Search

Background Although NKX 2.1 related chorea has been considered benign due to the favourable course of motor phenotype during life, the neurological condition is not limited to chorea, including non-motor symptoms in the developmental, cognitive and psychiatric domain. Aim of our study was to test working memory, attention and planning abilities of a cohort of NKX2.1 choreic patients compared to healthy controls. Methods patients and healthy controls were assessed for working memory (Visual Digit Span test), response inhibition and sustained attention (Cued Go/No-Go test), and spatial problem-solving and planning task (Tower of London test). For experimental protocol, we used a computer based tool for neuropsychological experiments, Inquisit 5.0 software (Millisecond Software®). Non-parametric tests were performed for statistical analysis. Results six patients and fifteen healthy paediatric controls were recruited. In the Digit Span test, both in forward and backward recall, patients showed statistically significant lower scores than controls. In the Cued Go/No-Go test as well as in the Tower of London, NKX 2.1 patients showed similar scores in the error rate and total score respectively, whereas in both tests they appeared to be slower than controls suggesting a poor performance in the execution of the tests. Conclusions our findings demonstrate that patients with NKX2.1-related chorea show a selective impairment in working memory with increased latencies in both planning and attention. A developmental alteration of the cholinergic neurotransmission in the basal forebrain and the disruption of striatal networks could explain, at least in part, this neuropsychological profile.

BackgroundNext-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.MethodsHere, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).ResultsWe identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from −4 SD to −8 SD), profound psychomotor delay, hypertonic–dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (−2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.ConclusionOur findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

ADAR1 variants are associated to rare and heterogenous neurological conditions, including Aicardi-Goutieres syndrome type 6, bilateral striatal necrosis, and dyschromatosis symmetrica hereditaria. Movement disorders (MDs) commonly occur in ADAR1-related diseases although a complete overview on the phenomenology has not been provided yet. Here, a cohort of 57 patients with ADAR1-related diseases, including 3 unpublished patients and 54 previously reported cases, was reviewed. Data on demographics, clinical features of MDs, genetics and biomarkers were collected and descriptive statistics, group analysis for genotype and logistic regression were run. Manifestations of MD characterized the onset of ADAR1-related disease in 60% of patients. Specifically, dystonia occurred in 39% of cases, even as severe status dystonicus, while prevalence of other MDs was lower. Patients often presented brain lesions (>90%) and progressive disease course (43%), fatal in some cases. Clinical presentation and outcome differed among patients with distinct genotype. This review shows that phenomenology of MDs in ADAR1-related diseases is wide and heterogeneous, although a severe motor syndrome (often characterized by dystonia) secondary to brain lesions represents the most common manifestation. Waiting for future development of disease-modifying treatments, an appropriate symptomatic intervention is crucial for ADAR1 patients. Accordingly, a deeper knowledge of phenomenology is fundamental.

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na+/K+ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p.Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na+/K+ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.

GNAO1 gene mutations are associated with a neurodevelopmental disorder characterized by developmental delay, epilepsy, and movement disorder. Eye tracking and eye movement analysis are an intriguing method to assess cognitive and language function and, to the best of our knowledge, it has never been tested in a standardized way in GNAO1. GNAO1 children are usually wheelchair-bound and with numerous motor constrains, including dystonic movements and postures, heterotropia, and hypotonia, making the cognitive assessment arduous. These contribute to the burden and disability, with a high level of frustration of caregivers and patients. We have herein demonstrated that, through an eye tracking system, six GNAO1 patients evaluated showed variable degrees of communicative intent through intentionally directed gaze. Moreover, three of these were able to complete a cognitive evaluation, and showed normal fluid intelligence and lexical comprehension. In conclusion, in GNAO1-related disorders, the degree of cognitive development is underestimated, eye tracking technologies may help in overcome these boundaries.

KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of KV4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. KV4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.

KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of KV4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. KV4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.

