Patient photographs and pedigree.

<p>In the pedigrees the two sisters couples are represented by grey circles (milder variant = Zappella Rett variant (Z-RTT)) and black circles (more severe phenotype = classical Rett (RTT)). Panel a) Sisters #139 and #138 at the age of 28 and 19, respectively, and pedigree. Presently, patient #139 is 40 years old and is still able to speak in short phrases. Although late stage RTT-associated motor deterioration began 10 years ago, she is still ambulatory. Her phenotype was previously described. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056599#pone.0056599-Zappella1" target="_blank">[3]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056599#pone.0056599-Zappella2" target="_blank">[35]</a> Her sister, patient #138, is 29 years old and has never been able to walk unassisted. Ten years ago she developed spastic tetraplegia with contractures that are still present and are further deteriorating. Panel b) Sisters #896 and #897 at the age of 32 and 26, respectively, and pedigree. Presently, patient #896 is 39 year-old and is still able to walk and to speak in short phrases. She has a friendly behavior and was extremely cooperative during examinations. Her somatic parameters is in the mean range (Occipital-Frontal Circumference (OFC): 54.5 cm, 50–75^th percentile; height 162 cm, 25–50^th percentile; weight 63 Kg, Body Mass Index (BMI) = 24), she has a severe kyphosis and mild pes planus. She has no hand stereotypes and possesses good manual abilities, being able to make simple drawings, eat independently, dress and wash herself. She has never had epilepsy, gastroesophageal reflux, breathing disorders and cold extremities. She has bruxism and a high pain threshold. Her 34 year-old sister (patient #897) shows spastic tetraplegia with severe contractures and hyperventilation. She shows somatic hypoevolutism (OFC 51,5 cm, <3rd percentile; height 150 cm, <3rd percentile; weight 29 Kg, BMI = 13), lordosis, and mild pes planus. She has constant hand stereotypes (pill counting and hand-mouthing), sialorrhea, bruxism, epilepsy that was not controlled by therapy, and cold extremities. She has never been able to speak.</p

Relevant pathways of altered genes in classical Rett (a) and Zappella Rett variant girls (b).

<p>Only pathways in which at least two altered genes were included, or where one gene was mutated in either both classical Rett (RTT) (a) or both Zappella Rett variant (Z-RTT) (b) patients have been included. Genes that are involved in only one pathway are in white. Genes that are involved in more than one pathway are indicated with the same color. For each pathway the code assigned in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database is indicated (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0056599#pone.0056599.s001" target="_blank">File S1</a>). For each gene the mutation type is indicated.</p

Comparison of oxidative stress markers in classical Rett versus Zappella Rett variant.

<p>In classical Rett (RTT) patients (N = 2), all the examined oxidative stress (OS) markers were significantly increased compared to healthy controls (N = 15, all females, mean age 36.5±4.2), whereas Zappella Rett variant (Z-RTT) patients (N = 2) behave as controls subjects except for plasma 4-HNE-PAs. Intra-erythrocyte and plasma non-protein bound iron (NPBI) are markers of hypoxia with hemoglobin oxidation and subsequent heme iron release. Plasma 4-HNE PAs is a marker of protein oxidation due to aldehyde binding from lipid peroxidation sources. F(2)-isoprostanes (F₂-IsoPs) are the end-products of arachidonic acid oxidation, a polyunsaturated fatty acid that is abundant in both brain grey and white matter. F(2)-dihomo-isoprostanes (F₂-dihomo-IsoPs) derive from oxidation of adrenic acid, a fatty acid abundant in white matter, specifically myelin. F(4)-neuroprostanes (F₄-NeuroPs) are the end-products of docosahexanoic acid, abundant in neuronal membranes. Statistical differences were evaluated using Mann-Whitney sum rank test, Kruskal-Wallis analysis of variance (ANOVA) Two-tailed P-values are shown. Values are expressed as means ± standard error means (SEM); intra-erythrocyte NPBI is reported as nmol/ml erythrocytes suspension; plasma 4-HNE-PAs are expressed as arbitrary units (AU), while isoprostanes (IsoPs) are expressed as pg/ml.</p

Variations predicted to impair protein function in disease/susceptibility genes related to muscle and brain.

<p>Variations predicted to impair protein function in disease/susceptibility genes related to muscle and brain.</p

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p