Genetic disorders of neurotransmitter release machinery.

Synaptic neurotransmitter release is an evolutionarily conserved process that mediates rapid information transfer between neurons as well as several peripheral tissues. Release of neurotransmitters are ensured by successive events such as synaptic vesicle docking and priming that prepare synaptic vesicles for rapid fusion. These events are orchestrated by interaction of different presynaptic proteins and are regulated by presynaptic calcium. Recent studies have identified various mutations in different components of neurotransmitter release machinery resulting in aberrant neurotransmitter release, which underlie a wide spectrum of psychiatric and neurological symptoms. Here, we review how these genetic alterations in different components of the core neurotransmitter release machinery affect the information transfer between neurons and how aberrant synaptic release affects nervous system function.

Gene therapy for selected neuromuscular and trinucleotide repeat disorders - An insight to subsume South Asia for multicenter clinical trials.

Background: In this article, the authors discuss how they utilized the genetic mutation data in Sri Lankan Duchenne muscular dystrophy (DMD), Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA) and Huntington's disease (HD) patients and compare the available literature from South Asian countries to identifying potential candidates for available gene therapy for DMD, SMA, SCA and HD patients. Methods: Rare disease patients (n = 623) with the characteristic clinical findings suspected of HD, SCA, SMA and Muscular Dystrophy were genetically confirmed using Multiplex Ligation Dependent Probe Amplification (MLPA), and single plex PCR. A survey was conducted in the "Wiley database on Gene Therapy Trials Worldwide" to identify DMD, SMA, SCA, and HD gene therapy clinical trials performed worldwide up to April 2021. In order to identify candidates for gene therapy in other neighboring countries we compared our findings with available literature from India and Pakistan which has utilized the same molecular diagnostic protocol to our study. Results: From the overall cohort of 623 rare disease patients with the characteristic clinical findings suspected of HD, SCA, SMA and Muscular Dystrophy, n = 343 (55%) [Muscular Dystrophy- 65%; (DMD-139, Becker Muscular Dystrophy -BMD-11), SCA type 1-3-53% (SCA1-61,SCA2- 23, SCA3- 39), HD- 52% (45) and SMA- 34% (22)] patients were positive for molecular diagnostics by MLPA and single plex PCR. A total of 147 patients in Sri Lanka amenable to available gene therapy; [DMD-83, SMA-15 and HD-49] were identified. A comparison of Sri Lankan finding with available literature from India and Pakistan identified a total of 1257 patients [DMD-1076, SMA- 57, and HD-124] from these three South Asian Countries as amenable for existing gene therapy trials. DMD, SMA, and HD gene therapy clinical trials (113 studies) performed worldwide up to April 2021 were concentrated mostly (99%) in High Income Countries (HIC) and Upper Middle-Income Countries (UMIC). However, studies on the potential use of anti-sense oligonucleotides (ASO) for treatment of SCAs have yet to reach clinical trials. Conclusion: Most genetic therapies for neurodegenerative and neuromuscular disorders have been evaluated for efficacy primarily in Western populations. No multicenter gene therapy clinical trial sites for DMD, SMA and HD in the South Asian region, leading to lack of knowledge on the safety and efficacy of such personalized therapies in other populations, including South Asians. By fostering collaboration between researchers, clinicians, patient advocacy groups, government and industry in gene therapy initiatives for the inherited-diseases community in the developing world would link the Global North and Global South and breathe life into the motto "Together we can make a difference".

Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study.

Background: This paper aimed to evaluate the frequency of observation of genetically determined developmental encephalopathies with epilepsy and movement disorders in a specialistic center, the distribution of etiologies and presenting clinical hallmarks, and the mean times for the achievement of molecular genetic diagnosis. Patients and Methods: Retrospective data about clinical phenotypes, etiology, and diagnostic pathways were collected in all the genetically confirmed patients with developmental encephalopathies with epilepsy and movement disorders referred to our institution between 2010 and 2020. The cohort was divided into two groups according to the predominant movement disorder type: 1) Group A: patients with hyperkinetic movement disorders; 2) Group B: patients with hypokinetic movement disorders. Both groups were analyzed in terms of developmental, epileptic, and movement disorder phenotypes. Results: The cohort included 69 patients (Group A = 53; Group B = 16). The etiological spectrum was heterogeneous with a predominance of Rett and Angelman syndrome in Group A and neurodegenerative disorders in Group B. A moderate/severe intellectual disability was assessed in 58/69 patients (mean age at the first signs of developmental impairment = 1,87 ± 1,72 years). Group A included patients with an earlier onset of epileptic seizures (2,63 ± 3,15 vs. 4,45 ± 5,55 years of group B) and a predominant generalized motor semiology of seizures at the onset. Focal seizures were the main initial epileptic manifestations in Group B. Seizures were noticed earlier than movement disorders in Group A while the opposite occurred in Group B. A higher increase in molecular genetic diagnosis was obtained in the last five years. Mean diagnostic delay was longer in Group B than in Group A (12,26 ± 13,32 vs. 5.66 ± 6.41 years). Chorea as an initial movement disorder was associated with a significantly longer diagnostic delay and a higher age at etiological diagnosis. Conclusions: This study suggested: (a) a higher frequency of genetic defects involving neurotransmission, neuronal excitability, or neural development in patients with hyperkinetic movement disorders; (b) a higher frequency of neurodegenerative courses and a longer diagnostic delay in patients with hypokinetic movement disorders.

