Expanding SPTAN1 monoallelic variant associated disorders: From epileptic encephalopathy to pure spastic paraplegia and ataxia.

PURPOSE: Nonerythrocytic αII-spectrin (SPTAN1) variants have been previously associated with intellectual disability and epilepsy. We conducted this study to delineate the phenotypic spectrum of SPTAN1 variants. METHODS: We carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Functional studies were performed on fibroblasts from 2 patients. RESULTS: Statistically significant enrichment of rare (minor allele frequency < 1 × 10-5) probably damaging SPTAN1 variants was identified in families with hereditary ataxia (HA) or hereditary spastic paraplegia (HSP) (12/1142 cases vs 52/23,847 controls, p = 2.8 × 10-5). We identified 31 individuals carrying SPTAN1 heterozygous variants or deletions. A total of 10 patients presented with pure or complex HSP/HA. The remaining 21 patients had developmental delay and seizures. Irregular αII-spectrin aggregation was noted in fibroblasts derived from 2 patients with p.(Arg19Trp) and p.(Glu2207del) variants. CONCLUSION: We found that SPTAN1 is a genetic cause of neurodevelopmental disorder, which we classified into 3 distinct subgroups. The first comprises developmental epileptic encephalopathy. The second group exhibits milder phenotypes of developmental delay with or without seizures. The final group accounts for patients with pure or complex HSP/HA.

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.

PURPOSE: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. METHODS: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. RESULTS: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. CONCLUSION: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration.

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy.

PURPOSE: Biallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses. METHODS: Gene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients' fibroblasts were used to perform mass spectrometry-based proteomics. RESULTS: UCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients' fibroblasts. CONCLUSION: Our bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.

Comparison of Adulthood Criteria Endorsed by Emerging Adults and Their Parents in Greece: A Mixed-Method Study.

Although there is extensive research on the adulthood criteria endorsed by emerging adults, there is very limited evidence on the comparison between emerging adults and their parents regarding this issue. Moreover, in these comparison studies, only quantitative methodology was used. Therefore, the present study uses a mixed-method design to investigate similarities and differences in the prevalence of the endorsed adulthood criteria between emerging adults and their parents, between male and female emerging adults, and between fathers and mothers. Participants were 251 emerging adult students, aged 18.0 to 25.9 (M = 19.9; 50.2% females), and 341 parents of these emerging adults, aged 33.6 to 61.9 (M = 50.4; 58.4% mothers). They completed the Markers of Adulthood Scale and named the three criteria that they considered most important for a person to be considered an adult. An inductive-deductive coding scheme was used. The analyses exhibited a high consensus between emerging adults and their parents in the endorsement of adulthood criteria. Only criteria related to Independence and to the Self were reported more frequently by emerging adults than their parents. A strong agreement between genders in both age groups was also found. The contribution of this study is twofold. First, it supports the idea that in Greece adulthood is a construct that is largely shared by emerging adults and their parents. Second, it illustrates how a mixed-method design can complement quantitative studies and extend their findings.

The impact of childhood trauma on borderline personality organization in a community sample of Greek emerging adults.

There is limited research on the role of childhood trauma in personality pathology according to Kernberg's psychodynamic model of internalized object relations. Because childhood trauma reflects the disruptions of these relations, it is expected to predict borderline personality organization, especially at the threshold of adulthood. Therefore, the main aim of this retrospective study was to examine the impact of childhood trauma on borderline personality organization in a community sample of emerging adults. Participants were 543 Greek individuals aged 18-29 (M = 21.45; 58.6 % females; 85.1 % university students). They completed the Greek versions of the Traumatic Antecedents Questionnaire (TAQ) and the Inventory of Personality Organization (IPO), which were tested for their factorial structure, reliability, and measurement invariance across gender, as few empirical data exist on the psychometric properties of these measures. Confirmatory factor analyses showed that the TAQ consisted of four factors, namely positive experiences, abuse, traumatic life events, and family chaos. The five-factor theoretical structure of the IPO, namely primitive defenses, identity diffusion, reality testing, aggression, and moral values, was confirmed. Low to moderate links between childhood trauma and borderline personality organization were found, with stronger links emerging for abuse and family chaos. Structural equation modeling showed that the various forms of childhood trauma across the age periods studied (i.e., 0-6, 7-12, 13-18) significantly and differentially predicted the dimensions of borderline personality organization. The finding that stronger links emerged when trauma occurred in older ages may be attributed to the retrospective method of the study. Gender differences were also found; for example, personality pathology was more likely in men when abuse and traumatic life events occurred in younger ages and abuse was a more important risk factor for personality pathology in women. This study highlights the impact of childhood adversity on personality pathology in emerging adulthood, provides empirical support for Kernberg's psychodynamic model, and has useful implications for trauma-informed early screening, prevention, and intervention regarding personality pathology in young people. Limitations of this study and suggestions for future research are outlined.