Tourette syndrome is a neurodevelopmental disorder characterized by motor and vocal tics. Co-occurrence of Attention deficit and hyperactivity disorder (ADHD) or Obsessive Compulsion Disorder (OCD) is very frequent in pediatric population as well as the presence of an impairment of the executive functions. The aim of our study was to investigate motor timing that is the temporal organization of motor behaviour, in a paediatric population of Tourette patients. Thirty-seven Tourette patients (divided in 22 “pure” Tourette patients and 15 with ADHD) were compared with 22 healthy age- and gender matched subjects. All subjects underwent a neuropsychiatric screening and were tested for their planning and decision-making abilities by using a standardized test as Tower of London. Two experimental paradigms were adopted: finger tapping test, a free motor tapping task, and the synchronization-continuation task. An accuracy index was calculated as measure of ability of synchronization. We found that “pure” TS as well as TS+ADHD showed lower scores in the finger tapping test for the dominant and non-dominant hand, compared with controls. Moreover, in the synchronization and continuation test, we observed an overall lack of accuracy in both TS groups in the continuation phase for 2000 ms (supra-second interval), interestingly, with opposite direction of accuracy index. Thus, “pure” TS patients were classified as “behind the beat”, whereas TS+ADHD as “ahead of the beat”. The performance in the finger tapping was inversely correlated to Tower of London total scores and execution time; while we did not find any correlation with the accuracy index of the synchronization and continuation test. In conclusion, here, we explored motor timing ability in a childhood cohort of Tourette patients confirming that patients exhibit an impaired temporal control of motor behavior and these findings may be explained by the common underlying neurobiology of Tourette syndrome and motor timing.

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na+/K+ATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30–43% of all cases, p.Glu815Lys is responsible for 16–35% of cases and p.Gly947Arg accounts for 8–15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na+/K+ATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.

Aim To critically analyse the management of status dystonicus and prestatus dystonicus in children and adolescents, in order to examine clinical features, acute management, and risk of relapse in a paediatric cohort. Method Clinical, demographic, and therapeutic features were analysed according to disease severity. Risk of subsequent relapse was estimated through Kaplan-Meier curves. Results Thirty-four patients (eight females, 26 males) experiencing 63 episodes of acute dystonia exacerbations at a tertiary referral Italian hospital were identified. Mean age at status dystonicus presentation was 9 years 11 months (11y at inclusion in the study). Onset of dystonia dated back to infancy in most cases. Fourteen patients experienced two or more episodes. Infections were the most common trigger (48%). Benzodiazepines were the most commonly used drugs for acute management. Stereotactic pallidotomy was performed in six cases during status dystonicus, and in two additional patients it was electively performed after medical management. The probability of survival free from status dystonicus relapses was 78% after 4 months and 61% after 27 months. Interpretation Dystonia exacerbations are potentially life-threating emergencies, with a considerable risk of relapse. Nevertheless, no obvious factors for relapse risk stratification exist. Pallidotomy is a feasible option in medical refractory status dystonicus for patients with limited deep brain stimulation applicability, but the risk of recurrence is elevated. What this paper adds Acute exacerbations may affect up to 10% of children with dystonia. Infections are the most common precipitant factor. In about 30% of the cases, intensive care unit admission is needed. Subsequent relapses are common, reaching 25% risk at 1 year. Pallidotomy can be considered in medical-refractory cases with no deep brain stimulation applicability.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

GNAO1 variants were recently discovered as causes of epileptic encephalopathies and heterogeneous syndromes presenting with movement disorders (MDs), whose phenomenology and clinical course are yet undefined. We herein focused on GNAO1-related MD, providing an analytical review of existing data to outline the main MD phenomenology and management, clinical evolution and genotype-phenotype correlations. Reviewing 41 previously published patients and assessing 5 novel cases, a comprehensive cohort of 46 patients was analyzed, reassuming knowledge about genotypes, phenotypes, disease course and treatment of this condition. GNAO1-related MD consisted of a severe early-onset hyperkinetic syndrome, with prominent chorea, dystonia and orofacial dyskinesia. Symptoms are poorly responsive to medical therapy and fluctuate, with critical and life-threatening exacerbations, such as status dystonicus. The presence of a choreiform MD appears to be predictive of a higher risk of movement disorder emergency. Surgical treatments are sometimes effective, although severe disabilities persist. Differently from the early infantile epileptic encephalopathy phenotype (associated with loss of function variants), no clear correlation between genotype and MD phenotype emerged, although some variants recurred more frequently, mainly affecting exons 6 and 7.

