Predominant cardiac sympathetic modulation during wake and sleep in patients with Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized by cognitive, social, and physical impairments, as well as sleep disorders and epilepsy. Notably, dysfunction of the autonomic nervous system is a key feature of the syndrome. Although Heart Rate Variability (HRV) has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness, there is still a significant lack of information regarding the same during sleep. Therefore, our aim was to investigate cardiovascular autonomic modulation during sleep in subjects with RTT compared to an age-matched healthy control group (HC). METHOD: A complete overnight polysomnographic (PSG) recording was obtained from 11 patients with Rett syndrome (all females, 10 ± 4 years old) and 11 HC (all females, 11 ± 4 years old; p = 0.48). Electrocardiogram and breathing data were extracted from PSG and divided into wake, non-REM, and REM sleep stages. Cardiac autonomic control was assessed using symbolic non-linear heart rate variability analysis. The symbolic analysis identified three patterns: 0 V% (sympathetic), 2UV%, and 2LV% (vagal). RESULTS: The 0 V% was higher in the RTT group than in the HC group during wake, non-REM, and REM stages (p < 0.01), while the 2LV and 2UV% were lower during wake and sleep stages (p < 0.01). However, the 0 V% increased similarly from the wake to the REM stage in both RTT and HC groups. CONCLUSIONS: Therefore, the sympatho-vagal balance shifted towards sympathetic predominance and vagal withdrawal during wake and sleep in RTT, although cardiac autonomic dynamics were preserved during sleep.

European expert guidance on management of sleep onset insomnia and melatonin use in typically developing children.

Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects.    Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.

Neuronal synchrony and critical bistability: Mechanistic biomarkers for localizing the epileptogenic network.

OBJECTIVE: Postsurgical seizure freedom in drug-resistant epilepsy (DRE) patients varies from 30% to 80%, implying that in many cases the current approaches fail to fully map the epileptogenic zone (EZ). We aimed to advance a novel approach to better characterize epileptogenicity and investigate whether the EZ encompasses a broader epileptogenic network (EpiNet) beyond the seizure zone (SZ) that exhibits seizure activity. METHODS: We first used computational modeling to test putative complex systems-driven and systems neuroscience-driven mechanistic biomarkers for epileptogenicity. We then used these biomarkers to extract features from resting-state stereoelectroencephalograms recorded from DRE patients and trained supervised classifiers to localize the SZ against gold standard clinical localization. To further explore the prevalence of pathological features in an extended brain network outside of the clinically identified SZ, we also used unsupervised classification. RESULTS: Supervised SZ classification trained on individual features achieved accuracies of .6-.7 area under the receiver operating characteristic curve (AUC). Combining all criticality and synchrony features further improved the AUC to .85. Unsupervised classification discovered an EpiNet-like cluster of brain regions, in which 51% of brain regions were outside of the SZ. Brain regions in the EpiNet-like cluster engaged in interareal hypersynchrony and locally exhibited high-amplitude bistability and excessive inhibition, which was strikingly similar to the high seizure risk regime revealed by our computational modeling. SIGNIFICANCE: The finding that combining biomarkers improves SZ localization accuracy indicates that the novel mechanistic biomarkers for epileptogenicity employed here yield synergistic information. On the other hand, the discovery of SZ-like brain dynamics outside of the clinically defined SZ provides empirical evidence of an extended pathophysiological EpiNet.

Early IGF-1 receptor inhibition in mice mimics preterm human brain disorders and reveals a therapeutic target.

Besides recent advances in neonatal care, preterm newborns still develop sex-biased behavioral alterations. Preterms fail to receive placental insulin-like growth factor-1 (IGF-1), a major fetal growth hormone in utero, and low IGF-1 serum levels correlate with preterm poor neurodevelopmental outcomes. Here, we mimicked IGF-1 deficiency of preterm newborns in mice by perinatal administration of an IGF-1 receptor antagonist. This resulted in sex-biased brain microstructural, functional, and behavioral alterations, resembling those of ex-preterm children, which we characterized performing parallel mouse/human behavioral tests. Pharmacological enhancement of GABAergic tonic inhibition by the U.S. Food and Drug Administration-approved drug ganaxolone rescued functional/behavioral alterations in mice. Establishing an unprecedented mouse model of prematurity, our work dissects the mechanisms at the core of abnormal behaviors and identifies a readily translatable therapeutic strategy for preterm brain disorders.

