Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders.

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Effectiveness of isolation measures with app support to contain COVID-19 epidemics: a parametric approach.

In this study, we analyze the effectiveness of measures aimed at finding and isolating infected individuals to contain epidemics like COVID-19, as the suppression induced over the effective reproduction number. We develop a mathematical model to compute the relative suppression of the effective reproduction number of an epidemic that such measures produce. This outcome is expressed as a function of a small set of parameters that describe the main features of the epidemic and summarize the effectiveness of the isolation measures. In particular, we focus on the impact when a fraction of the population uses a mobile application for epidemic control. Finally, we apply the model to COVID-19, providing several computations as examples, and a link to a public repository to run custom calculations. These computations display in a quantitative manner the importance of recognizing infected individuals from symptoms and contact-tracing information, and isolating them as early as possible. The computations also assess the impact of each variable on the mitigation of the epidemic.

A large and feasible national survey representative of population exposure to outdoor gamma radiation in urban areas.

Background: Although data on outdoor gamma radiation are available for many countries, they have generally been obtained with measurements performed in undisturbed environments instead of in urban areas where most of the population lives. Only one large national survey, with on-site measurements in urban areas, has been identified worldwide, probably due to high costs (e.g., personnel and instrumentation) and difficulties in selecting measuring points. Methods: A campaign of outdoor gamma radiation measurements has been carried out in the entire Italian territory. All measurement points were selected at the infrastructures of an Italian telecommunications company as representatives of all the possible situations of outdoor exposure to gamma radiation for population in urban areas. Ten replicates of portable gamma (X) detectors carried out all the measurements. Results: Approximately 4,000 measurements have been performed. They are distributed across 2,901 Italian municipalities, accounting for 75% of the Italian population. The national population-weighted mean of the gamma ambient dose equivalent rate (ADER) is 117 nSv h-1, and it ranges from 62 to 208 nSv h-1 and from 40 to 227 nSv h-1 for 21 regions and 107 provinces, respectively. The average variability at the municipal level, in terms of the coefficient of variation (CV) is 21%, ranging from 3 to 84%. The impact of land coverage and the distance from a building on the outdoor gamma radiation level was assessed with complementary measurements, leading to differences ranging from -40 to 50% and to 50%, respectively. Conclusion: A representative campaign of outdoor gamma dose rate measurements has been performed in Italy, only in urban areas, to assess the exposure effect due to outdoor gamma radiation on the population. It is the largest national campaign in urban areas worldwide, with a total of 3,876 on-site measurements. The land coverage and the distance from surrounding buildings were recognized to strongly affect outdoor gamma radiation levels, leading to high variability within small areas. The collaboration with a company that owns a network of facilities on a national territory as dense as the residing population made this survey feasible and affordable. Other countries might adopt this methodology to conduct national surveys in urban environments.

Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria.

3-Methylglutaconic aciduria is the biochemical marker of several inherited metabolic diseases. Four types of 3-methylglutaconic aciduria can be distinguished. In the type I form, accumulation of 3-methylglutaconate is due to deficient activity of 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine degradation pathway. In the other forms, 3-methylglutaconic acid is not derived from leucine but is of unidentified origin, possibly derived from other metabolic pathways, such as mevalonate metabolism. We report five patients, all presenting a severe early-onset phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, cataract, hypotonia/developmental delay, lactic acidosis, and normal 3-methylglutaconyl-CoA hydratase activity. This peculiar phenotype, for which a primary mitochondrial disorder is hypothesized, identifies a novel subtype of 3-methylglutaconic aciduria.

Newborn screening of homocystinuria: quantitative analysis of total homocyst(e)ine on dried blood spot by liquid chromatography with fluorimetric detection.

Identification of homocystinuric newborns is hindered by the pitfalls of neonatal screening programs. We propose a fluorimetric HPLC method with a rapid pre-analytical step for homocysteine determination from neonatal dried blood spot cards. Homocysteine in blood spots sampled among 2000 healthy newborns on living day 4, averaged 2.92+/-2.07 microM (range 0.4-7.5). In eight homocystinuric control children, mean values were 61.71+/-52.84 microM (range 18.9-145.7). The method showed a good linearity (r=0.999), precision (RSD<7%) and recovery (95%). The correlation between blood spots and plasma samples was r=0.90. This method has all the essential features for a homocystinuria screening program: an easy and rapid pre-analytical step combined with method linearity and precision.