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The Journal of Clinical Endocrinology... Mar 2024Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH)...
CONTEXT
Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency.
OBJECTIVE
We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency.
METHODS
We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past.
RESULTS
NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed.
CONCLUSIONS
In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.
PubMed: 38469646
DOI: 10.1210/clinem/dgae146 -
Development and Psychopathology Mar 2024We took a multilevel developmental contextual approach and characterized trajectories of alcohol misuse from adolescence through early midlife, examined genetic and...
We took a multilevel developmental contextual approach and characterized trajectories of alcohol misuse from adolescence through early midlife, examined genetic and environmental contributions to individual differences in those trajectories, and identified adolescent and young adult factors associated with change in alcohol misuse. Data were from two longitudinal population-based studies. FinnTwin16 is a study of Finnish twins assessed at 16, 17, 18, 25, and 35 years ( = 5659; 52% female; 32% monozygotic). The National Longitudinal Study of Adolescent to Adult Health (Add Health) is a study of adolescents from the United States, who were assessed at five time points from 1994 to 2018 ( = 18026; 50% female; 64% White, 21% Black, 4% Native American, 7% Asian, 9% Other race/ethnicity). Alcohol misuse was measured as frequency of intoxication in FinnTwin16 and frequency of binge drinking in Add Health. In both samples, trajectories of alcohol misuse were best described by a quadratic growth curve: Alcohol misuse increased across adolescence, peaked in young adulthood, and declined into early midlife. Individual differences in these trajectories were primarily explained by environmental factors. Several adolescent and young adult correlates were related to the course of alcohol misuse, including other substance use, physical and mental health, and parenthood.
PubMed: 38465371
DOI: 10.1017/S0954579424000543 -
The Journal of Genetic Psychology Mar 2024This study explored the influence of genetic and environmental factors on adolescent anxiety. Ninety-eight monozygotic and dizygotic twins from Chongqing, China (aged...
This study explored the influence of genetic and environmental factors on adolescent anxiety. Ninety-eight monozygotic and dizygotic twins from Chongqing, China (aged 15-18 years) were assessed for anxiety with the Self-Rating Anxiety Scale (SAS). The Parenting Styles and Dimensions Questionnaire (PSDQ) and Strengths and Difficulties Questionnaire (SDQ) were applied to assess environmental factors. Venous blood was drawn from the twins for zygosity determination. Structural equation modeling was performed to evaluate the effects of additive genetic factors (A), common environmental factors (C), and individual-specific environmental factors (E) on adolescent anxiety. The estimates of A and E on adolescent anxiety were 0.34 (95% CI = 0.12-0.53) and 0.66 (95% CI:0.47-0.89), respectively. The environment played an important role in adolescent anxiety. Adolescent anxiety was significantly positively correlated with peer relations ( = 0.606, < 0.05) and negatively correlated with prosocial behavior ( = 0.207, < 0. 05). No sex differences were observed. Adolescent anxiety was influenced by both genetic and environmental factors. The individual-specific environmental factors played an important role. Consideration of these variables will facilitate the targeted and individualized implementation of specific interventions for adolescent anxiety.
PubMed: 38456243
DOI: 10.1080/00221325.2024.2319235 -
JAMA Psychiatry Jun 2024Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given...
IMPORTANCE
Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders.
OBJECTIVE
To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding.
DESIGN, SETTING, AND PARTICIPANTS
This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023.
EXPOSURES
A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey.
MAIN OUTCOMES AND MEASURES
Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register.
RESULTS
Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11).
CONCLUSIONS AND RELEVANCE
This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.
Topics: Humans; Adult; Female; Male; Adverse Childhood Experiences; Sweden; Middle Aged; Young Adult; Adolescent; Mental Disorders; Registries; Cohort Studies; Twins, Monozygotic; Twins, Dizygotic; Mental Health
PubMed: 38446452
DOI: 10.1001/jamapsychiatry.2024.0039 -
Journal of Clinical Ultrasound : JCU Jun 2024Single fetal demise in monochorionic gestations in the 2nd and 3rd trimester is associated with adverse outcomes for the co-twin. We present a case of single demise in a...