Introduction. Tuberous Sclerosis Complex (TSC) is an autosomal-dominant disease caused by the loss of function of the heterodimeric complex hamartin/tuberin due to TSC1/TSC2 gene mutation. The consequent abnormal activation of mammalian target of rapamycin (mTOR), a serine threonine kinase regulating cellular growth, metabolism and proliferation, is responsible for the structural and functional abnormalities observed in TSC. mTOR inhibitors are a class of drugs specifically targeting the mTOR pathway with promising benefits as a specific targeted treatment of the disease. Areas covered. We have reviewed the literature focusing on the role of mTOR inhibitors in treating TSC-related conditions. They are currently approved for subependymal giant cell astrocytomas, renal angiomyolipomas and more recently for lymphangioleiomyomatosis, but a promising role has been shown also in the other clinical manifestation characteristics of TSC, such as cardiac rhabdomyomas, facial angiofibromas and epilepsy. Expert opinion. mTOR inhibition is considered a disease-modifying therapy and the best approach to prevent the progress of the natural history of the disease. For the first time we have the possibility not only to use a biologically targeted treatment, but also to address different manifestations at the same time, thus significantly improving the therapeutic outlook in this complex disease.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the development of widespread hamartomatous lesions in various organs, including brain, skin, kidneys, heart, and eyes. Central nervous system is almost invariably involved, with up to 85% of patients presenting with epilepsy, and at least half of patients having intellectual disability or other neuropsychiatric disorders including autism spectrum disorder. TSC is caused by the mutation in one of the 2 genes TSC1, at 9q34, and TSC2, at 16p13.3. They respectively encode for hamartin and tuberin, which form an intracellular complex inhibiting the mammalian target of rapamycin. Mammalian target of rapamycin overactivation following the genetic defect determines the cell growth and proliferation responsible for TSC-related lesions, as well as the alterations in neuronal excitability and synaptogenesis leading to epilepsy and neuropsychiatric disorders. A causative mutation for the disorder is identified in about 85% of patients with a clinical diagnosis of TSC. Mosaicism and technology limits likely explain most of the no mutation identified cases. This review confirms that patients with TSC2 mutations considered as a group usually present a more severe phenotype, characterized by higher number of tubers, earlier age at seizure onset and higher prevalence of intellectual disability. However, the clinical phenotype of the disease presents a high variability, thus making the prediction of the phenotype on an individual basis still challenging. The increasing application of new molecular techniques to subjects with TSC has the potential to significantly reduce the rate of patients with no mutation demonstrated and to identify an increasing higher number of mutations. This would hopefully allow a better characterization of higher risk mutations, which might help clinicians to plan individualized surveillance plans. Furthermore, the increasing availability of disease registries to collect clinical and genetics data of patients help to define more valid and clinically oriented genotype or phenotype correlations.

Genetic variants within components of the cohesin complex (NIPBL, SMC1A, SMC3, RAD21, PDS5, ESCO2, HDAC8) are believed to be responsible for a spectrum of human syndromes known as "cohesinopathies" that includes Cornelia de Lange Syndrome (CdLS). CdLS is a multiple malformation syndrome affecting almost any organ and causing severe developmental delay. Cohesinopathies seem to be caused by dysregulation of specific developmental pathways downstream of mutations in cohesin components. However, it is still unclear how mutations in different components of the cohesin complex affect the output of gene regulation. In this study, zebrafish embryos and SMC1A-mutated patient-derived fibroblasts were used to analyze abnormalities induced by SMC1A loss of function. We show that the knockdown of smc1a in zebrafish impairs neural development, increases apoptosis, and specifically down-regulates Ccnd1 levels. The same down-regulation of cohesin targets is observed in SMC1A-mutated patient fibroblasts. Previously, we have demonstrated that haploinsufficiency of NIPBL produces similar effects in zebrafish and in patients fibroblasts indicating a possible common feature for neurological defects and mental retardation in cohesinopathies. Interestingly, expression analysis of Smc1a and Nipbl in developing mouse embryos reveals a specific pattern in the hindbrain, suggesting a role for cohesins in neural development in vertebrates. J. Cell. Physiol. 231: 613-622, 2016. © 2015 Wiley Periodicals, Inc.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.

