Neuropathy target esterase activity defines phenotypes among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.

Climate change and air pollution impacts on cultural heritage building materials in Europe and Mexico.

Climate and air pollution have adverse effects on cultural heritage building materials. However, the quantified damage due to modeled changes in climate and air pollution is still poorly studied. Here, we review first the damage affecting these materials and the associated damage equations in the literature. Across all relevant studies (n = 87), we found only nine independent equations to estimate different damage categories, mainly limited to limestones. Then, by using current meteorological data and future bias-corrected CMIP6 climate and air pollution data at high resolution (1 km; historical and business-as-usual scenario) and applying these equations, we quantified the relative contributions of climate and air pollution changes on the building materials of eight cultural heritage sites of the European project Sustainable COnservation and REstoration of built cultural heritage (SCORE) from 2020 to 2100. On average across the sites, a significant decrease in damage is projected in surface recession (-10 % ± 10 %), biomass accumulation (-20 % ± 18 %), and wind-rain erosion (-7 % ± 6 %) in response to future climate and air pollution changes, except in the regions where precipitation substantially increases (Northern Europe). A large uncertainty in the relative magnitude of the damage to built cultural heritage materials was found for the same site, changes in surface recession vary up to a 40 % difference across the equations. Moreover, thermal expansion and lifetime multiplier equations project an increase in the related damage while all the other types of damage are significantly reduced. Finally, in general, but not systematically, climate-induced damage was found to be predominant over the pollution-induced one. Our results allow prioritizing cultural heritage maintenance decisions in regions where damage will further increase. Beyond simulated damages which are still limited use, we urge more campaign studies to determine real in situ damage in different climate locations to validate or build the best equations.

Neuropathy target esterase activity predicts retinopathy among PNPLA6 disorders.

Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism, and hair anomalies. PNPLA6 encodes Neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a clinical meta-analysis of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6 -associated clinical diagnoses unambiguously reclassified 10 variants as likely pathogenic and 36 variants as pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship and the generation of a preclinical animal model pave the way for therapeutic trials, using NTE as a biomarker.

Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Familial hypocalciuric hypercalcemia: new mutation in the CASR gene converting valine 697 to methionine.

Familial hypocalciuric hypercalcemia is an uncommon cause of hypercalcemia that arises from mutations in the calcium-sensing receptor gene. Inactivation of this receptor leads to a decreased receptor sensitivity to calcium, determining that higher concentrations of calcium are needed to inhibit the release of parathormone in the parathyroid glands. Patients usually are asymptomatic. Diagnosis is usually made casually after a routine blood analysis. The syndrome is characterized by mild or moderate hypercalcemia, hypocalciuria, and normal or slightly increased levels of parathormone. The degree of hypercalcemia depends on the type of mutation. The accurate diagnosis is important since it is a benign disorder that does not require medical or surgical treatment. We report a 9-year-old female with persistent hypercalcemia in several routine blood analyses, who was diagnosed with familial hypocalciuric hypercalcemia after genetic studies were performed. A new mutation determining a nucleotide change c.2089G>A in the calcium-sensing receptor gene (exon 7) was detected. This mutation was also found in the patient's mother and brother.

Reanimación cardiopulmonar y cerebral en la gestante / Cardiopulmonary and cerebral resuscitation in pregnants

Introducción. El paro cardiorrespiratorio, es un evento extremadamente grave en cualquier persona, máxime en el caso particular de una embarazada, pues resultan dos pacientes potenciales a reanimar y sus consecuencias suelen ser fatales tanto para la madre como para el feto. Objetivo. Hacer una puesta al día de la reanimación cardiopulmonar cerebral en la paciente obstétrica. Desarrollo. Se puso a la consideración del lector, los diferentes conceptos de reanimación cardiopulmonar en la gestante y las particularidades del diagnóstico y tratamiento. Conclusiones. Resulta imprescindible la actualización sobre la reanimación cardiopulmonar en la gestante, toda vez que es una situación que se puede presentar con relativa frecuencia e impone un gran reto al equipo que lo enfrenta sobre todo porque no existen guías basadas en la evidencia que permitan enunciar recomendaciones como las que existen para adultos no gestantes o población pediátrica.

The cardiac-respiratory arrest is a very severe event in any person specially in the case of a pregnant patient since arte two the potential patients to resuscitate and its consequences are terrible for mother and for fetus. Objective: To make an update of cerebral cardiac-pulmonary resuscitation in the obstetric patient. Development: The different concepts of cardiac-pulmonary resuscitation in pregnant and the peculiarities of diagnosis and treatment must to be assessed by lector. Conclusions: It is essential the update on the cardiac-pulmonary resuscitation in the pregnant, since that it is a possible situation with a relative frequency and to impose a great challenge to staff facing it mainly because of there are based on the evidence-guidances allowing to formulate recommendations as the existing ones for the non-pregnant adults patients or for the pediatric population.