Risk of lung disease in the PI*SS genotype of alpha-1 antitrypsin: an EARCO research project.

BACKGROUND: The PI*S variant is one of the most prevalent mutations within alpha-1 antitrypsin deficiency (AATD). The risk of developing AATD-related lung disease in individuals with the PI*SS genotype is poorly defined despite its substantial prevalence. Our study aimed to characterize this genotype and its risk for lung disease and compare it with the PI*ZZ and PI*SZ genotypes using data from the European Alpha-1 antitrypsin Deficiency Research Collaboration international registry. METHOD: Demographic, clinical, functional, and quality of life (QoL) parameters were assessed to compare the PI*SS characteristics with the PI*SZ and PI*ZZ controls. A propensity score with 1:3 nearest-neighbour matching was performed for the most important confounding variables. RESULTS: The study included 1007 individuals, with PI*SS (n = 56; 5.6%), PI*ZZ (n = 578; 57.4%) and PI*SZ (n = 373; 37.0%). The PI*SS population consisted of 58.9% men, with a mean age of 59.2 years and a mean FEV1(% predicted) of 83.4%. Compared to PI*ZZ individuals they had less frequent lung disease (71.4% vs. 82.2%, p = 0.037), COPD (41.4% vs. 60%, p = 0.002), and emphysema (23.2% vs. 51.9%, p < 0.001) and better preserved lung function, fewer exacerbations, lower level of dyspnoea, and better QoL. In contrast, no significant differences were found in the prevalence of lung diseases between PI*SS and PI*SZ, or lung function parameters, exacerbations, dyspnoea, or QoL. CONCLUSIONS: We found that, as expected, the risk of lung disease associated with the PI*SS genotype is significantly lower compared with PI*ZZ, but does not differ from that observed in PI*SZ individuals, despite having higher serum AAT levels. TRIAL REGISTRATION: www. CLINICALTRIALS: gov (ID: NCT04180319).

Predicting Exacerbations in Alpha-1 Antitrypsin Deficiency Using Clinical and Pulmonary Function Tests: Portuguese EARCO Registry.

INTRODUCTION: Exacerbations are common in individuals with alpha-1 antitrypsin deficiency (AATD)-related lung disease. This study intended to identify independent predictive factors for exacerbations in AATD using the Portuguese European Alpha-1 Research Collaboration (EARCO) registry. METHODS: This study includes patients from the Portuguese EARCO registry, a prospective multicenter cohort (NCT04180319). From October 2020 to April 2023, this registry enrolled 137 patients, 14 of whom were excluded for analysis for either missing 12 months of follow-up or baseline pulmonary function. RESULTS: Among the 123 AATD patients, 27 (22.0%) had at least one exacerbation in the last 12 months of follow-up. Patients with Pi*ZZ phenotype were three times more likely than the rest of the population to experience any exacerbation (32.7 vs. 14.1%, p = 0.014; OR 3.0). BODE index was significantly higher in exacerbators than in non-exacerbators (3.9 ± 2.4 vs. 1.3 ± 1.2; p < 0.001), including on multivariate analysis (p = 0.002). Similar results were found for BODEx (multivariate p < 0.001). DLCO was the only functional parameter independently associated with exacerbations (p = 0.024). CONCLUSIONS: DLCO, BODE, and BODEx were independent predictors of exacerbations at 12 months in AATD patients. Understanding these risk factors can aid decision-making on AATD-related lung disease management and improve patient outcomes.

Unlocking Hidden Treasures: LC-MS/MS Molecular Networks for Exploring Novel Passiflora Species with Pharmaceutical Potential.

