Eleni Mavraki

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.

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.

BACKGROUND: In recent years, accumulating evidence has linked vitamin D deficiency to cognitive dysfunction and dementia. This study aimed at determining the relevance of serum 25-hydroxyvitamin D concentrations in mild cognitive impairment (MCI) and Alzheimer's disease (AD) in older Greek adults. It also examined whether the vitamin D level could be considered a predisposing factor for conversion from MCI to AD. METHODS: The study enrolled 350 subjects aged 65 years and over, allocated into three groups consisting of 103 healthy subjects (HS), 109 individuals with MCI, and 138 patients with AD, respectively. Serum 25-hydroxyvitamin D [25(OH)D] concentrations, measured in ng/ml, were determined by electrochemiluminescence, and we used the Mini-Mental State Examination (MMSE) and the Cambridge Cognition Examination (CAMGOG) to evaluate the subjects' cognitive status. One follow-up examination was performed for the MCI patients 30 months ± three months after the initial evaluation. RESULTS: Compared to HS, serum 25(OH)D levels were significantly decreased in individuals with MCI (p =0.012) and patients with AD (p <0.001). Moreover, serum 25(OH)D concentrations were significantly decreased in patients with AD compared to individuals with MCI (p =0.003) and also significantly lower in individuals with MCI who progressed to AD compared to those who remained MCI (p =0.028). After adjusting for confounders, multivariate analysis revealed that an increase of vitamin D concentration by one ng/mL reduces the risk of MCI by 4 % (OR =0.96, 95 % CI =0.92-0.99, p =0.006), the risk of AD by 8 % (OR =0.92, 95 % CI =0.89-0.95, p <0.001), and in an individual with MCI reduces the risk of conversion to AD by 10 % (OR =0.90, 95 % CI =0.83-0.96, p =0.003). CONCLUSIONS: The present study reveals that serum vitamin D levels are significantly decreased in subjects with MCI and patients with AD compared to HS. Additionally, individuals with MCI who progressed to AD presented significantly lower vitamin D levels than those who remained MCI. These results suggest that preserving adequate vitamin D status in older adults could delay or prevent cognitive decline. HIPPOKRATIA 2020, 24(3): 120-126.