Consensus-based statements for the management of mitochondrial stroke-like episodes [version 1; peer review: 2 approved]

BACKGROUND: Focal-onset seizures and encephalopathy are prominent features of a stroke-like episode, which is a severe neurological manifestation associated with subtypes of mitochondrial disease. Despite more than 30 years of research, the acute treatment of stroke-like episodes remains controversial. METHODS: We used the modified Delphi process to harness the clinical expertise of a group of mitochondrial disease specialists from five European countries to produce consensus guidance for the acute management of stroke-like episodes and commonly associated complications. RESULTS: Consensus on a new definition of mitochondrial stroke-like episodes was achieved and enabled the group to develop diagnostic criteria based on clinical features, neuroimaging and/or electroencephalogram findings. Guidelines for the management of strokelike episodes were agreed with aggressive seizure management strongly recommended at the outset of stroke-like episodes. CONCLUSIONS: Our consensus statement defines stroke-like episodes in terms of an epileptic encephalopathy and we have used this to revise both diagnostic criteria and guidelines for management. A prospective, multi-centre, randomised controlled trial is required for evaluating the efficacy of any compound on modifying the trajectory of stroke-like episodes

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases

Simplifying the clinical classification of polymerase gamma (POLG) disease based on age of onset; studies using a cohort of 155 cases

Background: Variants in POLG are one of the most common causes of inherited mitochondrial disease. Phenotypic classification of POLG disease has evolved haphazardly making it complicated and difficult to implement in everyday clinical practise. The aim of our study was to simplify the classification and facilitate better clinical recognition. / Methods: A multinational, retrospective study using data from 155 patients with POLG variants recruited from seven European countries. / Results: We describe the spectrum of clinical features associated with POLG variants in the largest known cohort of patients. While clinical features clearly form a continuum, stratifying patients simply according to age of onset—onset prior to age 12 years; onset between 12 and 40 years and onset after the age of 40 years, permitted us to identify clear phenotypic and prognostic differences. Prior to 12 years of age, liver involvement (87%), seizures (84%), and feeding difficulties (84%) were the major features. For those with onset between 12 and 40 years, ataxia (90%), peripheral neuropathy (84%), and seizures (71%) predominated, while for those with onset over 40 years, ptosis (95%), progressive external ophthalmoplegia (89%), and ataxia (58%) were the major clinical features. The earlier the onset the worse the prognosis. Patients with epilepsy and those with compound heterozygous variants carried significantly worse prognosis. / Conclusion: Based on our data, we propose a simplified POLG disease classification, which can be used to guide diagnostic investigations and predict disease course

The impact of gender, puberty, and pregnancy in patients with POLG disease

OBJECTIVE: To study the impact of gender, puberty, and pregnancy on the expression of POLG disease, one of the most common mitochondrial diseases known. METHODS: Clinical, laboratory, and genetic data were collected retrospectively from 155 patients with genetically confirmed POLG disease recruited from seven European countries. We used the available data to study the impact of gender, puberty, and pregnancy on disease onset and deterioration. RESULTS: We found that disease onset early in life was common in both sexes but there was also a second peak in females around the time of puberty. Further, pregnancy had a negative impact with 10 of 14 women (71%) experiencing disease onset or deterioration during pregnancy. INTERPRETATION: Gender clearly influences the expression of POLG disease. While onset very early in life was common in both males and females, puberty in females appeared associated both with disease onset and increased disease activity. Further, both disease onset and deterioration, including seizure aggravation and status epilepticus, appeared to be associated with pregnancy. Thus, whereas disease activity appears maximal early in life with no subsequent peaks in males, both menarche and pregnancy appear associated with disease onset or worsening in females. This suggests that hormonal changes may be a modulating factor

