Causes of death in pedigrees with the 3243A>G mutation in mitochondrial DNA.

BACKGROUND: Causes of death of patients with the 3243A>G mutation have been described in case reports or case series with a limited number of subjects. METHODS: Eighty-two maternally related sibships of 11 families with 3243A>G were included in this survey. The lifespan of each subject in these families was compared with the life expectancy of the general population, adjusted with respect to year of birth and gender. Causes of death were determined among 3243A>G carriers and their first-degree maternal relatives. RESULTS: We identified 123 deceased subjects in families with 3243A>G and found an excess mortality during the early years of life and young adulthood. The median age at death for 3243A>G carriers and their first-degree maternal relatives was significantly lower than that of the general population. Neurological and cardiovascular diseases made up one-third of the causes of death. Sudden and unexpected death was not uncommon in patients with cardiovascular diseases, diabetes and epilepsy. CONCLUSIONS: 3243A>G carriers and their first-degree maternal relatives died younger than was predicted by their life expectancy at birth. Neurological disease was the most common cause of death.

A 3-year clinical follow-up of adult patients with 3243A>G in mitochondrial DNA.

OBJECTIVE: To follow the clinical course of patients with the mitochondrial DNA mutation 3243A>G for 3 years. METHODS: Thirty-three adult patients with the 3243A>G mutation entered a 3-year follow-up study. They were clinically evaluated annually, audiometry was performed, and samples were drawn for the analysis of blood chemistry and mutation heteroplasmy in leukocytes. Holter recording was performed three times during the follow-up and echocardiography, neuropsychological assessment, and quantitative EEG and brain imaging conducted at entry and after 3 years. RESULTS: The incidence of new neurologic events was low during the 3-year follow-up. Sensorineural hearing impairment (SNHI) progressed, left ventricular wall thickness increased, mean alpha frequency in the occipital and parietal regions decreased, and the severity of disease index (modified Rankin score) progressed significantly. The rate of SNHI progression correlated with mutation heteroplasmy in muscle. The increase in left ventricular wall thickness was seen almost exclusively in diabetic patients. Seven patients died during the follow-up, and they were generally more severely affected than those who survived. CONCLUSIONS: Significant changes in the severity of disease, sensorineural hearing impairment, left ventricular hypertrophy, and quantitative EEG were seen in adult patients with 3243A>G during the 3-year follow-up.

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

Time-resolved fluorometry (TRF)-based immunoassay concept for rapid and quantitative determination of biochemical myocardial infarction markers from whole blood, serum and plasma.

We report the development of a time-resolved fluorometry-based immunoassay concept for the rapid measurement of three cardiac markers from whole blood, serum or plasma. Using a universal all-in-one (AIO) dry reagent concept, all the analyte specific reagents are built into a single microtire well, to which an identical assay protocol is applied. Addition of 5-20 microL sample (whole blood, serum or plasma) together with a universal buffer initiates the reaction, which is brought close to equilibrium in 15 min. After the wash step the Eu chelate-derived signal is measured directly from the dried surface. Application of this concept to the three cardiac markers illustrates its ability to provide rapid, highly sensitive and fully quantitative results over a large dynamic range with good reproducibility. Such a performance, especially when using whole blood specimens, is largely a consequence of the inherently fluorescent and stable Eu-chelate employed in the system. Correlation to commercial assays was excellent for all three analytes, as was between-sample matrix correlation using the AIO assays. The presented assay concept enabling a simple automation is particularly suited for point-of-care applications, where the performance characteristics are fully comparable to state-of-the-art central laboratory immunoassays.

Improved adherence to practice guidelines yields better outcome in high-risk patients with acute coronary syndrome without ST elevation: findings from nationwide FINACS studies.

OBJECTIVES: Treatment options for acute coronary syndrome (ACS) without ST elevation have evolved rapidly during the recent years, but the successful implementation of practice guidelines incorporating new treatments into practice has been challenging. In this study, we evaluate whether targeted educational intervention could improve adherence to treatment guidelines of ACS without ST elevation. DESIGN, SETTING AND SUBJECTS: A previous study, FINACS I, evaluated the treatment and outcome of 501 consecutive non-ST elevation ACS patients that were referred in early 2001 to nine hospitals, covering nearly half of the Finnish population. That study revealed poor adherence to ESC guidelines, so targeted educational intervention on optimal practice was arranged before the second study (FINACS II), which was performed in the same hospitals using the same protocol as FINACS I. FINACS II, undertaken in early 2003, evaluated 540 consecutive patients. Interventions. Targeted educational programmes on optimal practice. MAIN OUTCOME MEASURES: The use of evidence-based therapies in non-ST elevation ACS patients. In-hospital event-free (death, new myocardial infarction, refractory angina, readmission with unstable angina and transient cerebral ischaemia/stroke) survival, and event-free survival at 6 months. RESULTS: Baseline characteristics and risk markers were similar in both studies, and no significant changes in resources were seen. In 2003, the in-hospital use of statins, ACE-inhibitors, clopidogrel and glycoprotein (GP) IIb/IIIa receptor antagonists increased significantly, and in-hospital angiography was performed more often, especially in high-risk patients (59% vs. 45%, P < 0.05); waiting time also shortened (4.2 +/- 5.5 vs. 5.8 +/- 4.7 days, P < 0.01). Overall no significant change was seen in the frequency of death either in-hospital (2% vs. 4%, P = NS) or at 6 months (7% vs. 10%, P = NS) in FINACS II. However, the survival of high-risk patients improved both in-hospital (95% vs. 90%, P = 0.05) and at 6 months (89% vs. 78%, P = 0.05). CONCLUSION: In patients with non-ST elevation ACS-targeted educational interventions appeared to be associated with improved adherence to practical guidelines, which yielded a better outcome in high-risk ACS patients.

Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population.

Mitochondrial diseases are characterized by considerable clinical variability and are most often caused by mutations in mtDNA. Because of the phenotypic variability, epidemiological studies of the frequency of these disorders have been difficult to perform. We studied the prevalence of the mtDNA mutation at nucleotide 3243 in an adult population of 245,201 individuals. This mutation is the most common molecular etiology of MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes), one of the clinical entities among the mitochondrial disorders. Patients with diabetes mellitus, sensorineural hearing impairment, epilepsy, occipital brain infarct, ophthalmoplegia, cerebral white-matter disease, basal-ganglia calcifications, hypertrophic cardiomyopathy, or ataxia were ascertained on the basis of defined clinical criteria and family-history data. A total of 615 patients were identified, and 480 samples were examined for the mutation. The mutation was found in 11 pedigrees, and its frequency was calculated to be >=16. 3/100,000 in the adult population (95% confidence interval 11.3-21. 4/100,000). The mutation had arisen in the population at least nine times, as determined by mtDNA haplotyping. Clinical evaluation of the probands revealed a syndrome that most frequently consisted of hearing impairment, cognitive decline, and short stature. The high prevalence of the common MELAS mutation in the adult population suggests that mitochondrial disorders constitute one of the largest diagnostic categories of neurogenetic diseases.