relatives. Single muscle fiber analysis showed significantly higher levels of mutant genomes in ragged-red fibers than in normal fibers. The T3273C mutation affects a strictly conserved base pair in the anticodon stem and was not found in controls, thus satisfying the accepted criteria for pathogenicity.

Myoglobinuria and COX deficiency in a patient taking cerivastatin and gemfibrozil.

The authors describe a patient who presented with myoglobinuria after starting cerivastatin-gemfibrozil therapy. Muscle histochemistry revealed ragged-red fibers and cytochrome c oxidase negative (COX) fibers, and biochemistry showed a defect of COX activity. Immunoblot analysis showed a 60% reduction of COX I and COX II polypeptides. Cerivastatin myotoxicity might be related to a depletion of essential metabolites needed to anchor COX subunit I to mitochondrial membrane.

A mitochondrial tRNALys gene mutation (T8316C) in a patient with mitochondrial myopathy, lactic acidosis, and stroke-like episodes

We studied a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes who had morphologically and biochemically abnormal muscle mitochondria. Molecular analysis revealed a T8316C transition in the mitochondrial DNA tRNA(Lys) gene. The mutation was homoplasmic in muscle from the proposita, heteroplasmic in her blood, and still less abundant in blood from her asymptomatic maternal relatives. The T8316C mutation affects a highly conserved base pair and was not found in controls, thus satisfying the accepted criteria for pathogenicity. Our data document the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, underlining that the same syndrome may be associated with mutations of different genes.

Cosegregation of the mitochondrial DNA A1555G and G4309A mutations results in deafness and mitochondrial myopathy

We report a patient with progressive external ophthalmoplegia (PEO), exercise intolerance, and deafness after aminoglycoside exposure, harboring two pathogenic mutations in her mtDNA: an A1555G in the 12S rRNA gene and a G4309A in the tRNAIle gene. Muscle histochemistry showed abundant ragged‐red fibers, and biochemistry revealed normal respiratory chain function. The A1555G mutation was homoplasmic in blood from the proband and from all maternal relatives. The G4309A mutation was abundant in the proband′s muscle, less abundant in her blood, still less abundant in the mother′s blood, and absent in blood from other maternal relatives. Family members were asymptomatic. Our data suggest that the former mutation resulted in aminoglycoside‐induced deafness and the latter caused PEO plus exercise intolerance.

Cuantificación del estudio de perfusión miocárdica en pacientes con baja probabilidad de cardiopatía isquémica. Valores normales de gated-SPECT con 201Tl

INTRODUCTION This study has aimed to establish quantitative normality parameters in the thallium-201 GATED SPECT and to assess the changes related to age, gender, risk factors and stress testing. METHODS A total of 427 patients with low pre-test likelihood of coronary artery disease were selected (45.5% men). The examinations were performed, by obtaining 32 25-second images on a 180% arc. The isotope used was thallium-201 and the SU SEGAMI software was using for the examination procedure. RESULTS Myocardial tracer uptake in each one of the vascular territories was: left descending artery 77%+/-4; circumflex artery 76%+/-5 and right coronary artery 70%+/-4 (P=.000). Uptake in the right coronary artery territory was lower in men (68.7% vs 70.5% in women, P=.000) and in the left descending artery territory in the obese. There were no gender-related differences in the post-stress ejection fraction for both genders (65.7% in men vs 66.8% in women). However, ventricular volumes were higher in men (end-diastolic volume 80ml+/-27 vs 61ml+/-22; P=0.000 and end-systolic volume 27.2ml+/-25 vs 19ml+/-8; P=0.000). There is an inverse relationship between age and end-diastolic volume. Smokers have higher end-diastolic volumes than non-smokers. CONCLUSIONS Quantification of T1201 uptake in patients having low pre-test probability of coronary artery disease and normal thallium GATED-SPECT in the RCA territory is lower in men. The ventricular function study shows that there are no differences in post-stress EF based on gender but that the end-diastolic and end-systolic volumes are higher in men.

McArdle's disease associated with homozygosity for the missense mutation Gly204Ser of the myophosphorylase gene in a Spanish patient

We studied a pateint whose clinical, morphological and biochemical findings were consistent with McArdles disease. Molecular genetic studies revealed that the patient did not harbor the common Arg49Stop mutation and was homozygous for the Gly204Ser mutation. Until now, no patient having the missense mutation in the two alleles has been documented.

Myocardial perfusion study in patients who do not reach submaximal frequency on ergometry

UNLABELLED The aim of the study was to evaluate the sensitivity and specificity of TI-201 myocardial perfusion SPECT for the diagnosis of ischaemic cardiopathy in a group of patients with chronotropic insufficiency. MATERIALS AND METHODS The examinations of 750 patients who had attended for the diagnosis of ischaemic cardiopathy during 2005-2006 were selected. 28 % (n = 209) did not reach submaximal frequency. Data on the diagnosis was collected in 112 by telephone interview. Ergometry and SPECT were carried out following the usual techniques. RESULTS Patients who reached submaximal frequency and patients with chronotropic insufficiency did not show differences in age and exercise time. The proportion of patients on beta-blocker treatment, with clinically positive ergometries and pathological SPECT was higher in the patient group which had not reached 85 % of their maximum frequency. The data obtained in the patient group which did not reach submaximal frequency and followed-up by telephone interview showed a SPECT sensitivity of 84 % and specificity of 96 %. The sensitivity of the ergometry was 25 % and its specificity was 96 %. CONCLUSIONS Ergometry with myocardial perfusion SPECT has adequate sensitivity and specificity for the diagnosis of ischaemic cardiopathy, even in patients with chronotropic incompetence. The proportion of pathological examinations is higher in those patients in whom tachycardia could not be sufficiently induced, which seems to indicate that the inability to reach submaximal frequency is related with a higher probability of having ischaemic cardiopathy.

La gammagrafía de reactividad hiperémica en el estudio de la función endotelial

Objective. The aim of this study was to compare a recently described method to evaluate endothelial function; the hyperemic reactivity scintigraphy (HRS) with the ultrasono- graphic flow-mediated dilatation (FMD) in brachial artery and its relationship with myocardial SPECT. Methods. 42 consecutive patients that underwent myocardial scintigraphy were included. Thirty-six patients had simultane- ous measurement of FMD. Both studies were obtained after 5 minutes occlusion of the upper arm with a blood pressure cuff inflated at 250 mmHg. HRS was performed dynamically at rate 1 frame/sec during 3 minutes after intravenous injection of 740 MBq of Tc-99 sestamibi. Time-activity curves allowed ob- taining the following indexes: medium hyperemic activity/medi- um contrallateral activity (MHA/MCA) and maximum hyperemic activity/maximum contrallateral activity (MxHA/CxHA). Results. In 13 patients SPECT was normal. Twenty-nine pa- tients had perfusion defects in scintigraphy. There was relation- ship between the FMD and the MHA/MCA (r = 0.23; p = 0.018) and the FMD and the MxHA/CxHA (r = 0.18; p = 0.05). Patients with alterations in the SPECT had an index MxHA/CxHA lower than patients with normal SPECT (1.8 ± 0.2 vs 1.5 ± 0.4; p = 0.04). We did not find relationship between FMD and alter- ations in SPECT. Conclusions. There is relationship between FMD and HRS. HRS is lower in patients with perfusion defects in the SPECT. HRS could provide additional value to myocardial scintigraphy.