Theory of Mind impairment in childhood narcolepsy type 1: a case-control study.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy and other rapid eye movement sleep-related manifestations. Neurophysiological studies suggest that narcolepsy type 1 patients may experience impairment in emotional processing due to structural and functional changes in limbic structures and associated areas. However, the only study exploring narcolepsy behavioural responses found no impairment in the ability to recognize emotions, possibly due to compensatory mechanisms. The present study was designed to fill this gap in the literature by investigating the behavioural impairment related to emotional processing focusing on an advanced socio-cognitive skill, namely Theory of Mind, in paediatric narcolepsy type 1 patients. Twenty-two narcolepsy type 1 children and adolescents (six female; age range: 8.0-13.5) and 22 healthy controls matched for age and sex (six female; age range: 8.9-13.0) underwent a neuropsychological evaluation to assess socio-economic status, verbal abilities, working memory, social anxiety and Theory of Mind via a verbal task (i.e. Strange Stories task) and a visual task (i.e. Silent Films). Narcolepsy type 1 patients were also evaluated for disease severity. Patients exhibited impairment in Theory of Mind skills, as assessed both through both verbal (controls median = 8; patients median = 5; P = 0.009) and visual tasks (controls median = 8; patients median = 6; P = 0.003), compared to healthy controls. Correlation analyses showed that verbal and visual Theory of Mind was negatively related to narcolepsy severity (ρ = -0.45, P = 0.035 and ρ = -0.52, P = 0.012), and daytime sleepiness (ρ = -0.48, P = 0.025 and ρ = -0.45, P = 0.038). Our study shows a selective impairment in the Theory of Mind domain in children and adolescents with narcolepsy type 1. In addition, our results highlight a link between symptom severity and Theory of Mind, suggesting that lower Theory of Mind levels are associated with higher symptom severity. Further, longitudinal studies are needed to disentangle the direction of this relation and to disambiguate if narcolepsy severity impaired children's Theory of Mind or if Theory of Mind skills modulate the severity of narcolepsy symptoms by providing a greater ability to avoid cataplexy.

Brain and spine malformations and neurodevelopmental disorders in a cohort of children with CAKUT.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20-30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of brain/spine malformations and neurological features in children with CAKUT. METHODS: We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using χ2 and Fisher exact tests. RESULTS: Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001). CONCLUSIONS: We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.

Somnambulism.

Somnambulism, also called sleepwalking, classified as a non-rapid eye movement sleep parasomnia, encompasses a range of abnormal paroxysmal behaviors, leading to sleepwalking in dissociated sleep in an altered state of consciousness with impaired judgment and configuring a kind of hierarchical continuum with confusional arousal and night terror. Despite being generally regarded as a benign condition, its potential severity entails social, personal, and even forensic consequences. This comprehensive review provides an overview on the current state of knowledge, elucidating the phenomenon of somnambulism and encompassing its clinical manifestations and diagnostic approaches.

Early Extra-Uterine Growth Restriction in Very-Low-Birth-Weight Neonates with Normal or Mildly Abnormal Brain MRI: Effects on a 2-3-Year Neurodevelopmental Outcome.

