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The SLC25A22 (Solute Carrier Family 25, Member 22) gene encodes for a mitochondrial glutamate/H+ symporter and is involved in the mitochondrial transport of metabolites across the mitochondrial membrane. We hereby report a 12-year-old girl presenting with early-onset epileptic encephalopathy, hypotonia, and global developmental delay. Whole exome sequencing identified a novel homozygous missense mutation in SLC25A22 gene (c.97A>G; p.Lys33Glu), as the likely cause of the disease. The phenotype of our patient and EEG recordings do not completely overlap with the phenotypes previously described, leading to a new and more complex form of disease associated with SLC25A22 variants, characterized by dyskinetic movements and oculogyric crisis.

The

Questo capitolo è una sintesi dei risultati più rilevanti emersi dalle attività del progetto CISAS, Centro internazionale di studi avanzati sull'ambiente, l'ecosistema e la salute umana, quelli che i protagonisti ritengono più promettenti per gli sviluppi della ricerca su ambiente e salute e degli interventi di bonifica delle aree inquinate , presidio prioritario per la prevenzione dei danni sulla salute delle persone e delle comunità.

Per la comprensione dei fenomeni di inquinamento ambientale e dei meccanismi di trasferimento dei contaminanti dell'ecosistema alle perrone è necessario il coinvolgimento di un ampio spettro di competenze scientifiche che interagiscono tra loro con approccio multidisciplinare

Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype–phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring–Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in ASXL1 mutation carriers.

The biogeochemical dynamics of Hg, and specifically of its three species Hg0, HgII, and MeHg (elemental, inorganic, and organic, respectively) in the marine coastal area of Augusta Bay (southern Italy) have been explored by the high resolution 3D Hg (HR3DHG) model, namely an advection-diffusion-reaction model for the dissolved mercury in the seawater compartment coupled with i) a diffusion-reaction model for dissolved mercury in the pore water of sediments and ii) a sorption/de-sorption model for total mercury in the sediments. The spatio-temporal variability of dissolved and total mercury concentration both in seawater ([HgD] and [HgT]) first layers of bottom sediments ([HgsedD] and [HgsedT]), and the Hg fluxes at the boundaries of the 3D model domain have been theoretically reproduced, showing an excellent agreement with the experimental data, collected in multiple field observations during six different oceanographic cruises. The mass-balance of the different Hg species in seawater has been calculated for the Augusta Harbor, improving previous estimations. The HR3DHG model includes modules that can be implemented for specific and detailed exploration of the effects of climate change on the spatio-temporal distribution of Hg in highly contaminated coastal-marine areas.

Nisyros Island (Greece) is an active volcano hosting a high-enthalpy geothermal system. During June 2013, an extensive survey on Hg concentrations in different matrices (fumarolic fluids, atmosphere, soils, and plants) was carried out at the Lakki Plain, an intracaldera area affected by widespread soil and fumarolic degassing. Concentrations of gaseous elemental mercury (GEM), together with H2S and CO2, were simultaneously measured in both the fumarolic emissions and the atmosphere around them. At the same time, 130 samples of top soils and 31 samples of plants (Cistus creticus and salvifolius and Erica arborea and manipuliflora) were collected for Hg analysis. Mercury concentrations in fumarolic gases ranged from 10,500 to 46,300 ng/m3, while Hg concentrations in the air ranged from high background values in the Lakki Plain caldera (10-36 ng/m3) up to 7100 ng/m3 in the fumarolic areas. Outside the caldera, the concentrations were relatively low (2-5 ng/m3). The positive correlation with both CO2 and H2S in air highlighted the importance of hydrothermal gases as carrier for GEM. On the other hand, soil Hg concentrations (0.023-13.7 μg/g) showed no significant correlations with CO2 and H2S in the soil gases, whereas it showed a positive correlation with total S content and an inverse one with the soil pH, evidencing the complexity of the processes involving Hg carried by hydrothermal gases while passing through the soil. Total Hg concentrations in plant leaves (0.010-0.112 μg/g) had no direct correlation with soil Hg, with Cistus leaves containing higher values of Hg with respect to Erica. Even though GEM concentrations in the air within the caldera are sometimes orders of magnitude above the global background, they should not be considered dangerous to human health. Values exceeding the WHO guideline value of 1000 ng/m3 are very rare (

