The novel P330L pathogenic variant of aromatic amino acid decarboxylase maps on the catalytic flexible loop underlying its crucial role

Aromatic amino acid decarboxylase (AADC) deficiency is a rare monogenic disease, often fatal in the first decade, causing severe intellectual disability, movement disorders and autonomic dysfunction. It is due to mutations in the gene coding for the AADC enzyme responsible for the synthesis of dopamine and serotonin. Using whole exome sequencing, we have identified a novel homozygous c.989C > T (p.Pro330Leu) variant of AADC causing AADC deficiency. Pro330 is part of an essential structural and functional element: the flexible catalytic loop suggested to cover the active site as a lid and properly position the catalytic residues. Our investigations provide evidence that Pro330 concurs in the achievement of an optimal catalytic competence. Through a combination of bioinformatic approaches, dynamic light scattering measurements, limited proteolysis experiments, spectroscopic and in solution analyses, we demonstrate that the substitution of Pro330 with Leu, although not determining gross conformational changes, results in an enzymatic species that is highly affected in catalysis with a decarboxylase catalytic efficiency decreased by 674- and 194-fold for the two aromatic substrates. This defect does not lead to active site structural disassembling, nor to the inability to bind the pyridoxal 5'-phosphate (PLP) cofactor. The molecular basis for the pathogenic effect of this variant is rather due to a mispositioning of the catalytically competent external aldimine intermediate, as corroborated by spectroscopic analyses and pH dependence of the kinetic parameters. Altogether, we determined the structural basis for the severity of the manifestation of AADC deficiency in this patient and discussed the rationale for a precision therapy

Variability in feeding habitats of red deer sensu lato in Eurasia in the Late Pleistocene and Holocene

Red deer (Cervus elaphus) is one of the species that is rather wide spread and survived across Europe over the Holocene. The analyses of carbon and nitrogen stable isotopes in bone collagen of ungulate remains have been applied in paleoecological studies as environmental and dietary indicators. In this study we present the carbon and nitrogen stable isotope compositions of previously radiocarbon-dated red deer bone samples (N = 68) found in Central, Southern and Eastern Europe and Asia and aligned to one of two species: European red deer (Cervus elaphus) and wapiti (Cervus canadensis). We showed that the values of carbon and nitrogen stable isotope ratios of European red deer and wapiti overlapped. Among all analysed independent factors (determined for the locality and time period relevant for each of the analysed samples), the variability of δ13C values in European red deer dated to the Holocene is best explained by forest cover and mean July temperature, and variability of δ15N values by the mean July temperature, annual precipitation and altitude. Additionally, combining the results of the present study with isotopic data on European red deer collected from published sources, we revealed that the values of δ13C and of δ15N in C. elaphus bones changed according to environmental oscillations that took place in Europe over the last 50 000 years. We concluded that red deer shifted their feeding habitats in relation to changing environmental conditions, for example, forest expansion during the climate warming, and in the mid to later Holocene in response to deforestation caused by human activity and the spread of agriculture. We also found out that red deer reacted in varied ways to changing local conditions in different regions of Europe. Modern individuals of C. elaphus had the lowest δ13C values among all analysed specimens, so they probably inhabited the most densely forested areas in comparison to other European red deer populations during the last 50 000 years

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management

P. W. is supported by the Clinical Research Fund, University Hospitals Leuven, Leuven, Belgium. This work is partially funded by the grant titled Frontiers in Congenital Disorders of Glycosylation (1U54NS115198-01) from the National Institute of Neurological Diseases and Stroke (NINDS), the National Center for Advancing Translational Sciences (NCATS), and the Rare Disorders Consortium Research Network (RDCRN) (E. M., K. R., C. F., H. F., C. L., and A. E.)Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients.preprintpublishe

Winter Temperature and Forest Cover Have Shaped Red Deer Distribution in Europe and the Ural Mountains Since the Late Pleistocene

