Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis

Mitochondrial disorders are among the most common inborn errors of metabolism; at least 15% are caused by mitochondrial DNA(mtDNA) mutations, which occur de novo or are maternally inherited. For familial heteroplasmic mtDNA mutations, the mitochondrial bottleneck defines the mtDNA mutation load in offspring, with an often high or unpredictable recurrence risk. Oocyte donation is a safe option to prevent the transmission of mtDNA disease, but the offspring resulting from oocyte donation are genetically related only to the father. Prenatal diagnosis (PND) is technically possible but usually not applicable because of limitations in predicting the phenotype. For de novo mtDNA point mutations, recurrence risks are low and PND can be offered to provide reassurance regarding fetal health. PND is also the best option for female carriers with low-level mutations demonstrating skewing to 0% or 100%. A fairly new option for preventing the transmission of mtDNA diseases is preimplantation genetic diagnosis (PGD), in which embryos with a mutant load below a mutation-specific or general expression threshold of 18% can be transferred. PGD is currently the best reproductive option for familial heteroplasmic mtDNA point mutations. Nuclear genome transfer and genome editing techniques are currently being investigated and might offer additional reproductive options for specific mtDNA disease cases

Rasch-built myotonic dystrophy type 1 activity and participation scale (DM1-Activ)

We describe the development of an outcome measure of activity and participation for patients with myotonic dystrophy type 1 using the Rasch measurement model. A 49-item questionnaire was completed by 163 DM1 patients. Data were subsequently analyzed with Rasch software to design the item set to fit model expectations. Through systematic investigation of response category ordering, model fit, item bias, and local response dependency, we succeeded in constructing a 20-item unidimensional scale of activity and participation (DM1-Activ). High internal consistency (PSI = 0.95) and good test-retest reliability values of item difficulty hierarchy and patient location were demonstrated. Patient measures had acceptable correlations with MRC sum scores and MIRS grades (ICC = 0.69 and 0.71, respectively), indicating good external construct validity. DM1-Activ is a practical, reliable and valid outcome measure that fulfils all clinimetric requirements. Further evaluation of this scale is needed to provide a nomogram for clinical use. (C) 2010 Elsevier B.V. All rights reserved

Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections

BACKGROUNDHuntington's disease (HD) is an autosomal dominant neurodegenerative late onset disorder. This review of reproductive options aims to increase reproductive confidence and to prevent suffering in relation to family planning around HD and possibly other late onset neurodegenerative disorders.METHODSSelected relevant literature and own views and experiences as clinical geneticists, psychologists and ethicists have been used.RESULTSPossible options, with emphasis on prenatal diagnosis (PD) and preimplantation genetic diagnosis (PGD) to prevent the transmission of HD to the next generation, are described and discussed. They are formally presented in a decision tree, taking into account the presence or absence of a fully penetrant allele (FPA), a reduced penetrant allele (RPA) or an intermediate allele (IA). A table compares invasive and non-invasive PD and PGD. From a psychological perspective, the complex process of counselling and decision-making regarding reproductive options is discussed. Special attention is paid to the decision to avoid the transmission of the mutation and to the confrontation and coping of a mutation-free child growing up with a parent developing disease symptoms. From an ethical point of view, reflections on both PD and PGD are brought forward taking into account the difference between FPA, RPA and IA, direct testing or exclusion testing and taking into account the welfare of the child in the context of medically assisted reproduction.CONCLUSIONRecommendations and suggestions for good clinical practice in the reproductive care for HD families are formulated.status: publishe

Epidermolysis bullosa simplex with mottled pigmentation:Clinical aspects and confirmation of the P24L mutation in the KRT5 gene in further patients

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) is a rare dermatologic disorder of autosomal dominant inheritance with intraepidermal blistering after minor trauma, reticular hyperpigmentation unrelated to the blistering, nail dystrophy, and mild palmoplantar keratosis. Keratin 5 and keratin 14 are known to be essential for the basal keratinocyte cytoskeleton and are defective in several forms of epidermolysis bullosa simplex. Recently, a 71C-->T transition in the keratin 5 gene (KRT5) causing a P24L substitution was identified in some patients with EBS-MP. We present a family with three affected members and a sporadic patient with EBS-MP. They exemplify clinically mild expression with intrafamilial variability and the possibility of improvement with time. In all of them, mutation analysis of the KRT5 gene showed the P24L mutation. So far, other mutations in the same or in other genes have not been reported in patients with EBS-MP. Am. J. Med. Genet. 86:376-379, 1999. (C) 1999 Wiley-Liss, Inc