La Convenzione di Minamata sul mercurio è entrata in vigore il 26 agosto 2017. L'Italia, assieme a Stati Uniti, Cina, Canada, Australia, ai paesi dell'Unione Europea e ad alcuni paesi di Africa ed Asia, rientra tra i primi paesi firmatari, ma, tra i Paesi dell'UE, l'Italia e la Spagna non hanno ancora ratificato. Nel settembre 2017 si è tenuta a Ginevra la prima conferenza, nella quale i governi provenienti da tutto il mondo si sono impegnati nella riduzione di emissioni e rilascio di mercurio a livello mondiale che minacciano l'ambiente e la salute di milioni di persone. Il progetto CISAS (Centro Internazionale di Studi avanzati su Ambiente, ecosistema e Salute umana), coordinato dal CNR (Consiglio Nazionale delle Ricerche), sta studiando l'associazione tra ambiente e salute in siti contaminati, e specificamente nei SIN (Siti di Bonifica di Interesse Nazionale) di Priolo, Milazzo e Crotone. Tra i tanti inquinanti presenti nei tre SIN, l'attenzione dei ricercatori si è concentrata anche sul mercurio, rappresentato in particolare nel SIN di Priolo, dove la preoccupazione per la contaminazione si accompagna a quella per la ritardata bonifica. L'eliminazione dovrebbe avvenire sequestrando e isolando la sostanza perché i cicli naturali non riescono né a far diminuire il mercurio né ad annullarne gli effetti negativi. La rassegna delle conoscenze che proponiamo di seguito nasce dall'esigenza di riportare il mercurio all'attenzione degli studiosi, degli operatori del settore ambientale e della sanità pubblica e degli amministratori ai diversi livelli di competenza.

Mutations in genes involved in chromatin remodelling have been implicated in broad phenotypes of congenital abnormalities and neurodevelopment. However, limited genotype-phenotype correlations are available for some of the rarest genetic disorders that affect chromatin regulation. We hereby describe a 12-year-old girl presented at birth with severe hypotonia, developmental delay, a mid-line capillary malformation and distinctive craniofacial features. During the natural history of her disease, the girl developed severe spasticity and drug-resistant seizures, leading to a diagnosis of Bohring-Opitz syndrome (BOS). We performed whole-exome sequencing (WES) and identified a de novo mutation in ASXL1 (c.2033dupG) which results in the introduction of a premature stop codon (p.R678fs*6). ASXL1 encodes a polycomb repressive complex protein implicated in chromatin regulation and de novo mutations are a known cause of BOS. Phenotypes with segmental craniofacial overgrowth associated to midline capillary malformations enlarge the clinical spectrum of BOS at onset and further expand the differential diagnosis in ASXL1 mutation carriers.

The flux (Φ) of mercury (Hg) at the sediment-seawater interface was investigated in Augusta Bay (southern Italy) where uncontrolled industrial discharge from one of the most important chlor-alkali plant in Europe has caused significant negative effects on the environment. Hg fluxes were measured by the deployment of in-situ benthic chamber. The obtained value of 1.3 kmol y −1 clearly emphasizes the role of the sediments as source of Hg for the overlying water column. Moreover, Hg concentrations in the outflowing bottom waters were measured to estimate the export of this pollutant from Augusta Bay to the open sea. The calculated value of 0.54 kmol y −1 , corresponding to ∼4% of the anthropogenic input of Hg from coastal point/diffuse sources to the Mediterranean Sea (12.5 kmol y −1 ; Rajar et al., 2007; UNEP-MAP, 2001), assigns this area a crucial role in the Hg inventory of the entire Mediterranean basin. Finally, a consistent and robust mass balance for Hg in Augusta Bay was provided by combining the obtained data with Hg fluxes at seawater-atmosphere interface.