Extra-uterine growth restriction (EUGR) is a common complication and a known risk factor for impaired development in very-low-birth-weight (VLBW) neonates. We report a population of 288 patients with no or with low-grade MRI lesions scanned at a term equivalent age (TEA) born between 2012 and 2018. Griffiths Mental Development Scale II (GMDS II) at 2 and 3 years, preterm complications and weight growth were retrospectively analyzed. EUGR was defined for weight z-score ˂ 10 percentile at TEA, 6 and 12 months of correct age or as z-score decreased by 1-point standard deviation (SDS) from birth to TEA and from TEA to 6 months. Multivariate analysis showed that a higher weight z-score at 6 months is protective for the global developmental quotient (DQ) at 2 years (OR 0.74; CI 95% 0.59-0.93; p = 0.01). EUGR at 6 months was associated with worse locomotor, personal/social, language and performance DQ at 2 years and worse language and practical reasoning DQ at 3 years. In conclusion, a worse weight z-score at 6 months of age seems to be an independent risk factor for significantly reduced GMDS in many areas. These results suggest that we should invest more into post-discharge nutrition, optimizing family nutritional education.

Role of Daytime Continuous Polysomnography in the Diagnosis of Pediatric Narcolepsy Type 1.

BACKGROUND AND OBJECTIVES: Narcolepsy type 1 (NT1) is still largely underdiagnosed or diagnosed too late in children. Difficulties in obtaining rapid and reliable diagnostic evaluations of the condition in clinical practice partially explain this problem. Predictors of NT1 include cataplexy and sleep-onset REM periods (SOREMPs), documented during nocturnal polysomnography (N-PSG) or through the multiple sleep latency test (MSLT), although low CSF hypocretin-1 (CSF hcrt-1) is the definitive biological disease marker. Obtaining reliable MSLT results is not always feasible in children; therefore, this study aimed to validate daytime continuous polysomnography (D-PSG) as an alternative diagnostic tool. METHODS: Two hundred consecutive patients aged younger than 18 years (112 with NT1; 25 with other hypersomnias, including narcolepsy type 2 and idiopathic hypersomnia; and 63 with subjective excessive daytime sleepiness) were randomly split into 2 groups: group 1 (n = 133) for the identification of diagnostic markers and group 2 (n = 67) for the validation of the detected markers. The D-PSG data collected included the number of spontaneous naps, total sleep time, and the number of daytime SOREMPs (d-SOREMP). D-PSG data were tested against CSF hcrt-1 deficiency (NT1 diagnosis) as the gold standard using receiver operating characteristic (ROC) curve analysis in group 1. ROC diagnostic performances of single and combined D-PSG parameters were tested in group 1 and validated in group 2. RESULTS: In group 1, the areas under the ROC curve (AUCs) were 0.91 (95% CI 0.86-0.96) for d-SOREMPs, 0.81 (95% CI 0.74-0.89) for the number of spontaneous naps, and 0.70 (95% CI 0.60-0.79) for total sleep time. A d-SOREMP count ≥1 (sensitivity of 95% and specificity of 72%), coupled with a diurnal total sleep time above 60 minutes (sensitivity of 89% and specificity of 91%), identified NT1 in group 1 with high reliability (area under the ROC curve of 0.93, 95% CI 0.88-0.97). These results were confirmed in the validation group with an AUC of 0.88 (95% CI 0.79-0.97). DISCUSSION: D-PSG recording is an easily performed, cost-effective, and reliable tool for identifying NT1 in children. Further studies should confirm its validity with home D-PSG monitoring. These alternative procedures could be used to confirm NT1 diagnosis and curtail diagnostic delay.

NLP-based tools for localization of the epileptogenic zone in patients with drug-resistant focal epilepsy.

Epilepsy surgery is an option for people with focal onset drug-resistant (DR) seizures but a delayed or incorrect diagnosis of epileptogenic zone (EZ) location limits its efficacy. Seizure semiological manifestations and their chronological appearance contain valuable information on the putative EZ location but their interpretation relies on extensive experience. The aim of our work is to support the localization of EZ in DR patients automatically analyzing the semiological description of seizures contained in video-EEG reports. Our sample is composed of 536 descriptions of seizures extracted from Electronic Medical Records of 122 patients. We devised numerical representations of anamnestic records and seizures descriptions, exploiting Natural Language Processing (NLP) techniques, and used them to feed Machine Learning (ML) models. We performed three binary classification tasks: localizing the EZ in the right or left hemisphere, temporal or extra-temporal, and frontal or posterior regions. Our computational pipeline reached performances above 70% in all tasks. These results show that NLP-based numerical representation combined with ML-based classification models may help in localizing the origin of the seizures relying only on seizures-related semiological text data alone. Accurate early recognition of EZ could enable a more appropriate patient management and a faster access to epilepsy surgery to potential candidates.