Cohesin complex components exert fundamental roles in animal cells, both canonical in cell cycle and non-canonical in gene expression regulation. Germline mutations in genes coding for cohesins result in developmental disorders named cohesinopaties, of which Cornelia de Lange syndrome (CdLS) is the best-known entity. However, a basic description of mammalian expression pattern of cohesins in a physiologic condition is still needed. Hence, we report a detailed analysis of expression in murine and human tissues of cohesin genes defective in CdLS. Using both quantitative and qualitative methods in fetal and adult tissues, cohesin genes were found to be ubiquitously and differentially expressed in human tissues. In particular, abundant expression was observed in hematopoietic and central nervous system organs. Findings of the present study indicate tissues which should be particularly sensitive to mutations, germline and/or somatic, in cohesin genes. Hence, this expression analysis in physiological conditions may represent a first core reference for cohesinopathies.

Adamantinomatous craniopharyngiomas (aCPs) are complex epithelial neoplasms that arise from the progenitors of the pituitary gland. Although benign, these tumours can be locally aggressive invading vital neighbouring structures such as the hypothalamus, the cranial and optic nerves. Congenital forms of aCPs diagnosed during foetal development are very rare. The purpose of this article is to present with a histopathological and molecular characterisation of congenital craniopharyngioma. Here we report a case of in utero diagnosed aCP, detected at 21 weeks of gestation by ultrasound, visualised by MRI at 22 weeks and histologically diagnosed at 23 weeks. We provide with histopathological characterisation of rare form of congenital aCPs. Detailed examination of the tumour reveals the classical histological hallmarks of aCPs with the presence of stellate reticulum, palisading epithelium, wet keratin and calcification deposits. The tumour demonstrated complete absence of all pituitary hormones and the absence of the neuroendocrine marker, synaptophysin. Immunohistochemistry against β-catenin revealed occasional cells with nuclear-β-catenin localisation and the presence of pituitary progenitors positive for SOX9 and SOX2. Targeted Sanger sequencing revealed no genetic variants in oncogenes CTNNB1 and BRAF, previously associated with CP. In this article, we provide with in-depth molecular and histological characterisation of in utero aCP due to an unknown driving mutation that could represent a sub-cohort of congenital aCPs.

Background Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na + -K + ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported. Case report Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development. Conclusions Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary.

Recent advances in molecular genetics and preclinical studies of tuberous sclerosis complex (TSC) have helped to better understand the pathophysiology of TSC-related autism spectrum disorder (ASD). Furthermore, developmental studies have shown that infants with TSC begin to diverge from the neurotypical trajectories at the age of 6 months. Early abnormalities are often characterized by a delay in nonverbal cognitive skills, such as fine motor and visual reception domains followed by qualitative impairment of social communication. The expanding possibilities of an early diagnosis of TSC should increasingly allow the prompt identification of a population of infants at high risk for developing ASD. A presymptomatic diagnosis of TSC could facilitate not only the prospective investigation of developmental trajectories and early markers of ASD but also the evaluation of the efficacy of early interventions. Early identification of infants at high-risk for ASD, such as TSC infants, can allow designing individualized treatment strategies to address deficits in specific developmental domains associated with autism. The involvement of mammalian target of rapamycin (mTOR) in determining the behavioral phenotypes associated with TSC led to the hypothesis that mTOR inhibitors could also have a benefit on ASD symptoms. After the promising results from preclinical studies administrating rapamycin, clinical trials studying mTOR inhibitors are now undergoing.