The availability of dissolved inorganic mercury (DHg) in sediment pore water is a crucial step for the mechanisms of methylmercury (MeHg) generation in the aquatic system. The geochemical form of Hg in sediments and the redox-controlled microbial reactions taking place during early diagenesis regulate the pool of DHg and, consequently, the bioavailability of Hg for methylation. Here, we report new evidence on the biogeochemical mechanisms controlling the pool of DHg in sediment pore water from two box-cores collected from Augusta Bay (Sicily), a marine coastal zone heavily contaminated by chlor-alkali discharges. The content of the total Hg (THg) in the studied sediments (4.13 ÷ 22.2 mg Kg − 1 ) is largely present as an “immobile” phase, while the labile fractions account for minor percentages ( − 1 ) mainly in the deeper levels of the investigated sedimentary column. Specifically, most of the THg appears to be partially mobilized in the “Fe-Mn reduction” zone, as clearly suggested by significant correlations between DHg and dissolved Fe-Mn concentrations in the pore water. The irregular vertical distribution of SO 4 2 − , with evident enrichment in the Fe-Mn reduction zone, could also indicate mechanisms of sulphate generation by sulphide oxidation. Specific microbial populations identified in the sediments appear dominated by chemolithoautotrophic sulphur oxidizing bacteria (SOB, genera Sulfurovum and Thioalkalispira ) which could drive the microbial oxidation of sulphides and support, with effects of Mn-Fe oxide reduction, processes of Hg mobilization.

Here we investigate mercury concentrations in the blood (HgB), urine (HgU) and human hair (HgH) of 224 individuals from a coastal area (Eastern Sicily, SE Italy) strongly affected by Hg contamination from one of the largest chlor-alkali plants in Europe. The factors affecting the distribution of Hg and the extent of the exposure of individuals have been explored with a multidisciplinary approach. Multiple regression analyses, together with evidence of high levels of HgB (exceeding the HBMI recommended levels in 50% of cases) and HgH (exceeding the EPA reference dose in 70% of cases), primarily suggest that the consumption of local fish is the main source of Hg for humans. no. significant exposure to inorganic mercury was identified. Toxicokinetic calculations produced a provisional tolerable weekly intake (PTWI) level that, in most cases, exceeds international recommendations, particularly for residents in the studied area.

The mercury (Hg) pollution of sediments is the main carrier of Hg for the biota and, subsequently, for the local fish consumers in Augusta Bay area (SE Sicily, Italy), a coastal marine system affected by relevant sewage from an important chlor-alkali factory. This relationship was revealed by the determination of Mass Dependent (MDF) and Mass Independent Fractionation (MIF) of Hg isotopes in sediment, fish and human hair samples. Sediments showed MDF but no MIF, while fish showed MIF, possibly due to photochemical reduction in the water column and depending on the feeding habitat of the species. Benthic and demersal fish exhibited MDF similar to that of sediments in which anthropogenic Hg was deposited, while pelagic organisms evidenced higher MDF and MIF due to photoreduction. Human hair showed high values of δ(202)Hg (offset of +2.2‰ with respect to the consumed fish) and Δ(199)Hg, both associated to fish consumption.