Phenotypic and Genetic Complexity in Pediatric Movement Disorders.

The complex and evolving nature of clinical phenotypes have made genetically diagnosing pediatric patients with movement disorders difficult. Here, we describe this diverse complexity in the clinical and genetic features of a pediatric cohort examined by whole-exome sequencing (WES) and demonstrate the clinical benefit of WES as a diagnostic tool in a pediatric cohort. We evaluated 75 patients with diverse single or combined movement phenomenologies using WES. WES identified 42 variants in 37 genes (56.0%). The detection rate was highest in patients with dystonia (11/13, 84.6%), followed by ataxia (21/38, 55.3%), myoclonus (3/6, 50.0%), unspecified dyskinesia (1/4, 25.0%), tremor (1/1, 100%), respectively. Most genetically diagnosed patients (90.5%) were affected by other neurologic or systemic manifestations; congenital hypotonia (66.7%), and epilepsy (42.9%) were the most common phenotypes. The genetic diagnosis changed the clinical management for five patients (6.7%), including treatments targeting molecular abnormalities, and other systemic surveillance such as cancer screening. Early application of WES yields a high diagnostic rate in pediatric movement disorders, which can overcome the limitations of the traditional phenotype-driven strategies due to the diverse phenotypic and genetic complexity. Additionally, this early genetic diagnosis expands the patient's clinical spectrum and provides an opportunity for tailored treatment.

Neurobehavioral Dimensions of Prader Willi Syndrome: Relationships Between Sleep and Psychosis-Risk Symptoms.

Background: Prader Willi Syndrome (PWS) is a genetic disorder caused by the absence of expression of the paternal copies of maternally imprinted gene(s) located at 15q11-q13. While the physical and medical characteristics of PWS, including short stature, hyperphagia and endocrine dysfunction are well-characterized, systematic investigation of the long-recognized psychiatric manifestations has been recent. Methods: Here, we report on the first remote (web-based) assessment of neurobehavioral traits, including psychosis-risk symptoms (Prodromal Questionnaire-Brief Version; PQ-B) and sleep behaviors (Pittsburgh Sleep Quality Index), in a cohort of 128 participants with PWS, of whom 48% had a paternal deletion, 36% uniparental disomy, 2.4% an imprinting mutation and 13% unknown mutation (mean age 19.3 years ± 8.4; 53.9% female). We aimed to identify the most informative variables that contribute to psychosis-risk symptoms. Multiple domains of cognition (accuracy and speed) were also assessed in a subset of PWS participants (n = 39) using the Penn Computerized Neurocognitive Battery (Penn-CNB). Results: Individuals with PWS reported a range of psychosis-risk symptoms, with over half reporting cognitive disorganization (63.1%) and about one third reporting unusual beliefs (38.6%) and/or suspiciousness (33.3%). Subjectively-reported sleep quality, nap frequency, sleep duration, sleep disturbance, and daytime dysfunction were significant predictors of psychosis-risk symptom frequency and severity (all p's < 0.029). Sleep disturbance ratings were the strongest predictors of psychosis-risk symptoms. Regarding cognition, individuals with PWS showed the most prominent deficits in accuracy on measures of social cognition involving faces, namely Face Memory, Age Differentiation and Emotion Recognition, and greatest slowing on measures of Attention and Emotion Recognition. However, there were no significant differences in psychosis-risk symptoms or cognitive performance as a function of PWS genetic subtype. Conclusions: PWS is associated with a high prevalence of distressing psychosis-risk symptoms, which are associated with sleep disturbance. Findings indicate that self/parent-reported neurobehavioral symptoms and cognition can be assessed remotely in individuals with PWS, which has implications for future large-scale investigations of rare neurogenetic disorders.

Empathic Accuracy in Adolescent Girls with Turner Syndrome.