IIn this study, we report the metabolic profiling of several previously uncharacterized Passiflora species native to Brazil, employing molecular networks to delve deeper into chemical constituents. Using the GNPS platform, in silico tools, and substructure annotation techniques, we expanded the chemical annotations. Principal Coordinate Analysis (PCoA) revealed significant metabolic similarities between several species, including P. incarnata, suggesting shared pharmacological potential. Our identification of metabolic compounds facilitated comparisons between understudied species with medicinal properties. Notably, we documented 25 previously uncharacterized species, paving the way for the development of novel products aimed at improving human well-being. This research focused on several native Passiflora species from Brazil, highlighting their unexplored therapeutic potential.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

The executive profile of children with Benign Epilepsy of Childhood with Centrotemporal Spikes and Temporal Lobe Epilepsy.

RATIONALE: Benign Epilepsy of Childhood with Centrotemporal Spikes (BECTS) and temporal lobe epilepsy (TLE) represent two distinct models of focal epilepsy of childhood. In both, there is evidence of executive dysfunction. The purpose of the present study was to identify particular deficits in the executive function that would distinguish children with BECTS from children with TLE. METHODS: We prospectively evaluated 19 consecutive children and adolescents with TLE with hippocampal sclerosis (HS) (57.9% male; mean 11.74years [SD 2.05]; mean IQ 95.21 [SD 15.09]), 19 with BECTS (36.8% male; mean 10.95years [SD 2.33]; mean IQ 107.40 [SD 16.01]), and 21 age and gender-matched controls (33.3% male; mean 11.86years [SD 2.25]; mean IQ 108.67 [15.05]). All participants underwent a neuropsychological assessment with a comprehensive battery for executive and attentional functions. We used ANOVA and chi-square to evaluate differences on demographic aspects among groups (BECTS, TLE-HS, and control groups). Group comparisons on continuous variables were complemented by MANOVA and Bonferroni posthoc comparisons. RESULTS: Patients with BECTS had worse performance than controls in: Matching Familiar Figures Test, time (p=0.001); Matching Familiar Figures Test, time×errors index (p<0.001); Verbal Fluency for foods (p=0.038); Trail Making Test, part B time (p=0.030); Trail Making Test, part B number of errors (p=0.030); and WCST, number of categories achieved (p=0.043). Patients with BECTS had worse performance than patients with TLE-HS on Matching Familiar Figures Test, time (p=0.004), and Matching Familiar Figures Test, time×errors index (p<0.001). Patients with TLE-HS had worse performance than controls on the following tests: Verbal Fluency for foods (p=0.004); Wisconsin Card Sorting Test, the number of categories achieved (p<0.001); and Wisconsin Card Sorting Test, the number of perseverative errors (p=0.028). Patients with TLE-HS had worse performance than patients with BECTS on Digit Backward (p=0.002); and the Wisconsin Card Sorting Test, the number of perseverative errors (p<0.001). CONCLUSIONS: Patients with TLE and BECTS present distinct cognitive profiles. Patients with TLE-HS had worse performance in mental flexibility, concept formation, and working memory compared to BECTS. Patients with BECTS had worse inhibitory control compared to children with TLE-HS. Both TLE-HS and BECTS had a higher number of errors on an inhibitory control test. However, patients with BECTS had a slower mental processing even when compared to patients with TLE-HS. Rehabilitation programs for children with epilepsy must include children with benign epilepsies and must take into account the epileptic syndrome and its particular neurocognitive phenotype.