The first attempt to systematically investigate the atmospheric mercury (Hg) in the MBL of the Augusta basin (SE Sicily, Italy) has been undertaken. In the past the basin was the receptor for Hg from an intense industrial activity which contaminated the bottom sediments of the Bay, making this area a potential source of pollution for the surrounding Mediterranean. Three oceanographic cruises have been thus performed in the basin during the winter and summer 2011/2012, where we estimated averaged Hg atm concentrations of about 1.5 ± 0.4 (range 0.9–3.1) and 2.1 ± 0.98 (range 1.1–3.1) ng m −3 for the two seasons, respectively. These data are somewhat higher than the background Hg atm value measured over the land (range 1.1 ± 0.3 ng m −3 ) at downtown Augusta, while are similar to those detected in other polluted regions elsewhere. Hg evasion fluxes estimated at the sea/air interface over the Bay range from 3.6 ± 0.3 (unpolluted site) to 72 ± 0.1 (polluted site of the basin) ng m −2 h −1 . By extending these measurements to the entire area of the Augusta basin (∼23.5 km 2 ), we calculated a total sea–air Hg evasion flux of about 9.7 ± 0.1 g d −1 (∼0.004 t yr −1 ), accounting for ∼0.0002% of the global Hg oceanic evasion (2000 t yr −1 ). The new proposed data set offers a unique and original study on the potential outflow of Hg from the sea–air interface at the basin, and it represents an important step for a better comprehension of the processes occurring in the marine biogeochemical cycle of this element.

Background Developmental milestones are useful signposts developed to assess the pace and the trajectory of maturation occurring during specific time-windows called critical periods . The predictive role of their clinical assessment in premature infants is challenging, however, it actually represents an easy and reliable tool at follow-up. Aim and study design Relying on a milestone-based neurological examination, we aimed to detect the interdependence between time of achievement of each milestone with long-term neuropsychological and neurodevelopmental outcomes. The influence of pre-perinatal events was also considered. Patients & methods Two-hundred-eighty patients (53.2% M) were serially assessed by classic neurological examination during the first 18 months and subsequently evaluated by Griffiths Developmental Mental Scale. Children were sorted by ranges of gestational age and compared according to their different profiles. Results The Extremely PreTerms appeared to have a globally delayed development with subsequent attentional and behavioral troubles. Differently, the older peers, from Moderately to Full Term ones, although did not show significant differences in achievement of gross motor skills, had a stable delay of visual and social skills across the age ranges. This gap was not evidenced at the long-term evaluation, except for the Extremely PreTerm children. Pre-perinatal factors played a significant role on short and long term neurodevelopmental outcome. Conclusions Early assessed classic neurological examination might address neurodevelopmental trajectories in PreTerm children in which visual and social skills appear to be the mostly affected. It remains the easiest and most reliable tool of evaluation throughout the follow-up programs.

Higher total homocysteine (tHcy) levels, and C677T and A1298C methylenetetrahydrofolate (MTHFR) polymorphisms, have been reported in preterm or full term newborns with neonatal encephalopathy following perinatal hypoxic-ischemic insult. This study investigated the causal role of tHcy and MTHFR polymorphisms together with other acquired risk factors on the occurrence of brain white matter abnormalities (WMA) detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. A total of 171 newborns (81 M, 47.4%), 45 (26.3%) born (P<0.014), lower GA(P<0.000), lower Apgar score at 1 minutes(P<0.000)and 5 minutes(P<0.000), and 1298AC and 677CT/1298AC genotypes (P<0.000andP<0.000). In conclusion, both acquired and genetic predisposing antenatal factors were significantly associated with adverse neonatal outcome and WMA. The role of A1298C polymorphism may be taken into account for prenatal assessment and treatment counseling.

Lo studio degli isotopi di Hg in diverse matrici prelevate nella Rada di Augusta si pone come obiettivo quello di supportate i modelli interpretativi emersi dai diversi approcci investigativo utilizzati. In particolare, lo studio isotopi di sedimenti, pesci e capelli umani provenienti da popolazioni residenti nell'area limitrofa alla Rada, offre un'opportunità senza precedenti per determinare in maniera inequivocabile sorgenti e sistemi di trasferimento del Hg nei diversi comparti ambientali analizzati.