Single fetal demise in monochorionic gestations in the 2nd and 3rd trimester is associated with adverse outcomes for the co-twin. We present a case of single demise in a monochorionic gestation in the 1st trimester with evidence of subsequent hemodynamic aberrations in the co-twin, supportive of feto-fetal hemorrhage occurring early in gestation.
Topics: Humans; Pregnancy; Female; Pregnancy Trimester, First; Ultrasonography, Prenatal; Fetal Death; Pregnancy, Twin; Adult; Twins, Monozygotic; Chorion
PubMed: 38445880
DOI: 10.1002/jcu.23664 -
Twin Research and Human Genetics : the... Feb 2024There are sex-dependent differences in hematological and biochemical variables in adulthood attributed to the predominant effects of testosterone in males and estrogen...
There are sex-dependent differences in hematological and biochemical variables in adulthood attributed to the predominant effects of testosterone in males and estrogen in females. The Twin Testosterone Transfer (TTT) hypothesis proposes that opposite-sex females may develop male-typical traits due to exposure to relatively higher levels of prenatal testosterone than same-sex females. Additionally, prenatal testosterone exposure has been suggested as a correlate of current circulating testosterone levels. Consequently, opposite-sex females might exhibit male-typical patterns in their hematological and biochemical variables. Despite this hypothesis, routine laboratory investigations assign the same reference range to all females. Our cross-sectional study, conducted in Tamale from January to September 2022, included 40 twins, comprising 10 opposite-sex (OS) males (25%), 10 OS females (25%), and 20 same-sex (SS) females (50%), all aged between 18 and 27 years. Fasting venous blood samples were collected and analyzed using automated hematology and biochemistry laboratory analyzers. Results indicated that levels of hemoglobin, serum creatinine, gamma-glutamyl transferase, total protein, globulins, and total testosterone were significantly higher in OS males than OS females. Conversely, total cholesterol and low-density lipoprotein cholesterol were significantly higher in OS females than OS males. Unexpectedly, levels of low-density lipoprotein cholesterol and total testosterone were significantly higher in SS females than OS females. Contrary to expectations, opposite-sex females did not exhibit male-typical patterns in their hematological and biochemical variables. This suggests that the TTT effect may not occur or may not be strong enough to markedly affect hematological and biochemical variables in OS females.
Topics: Humans; Female; Male; Adult; Ghana; Testosterone; Cross-Sectional Studies; Adolescent; Twins, Dizygotic; Twins, Monozygotic; Young Adult
PubMed: 38444332
DOI: 10.1017/thg.2024.7 -
Acta Paediatrica (Oslo, Norway : 1992) Jun 2024Genetic influences on cerebral activity have been described previously, but data are scarce in preterms. We aimed to investigate whether a genetic influence causes... (Comparative Study)
Comparative Study
AIM
Genetic influences on cerebral activity have been described previously, but data are scarce in preterms. We aimed to investigate whether a genetic influence causes amplitude-integrated electroencephalography (aEEG) signals to differ between singletons and twin preterm newborns.
METHODS
This was a retrospective single-centre study conducted at Innsbruck Medical University Hospital, Austria. Preterm infants born before 32 weeks of gestation between 6 November 2010 and 6 December 2022 were eligible for the study. The aEEG was analysed for the total maturation score, its component scores and the number of sleep-wake cycles per hour.
RESULTS
We enrolled 240 preterm twin infants (57.5% male) with a mean gestational age of 30 (range: 24-32) weeks and a mean birth weight of 1324 (range: 600-2116) grams. We compared 240 singleton matched preterms. No differences were found between preterm singletons and twin preterm infants regarding the total maturation and component scores, or the number of sleep-wake cycles. aEEG showed no difference between monozygotic and dizygotic twins.
CONCLUSION
Compared to singletons, twin infants born preterm showed no differences in aEEG signals in the first 4 weeks of life. Future studies should include more complex non-invasive functional neuroimaging methods to gain more insight into this important topic.
Topics: Humans; Electroencephalography; Infant, Newborn; Female; Male; Retrospective Studies; Infant, Premature; Twins
PubMed: 38441276
DOI: 10.1111/apa.17190 -
European Review For Medical and... Feb 2024Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease...