Adult friendship and wellbeing: A systematic review with practical implications.

This study aimed to systematically review research findings regarding the relationship between adult friendship and wellbeing. A multidimensional scope for wellbeing and its components with the use of the PERMA theory was adopted. A total of 38 research articles published between 2000 and 2019 were reviewed. In general, adult friendship was found to predict or at least be positively correlated with wellbeing and its components. In particular, the results showed that friendship quality and socializing with friends predict wellbeing levels. In addition, number of friends, their reactions to their friend's attempts of capitalizing positive events, support of friend's autonomy, and efforts to maintain friendship are positively correlated with wellbeing. Efforts to maintain the friendship, friendship quality, personal sense of uniqueness, perceived mattering, satisfaction of basic psychological needs, and subjective vitality mediated this relationship. However, research findings highlighted several gaps and limitations of the existing literature on the relationship between adult friendship and wellbeing components. For example, for particular wellbeing components, findings were non-existent, sparse, contradictory, fragmentary, or for specific populations only. Implications of this review for planning and implementing positive friendship interventions in several contexts, such as school, work, counseling, and society, are discussed.

Exploring friendship quality and the practice of savoring in relation to the wellbeing of Greek adults.

Previous research findings demonstrate that both savoring ability and the presence of high-quality friendships play a significant role in enhancing one's overall sense of wellbeing. However, these associations have not been thoroughly investigated within a diverse range of adults across their lifespans, nor have they been explored in the specific cultural context of Greece. Thus, the primary objective of this study was to delve into the relationships between close friendship quality, the utilization of savoring techniques, and wellbeing within the Greek cultural framework. The study involved 771 adults from Greece with an average age of 38.35 years, who completed the McGill Friendship Functions Questionnaire, the PERMA Profiler, and the Abridged Ways of Savoring Checklist. Results revealed that there exists a positive correlation between friendship quality and savoring strategies with overall wellbeing. Moreover, the study identified a significant association wherein a greater employment of savoring strategies was linked to higher levels of friendship quality. While this study contributes valuable insights, it also has limitations that warrant acknowledgment. Furthermore, suggestions for potential future research directions are proposed, and the implications of these findings are discussed in relation to interventions aimed at enhancing both friendships and the practice of savoring across various contexts.

Criteria for the Transition to Adulthood, Developmental Features of Emerging Adulthood, and Views of the Future Among Greek Studying Youth.

This study investigated emerging adulthood and transition to adulthood in Greece, a highly underresearched issue in this country. Participants were 784 university students aged 17.5-27.5 years. Criteria for the transition to adulthood, developmental features of emerging adulthood, perceived adult status, views of the future (optimism), and sociodemographic variables were assessed. The results support the existence of emerging adulthood as a distinct life period in Greece. More than two thirds of the sample were self-perceived emerging adults. Most prevalent criteria were Norm compliance and Family capacities. Developmental features of emerging adulthood ranked high, especially Identity exploration, Experimentation/possibilities, and Feeling "in-between". Statistically significant variations emerged as a function of gender, age, living arrangement, job experience, and perceived adult status. Views of the future were cautiously optimistic. Similarities with existing data and differences related to the specific characteristics of the Southern European context are discussed.