Evaluation and management of insomnia in the clinical practice in Italy: a 2023 update from the Insomnia Expert Consensus Group.

BACKGROUND: Insomnia is the most reported sleep disorder in industrialized countries, affecting, in the chronic form, around 10% of the European population. In Italy, such a percentage seems to be even higher. Although insomnia can be an independent disorder, it is frequently described as comorbid condition and may precipitate, exacerbate, or prolong a broad range of physical and mental disorders. Evaluating and targeting insomnia in the Italian clinical practice should be a priority. METHODS: The present expert opinions and recommendations represent an update from 2020 and insights from Insomnia Expert Consensus Group, based on systematic reviews according to PRISMA on available options in Italy from January 2020 to March 2023. RESULTS: We evaluated 28 papers among international guidelines, expert opinions, systematic reviews, and meta-analysis produced during the last 26 months. CONCLUSIONS: Our findings suggest that symptoms of insomnia must be assessed in the Italian clinical practice by evaluating nocturnal and daytime symptoms, comorbid conditions, and lifestyle. Cognitive behavioral therapy for insomnia should be the first option according to availability. The choice of the drug should be based on different factors including type of insomnia, age, comorbidities, and potential side effects. If the choice would be a Z-drug or a short-acting benzodiazepine (in subjects < 65 years old), the use should be in the short term (≤ 4 weeks). Indeed, eszopiclone, as a new option in Italy, may present a different profile and may be used for up to 6 months, also in the elderly. If the choice is melatonin, it should be used melatonin 2 mg prolonged release in adults ≥ 55 years for up to 13 weeks. A new dual orexin antagonist, daridorexant, is available in Italy; it has been shown to be effective in adults and elderly and it can be used for at least 3 months and up to 1 year.

Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities.

PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.

Novel SYNGAP1 Variant in an Adult Individual Affected by Intellectual Disability and Epilepsy: A Cold Case Solved through Whole-Exome Sequencing.

Introduction: Nowadays, whole-exome sequencing (WES) analysis is an essential part in the diagnostic pathway of individuals with complex phenotypes when routine exams, such as array-CGH and gene panels, have proved inconclusive. However, data on the diagnostic rate of WES analysis in adult individuals, negative to first-tier tests, are lacking. This is because initiatives with the aim of diagnosing rare diseases focus mainly on pediatric unsolved cases. Case Presentation: We hereby present a 45-year-old woman with severe intellectual disability, previous psychomotor developmental delay, behavioral disorders, stereotypies, nonconvulsive epilepsy, and dysmorphisms. The proband first came to our attention when she was 4 years old (in 1982); since then, she has undergone several clinical and instrumental assessments, without reaching a genetic diagnosis. At last, through WES analysis, a novel de novo variant in SYNGAP1 was found. The clinical characteristics associated with SYNGAP1 are similar to those presented by the proband. Conclusion: The variant is predicted to be deleterious and is most probably the cause of the proband's phenotype. The perseverance of the clinicians and the family allowed us to reach a diagnosis in a woman with a more than 30-year history of clinical evaluations, instrumental assessments, and genetic tests. This diagnosis was of significant relevance in genetic counseling for family members and the proband herself.

The effects of ketogenic dietary therapies on sleep: A scoping review.

Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed.

Critical-like Brain Dynamics in a Continuum from Second- to First-Order Phase Transition.