Aberrant embryonic development of the hypothalamus and/or pituitary gland in humans results in congenital hypopituitarism (CH). Transcription factor 7-like 1 (TCF7L1), an important regulator of the WNT/β-catenin signaling pathway, is expressed in the developing forebrain and pituitary gland, but its role during hypothalamo-pituitary (HP) axis formation or involvement in human CH remains elusive. Using a conditional genetic approach in the mouse, we first demonstrate that TCF7L1 is required in the prospective hypothalamus to maintain normal expression of the hypothalamic signals involved in the induction and subsequent expansion of Rathke's pouch progenitors. Next, we reveal that the function of TCF7L1 during HP axis development depends exclusively on the repressing activity of TCF7L1 and does not require its interaction with β-catenin. Finally, we report the identification of two independent missense variants in human TCF7L1, p.R92P and p.R400Q, in a cohort of patients with forebrain and/or pituitary defects. We demonstrate that these variants exhibit reduced repressing activity in vitro and in vivo relative to wild-type TCF7L1. Together, our data provide support for a conserved molecular function of TCF7L1 as a transcriptional repressor during HP axis development in mammals and identify variants in this transcription factor that are likely to contribute to the etiology of CH.

Tuberous sclerosis complex (TSC) is a multisystem disease associated with an overall reduction in life expectancy due to the possible occurrence of different life-threatening conditions. Subjects affected by TSC are, in fact, at risk of hydrocephalus secondary to the growth of subependymal giant cell astrocytomas, or of sudden unexpected death in epilepsy. Other nonneurological life-threatening conditions include abdominal bleeding owing to renal angiomyolipomas rupture, renal insufficiency due to progressive parenchymal destruction by multiple cysts, pulmonary complications due to lymphangioleiomyomatosis, and cardiac failure or arrhythmias secondary to rhabdomyomas. In the last decades, there has been a great progress in understanding the pathophysiology of TSC-related manifestations, which are mainly linked to the hyperactivation of the so-called mammalian target of rapamycin (mTOR) pathway, as a consequence of the mutation in 1 of the 2 genes TSC1 or TSC2. This led to the development of new treatment strategies for this disease. In fact, it is now available as a biologically targeted therapy with everolimus, a selective mTOR inhibitor, which has been licensed in Europe and USA for the treatment of subependymal giant cell astrocytomas and angiomyolipomas in subjects with TSC. This drug also proved to benefit other TSC-related manifestations, including pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and presumably epileptic seizures. mTOR inhibitors are thus proving to be a systemic therapy able to simultaneously address different and potentially life-threatening complications, giving the hope of improving life expectation in individuals with TSC.

Tuberous sclerosis is associated with epilepsy in up to 85% of cases, and in 2/3, the onset is within the first year of life. An early antiepileptic treatment is crucial to minimize the consequences of epilepsy on cognition and behavior. We present a case report of a child with tuberous sclerosis who presented with infantile spasms at the age of 6months, immediately treated with vigabatrin. Because of the presence of a subependymal giant cell astrocytoma, he also received everolimus since 18months of age. We might wonder if an earlier treatment could have produced a better outcome; in fact, despite a targeted combined treatment, he continues to suffer from sporadic focal motor seizures, and at the age of 40months, he presents severe developmental delay with autism-like behavior.

Background Subependymal giant cell astrocytomas (SEGAs) are low-grade tumors affecting up to 20% of patients with tuberous sclerosis complex (TSC). Early neurosurgical resection has been the only standard treatment until few years ago when a better understanding of the molecular pathogenesis of TSC led to the use of mammalian target of rapamycin (mTOR) inhibitors. Surgical resection of SEGAs is still considered as the first line treatment in individuals with symptomatic hydrocephalus and intratumoral hemorrhage. We describe four patients with symptomatic or asymptomatic hydrocephalus who were successfully treated with the mTOR inhibitor everolimus. Methods We collected the clinical data of four consecutive patients presenting with symptomatic or asymptomatic hydrocephalus due to a growth of subependymal giant cell atrocytomas and who could not undergo surgery for different reasons. Results All patients experienced a clinically significant response to everolimus and an early shrinkage of the SEGA with improvement in ventricular dilatation. Everolimus was well tolerated by all individuals. Conclusions Our clinical series demonstrate a possible expanding indication for mTOR inhibition in TSC, which can be considered in patients with asymptomatic hydrocephalus or even when the symptoms already appeared. It offers a significant therapeutic alternative to individuals that once would have undergone immediate surgery. Everolimus might also allow postponement of a neurosurgical resection, making it elective with an overall lower risk.