Το καλοκαίρι του 2013, προσδιορίστηκαν οι συγκεντρώσεις υδραργύρου στο έδαφος και τον αέρα του ενεργού ηφαιστείου της Νισύρου (Ελλάδα), το οποίο ανήκει στο ενεργό ηφαιστειακό τόξο του νοτίου Αιγαίου. 102 δείγματα εδάφους συλλέχθηκαν και 2119 αναλύθηκαν για υδράργυρο με τη χρήση ψυχρού ατμού ατομικής απορρόφησης αναλυτή, σύμφωνα με τη μέθοδο ΕΡΑ 7473. Ταυτόχρονα, στα ίδια σημεία πραγματοποιήθηκαν συγκεντρώσεις υδραργύρου στον αέρα, με φορητό φασματοφωτόμετρο (Lumex RA- 915M). Οι τιμές των εδαφικών συγκεντρώσεων υδραργύρου κυμαίνονται από 0.023 έως 13.7 mg/g. Οι συγκεντρώσεις υδραργύρου στον αέρα έδειξαν υψηλότερες τιμές υποβάθρου στην περιοχή Λακκί της καλδέρας, μεταξύ 21 και 36 ng/m3 και μέγιστες τιμές μεγαλύτερες από 493 ng/m3 κοντά στις φουμαρολικές περιοχές, σε αντίθεση με τις σχετικά χαμηλότερες τιμές (από 2 μέχρι 5 ng/m3 ) που μετρήθηκαν σε σημεία μακριά από την Καλδέρα. Η θετική συσχέτιση μεταξύ υδραργύρου, διοξειδίου του άνθρακα και υδροθείου στην ατμόσφαιρα υποδηλώνει το σημαντικό ρόλο των φουμαρολικών αερίων ως φορείς αερίου υδραργύρου (Hg0 ). Αντίθετα ο υδράργυρος δεν παρουσιάζει σημαντική συσχέτιση με το CO2 και H2S των εδαφικών αερίων δειγμάτων. Αυτό το συμπέρασμα υποδηλώνει την πολυπλοκότητα των διαδικασιών που επηρεάζει τον υδράργυρο που βρίσκεται στα υδροθερμικά αέρια εντός του εδάφους., In the summer 2013, mercury concentrations in soils and air from Nisyros (Greece), an active volcanic island located in the Aegean Sea, were determined. Up to 102 samples of soil were collected in the Lakki plain caldera and analyzed for mercury by using a cold vapour atomic absorption analyzer, following 7473 US EPA method. Concentrations of mercury in air were also investigated in the same sites with a portable spectrophotometer (Lumex RA-915M). Soil mercury concentrations were in the range from 0.023 to 13.7 µg/g. The mercury concentrations in air showed high background values in the Lakki plain caldera, ranging from 21 to 36 ng/m3 and maximum values up to 493 ng/m3 in the proximity of the fumarolic areas, in contrast with the relatively low values (from 2 to 5 ng/m3 ) measured in the distal sites outside of the caldera. The positive correlation between mercury and CO2 and H2S in the atmosphere highlights the important role of fumarolic gases as carrier for gaseous mercury (Hg0 ). On the contrary, mercury does not show significant correlations with CO2 and H2S in the soil gases. This finding evidences the complexity of the processes affecting mercury in hydrothermal gases passing through the soil.

Type I hyperprolinemia (HPI) is an autosomal recessive disorder caused by proline oxidase deficiency. This enzyme is encoded by the proline dehydrogenase (PRODH) gene on 22q11. The functional consequences of different PRODH mutations on proline oxidase activity have been characterized in vitro. Few patients with HPI with epilepsy and cognitive/behavioral disturbances have been described so far. We screened four Italian children with HPI presenting epilepsy, mental retardation, and behavioral disorders for PRODH gene mutations, and attempted a genotype-phenotype correlation.