Alpha-1 antitrypsin deficiency and Pi*Z allele as important co-factors in the development of liver fibrosis.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a codominant autosomal hereditary condition that predisposes patients to the development of lung and/or liver disease, and Pi*Z allele is the most clinically relevant mutation. AIM: To evaluate the impact of clinical parameters and AATD phenotypes, particularly the Pi*Z allele, in liver fibrosis. METHODS: Cross-sectional cohort study including consecutive patients with AATD followed in Pulmonology or Hepatology consultation. RESULTS: Included 69 patients, 49.3% had Pi*MZ phenotype and 10.1% Pi*ZZ. An age ≥ 55 years, age at diagnosis ≥ 41 years and AAT at diagnosis < 77 mg/dL predicted a nonalcoholic fatty liver disease fibrosis score (NFS) not excluding advanced fibrosis [area under the curve (AUC) = 0.840, P < 0.001; AUC = 0.836, P < 0.001; AUC = 0.681, P = 0.025]. An age ≥ 50 years and age at diagnosis ≥ 41 years predicted a fibrosis-4 index of moderate to advanced fibrosis (AUC = 0.831, P < 0.001; AUC = 0.795, P < 0.001). Patients with hypertension, type 2 diabetes mellitus (DM), dyslipidaemia, metabolic syndrome, and regular alcohol consumption were more likely to have a NFS not excluding advanced fibrosis (P < 0.001, P = 0.002, P = 0.008, P < 0.001, P = 0.033). Patients with at least one Pi*Z allele and type 2 DM were 8 times more likely to have liver stiffness measurement ≥ 7.1 kPa (P = 0.040). CONCLUSION: Risk factors for liver disease in AATD included an age ≥ 50 years, age at diagnosis ≥ 41 years, metabolic risk factors, regular alcohol consumption, at least one Pi*Z allele, and AAT value at diagnosis < 77 mg/dL. We created an algorithm for liver disease screening in AATD patients to use in primary care, selecting those to be referred to Hepatology consultation.

Sex-Differences in Alpha-1 Antitrypsin Deficiency: Data From the EARCO Registry.

BACKGROUND: Sex and gender influence many aspects of chronic obstructive pulmonary disease (COPD). Limited data are available on this topic in alpha-1 antitrypsin deficiency (AATD). We therefore aimed to investigate sex issues in the EARCO registry, a prospective, international, observational cohort study. METHODS: Baseline data from PiZZ individuals, enrolled in the registry with complete data on sex and smoking history were analysed by group comparisons and binary logistic regression analyses. RESULTS: 1283 patients with AATD, 49.3% women were analysed. Females reported less tobacco consumption (16.8±12.2 vs. 19.6±14.5 PY, p=0.006), occupational exposures towards gases, dusts or asbestos (p<0.005 each) and consumed less alcohol (5.5±7.6 vs. 8.4±10.3u/week, p<0.001). Females reported COPD (41% vs. 57%, p<0.001) and liver disease (11% vs. 20%, p<0.001) less often. However, they had a higher prevalence of bronchiectasis (24% vs. 13%, p<0.001). Despite better lung function (FEV1%pred. 73.6±29.9 vs. 62.7±29.5, p<0.001) females reported a similar symptom burden (CAT 13.4±9.5 vs. 12.5±8.9, p=ns) and exacerbation frequency (at least one in the previous year 30% vs. 26%, p=ns) compared to males. In multivariate analyses, female sex was an independent risk factor for exacerbations in the previous year OR 1.6 p=0.001 in addition to smoking history, COPD, asthma and bronchiectasis and was also identified as risk factors for symptom burden (CAT≥10) OR 1.4 p=0.014 besides age, BMI, COPD and smoking history. CONCLUSION: Men had higher rates of COPD and liver disease, women were more likely to have bronchiectasis. Women's higher symptom burden and exacerbation frequency suggest they may need tailored treatment approaches.

Expert Perspectives on the Management of Alpha 1-Antitrypsin Deficiency.

Alpha 1-antitrypsin deficiency is an inherited autosomal codominant disorder, which predisposes patients to lung and/or liver disease. Even though it is considered rare, it is one of the most frequent genetic disorders worldwide, albeit remaining underdiagnosed. Several organizations and societies, including the Portuguese Society of Pulmonology have been elaborating guidelines and recommendations for the diagnosis and management of alpha 1-antitrypsin deficiency. Nevertheless, some important matters are yet to be included in those, mainly due to lack of robust scientific evidence, and continue to represent a point of discussion. This article reviews some important scientific publications and expresses the perspectives of a group of Portuguese experts regarding the management of alpha 1-antitrypsin deficiency, namely in terms of the pre and neonatal diagnosis, the impact of the COVID-19 pandemic, the validity of replacement therapy in lung transplant-receiving, and finally, alternative strategies of alpha 1-antitrypsin deficiency treatment to improve the patients' quality of life.

