The natural history of classic galactosemia: lessons from the GalNet registry.

BACKGROUND Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. METHODS Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. RESULTS Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. CONCLUSION This study describes the natural history of classic galactosemia based on the hitherto largest data set

Cooperation in wild Barbary macaques: factors affecting free partner choice

A key aspect of cooperation is partner choice: choosing the best available partner improves the chances of a successful cooperative interaction and decreases the likelihood of being exploited. However, in studies on cooperation subjects are rarely allowed to freely choose their partners. Group-living animals live in a complex social environment where they can choose among several social partners differing in, for example, sex, age, temperament, or dominance status. Our study investigated whether wild Barbary macaques succeed to cooperate using an experimental apparatus, and whether individual and social factors affect their choice of partners and the degree of cooperation. We used the string pulling task that requires two monkeys to manipulate simultaneously a rope in order to receive a food reward. The monkeys were free to interact with the apparatus or not and to choose their partner. The results showed that Barbary macaques are able to pair up with a partner to cooperate using the apparatus. High level of tolerance between monkeys was necessary for the initiation of successful cooperation, while strong social bond positively affected the maintenance of cooperative interactions. Dominance status, sex, age, and temperament of the subjects also affected their choice and performance. These factors thus need to be taken into account in cooperative experiment on animals. Tolerance between social partners is likely to be a prerequisite for the evolution of cooperation

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

Solar wind protons forming partial ring distributions at comet 67P

We present partial ring distributions of solar wind protons observed by the Rosetta spacecraft at comet 67P/Churyumov-Gerasimenko. The formation of ring distributions is usually associated with high activity comets, where the spatial scales are larger than multiple ion gyroradii. Our observations are made at a low-activity comet at a heliocentric distance of 2.8 AU on 19 April 2016, and the partial rings occur at a spatial scale comparable to the ion gyroradius. We use a new visualization method to simultaneously show the angular distribution of median energy and differential flux. A fitting procedure extracts the bulk speed of the solar wind protons, separated into components parallel and perpendicular to the gyration plane, as well as the gyration velocity. The results are compared with models and put into context of the global comet environment. We find that the formation mechanism of these partial rings of solar wind protons is entirely different from the well-known partial rings of cometary pickup ions at high-activity comets. A density enhancement layer of solar wind protons around the comet is a focal point for proton trajectories originating from different regions of the upstream solar wind. If the spacecraft location coincides with this density enhancement layer, the different trajectories are observed as an energy-angle dispersion and manifest as partial rings in velocity space

Free asymmetric dimethylarginine (ADMA) is low in children and adolescents with classical phenylketonuria (PKU)

INTRODUCTION: Free asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide synthases (NOS). Suppression of nitric oxide (NO) synthesis increases the risk of atherosclerosis. Nevertheless, in the condition of oxidative stress, NOS blockade by ADMA may exert protective effects. Protein metabolism is altered in patients with phenylketonuria (PKU) on dietary treatment and as shown recently, oxidative stress is high in PKU. Since free ADMA concentrations are determined by both protein metabolism and oxidative stress we hypothesized, that free ADMA levels may be elevated in PKU patients. DESIGN: Sixteen patientswith PKU on dietary treatment (mean age 10.1 ± 5.2 yrs), and 91 healthy children (mean age 11.6 ± 3.7 yrs) participated in a cross sectional study. RESULTS: ADMA, total homocysteine (tHcy) and blood glucose were lower and the L-arginine/ADMA ratio was higher in PKU patients compared to controls. No significant correlation was present between phenylalanine (Phe) concentrations, protein intake, and lipid profile, history of cardiovascular disease or ADMA. DISCUSSION: In contrast to our hypothesis, ADMAwas lower and the L-arginine/ADMA ratio was higher in PKU patients. Therefore, in PKU patients, the regulating function of ADMA on NO synthesis is altered and may thus contribute to oxidative stress

Upstream solar wind speed at comet 67P : reconstruction method, model comparison, and results

Context: Rosetta followed comet 67P at heliocentric distances from 1.25 to 3.6 au. The solar wind was observed for much of this time, but was significantly deflected and to some extent slowed down by the interaction with the coma. Aims: We use the different changes in the speed of H+ and He2+ when they interact with the coma to estimate the upstream speed of the solar wind. The different changes in the speed are due to the different mass per charge of the particles, while the electric force per charge due to the interaction is the same. A major assumption is that the speeds of H+ and He2+ were the same in the upstream region. This is investigated. Methods: We derived a method for reconstructing the upstream solar wind from H+ and He2+ observations. The method is based on the assumption that the interaction of the comet with the solar wind can be described by an electric potential that is the same for both H+ and He2+. This is compared to estimates from the Tao model and to OMNI and Mars Express data that we propagated to the observation point. Results: The reconstruction agrees well with the Tao model for most of the observations, in particular for the statistical distribution of the solar wind speed. The electrostatic potential relative to the upstream solar wind is derived and shows values from a few dozen volts at large heliocentric distances to about 1 kV during solar events and close to perihelion. The reconstructed values of the solar wind for periods of high electrostatic potential also agree well with propagated observations and model results. Conclusions: The reconstructed upstream solar wind speed during the Rosetta mission agrees well with the Tao model. The Tao model captures some slowing down of high-speed streams as compared to observations at Earth or Mars. At low solar wind speeds, below 400 km s-1, the agreement is better between our reconstruction and Mars observations than with the Tao model. The magnitude of the reconstructed electrostatic potential is a good measure of the slowing-down of the solar wind at the observation point

Pompe disease in Austria: clinical, genetic and epidemiological aspects

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD

Biotinidase

Biotinidase (EC 3.5.1.12) is required for the recycling of biotin and for the utilization of protein bound biotin from the diet. Biotinidase deficiency (MIM 253260) is inherited as an autosomal recessively trait. Patients become progressively biotin deficient which results in reduced activity of the 4 biotin-dependent carboxylases existing in man, and severe life-threatening illness. Oral biotin substitution effectively protects against disease or reverses symptoms. Delayed treatment may result in irreversible neurological damage. Time of onset and severity of illness depend on the level of residual enzyme activity necessitating early (preferably neonatal) assessment of biotinidase activity. Patients are classified as having profound (0-10% residual activity) or partial (residual activity >10-30%) deficiency, or a Km defect due to reduced affinity of biotinidase for its substrate biocytin. Heterozygous individuals show activities intermediate between the deficient and normal activity. The natural substrate of biotinidase is biocytin but it can also act on artificial biotinyl-derivatives. Biotinidase activity in plasma is usually assayed using biotinyl-p-aminobenzoic acid (biotinyl-PABA) as substrate. Liberated PABA is converted to a purple azo dye and quantitated spectrophotometrically. This simple, reproducible and easy to perform colorimetric assay for the diagnosis of patients with different forms of biotinidase deficiency, including those with a Km defect, is described