The classic brain criticality hypothesis postulates that the brain benefits from operating near a continuous second-order phase transition. Slow feedback regulation of neuronal activity could, however, lead to a discontinuous first-order transition and thereby bistable activity. Observations of bistability in awake brain activity have nonetheless remained scarce and its functional significance unclear. Moreover, there is no empirical evidence to support the hypothesis that the human brain could flexibly operate near either a first- or second-order phase transition despite such a continuum being common in models. Here, using computational modeling, we found bistable synchronization dynamics to emerge through elevated positive feedback and occur exclusively in a regimen of critical-like dynamics. We then assessed bistability in vivo with resting-state MEG in healthy adults (7 females, 11 males) and stereo-electroencephalography in epilepsy patients (28 females, 36 males). This analysis revealed that a large fraction of the neocortices exhibited varying degrees of bistability in neuronal oscillations from 3 to 200 Hz. In line with our modeling results, the neuronal bistability was positively correlated with classic assessment of brain criticality across narrow-band frequencies. Excessive bistability was predictive of epileptic pathophysiology in the patients, whereas moderate bistability was positively correlated with task performance in the healthy subjects. These empirical findings thus reveal the human brain as a one-of-a-kind complex system that exhibits critical-like dynamics in a continuum between continuous and discontinuous phase transitions.SIGNIFICANCE STATEMENT In the model, while synchrony per se was controlled by connectivity, increasing positive local feedback led to gradually emerging bistable synchrony with scale-free dynamics, suggesting a continuum between second- and first-order phase transitions in synchrony dynamics inside a critical-like regimen. In resting-state MEG and SEEG, bistability of ongoing neuronal oscillations was pervasive across brain areas and frequency bands and was observed only with concurring critical-like dynamics as the modeling predicted. As evidence for functional relevance, moderate bistability was positively correlated with executive functioning in the healthy subjects, and excessive bistability was associated with epileptic pathophysiology. These findings show that critical-like neuronal dynamics in vivo involves both continuous and discontinuous phase transitions in a frequency-, neuroanatomy-, and state-dependent manner.

Electroclinical Features of Epilepsy in Kleefstra Syndrome.

BACKGROUND: Kleefstra syndrome (KS) or 9q34.3 microdeletion syndrome (OMIM #610253) is a rare genetic condition featuring intellectual disability, hypotonia, and dysmorphic facial features. Autism spectrum disorder, severe language impairment, and sleep disorders have also been described. The syndrome can be either caused by a microdeletion in 9q34.3 or by pathogenic variants in the euchromatin histone methyltransferase 1 gene (EHMT1, *607001). Although epilepsy has been reported in 20 to 30% of subjects, a detailed description of epileptic features and underlying etiology is still lacking. The purpose of this study is to investigate epilepsy features in a cohort of epileptic patients with KS. METHODS: This multicenter study investigated eight patients with KS and epilepsy. Our findings were compared with literature data. RESULTS: We included five patients with 9q or 9q34.33 deletions, a subject with a complex translocation involving EHMT1, and two with pathogenic EHMT1 variants. All patients presented with moderate to severe developmental delay, language impairment, microcephaly, and infantile hypotonia. Although the epileptic manifestations were heterogeneous, most patients experienced focal seizures. The seizure frequency differs according to the age of epilepsy onset, with patients with early-onset epilepsy (before 36 months of age) presenting more frequent seizures. An overtime reduction in seizure frequency, as well as in antiseizure drug number, was observed in all patients. Developmental delay degree did not correlate with seizure onset and frequency or drug resistance. CONCLUSION: Epilepsy is a frequent finding in KS, but the underlying pathogenetic mechanism and specific features remain elusive.

Asynchronous combined central and peripheral demyelination (CCPD) in a girl with anti-MOG positivity: A case report and review of the literature.

The occurrence of combined central and peripheral demyelination (CCPD) is rare, data are limited to small case and cohort studies, mainly concerning adults. In few patients positivity to anti MOG antibody is reported, thus widening the spectrum of anti-MOG associated disorders (MOGAD). We describe a 7-year-old girl with optic neuritis followed 8 years later by peripheral demyelination, with fluctuating anti-MOG antibody positivity at cell-based assay. From the review of the literature, MOGAD-CCPD appear very rare in childhood, especially with asynchronous course. Clinicians should keep this possibility in mind to better define diagnosis in atypical demyelination syndromes, with therapeutical implications.