We detected a novel CLN1 mutation (c.125-15t>g) in two Italian siblings. The clinical phenotype is that of a variant late-infantile neuronal ceroid lipofuscinosis and consisted of early-onset visual loss, psychomotor deterioration, and seizures. Ultrastructurally, granular osmiophilic deposits were found in skin biopsy of both patients. The novel mutation occurs in the acceptor sequences for splicing and leads to skipping of multiple exons. This predicts a protein lacking part or all of the active site of the enzyme and the palmitate-binding pocket. Consequently, biochemical activity of the palmitoyl protein thioesterase-1 enzyme was drastically reduced. The new mutation was not identified in a large set of ethnically matched control chromosomes. Our findings support the notion that CLN1 patients are not rare in Southern Europe and facilitate DNA-based mutation and carrier testing in this family.

Our study reports on the total mercury (HgT) concentrations measured in the muscles and livers of several benthic, demersal and pelagic fish species caught inside and outside of Augusta Bay (southern Italy), a semi-enclosed marine area, highly contaminated by the uncontrolled (since the 1950s to 1978s) discharge of the largest European petrochemical plant. Mercury levels in fish tissues are discussed with regard to specific habitat, size and/or age of the specimens and HgT distribution in the bottom sediments. Results suggest a still active Hg release mechanism from the polluted sediments to the marine environment. Also, the high HgT concentrations measured in fishes caught in the external area of the bay imply a potential role of Augusta Bay as a pollutant source for the Mediterranean ecosystem. Finally, values of hazard target quotient (THQ) and estimated weekly intake (EWI) demonstrate that consumption of fishes caught inside the bay represents a serious risk for human health. Also, data indicate that intake of fishes caught from the external area of the bay, especially for that concern demersal and benthic species, could be represent a significant component of risk for the local population.

The neuronal ceroid lipofuscinoses are a heterogeneous group of inherited degenerative disorders of the central nervous system. Cases of ceroid lipofuscinosis with cytoplasmic storage of granular osmiophilic deposits are associated with reduced activity of palmitoyl-protein thioesterase-1 (PPT-1) and mutations in CLN1, and occur from infancy to adulthood. We present clinical and diagnostic investigations in six children with variant late infantile neuronal ceroid lipofuscinosis and mutations in CLN1. The main clinical features at onset were behavioral disturbances and cognitive decline. Myoclonic jerks constituted the most prominent paroxysmal phenomenon. An electroencephalogram revealed the "vanishing" pattern described in infantile ceroid lipofuscinosis. Neurologic regression was associated with dramatic shrinkage of cortical structures, evident upon brain magnetic resonance imaging. Three unrelated children harboring the same homozygous mutation in CLN1 and a girl who carried a novel mutation resulting in skipping of multiple exons presented with a similar clinical phenotype. The most severe picture occurred in two siblings who carried a homozygous mutation predicting a prematurely truncated protein. Similar to the infantile form, the clinical evolution in this group of patients was characterized by an onset of severe neurologic impairment, peaking within a relatively short period of time, followed by a slower evolution of the disease.

MTHFR gene variants C677T and A1298C seem to be related to an increased risk of migraine. Folates' metabolism could play a role in the pathophysiology of migraine. We supplemented 16 children with migraine, hyperhomocysteinemia, and MTHFR polymorphisms with folic acid and obtained a resolution/reduction of migraine attacks. Although the mechanism leading to these effects has been not made clear, we believe that the use of folic acid needs further investigations in migraineurs with hyperhomocysteinemia and MTHFR variants. A randomized, double-blind, placebo controlled crossover trial is needed to support these findings.