A deficiência de alfa 1-antitripsina é uma doença hereditária autossómica codominante que aumenta a predisposição para o desenvolvimento de doença pulmonar e/ou hepática. Esta doença, embora seja considerada rara, é um dos distúrbios genéticos mais comuns em todo o mundo. Contudo, atualmente ainda constitui uma doença subdiagnosticada. Várias organizações e sociedades, incluindo a Sociedade Portuguesa de Pneumologia, elaboraram recomendações e diretrizes para o diagnóstico e gestão da deficiência de alfa 1-antitripsina. Porém, estes documentos ainda não abordam alguns temas relevantes associados à gestão da deficiência de alfa 1-antitripsina, principalmente devido à falta de robustez na evidência científica, que continuam a representar um ponto de discussão entre a comunidade médica. Neste artigo é feita a revisão de publicações científicas relevantes acerca da deficiência de alfa 1-antitripsina, e são descritas as perspetivas de especialistas portugueses sobre a gestão da deficiência de alfa 1-antitripsina, nomeadamente ao nível do diagnóstico pré e neonatal, do impacto da pandemia COVID-19, da validação da terapêutica de aumento em doentes que receberam um transplante pulmonar e, por fim, estratégias alternativas para a melhoria do tratamento da deficiência de alfa 1-antitripsina de modo a promover a qualidade de vida dos doentes.

Memory in children with temporal lobe epilepsy is at least partially explained by executive dysfunction.

An association between memory and executive dysfunction (ED) has been demonstrated in patients with mixed neurological disorders. We aimed to investigate the impact of ED in memory tasks of children with temporal lobe epilepsy (TLE). We evaluated 36 children with TLE and 28 controls with tests for memory, learning, attention, mental flexibility, and mental tracking. Data analysis was composed of comparison between patients and controls in memory and executive function; correlation between memory and executive function tests; and comparison between patients with mild and severe ED in memory tests. Children with TLE had worse performance in focused attention, immediate and delayed recall, phonological memory, mental tracking, planning, and abstraction. Planning, abstraction, and mental tracking were correlated with visual and verbal memory. Children with severe ED had worse performance in verbal and visual memory and learning tests. This study showed that ED was related to memory performance in children with TLE.

Neuropsychological assessment of children with rolandic epilepsy: executive functions.

Rolandic epilepsy (RE) is the most common type of childhood focal epilepsy. Although there is no intellectual deficit, children with RE may have specific cognitive impairments. The aims of this study were to identify changes in executive functions in children with RE and to verify the influence of epilepsy and seizure variables. We evaluated 25 children with RE and 28 healthy controls. A comprehensive neuropsychological battery was utilized. The results showed that the RE children had worse performance than the control group in some categories of the Wisconsin Card Sorting Test, the Trail Making Test part B, and the Verbal Fluency Test (FAS). Children with earlier onset of epilepsy had worse performance when compared with children with later onset of epilepsy. We conclude that children with RE may show a deficit in executive function despite their normal IQ. The set of tests was more extensive than what was previously used in other studies. Our study suggests that early seizures can interfere with brain development. Regarding cognition, the term benign should be used cautiously in RE.

Episodic and semantic memory in children with mesial temporal sclerosis.

The aim of this study was to analyze semantic and episodic memory deficits in children with mesial temporal sclerosis (MTS) and their correlation with clinical epilepsy variables. For this purpose, 19 consecutive children and adolescents with MTS (8 to 16 years old) were evaluated and their performance on five episodic memory tests (short- and long-term memory and learning) and four semantic memory tests was compared with that of 28 healthy volunteers. Patients performed worse on tests of immediate and delayed verbal episodic memory, visual episodic memory, verbal and visual learning, mental scanning for semantic clues, object naming, word definition, and repetition of sentences. Clinical variables such as early age at seizure onset, severity of epilepsy, and polytherapy impaired distinct types of memory. These data confirm that children with MTS have episodic memory deficits and add new information on semantic memory. The data also demonstrate that clinical variables contribute differently to episodic and semantic memory performance.

