Exploring genotype-phenotype correlations in glutaric aciduria type 1.

Glutaric aciduria type 1 (GA1) is a rare neurometabolic disease caused by pathogenic variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotype-phenotype correlation, as this is still poorly understood. From this search, 421 different GCDH pathogenic variants have been identified, including four novel variants; c.179T>C (p.Leu60Pro), c.214C>T (p.Arg72Cys), c.309G>C (p.Leu103Phe), and c.665T>C (p.Phe222Ser).The variants are mostly distributed across the entire gene; although variant frequency in GA1 patients is relatively high in the regions encoding for active domains of GCDH. To investigate potential genotype-phenotype correlations, phenotypic descriptions of 532 patients have been combined and evaluated using novel combinatorial analyses. To do so, various clinical phenotypes were determined for each pathogenic variant by combining the information of all GA1 patients reported with this pathogenic variant, and subsequently mapped onto the 2D and 3D GCDH protein structure. In addition, the predicted pathogenicity of missense variants was analyzed using different in silico prediction score models. Both analyses showed an almost similar distribution of the highly pathogenic variants across the GCDH protein, although some hotspots, including the active domain, were observed. Moreover, it was demonstrated that highly pathogenic variants are significantly correlated with lower residual enzyme activity and the most accurate estimation was achieved by the REVEL score. A clear correlation of the genotype and the clinical phenotype however is still lacking.

Clinical outcomes and antibody transfer in a cohort of infants with in utero or perinatal exposure to SARS-CoV-2 (Coronascope Study).

We aimed to describe the outcomes, focusing on the hearing and neurological development, of infants born to mothers with COVID-19 during pregnancy and to evaluate the persistence of maternal antibodies in the first months of life. An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers with COVID-19 during pregnancy between March and September 2020 was conducted. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on nasopharyngeal swab, and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age. Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected, and neurodevelopment was normal in 96% of the infants (median Z score: 0). CONCLUSION: In this cohort, the majority of infants born to mothers with COVID-19 during pregnancy were healthy infants with a normal cUS, no hearing loss, and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up. WHAT IS KNOWN: • Hearing loss and neurodevelopmental delay in infants born to mothers with COVID-19 during pregnancy has been suggested, although data is inconsistent. Maternal antibody transfer seems to be high, with a rapid decrease during the first weeks of life. WHAT IS NEW: • Most infants born to mothers with COVID-19 during pregnancy had normal hearing screening, cranial ultrasound, and neurodevelopmental status at 12 months of life. Antibodies against SARS-CoV-2 were only detected in 50% of the infants at two months of life.

Natural history and mid-term neurodevelopmental outcome of fetuses with isolated mild ventriculomegaly diagnosed in the second half of pregnancy.

INTRODUCTION: Prenatal diagnosis and counseling of isolated ventriculomegaly (VM) represent a considerable challenge. We aimed to analyze the intrauterine evolution, associated anomalies, and neurodevelopmental outcome using the Battelle Development Inventory (BDI) of fetuses with an initial diagnosis of isolated mild VM. MATERIAL AND METHODS: Retrospective cohort study of fetuses diagnosed with mild isolated VM (10 -12 mm) between 2012 and 2016 in a tertiary hospital. In 2018, parents were invited to complete the structured BDI test for the neurodevelopmental evaluation of their children in five domains (personal-social skills, adaptive behavior, psychomotor ability, communication, and cognition). Results exceeding two standard deviations were considered abnormal and referred to an expert neuropediatrician. RESULTS: We identified 43 cases of mild isolated VM. In 5 (11%), structural abnormalities were detected during prenatal follow-up, being related to non-regressive forms (p = .01) and bilateral VM (p = .04). The BDI test was completed by 19/43 (44%). The global score was abnormal in 10/19 (53%). Of them, the neuropediatrician confirmed a neurodevelopmental delay solely in 3 cases that had already been diagnosed with neurological disorders. The most affected domains were gross motor skills (63%), personal-social (63%), and adaptive domains (47%). Communicative and cognitive areas were abnormal in 26% of cases. CONCLUSION: In fetuses with isolated mild VM detected in the second half of pregnancy, 53% had an abnormal BDI test at 2-6 years, but a neurological disorder was only confirmed in the 30% of them.