BACKGROUND
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease caused by Neurogenic locus notch homolog protein 3 (NOTCH3) gene mutations. The main clinical features include migraine with aura, recurrent ischemic strokes and dementia. Brain MRI typically shows multiple small lacunar infarcts and severe, diffuse, symmetrical white matter hyperintensities (WMHs), with characteristic involvement of the anterior temporal pole, external capsule, and superior frontal gyrus. Reports of twins with CADASIL are scarce. Herein we describe a pair of monozygotic twins with peculiar CADASIL phenotype, carrying a new NOTCH3 variant.
CASE PRESENTATION
Twin A was a 45-year-old male suffering from migraine, obesity, arterial hypertension, and polycythemia (with negative genetic analysis), who complained of a transient, short-lasting (~ 5 minutes) episode of speech difficulties. Brain MRI showed diffuse, symmetrical, confluent periventricular WMHs involving frontal, parietal, and temporal lobes and external capsules, with sparing of anterior temporal poles. Genetic analysis of NOTCH3 gene demonstrated the presence of missense c.3329G>A, p.(Cys1110Tyr) variant, confirming CADASIL diagnosis. Twin B, affected by migraine and polycythemia, as well as his monozygotic twin, presented with a 2-month history of trigeminal neuralgia. Brain MRI demonstrated diffuse WMHs with a pattern of distribution like his twin. Genetic analysis revealed the same NOTCH3 pathogenic variant.
CONCLUSIONS
Our monozygotic twins have a strikingly similar neuroimaging picture with sparing of anterior temporal poles. They also have a peculiar phenotype, both presenting polycythemia without genetically confirmed cause. Twin B had trigeminal neuralgia, that is unusual in CADASIL. The possible association of the peculiar findings with the newly reported NOTCH3 variant needs to be confirmed with further observations.
Topics: Male; Humans; Middle Aged; Twins, Monozygotic; CADASIL; Polycythemia; Receptor, Notch3; Trigeminal Neuralgia; Migraine Disorders
PubMed: 38436192
DOI: 10.26355/eurrev_202402_35489 -
Frontiers in Immunology 2024A limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting...
INTRODUCTION
A limited subset of HIV-1 infected adult individuals typically after at least 2-3 years of chronic infection, develop broadly neutralizing antibodies (bnAbs), suggesting that highly conserved neutralizing epitopes on the HIV-1 envelope glycoprotein are difficult for B cell receptors to effectively target, during natural infection. Recent studies have shown the evolution of bnAbs in HIV-1 infected infants.
METHODS
We used bulk BCR sequencing (BCR-seq) to profile the B cell receptors from longitudinal samples (3 time points) collected from a rare pair of antiretroviralnaïve, HIV-1 infected pediatric monozygotic twins (AIIMS_329 and AIIMS_330) who displayed elite plasma neutralizing activity against HIV-1.
RESULTS
BCR-seq of both twins revealed convergent antibody characteristics including V-gene use, CDRH3 lengths and somatic hypermutation (SHM). Further, antibody clonotypes with genetic features similar to highly potent bnAbs isolated from adults showed ongoing development in donor AIIMS_330 but not in AIIMS_329, corroborating our earlier findings based on plasma bnAbs responses. An increase in SHM was observed in sequences of the IgA isotype from AIIMS_330.
DISCUSSION
This study suggests that children living with chronic HIV-1 can develop clonotypes of HIV-1 bnAbs against multiple envelope epitopes similar to those isolated from adults, highlighting that such B cells could be steered to elicit bnAbs responses through vaccines aimed to induce bnAbs against HIV-1 in a broad range of people including children.
Topics: Adult; Infant; Humans; Child; Broadly Neutralizing Antibodies; HIV-1; Receptors, Antigen, B-Cell; Antibodies; Antigens, Viral; Epitopes; HIV Seropositivity; Twins, Monozygotic
PubMed: 38433846
DOI: 10.3389/fimmu.2024.1272493 -
NeoReviews Mar 2024
Topics: Pregnancy; Female; Humans; Pregnancy, Twin; Twins, Monozygotic; Placenta
PubMed: 38425203
DOI: 10.1542/neo.25-3-e169