Executive dysfunction in children and adolescents with temporal lobe epilepsy: is the Wisconsin Card Sorting Test enough?

The Wisconsin Card Sorting Test (WCST) is the gold standard in the evaluation of executive dysfunction (ED) in patients with temporal lobe epilepsy (TLE). We evaluated 35 children with TLE and 25 healthy controls with the WCST and with a more comprehensive battery. Among the children with TLE, 77.14% showed impairment on the WCST. On other tests (Wechsler Intelligence Scale for Children-Digit Forward, Matching Familiar Figures Test, Trail Making Test, Word Fluency, Finger Windows, and Number-Letter Memory), impairment was demonstrated in 94.29%. The authors concluded that the WCST is a good paradigm to measure executive impairment in children with TLE; however, it may be not enough. Evaluation performed only with the WCST not only underestimated the number of patients with ED, but also missed relevant information regarding the type of ED.

A new candidate locus for bilateral perisylvian polymicrogyria mapped on chromosome Xq27.

Polymicrogyria (PMG) is characterized by an excessive number of small and prominent brain gyri, separated by shallow sulci. Bilateral perisylvian polymicrogyria (BPP) is the most common form of PMG. Clinical signs include pseudobulbar paresis, mental retardation, and epilepsy. Familial forms of BPP have been described and a candidate locus was previously mapped to chromosome Xq28, distal do marker DXS8103. The objective of this study was to perform linkage analysis in one family segregating BPP. A total of 15 individuals, including 8 affected patients with BPP were evaluated. Family members were examined by a neurologist and subjected to magnetic resonance imaging scans. Individuals were genotyped for 18 microsatellite markers, flanking a 42.3 cM interval on ch Xq27-q28. Two-point and multipoint linkage analysis was performed using the LINKAGE package and haplotype reconstruction was performed by GENEHUNTER software. Our results showed a wide spectrum of clinical manifestations in affected individuals with BPP, ranging from normal to mild neurological abnormalities. Two-point linkage analysis yield a Zmax = 2.06 at theta = 0.00 for markers DXS1205 and DXS1227. Multipoint lod-scores indicate a candidate interval of 13 cM between markers DSXS1205 and DXS8043, on ch Xq27.2-Xq27.3. These results point to a new locus for BPP in a more centromeric location than previously reported.

Characterization of language and reading skills in familial polymicrogyria.

Polymicrogyria (PMG) is a malformation of cortical development characterized by an excessive number of small gyri and abnormal cortical lamination, giving the cortical surface an irregular and gross appearance. The severity of clinical manifestations correlates with the extent of cortical involvement. The objective of the present study was to describe three families with linguistic features of developmental language disorder and reading impairment, and to establish a neuroanatomic correlation through neuroimaging. Subjects have been submitted to a comprehensive protocol including psychological assessment, language evaluation, neurological examination, and neuroimaging investigation. In our families, children usually had the diagnosis of developmental language disorder while adults had the diagnosis of reading impairment. MRI showed perisylvian polymicrogyria in several subjects of each family. Our data support the idea that there is a co-occurrence of developmental language disorder and reading impairment and both conditions may be associated with polymicrogyria.

Interictal EEG in temporal lobe epilepsy in childhood.

The authors clarified the value of interictal discharges and verified which extratemporal regions may also show epileptiform activity in temporal lobe epilepsy (TLE) in childhood. Thirty consecutive patients aged 3 to 18 years (mean age = 12.16 years; 16 male) with TLE associated with hippocampal atrophy were studied. Each patient had 1 to 15 interictal EEG recordings (mean: 5.6; total = 192 EEGs). Video-EEG monitoring was performed in 20 patients. All patients had MRI. The findings were compared with a control group of 53 consecutive TLE adult outpatients with hippocampal atrophy. Each adult patient underwent 3 to 21 routine EEGs (mean: 10.67; total = 566). Interictal EEGs of children with TLE showed extratemporal epileptiform discharges more frequently than EEGs of adults with TLE. Frontal, parietal, and occipital discharges were more frequently seen in children (P < 0.05). These results suggest a close interaction between temporal and other cerebral regions in children with epilepsy and provide further evidence of the existence of neural networks.