"Maternal Vaccination Greatly Depends on Your Trust in the Healthcare System": A Qualitative Study on the Acceptability of Maternal Vaccines among Pregnant Women and Healthcare Workers in Barcelona, Spain.

The World Health Organization (WHO) identified vaccine hesitancy as one of the top 10 threats to global health in 2019. Health promotion and education have been seen to improve knowledge and uptake of vaccinations in pregnancy. This qualitative study was conducted based on phenomenology, a methodological approach to understand first-hand experiences, and grounded theory, an inductive approach to analyse data, where theoretical generalisations emerge. Data were collected through semi-structured interviews with pregnant women attending antenatal care services and healthcare workers (HCWs) in Barcelona, Spain. Interviews were audio-recorded, transcribed, and coded, and notes were taken. Inductive thematic analysis was performed, and data were manually coded. Pertussis was reported as the most trusted vaccine among pregnant women due to its long-standing background as a recommended vaccine in pregnancy. The influenza vaccine was regarded as less important since it was perceived to cause mild disease. The COVID-19 vaccine was the least trustworthy for pregnant women due to uncertainties about effectiveness, health effects in the mid- and long-term, the fast development of the vaccine mRNA technology, and the perceptions of limited data on vaccine safety. However, the necessity to be vaccinated was justified by pregnant women due to the exceptional circumstances of the COVID-19 pandemic. The recommendations provided by HCW and the established relationship between the HCW, particularly midwives, and pregnant women were the main factors affecting decision-making. The role of mass media was perceived as key to helping provide reliable messages about the need for vaccines during pregnancy. Overall, vaccines administered during pregnancy were perceived as great tools associated with better health and improved quality of life. Pregnancy was envisioned as a vulnerable period in women's lives that required risk-benefits assessments for decision-making about maternal vaccinations. A holistic approach involving the community and society was considered crucial for health education regarding maternal vaccines in support of the work conducted by HCWs.

A Systematic Review of Magnetic Resonance Imaging Studies in Perinatally HIV-Infected Individuals.

Over the past few years, neuroimaging studies have been performed in young adults with perinatally acquired HIV (PHIV) to study the impact of HIV infection on the central nervous system (CNS), but no recent review have been published. This review aims to identify brain areas where PHIV eems to have greater impact taking into account demographic, behavioral, and clinical characteristics in PHIV infected patients. For this purpose, PubMed and Medline searches were carried out which included studies from 2010 to April 2020. We performed a systematic review and included 26 articles using structural (brain morphometry and diffusion tensor imaging) and functional magnetic resonance imaging methods involving 1182 PHIV-infected participants. Ample evidence has been provided of HIV effects on underlying brain structure. However, information recorded in the studies is commonly incomplete and results sometimes contradictory. In addition to future improvements and dissemination of tools for the developing brain MRI processing and analysis, the inclusion of data related to HIV infection itself (including clinical and immunovirological characteristics as well as detailed information about antiretroviral treatment such as age at ART initiation) may be of vital importance to the better understanding of the impact of the disease on CNS.

Effects of perinatal HIV-infection on the cortical thickness and subcortical gray matter volumes in young adulthood.

