http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise.

Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

ROS Function in Redox Signaling and Oxidative Stress

Interpretation of clinical trials comparing different drug regimens for Parkinson's disease (PD) is complicated by the different dose intensities used: higher doses of levodopa and, possibly, other drugs produce better symptomatic control but more late complications. To address this problem, conversion factors have been calculated for antiparkinsonian drugs that yield a total daily levodopa equivalent dose (LED). LED estimates vary, so we undertook a systematic review of studies reporting LEDs to provide standardized formulae. Electronic database and hand searching of references identified 56 primary reports of LED estimates. Data were extracted and the mean and modal LEDs calculated. This yielded a standardized LED for each drug, providing a useful tool to express dose intensity of different antiparkinsonian drug regimens on a single scale. Using these conversion formulae to report LEDs would improve the consistency of reporting and assist the interpretation of clinical trials comparing different PD medications.

Systematic review of levodopa dose equivalency reporting in Parkinson's disease

Diagnosis of fatal infantile defects of the mitochondrial respiratory chain: age dependence and postmortem analysis of enzyme activities

Reliable quantification by PCR requires careful experimental design and conditions, often involving sampling of the PCR reactions at different time points or amplifying multiple dilutions of a standard DNA We describe here an accurate, quantitative and easily automatizable solid-phase method based on competetive PCR The PCR products are analyzed by solid-phase minisequencing after capture of biotinylated PCR products in streptavidin-coated microtiter wells and single-nucleotide extension of a specific detection primer by a radioactively labelled nucleotide The results are expressed as numeric cpm-values, and the incorporated label expresses the relative amount of sequence variants in the original template mixture We have applied the method to determination of allele frequencies in pooled DNA samples, of mitochondrial heteroplasmy, of gene copy numbers, and to forensic DNA analysis

Quantitative analysis of human DNA sequences by PCR and solid-phase minisequencing.

Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia.

The lethal congenital contracture syndrome (LCCS) is an autosomal recessive syndrome (McKusick 253310) leading to perinatal death owing to early onset degeneration of the anterior horn motor neurones of the spinal cord. The neuropathological findings in the LCCS closely resemble those of spinal muscular atrophy (SMA). Since all the three types of SMA have been localised to the same gene locus on the long arm of chromosome 5, we analysed samples from seven families with 10 LCCS fetuses with the microsatellite markers assigned to the SMA 5q region. Linkage analyses between the SMA linked DNA markers and the disease allele in the LCCS families excluded the critical chromosomal region around the SMA locus as the critical chromosomal region for the LCCS locus.

https://jmg.bmj.com/content/jmedgenet/32/1/36.full.pdf

Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus.

The hallmark of acute necrotizing encephalopathy (ANE) is multiple, symmetric brain lesions.1 ANE is triggered by a viral infection in previously healthy children. The presenting symptoms are coma, convulsions, vomiting, hyperpyrexia, and hepatomegaly. Recently a dominant mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) has been reported in familial, recurrent ANE (ANE1).2 In isolated ANE the typical brain lesions are located in the thalami bilaterally, putamina, deep periventricular white matter, cerebellum, and brainstem,3,4 while in ANE1 the MRI changes are seen in the external capsules, claustrum, limbic structure, or temporal lobes.2 Hepatic involvement is common in Asian patients with ANE, but not in ANE1.2 Differential diagnosis of ANE includes mitochondrial disorders, especially Leigh/Alpers syndrome,5 inflammatory, demyelinating brain diseases, acute disseminating encephalomyelitis (ADEM), or even multiple sclerosis (MS).6

We report the clinical, MRI, and molecular genetic findings of ANE in a 3-generation family, and discuss the differential diagnosis.

### Patients.

We included 6 patients with ANE in 3 generations (figure, G). ANE was recurrent in patients 2 and 5. Five of the episodes appeared in infancy, …

Anu Suomalainen

Papers

Diagnosis of fatal infantile defects of the mitochondrial respiratory chain: age dependence and postmortem analysis of enzyme activities

Quantitative analysis of human DNA sequences by PCR and solid-phase minisequencing.

Mitochondrial recessive ataxia syndrome mimicking dominant spinocerebellar ataxia.

Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus.

Dominant encephalopathy mimicking mitochondrial disease