Objective High plasma homocysteine (Hcy) levels and, C677T and A1298C MTHFR polymorphysms, have been reported in preterm or full term newborns with neonatal encephalopathy following an hypoxic-ischemic insult. Beyond the well-defined pattern of white matter injury such as periventricular leukomalacia, several qualitative neonatal white matter abnormalities (WMA) may account for different degrees of neurobehavioral impairment at long-term observation, either in very preterm or full term infants. Environmental factors may contribute to WMA. We assessed the causal role of Hcy and MTHFR polymorphisms together with acquired risk factors on the occurrence of WMA detected by cranial ultrasound scans (cUS) in a population of late preterm and full term infants. Methods Newborn infants were recruited at the Intensive Care Unit of University Hospital of Messina. Antenatal, perinatal and neonatal details were obtained. Hcy levels were assessed in whole blood within the first week of life. The assessment of C677T and A1298C MTHFR genotypes was carried out. Cerebral ultrasound was performed to all newborns from 1 to 3 days of life and 44 postmenstrual age. Results 171 newborns (81 M, 47.4%), 45 (26.3%) born Conclusion Hcy and MTHFR polymorphisms significantly predisposed to WMA, either full-term or late preterm newborns, in our study. However, WMA was also significantly associated to acquired factors as GA and perinatal status, measured by Apgar scores. The role of A1298C polymorphism might be taken into account for prenatal assessment and treatment counseling.

Mitochondrial deoxyribonucleic acid depletion syndromes are autosomal recessive disorders characterized by a reduction of the amount of mitochondrial deoxyribonucleic acid, which impairs the synthesis of respiratory chain complexes. Mutations in the deoxyguanosine kinase and polymerase gamma genes have been identified in hepatocerebral forms, whereas thymidine kinase 2 gene mutations have been found in patients with isolated myopathy, encephalomyopathy, or spinal muscular atrophy. Mutations in the gene encoding the beta subunit of the adenosine diphosphate-forming succinyl-coenzyme A synthetase have also been reported in a family. In this report, the clinical, molecular, morphologic, and biochemical features of five children from two independent families with an infantile encephalomyopathy are characterized. The affected children manifested muscle mitochondrial deoxyribonucleic acid depletion and three novel thymidine kinase 2 gene mutations. They consist of a homozygous substitution resulting in Ala to Val change at the highly conserved position 181 of thymidine kinase in the first family, and two heterozygous substitutions in the second family: a Cys to Trp change at residue 108 and a Leu to Pro change at residue 257 of the enzyme. Common clinical features associated with these TK2 mutations are a normal early developmental phase followed by psychomotor regression, encephalopathy often with epileptic seizures, and myopathy with features of a progressive dystrophic process.

Specimens of Sparus aurata were exposed to sub-lethal concentrations of Hg and Cd for 25 days and the levels of both metals were investigated in organs and tissues. Bioaccumulation of Hg decreased as follow: gills > kidney > liver > skin > muscle, while the order of Cd bioaccumulation was: liver > kidney > gills > skin > muscle. Immediately after exposure, both metals showed the highest bioaccumulation in gills and skin indicating that these organs are reliable targets for biomonitoring studies after short term exposure. Metals introduction caused a significant time-dependent concentrations increase in kidney and liver, while in the muscle a significant in-crease of Hg was recorded only at the end of the experimentation.The effects of exposure were also investigated, at biochemical level, in the liver, which represents the main target of xenobiotics biotransformation and metabolism in fish. Exposed fishes exhibited a reduction of total lipid level, a decrease of polyunsaturated fatty acids (PUFA), together with a MDA increase. This suggests a direct effect of contaminants on oxidative stress induction that, through the MDA increase, altered the membrane fatty acids composition decreasing the PUFA content. As it regards molecular markers related to oxidative stress and lipid metanolism, a significant increase of Nrf2, Hif- 1 alpha and Ampk and a decrease of Fas were observed after exposure to both metals, while an Nf-kB increase was recorded in specimens exposed to Hg, docuemnting a correlation with oxidative stress and consequent metabolism adaptation. Finally, these results suggest the pos-sibility to adopt these biomarkers to explore fish metabolic responses to environmental pollution.