Aim: The Expansion-Contraction model has been used to explain the responses of species to climatic changes. During periods of unfavourable climatic conditions, species retreat to refugia from where they may later expand. This paper focuses on the palaeoecology of red deer over the past 54 ka across Europe and the Urals, to reveal patterns of change in their range and explore the role of environmental conditions in determining their distribution. Location: Europe and western Asia to 63°E. Taxon: Red deer (Cervus elaphus). Methods: We collected 984 records of radiocarbon-dated red deer subfossils from the Late Pleistocene and the Holocene, including 93 original dates. For each deer sample we compiled climatic and biome type data for the corresponding time intervals. Results: During the last 54 ka changes in red deer range in Europe and the Urals were asynchronous and differed between western and eastern Europe and western Asia due to different environmental conditions in those regions. The range of suitable areas for deer during the Last Glacial Maximum (LGM) was larger than previously thought and covered vast regions not only in southern but also in western and eastern Europe. Throughout the period investigated the majority of specimens inhabited forests in the temperate climatic zone. The contribution of forests in deer localities significantly decreased during the last 4 ka, due to deforestation of Europe caused by humans. Mean January temperature was the main limiting factor for species distribution. Over 90% of the samples were found in areas where mean January temperature was above −10°C. Main conclusions: Red deer response to climatic oscillations are in agreement with the Expansion-Contraction model but in contradiction to the statement of only the southernmost LGM refugia of the species. During the last 54 ka red deer occurred mostly in forests of the temperate climatic zone. © 2020 John Wiley & Sons Ltd.European Social Fund, Grant/Award Number: UDA-POKL.04.01.01-00-072/09-00; University of Wroclaw, Grant/Award Number: 0410/2990/18; Institute of Environmental Biology, University of Wrocław, Grant/Award Number: 0410/2990/18; Mammal Research Institute Polish Academy of Sciences; Narodowe Centrum Nauki , Grant/Award Number: DEC-2013/11/B/NZ8/00888 and UMO-2016/23/B/HS3/00387; Romanian National Authority for Scientific Research, UEFISCDI, Grant/Award Number: PN-IIIP4-ID-PCE-2016-0676; National Centre for Atmospheric Science and the Centre for Environmental Data Analysis, UK; Faunal Database of the Stage Three Project; Leverhulme Trust, Grant/Award Number: F00568W

Winter temperature and forest cover have shaped red deer distribution in Europe and the Ural Mountains since the Late Pleistocene

Aim: The Expansion-Contraction model has been used to explain the responses of species to climatic changes. During periods of unfavourable climatic conditions, species retreat to refugia from where they may later expand. This paper focuses on the palaeoecology of red deer over the past 54 ka across Europe and the Urals, to reveal patterns of change in their range and explore the role of environmental conditions in determining their distribution. Location: Europe and western Asia to 63°E. Taxon: Red deer (Cervus elaphus). Methods: We collected 984 records of radiocarbon-dated red deer subfossils from the Late Pleistocene and the Holocene, including 93 original dates. For each deer sample we compiled climatic and biome type data for the corresponding time intervals. Results: During the last 54 ka changes in red deer range in Europe and the Urals were asynchronous and differed between western and eastern Europe and western Asia due to different environmental conditions in those regions. The range of suitable areas for deer during the Last Glacial Maximum (LGM) was larger than previously thought and covered vast regions not only in southern but also in western and eastern Europe. Throughout the period investigated the majority of specimens inhabited forests in the temperate climatic zone. The contribution of forests in deer localities significantly decreased during the last 4 ka, due to deforestation of Europe caused by humans. Mean January temperature was the main limiting factor for species distribution. Over 90% of the samples were found in areas where mean January temperature was above −10°C. Main conclusions: Red deer response to climatic oscillations are in agreement with the Expansion-Contraction model but in contradiction to the statement of only the southernmost LGM refugia of the species. During the last 54 ka red deer occurred mostly in forests of the temperate climatic zone. © 2020 John Wiley & Sons Ltd.European Social Fund, Grant/Award Number: UDA-POKL.04.01.01-00-072/09-00; University of Wroclaw, Grant/Award Number: 0410/2990/18; Institute of Environmental Biology, University of Wrocław, Grant/Award Number: 0410/2990/18; Mammal Research Institute Polish Academy of Sciences; Narodowe Centrum Nauki , Grant/Award Number: DEC-2013/11/B/NZ8/00888 and UMO-2016/23/B/HS3/00387; Romanian National Authority for Scientific Research, UEFISCDI, Grant/Award Number: PN-IIIP4-ID-PCE-2016-0676; National Centre for Atmospheric Science and the Centre for Environmental Data Analysis, UK; Faunal Database of the Stage Three Project; Leverhulme Trust, Grant/Award Number: F00568W

Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs