Primary Coenzyme Q deficiency Due to Novel ADCK3 Variants,Studies in Fibroblasts and Review of Literature

Primary deficiency of coenzyme Q10 (CoQ10 ubiquinone), is classified as a mitochondrial respiratory chain disorder with phenotypic variability. The clinical manifestation may involve one or multiple tissue with variable severity and presentation may range from infancy to late onset. ADCK3 gene mutations are responsible for the most frequent form of hereditary CoQ10 deficiency (Q10 deficiency-4 OMIM #612016) which is mainly associated with autosomal recessive spinocerebellar ataxia (ARCA2, SCAR9). Here we provide the clinical, biochemical and genetic investigation for unrelated three nuclear families presenting an autosomal form of Spino-Cerebellar Ataxia due to novel mutations in the ADCK3 gene. Using next generation sequence technology we identified a homozygous Gln343Ter mutation in one family with severe, early onset of the disease and compound heterozygous mutations of Gln343Ter and Ser608Phe in two other families with variable manifestations. Biochemical investigation in fibroblasts showed decreased activity of the CoQ dependent mitochondrial respiratory chain enzyme succinate cytochrome c reductase (complex II?+?III). Exogenous CoQ slightly improved enzymatic activity, ATP production and decreased oxygen free radicals in some of the patient’s cells. Our results are presented in comparison to previously reported mutations and expanding the clinical, molecular and biochemical spectrum of ADCK3 related CoQ10 deficiencies.

     

Form and Function of Early Neolithic Bifacial Stone Tools Reflects Changes in Land Use Practices during the Neolithization Process in the Levant

For many, climate change is no longer recognized as the primary cause of cultural changes in the Near East. Instead, human landscape degradation, population growth, socioeconomic adjustments, and conflict have been proposed as the mechanisms that shaped the Neolithic Revolution. However, as Bar-Yosef noted, even if there is chronological correlation between climate changes and cultural developments, what is important is to understand how Neolithic societies dealt with these improving or deteriorating environments. Changes in bifacial stone tools provide a framework for examining some of these interactions by focusing on changing land use practices during the Neolithization process. The results of microwear analysis of 40 bifacial artifacts from early Pre-Pottery Neolithic (EPPNB) levels at Motza in the Judean hills document changes during the PPNA-PPNB transition at the onset of the Levantine Moist Period (ca. 8000 cal B.C.) when conditions for agriculture improved. EPPNB villagers added heavy-duty axes to a toolkit they had used for carpentry and began to clear forests for fields and grazing lands. Sustainable forest management continued for the duration of the PPN until the cumulative effects of tree-felling and overgrazing seem to have led to landscape degradation at end of the Pre-Pottery Neolithic C (PPNC), when a cold, dry climatic anomaly (6600-6000 cal B.C.) may have accelerated the reduction of woodlands. Early PPNB components at sites like Motza, with data from nearly five millennia of Neolithic occupations, show how complex hunter-gatherers and early food producers were able to establish sustainable resource management systems even as climate changed, population increased, and social relations were redefined.