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

High anthropogenic carbon content in the eastern Mediterranean

This work presents data of dichlorodifluoromethane (CFC-12), dissolved inorganic carbon and total alkalinity from a cruise to the Mediterranean Sea during October–November 2001, with the main focus on the CFC-12 data and on the eastern basin. Using the transit time distribution method, the anthropogenic carbon concentrations in the basin were estimated. Results were cross-checked with a back-calculation technique. The entire water column of the Mediterranean Sea contains anthropogenic CO2, with minimum concentrations of 20.5 μmol kg−1 (error range: 16.9–27.1 μmol kg−1) in the most eastern part of the basin at intermediate depths, where the waters' mean age is >130 yr. Column inventories of up to 154 mol m−2 (132–179 mol m−2) are found and a total inventory of 1.7 Pg (1.3–2.1 Pg) of anthropogenic carbon in the Mediterranean Sea was estimated. There is a net flux of 38 Tg yr−1 (30–47 Tg yr−1) of dissolved inorganic carbon through the Strait of Gibraltar into the Atlantic Ocean and an opposite net flux of 3.5 Tg yr−1 (−1.8–9.2 Tg yr−1) of anthropogenic carbon into the Mediterranean Sea

Sensory Ataxic Neuropathy in Golden Retriever Dogs Is Caused by a Deletion in the Mitochondrial tRNATyr Gene

Sensory ataxic neuropathy (SAN) is a recently identified neurological disorder in golden retrievers. Pedigree analysis revealed that all affected dogs belong to one maternal lineage, and a statistical analysis showed that the disorder has a mitochondrial origin. A one base pair deletion in the mitochondrial tRNATyr gene was identified at position 5304 in affected dogs after re-sequencing the complete mitochondrial genome of seven individuals. The deletion was not found among dogs representing 18 different breeds or in six wolves, ruling out this as a common polymorphism. The mutation could be traced back to a common ancestor of all affected dogs that lived in the 1970s. We used a quantitative oligonucleotide ligation assay to establish the degree of heteroplasmy in blood and tissue samples from affected dogs and controls. Affected dogs and their first to fourth degree relatives had 0–11% wild-type (wt) sequence, while more distant relatives ranged between 5% and 60% wt sequence and all unrelated golden retrievers had 100% wt sequence. Northern blot analysis showed that tRNATyr had a 10-fold lower steady-state level in affected dogs compared with controls. Four out of five affected dogs showed decreases in mitochondrial ATP production rates and respiratory chain enzyme activities together with morphological alterations in muscle tissue, resembling the changes reported in human mitochondrial pathology. Altogether, these results provide conclusive evidence that the deletion in the mitochondrial tRNATyr gene is the causative mutation for SAN

Aragonite saturation state in a continental shelf (Gulf of Cádiz, SW IberianPeninsula): Evidences of acidification in the coastal area

The spatiotemporal variability of aragonite saturation state (ΩAr) has been studied in the eastern shelf of the Gulf of Cádiz (GoC) (SW Iberian Peninsula). The study was carried out during the years 2014 and 2016 aboard twelve oceanographic cruises, along three or five transects, located between Cape Trafalgar and the Guadiana River. The GoC exhibited oversaturated of calcium carbonate with ΩAr mean values of 2.68 ± 0.30 in surface and 2.05 ± 0.15 in deep waters. pH, total alkalinity (TA), calcium concentration (Ca2+) and ΩAr showed a high variability within the surface mixed layer (SML, z 100 m), TA and Ca2+ concentration presented a conservative behaviour related to the distribution of the different water masses located in the GoC. The vertical variation of ΩAr also depends on the degree of mineralization of these water masses, obtaining the maximum values in the Subtropical North Atlantic Central Water (100–200 m), minimum values in the Subpolar North Atlantic Central Water (about 400 m), and intermediate values associated to the presence of the Mediterranean Water (>500 m). Results showed a significative acidification of the coastal areas, for those depths lower than 100 m from 2006 to 2016, with a mean decrease of pH and ΩAr of −0.0089 and −0.0552 yr−1, respectively. © 2021 The AuthorsThis work was funded by the Spanish CICYT (Spanish Program for Science and Technology) under the contract RTI2018-100865-B-C21 . Dolores Jiménez-López was financed by the University of Cádiz with a FPI fellowship (FPI-UCA) and Ana Sierra was financed by the Spanish Ministry of Education with a FPU fellowship (FPU2014-04048)