ABSTRACT: Brain atrophy has been observed in perinatally HIV-infected patients (PHIV) despite initiation on combined antiretroviral treatment (cART), but neuroimaging studies are limited. We aimed to evaluate cortical thickness (CT) and subcortical gray matter (GM) volumes of PHIV youths with stable immunovirological situation and with a normal daily performance.A prospective cross-sectional study was conducted. A total of 25 PHIV patients on cART and 25 HIV-negative (HIV-) controls matched by age, sex, level of education, and socioeconomic status underwent a magnetic resonance imaging scan. CAT12 toolbox was used to extract CT values from T1w images using parcellations from Desikan-Killiany atlas (DK40). To measure regional brain volumes, native segmented images were parceled in regions of interest according to the Neuromorphometrics Atlas. Neuropsychological assessment and psychopathological symptoms were documented.Fifty participants were included (60% females, median age 20 years [interquartile range, IQR 19-23], 64% Whites). No differences regarding neuropsychological tests or psychopathological symptoms were found between groups (all P > .05). All participants presented an average performance in the Fluid Intelligence (FI) test (PHIV mean: -0.12, HIV- mean: 0.24), When comparing CT, PHIV-infected patients showed thinner cortices compared with their peers in fusiform gyrus (P = .000, P = .009), lateral-orbitofrontal gyrus (P = .006, P = .0024), and right parsobitalis gyrus (P = .047). Regarding subcortical GM volumes, PHIV patients showed lower right amygdala (P = .014) and left putamen (P = .016) volumes when compared with HIV- controls. Within the PHIV group, higher CD4 count was associated with higher volumes in right putamen (B = 0.00000038, P = .045). Moreover, increased age at cART initiation and lower nadir CD4 count was associated with larger volumes in left accumbens (B = 0.0000046, P = .033; B = -0.00000008, P = .045, respectively).PHIV patients showed thinner cortices of areas in temporal, orbito-frontal and occipital lobes and lower volumes of subcortical GM volumes when compared with the HIV- control group, suggesting cortical and subcortical brain alterations in otherwise neuroasymptomatic patients. Nevertheless, larger and longitudinal studies are required to determine the impact of HIV on brain structure in PHIV patients and to further identify risk and protective factors that could be implicated.

Neurocognitive and quality of life study in perinatally HIV-infected young people and their peers. NeuroCoRISpeS study.

BACKGROUND: Assessing the role of HIV and non-HIV related factors is essential for a better understanding of the neurocognitive outcomes in perinatally HIV-infected (PHIV+) young people. The aim of our study was to assess cognition and quality of life (QoL) of a PHIV+ cohort of young people and to compare it with a control group. METHODS: Thirty PHIV+ and 30 HIV(-) healthy young adults matched by age, sex and socioeconomic status completed a protocol that included neurocognitive tests, a psychosocial semi-structured interview and a QoL questionnaire (PedsQL). Neurocognitive domain-specific and domain-general (NPZ-5) Z-scores were calculated. CDC AIDS-defining category C or not C (PHIV+/C, PHIV+/noC) was considered to evaluate differences within the PHIV+ group. Univariate and multivariate analysis were performed. RESULTS: Sixty patients were included; 67% were female; median age (IQR) 19 years (18-21). Regarding PHIV+ young people, 27% showed CDC C category (none encephalopathy), 93% were on ART and 77% had undetectable viral load. No differences regarding occupation were found, although the HIV(-) group repeated less grades (p=0.028) and had a higher education level (p=0.021). No differences were found between PHIV+/noC and HIV(-) participants. However, the PHIV+/C group showed poorer performance than PHIV+/noC (NPZ-5, p=0.037) and HIV(-) subjects (crystallised intelligence, p=0.025; intelligence quotient, p=0.016). Higher nadir CD4+ T-cell count was related to better Z-score in memory (p=0.007) and NPZ-5 (p=0.025). Earlier and longer exposure to ART resulted in better performance in memory (p=0.004) and executive functions (p=0.015), respectively. CONCLUSIONS: No significant differences were found in the neurocognitive profile nor QoL between PHIV+/noC and HIV(-) adolescents; however, PHIV+/C participants obtained lower scores. The use of longer and earlier ART seems to have a beneficial effect.

