Prenatal diagnosis of myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome: contribution to understanding mitochondrial DNA segregation during human embryofetal development

Abstract

Introduction: Myopathy, encephalopathy, lactic acidosis, and stroke-like (MELAS) syndrome, a maternally inherited disorder that is among the most common mitochondrial DNA (mtDNA) diseases, is usually associated with the m.3242A.G mutation of the mitochondrial tRNA leu gene. Very few data are available with respect to prenatal diagnosis of this serious disease. The rate of mutant versus wild-type mtDNA (heteroplasmy) in fetal DNA is indeed considered to be a poor indicator of postnatal outcome. Materials and methods: Taking advantage of a novel semi-quantitative polymerase chain reaction test for m.3243A.G mutant load assessment, we carried out nine prenatal diagnoses in five unrelated women, using two different fetal tissues (chorionic villi v amniocytes) sampled at two or three different stages of pregnancy. Results: Two of the five women, although not carrying m.3243A.G in blood or extra-blood tissues, were, however, considered at risk for transmission of the mutation, as they were closely related to MELASaffected individuals. The absence of 3243A.G in the blood of first degree relatives was associated with no mutated mtDNA in the cardiovascular system (CVS) or amniocytes, and their three children are healthy, with a follow-up of 3 months-3 years. Among the six fetuses from the three carrier women, three were shown to be homoplasmic (0% mutant load), the remaining three being heteroplasmic, with a mutant load ranging from 23% to 63%. The fetal mutant load was fairly stable at two or three different stages of pregnancy in CVS and amniocytes. Although pregnancy was terminated in the case of the fetus with a 63% mutant load, all other children are healthy with a follow-up of 3 months-6 years. Conclusion: These data suggest that a prenatal diagnosis for MELAS syndrome might be helpful for at-risk families.

Application of molecular imaging combined with genetic screening in diagnosing MELAS, diabetes and recurrent pancreatitis

“…Wang ZP, Department of Radiology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China, e-mail: ping1023@139.com fatal [1,5]. In this paper, we report on a Chinese family afflicted by MELAS combined with diabetes and recurrent pancreatitis.…”

“…MELAS, which forms a major clinical subgroup of the mitochondrial encephalomyopathies, is caused by any of several different single base replacements in the mt tRNA Leu(UUR) gene, which is responsible for the translation of UUR (R = A or G) leucine codons in mitochondrial genes [1][2][3][4][5]. It has been reported that 15% of patients with mitochondriopathies have symptoms of digestive disorders [3,7,14].…”

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

“…Although it is not possible to estimate heteroplasmy levels in individual tissues, and therefore not possible to predict clinical outcomes, prenatal genetic diagnosis has reportedly been applied successfully in several cases (Bouchet et al, 2006). Due to these uncertainties, parents are aiming to have offspring without any mutated mtDNA copies by the help of preimplantation genetic diagnosis (PGD) (Hellebrekers et al, 2012).…”

Prévenir la transmission des mutations de l’ADN mitochondrial par don de cytoplasme : où en est-on ?

“…< Les femmes porteuses d'une mutation de l'ADNmt ont un risque élevé de transmettre une maladie grave à leur descendance, et beaucoup font la demande d'une prise en charge en diagnostic prénatal (DPN) et/ ou préimplantatoire (DPI). Ces procédures diagnostiques consistent à mesurer le taux d'hétéroplasmie foetal ou embryonnaire, et à considé-rer que les embryons et les foetus porteurs d'un taux d'hétéroplasmie inférieur au taux seuil de la mutation ont un risque faible de dévelop-per une cytopathie mitochondriale [1][2][3][4]. Cependant, la majorité des enfants nés après ce type de diagnostic sont porteurs de la mutation de l'ADNmt ce qui les expose à un risque résiduel de développer la maladie.…”