Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.

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.

"Sleeping Beauty Syndrome" and Psychosis as Precursory Symptoms of Multiple Sclerosis: A Rare Case and Literature Review.

ABSTRACT: Frequently, patients with multiple sclerosis (MS) experience comorbid psychiatric symptoms. Mental disorders primarily occur simultaneously with or after an MS diagnosis; however, the probability of them being the initial manifestation of the disease is rare. We describe the case of a 22-year-old man who had previously been hospitalized because a single psychotic episode alongside symptoms of Kleine-Levin syndrome and a diagnosis of "acute and transient psychotic disorders." Two years later, he was diagnosed with MS. A literature review of the possibility of a psychiatric episode overshadowing an MS diagnosis is then presented. Clinicians should always consider the possibility of an underlying organicity in a case of psychiatric presentation with atypical features, with special attention being given during the investigation process. This approach will lead to the early diagnosis of an organic disease, which can be treated accordingly and as early as possible.

Multiple sclerosis in a patient with cryopyrin-associated autoinflammatory syndrome: Evidence that autoinflammation is the common link.

The co-existence of an autoinflammatory syndrome with a demyelinating disorder is a very rare occurrence raising the question whether there is a pathophysiological connection between them. We describe the case of a man with symptoms of cryopyrin-associated periodic syndrome (CAPS) since infancy who later developed multiple sclerosis (MS). As CAPS was genetically confirmed, the inhibition of interleukin-1 (IL-1) with anakinra led to a swift resolution of the CAPS symptoms and also, in combination with teriflunomide, to a clinical and imaging improvement of MS. In vitro studies showed that, upon a CAPS flare, the patient's peripheral neutrophils released neutrophil extracellular traps (NETs) decorated with IL-1ß, while NET release was markedly decreased following anakinra-induced remission of CAPS. Taking into account the growing evidence on the involvement of IL-1ß in experimental models of MS, this rare patient case suggests that the role of neutrophils/NETs and IL-1ß in MS should be further studied.

Molecular analysis of pheochromocytoma after maternal transmission of SDHD mutation elucidates mechanism of parent-of-origin effect.

CONTEXT: Pheochromocytoma/paraganglioma occurs almost exclusively after paternal transmission of succinate dehydrogenase D (SDHD) mutations. This parent-of-origin effect has not been fully explained but is accompanied by obligate loss of the maternal copy of chromosome 11. Loss of wild-type SDHD and an additional imprinted gene (hypothesized to be H19) appears necessary for tumor formation. Two previous reports suggested tumor formation after maternal transmission of SDHD mutation, but histological and molecular characterization was unavailable. OBJECTIVE: We report the first kindred in which histologically confirmed pheochromocytoma/paraganglioma occurred after maternal transmission of an SDHD mutation and investigate the molecular mechanism of tumor formation. DESIGN: The design of the investigation was the study of a three-generation family with SDHD c.242C>T (p.Pro81Leu) mutation. RESULTS: The index patient had a histologically confirmed pheochromocytoma and an identical SDHD germline mutation (p.Pro81Leu) to her mother (who had a glomus jugulare tumor) and paraganglioma tissue from her maternal grandfather. Tumor DNA from the index patient revealed loss of heterozygosity (LOH) at 11q23, causing loss of the wild-type paternal SDHD allele and LOH affecting maternal 11p15, including H19. These two regions of LOH were separated by a region exhibiting clearly retained heterozygosity, including SDHAF2, a recently reported paraganglioma susceptibility gene. CONCLUSIONS: 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.

Association of demographic, clinical and treatment variables with quality of life of patients with epilepsy in Greece.

PURPOSE: The aim was to study the influence of patients' age, frequency and type of seizures, disease duration, number of AEDs and use of benzodiazepines on the quality of life of patients with epilepsy. PATIENTS AND METHODS: We consecutively identified 223 patients with epilepsy who attended the epilepsy outpatient clinics at three university hospitals in Greece. Quality of life was evaluated by QOLIE-31. One-way analysis was used to assess the association of the studied factors and QOLIE-31 subscales. After checking for co-linearity, we performed multivariate stepwise linear regression analysis with all the variables that on univariate analysis showed a statistically significant effect on each subscale of QOLIE-31 to explore which of the studied factors affect independently on QOLIE-31 scores. RESULTS: Of a total of 223 patients, 118 (52.95%) were men; mean age was 35.18 +/- 13.22; mean duration of the disease was 13 years; 58 (26%) patients had generalized seizures, 93 (41.7%) had PS, and 72 (32.3%) of the patients had PsG; 85 (38.1%) were on polytherapy and 38 (17%) were taking benzodiazepines. Independent factors affecting QoL were: seizure frequency (Overall QoL P = 0.0001, Seizure worry and Emotional well-being P < 0.0001, Energy/fatigue and Social functioning P = 0.01); duration of the disease (Overall QoL and Energy/fatigue P = 0.01, Seizure worry P = 0.008, Cognitive functioning P < 0.0001); polytherapy only for the Emotional well-being P < 0.0001; and use of benzodiazepines (Overall QoL, Energy/fatigue, Social functioning P = 0.002, Cognitive functioning P < 0.0001). CONCLUSION: 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.