Prevalence and Clinical Manifestations of Congenital Cytomegalovirus Infection in a Screening Program in Madrid (PICCSA Study).

BACKGROUND: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Up to 15%-20% of infected newborns will develop long-term sequelae such as hearing loss and neurologic abnormalities. The aim of this study was to investigate the prevalence of congenital CMV infection (cCMV) and associated clinical abnormalities in Spain. METHODS: A prospective screening for cCMV by viral load in saliva was performed. Saliva samples were obtained within the first 72 hours of life in a maternity ward in Madrid (Spain), during a 1-year period. All positive screening tests were confirmed with viral load in urine. Clinical, laboratory, auditory, visual and cerebral imaging assessments were performed in all children with cCMV. RESULTS: Of the 4097 neonates born during the study period, 3190 (78%) were included. CMV viral load in saliva was detectable in 24/3190 (0.75%) children, and congenital infection was confirmed in 15/3190 (0.47%, CI 95%: 0.29%-0.77%). Positive predictive value was 62.5% (CI 95%: 46.5%-76.1%). Two infants presented symptoms at birth. Eight (53.3%) children showed abnormalities in magnetic resonance imaging; most of them isolated white matter abnormalities. Newborns with abnormalities in magnetic resonance imaging showed higher viral loads in blood and saliva (P = 0.04). CONCLUSIONS: One in 200 neonates born in our hospital presented a cCMV infection. CMV viral load in saliva has been shown to be a simple and highly accepted screening method but should be confirmed by CMV detection in urine. In spite of the fact that half of infected children had abnormalities in cerebral imaging, diagnosis during the neonatal period would have been impossible without a screening program in most cases.

Systemic administration of a fibroblast growth factor receptor 1 agonist rescues the cognitive deficit in aged socially isolated rats.

Social isolation predominantly occurs in elderly people and it is strongly associated with cognitive decline. However, the mechanisms that produce isolation-related cognitive dysfunction during aging remain unclear. Here, we evaluated the cognitive, electrophysiological, and morphological effects of short- (4 weeks) and long-term (12 weeks) social isolation in aged male Wistar rats. Long-term but not short-term social isolation increased the plasma corticosterone levels and impaired spatial memory in the Morris water maze. Moreover, isolated animals displayed dampened hippocampal long-term potentiation in vivo, both in the dentate gyrus (DG) and CA1, as well as a specific reduction in the volume of the stratum oriens and spine density in CA1. Interestingly, social isolation induced a transient increase in hippocampal basic fibroblast growth factor (FGF2), whereas fibroblast growth factor receptor 1 (FGFR1) levels only increased after long-term isolation. Importantly, subchronic systemic administration of FGL, a synthetic peptide that activates FGFR1, rescued spatial memory in long-term isolated rats. These findings provide new insights into the neurobiological mechanisms underlying the detrimental effects on memory of chronic social isolation in the aged.

Neurocognitive and quality of life study in perinatally HIV-infected young people and their peers. NeuroCoRISpeS study / Estudio neurocognitivo y de calidad de vida en jóvenes infectados por el VIH y sus pares. NeuroCoRISpeS

