Tumor formation can occur after maternal transmission of SDHD, a finding with important clinical implications for SDHD families. Tumor formation in SDHD mutation requires the loss of both the wild-type SDHD allele and maternal 11p15, leading to the predominant but now not exclusive pattern of disease inheritance after paternal SDHD transmission.

Our findings suggest that QoL in epileptic patients might be affected, in addition to the other established factors (high frequency of seizures and polytherapy), by the daily use of benzodiazepines as adjunctive therapy. Change of medical strategy concerning this medication may lead to improving the QoL of these patients.

The aim of this study is to investigate the electromagnetic sources of epileptic activity in two patients with juvenile myoclonus epilepsy (JME). The first patient was a 22-year old female with JME diagnosis by the age of 17 years old. Her initial EEG recording showed characteristic paroxysmal generalized activity with polyspike-wave complexes. She was on remission for 9 months. The second patient was a 29-year old male with JME diagnosis by the age 18 of years old. He showed an EEG recording with generalized spike-wave complexes of 3.5-4 Hz and presented a great improvement after therapeutic treatment. The MRI examinations for both patients did not disclose any focal lesions or areas of abnormal signal intensity or enhancement by contrast media. Magnetoencephalography (MEG) was recorded with a 122-channel whole-head system, 5 years after the disease onset for the first patient and 11 years for the second patient. For the first patient dipolar sources of MEG paroxysmal activity were localised at the vermis with extension up to the occipital region, whereas, for the second patient dipolar sources of MEG paroxysmal activity were localised at the cerebellar area (vermis and hemisphere). Implication of the cerebellum in JME, as suggested by MEG data in this study, is in accordance with previous reports employing functional MRI or cerebral blood flow evaluation in JME.

Primary mitochondrial disease describes a diverse group of neuro-metabolic disorders characterised by impaired oxidative phosphorylation. Diagnosis is challenging; >350 genes, both nuclear and mitochondrial DNA (mtDNA) encoded, are known to cause mitochondrial disease, leading to all possible inheritance patterns and further complicated by heteroplasmy of the multicopy mitochondrial genome. Technological advances, particularly next-generation sequencing, have driven a shift in diagnostic practice from ‘biopsy first’ to genome-wide analyses of blood and/or urine DNA. This has led to the need for a reference framework for laboratories involved in mitochondrial genetic testing to facilitate a consistent high-quality service. In the United Kingdom, consensus guidelines have been prepared by a working group of Clinical Scientists from the NHS Highly Specialised Service followed by national laboratory consultation. These guidelines summarise current recommended technologies and methodologies for the analysis of mtDNA and nuclear-encoded genes in patients with suspected mitochondrial disease. Genetic testing strategies for diagnosis, family testing and reproductive options including prenatal diagnosis are outlined. Importantly, recommendations for the minimum levels of mtDNA testing for the most common referral reasons are included, as well as guidance on appropriate referrals and information on the minimal appropriate gene content of panels when analysing nuclear mitochondrial genes. Finally, variant interpretation and recommendations for reporting of results are discussed, focussing particularly on the challenges of interpreting and reporting mtDNA variants.

We investigated the localization of current sources in the time and frequency domain from spontaneous MEG data recorded from nine epileptic patients (six females; three males) randomly selected, who had a mean age of 41 years old (range of 17-78 years old), with different types of epilepsy. The MEG data were recorded in a magnetically shielded room with a whole-head 122 channel biomagnetometer. For each MEG spike, we calculated the single Equivalent Current Dipole (ECD) sources at the initial spike peaks with a spherical model. MRI and EEG findings were available in patients' records. Prominent low frequencies can be seen in the majority of channels. For each patient there was an increase of the frequency range after the ECD in comparison with the frequency range before the ECD, in the whole study group due to epileptic discharge which is statistically significant (p=0.02). There was also a statistical significant difference in the increase of the frequency range in four patients with pathologic MRI (p=0.05), in five patients with normal MRI (p=0.02), in five patients with a high incidence of seizures (p=0.04) and in four patients with onset<10 years (p=0.04). The MEG analysis of neuromagnetic data gives information about the modification of the frequency range in the epileptic brains.

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In SDHD mutation families, paragangliomas and pheochromocytomas usually occur only after paternal transmission of the mutation. This important but unexplained parent-of-origin effect is not due to imprinting of SDHD itself, as was initially suspected, since SDHD is biallelically expressed in several tissues. In clinically affected individuals who possess a paternally inherited SDHD mutation, there is loss of the entire maternal chromosome 11 in tumour DNA, implying that tumorigenesis requires loss of not only maternal (wild type) SDHD but also a further, imprinted, tumor suppressor gene (TSG). We report the second case of an SDHD-related tumor (a pheochromocytoma in a 33 year old woman possessing the common pathogenic mutation, p.Pro81Leu) occurring after maternal transmission. It is the first reported investigation of tumor DNA in this situation. Tumor DNA revealed loss of heterozygosity (LOH) at paternal 11q23 causing loss of the wild-type SDHD allele and also LOH affecting maternal 11p15, including H19. These two LOH regions were separated by a region exhibiting clearly retained heterozygosity, containing SDHAF2 (a recently reported paraganglioma TSG), which therefore appears uninvolved here. This case provides strong molecular evidence that the tumorigenic requirement for maternal 11p15 loss (in addition to inactivation of both SDHD alleles) drives the observed parent-of-origin effect. Thus, SDHD-related tumorigenesis most likely involves a “three-hit” mechanism that includes (as one of the hits) loss of an imprinted (paternally silenced and maternally active) TSG from chromosome 11, such as H19). Tumor formation more commonly results from paternal inheritance of SDHD mutations, as the necessary loss of both the wild type SDHD allele and maternal 11p15 can then occur by a single event (loss of maternal chromosome 11). These findings have important implications regarding the clinical management of carriers of maternally inherited SDHD mutations, who we confirm can develop pheochromocytomas, and the understanding of the parent-of-origin effect. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3673. doi:1538-7445.AM2012-3673