Clinical and electroencephalographic features of patients with polymicrogyria.

Polymicrogyria is a malformation of cortical organization. The aim of this historic cohort study was to describe clinical and EEG features of patients with polymicrogyria. Patients underwent clinical and neurologic examination and a prolonged routine EEG to allow recording during sleep. Neuroimaging data were classified as: perisylvian polymicrogyria (subdivided into holosylvian, posterior parietal, and generalized), hemispheric polymicrogyria, and frontal polymicrogyria. Forty patients were studied: 16 with holosylvian polymicrogyria, 14 with posterior parietal polymicrogyria, 4 with generalized polymicrogyria, 3 with hemispheric polymicrogyria, and 3 with frontal polymicrogyria. Patients with polymicrogyria usually did not have epilepsy and their EEGs were mostly normal (55%); the severity of the clinical and EEG features correlated with the extent of the cortical lesion. In perisylvian polymicrogyria, epileptiform abnormalities predominated in fronto-temporal regions. Dour patients had focal electrical status (FES) in awakeness and electrical status epilepticus of sleep (ESES); these four patients had right hemispheric polymicrogyria and asymmetric bilateral perisylvian polymicrogyria, mostly on the right hemisphere. The authors conclude that the EEG is usually normal in patients with polymicrogyria, despite it being associated with FES and ESES in certain patients.

Temporal lobe epilepsy in childhood: comprehensive neuropsychological assessment.

The neuropsychological features of children with temporal lobe epilepsy are not yet well defined. The aim of this study was to identify the neuropsychological deficits in children with temporal lobe epilepsy. We evaluated 25 patients and compared them with 25 normal children. All children underwent a comprehensive neuropsychological assessment. We found a significant difference in favor of the control group in the following measures: IQ; forward digit; Trail Making Test for Children B; Wisconsin Card Sorting Test; block design; Boston naming test, verbal fluency; and Wide Range Assessment of Memory and Learning verbal learning, visual learning, verbal memory, visual memory, delayed recall of verbal learning, delayed recall of stories, and recognition of stories. Our findings show that children with temporal lobe epilepsy present with several neuropsychological deficits, despite normal IQ. These findings point to a dysfunction of cerebral areas other than temporal lobe, particularly the frontal lobes.

Frontal lobe dysfunction in children with temporal lobe epilepsy.

There is evidence that adults with temporal lobe epilepsy present executive impairments. However, there is limited information in children, especially when using a comprehensive neuropsychologic battery. We aimed to: 1) investigate the presence and severity of executive dysfunctions in children with temporal lobe epilepsy, and 2) determine the implications of clinical variables (including etiology) in the occurrence and severity of executive dysfunction, using eight paradigms. Thirty-one children with temporal lobe epilepsy were evaluated and compared with 21 age-matched controls. Patients with temporal lobe epilepsy had significantly worse performance than controls. Intragroup analysis indicated that patients with symptomatic epilepsy were more impaired than those with cryptogenic epilepsy. In the former group, patients with mesial lesions performed worse than those with lateral lesions. Regarding the severity of executive dysfunction, 83.87% manifested severe to moderate executive impairment. Early age of onset, longer duration of epilepsy, and use of polytherapy were correlated with worse executive dysfunction. These findings indicated the presence of frontal lobe dysfunction in children with temporal lobe epilepsy, with worse performance in those with mesial temporal lobe epilepsy, early onset, longer duration of disease, and use of polytherapy. Our study corroborates the hypothesis that temporal lobe epileptogenic activity affects the extratemporal regions that mediate attentional and executive functions.