BACKGROUND: Assessing the role of HIV and non-HIV related factors is essential for a better understanding of the neurocognitive outcomes in perinatally HIV-infected (PHIV+) young people. The aim of our study was to assess cognition and quality of life (QoL) of a PHIV+ cohort of young people and to compare it with a control group. METHODS: Thirty PHIV+ and 30 HIV(-) healthy young adults matched by age, sex and socioeconomic status completed a protocol that included neurocognitive tests, a psychosocial semi-structured interview and a QoL questionnaire (PedsQL). Neurocognitive domain-specific and domain-general (NPZ-5) Z-scores were calculated. CDC AIDS-defining category C or not C (PHIV+/C, PHIV+/noC) was considered to evaluate differences within the PHIV+ group. Univariate and multivariate analysis were performed. RESULTS: Sixty patients were included; 67% were female; median age (IQR) 19 years (18-21). Regarding PHIV+ young people, 27% showed CDC C category (none encephalopathy), 93% were on ART and 77% had undetectable viral load. No differences regarding occupation were found, although the HIV(−) group repeated less grades (p = 0.028) and had a higher education level (p = 0.021). No differences were found between PHIV+/noC and HIV(−) participants. However, the PHIV+/C group showed poorer performance than PHIV+/noC (NPZ-5, p = 0.037) and HIV(-) subjects (crystallised intelligence, p = 0.025; intelligence quotient, p = 0.016). Higher nadir CD4+ T-cell count was related to better Z-score in memory (p = 0.007) and NPZ-5 (p = 0.025). Earlier and longer exposure to ART resulted in better performance in memory (p = 0.004) and executive functions (p = 0.015), respectively. CONCLUSIONS: No significant differences were found in the neurocognitive profile nor QoL between PHIV+/noC and HIV(-) adolescents; however, PHIV+/C participants obtained lower scores. The use of longer and earlier ART seems to have a beneficial effect

ANTECEDENTES: Para estudiar el perfil neurocognitivo de jóvenes infectados perinatalmente por VIH (PVIH+) es importante valorar tanto los factores asociados al virus como los no relacionados. El objetivo de nuestro estudio fue evaluar la cognición y la calidad de vida de una cohorte de jóvenes PVIH+ y compararlas con las de un grupo control. MÉTODOS: Treinta jóvenes PVIH+ y 30 sujetos sanos VIH− pareados por edad, sexo y nivel socioeconómico completaron un protocolo que incluía pruebas neurocognitivas, entrevista psicosocial semiestructurada y cuestionario de calidad de vida PedsQL. Se calculó el Z-score global (NPZ-5) y específico para cada dominio neurocognitivo. Adicionalmente, se consideró la categoría SIDA (PVIH+/C, PVIH+/noC). Se realizó análisis univariante y multivariante. RESULTADOS: De los 60 pacientes incluidos, el 67% eran mujeres; edad media (IQR) 19años (18-21). Respecto al grupo PVIH+, el 27% tenían categoría CDCC (ninguna encefalopatía), el 93% tomaban antirretrovirales y el 77% tenían carga viral indetectable. No hubo diferencias en cuanto a ocupación, aunque el grupo VIH− repitió menos cursos académicos (p = 0,028) y tuvo mayor nivel educativo (p = 0,021). No hubo diferencias entre los grupos PVIH+/noC y VIH−. El grupo PVIH+/C tuvo un rendimiento inferior al de PVIH+/noC (NPZ-5, p = 0,037) y VIH− (inteligencia cristalizada, p = 0,025; cociente de inteligencia, p = 0,016). Mayor nadir de célulasT CD4+ se relacionó con mejor Z-score en Memoria (p = 0,007) y NPZ-5 (p = 0,025). La exposición temprana y prolongada a la terapia antirretroviral favoreció un mejor rendimiento en Memoria (p = 0,004) y en Funciones Ejecutivas (p = 0,015), respectivamente. CONCLUSIONES: No hubo diferencias significativas en el perfil neurocognitivo ni en calidad de vida entre los adolescentes PVIH+/noC y VIH−; sin embargo, los participantes PVIH+/C obtuvieron puntuaciones más bajas. La exposición temprana y prolongada a la terapia antirretroviral parece tener un efecto beneficioso

[Neurodevelopmental disorders as the presenting symptom of Duchenne's muscular dystrophy]. / Trastornos del neurodesarrollo como forma de presentación de la distrofia muscular de Duchenne.

TITLE: Trastornos del neurodesarrollo como forma de presentacion de la distrofia muscular de Duchenne.

Trastornos del neurodesarrollo como forma de presentación de la distrofia muscular de Duchenne / Neurodevelopmental disorders as the presenting symptom of Duchenne's muscular dystrophy

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