To examine the potential mechanisms underlying social deficits in Turner Syndrome, we administered the empathic accuracy task (EAT) -a naturalistic social cognition task- and a (control) visual-motor line-tracking task to 14 girls with TS was compared to 12 age-matched typically developing girls (TD; ages 12 to 17). Empathic accuracy was compared across positive and negative emotionally valanced videos. We found that TS differs from TD on empathic accuracy ratings for negative videos; no differences were detected for the positive videos or for the control line tracking task. Thus, our findings suggest impaired detection of negatively valanced empathic interactions in TS and may help inform the future development of social-cognition treatment strategies for girls with TS.

NGS-Based Diagnosis of Treatable Neurogenetic Disorders in Adults: Opportunities and Challenges.

The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies.

Cou Cou, flying fish and a whole exome please... lessons learned from genetic testing in Barbados.

Millions of patients, with suspected complex neurogenetic disorders, living in resource limited regions around the world have no access to genetic testing despite the rapidly expanding availability and decreasing costs of genetic testing in first world nations. The barriers to increasing availability of genetic testing in resource limited nations are multifactorial but can be attributed, in large part, to a lack of awareness of the power of genetic testing to lead to a rapid, cost-effective, diagnosis that potentially will have profound clinical implications on treatment and patient outcomes. We report our experience with whole exome sequencing (WES) done for the first time in 5 patients of African descent with a suspected neurogenetic disorder living in a resource limited setting on the Eastern Caribbean island of Barbados. A diagnostic pathogenic mutation was found in 3 patients in the SCN1A, STXBP1 and SCN4A, who clinically were diagnosed with Dravet syndrome, Lennox-Gastaut syndrome, paramytonia and seizures respectively. A variant of undetermined significance was found in a patient with global developmental delays, hypotonia, with abnormal eye movements. In one patient WES was non-diagnostic. This result highlights the high yield of WES in carefully selected patients with a neurologic disease and the need for increase access to genetic testing in resource limited settings globally.

A binational study assessing risk and resilience factors in 22q11.2 deletion syndrome.

BACKGROUND: The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations. METHOD: We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures. RESULTS: Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression. CONCLUSION: The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions.

Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome.

BACKGROUND: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology. METHODS: We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. RESULTS: Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R2 ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. CONCLUSIONS: We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." Date of registry: 01 October 1989.

Multiple functions of TBCK protein in neurodevelopment disorders and tumors.

TBC1 domain containing kinase (TBCK) protein is composed of three conserved domains, including N-terminal Serine/Threonine kinase domain, central TBC domain and C-terminal rhodanese homology domain (RHOD). A total of 9 different transcripts (classified as long and short TBCK) generated by alternative splicing have been reported in different cell lines. Exogenous expression of long TBCK has been identified to function as a suppressor of cell growth in certain cell types. On the contrary, TBCK has also been reported to serve a tumor-promoting role in other cell lines, indicating that TBCK might function differentially, depending on the context in different cellular environments. Furthermore, deleterious homozygous or compound heterozygous mutations identified by whole-exome sequencing in the TBCK gene could ablate the function of TBCK, further impacting the mTOR signaling pathway and leading to neurogenetic disorders, such as hypotonia, global developmental delay, facial dysmorphic features and brain abnormalities. However, as a poorly explored protein, there are a lot of studies associated with the functions of TBCK that need to be performed in the future. The present review summarizes data regarding the structural features and potential roles of TBCK in developmental and neurological diseases and tumorigenesis. Future prospects of TBCK research lie in revealing numerous biological functions of TBCK.

Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders.

BACKGROUND: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. METHODS: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. RESULTS: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients' major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). CONCLUSIONS: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

Semantic Similarity Analysis Reveals Robust Gene-Disease Relationships in Developmental and Epileptic Encephalopathies.

More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.

Viral-Mediated Gene Replacement Therapy in the Developing Central Nervous System: Current Status and Future Directions.

The past few years have witnessed rapid developments in viral-mediated gene replacement therapy for pediatric central nervous system neurogenetic disorders. Here, we provide pediatric neurologists with an up-to-date, comprehensive overview of these developments and note emerging trends for future research. This review presents the different types of viral vectors used in viral-mediated gene replacement therapy; the fundamental properties of viral-mediated gene replacement therapy; the challenges associated with the use of this therapy in the central nervous system; the pathway for therapy development, from translational basic science studies to clinical trials; and an overview of the therapies that have reached clinical trials in patients. Current viral platforms under investigation include adenovirus vectors, adeno-associated viral vectors, lentiviral/retroviral vectors, and herpes simplex virus type 1 vectors. This review also presents an in-depth analysis of numerous studies that investigated these viral platforms in cultured cells and in transgenic animal models for pediatric neurogenetic disorders. Viral vectors have been applied to clinical trials for many different pediatric neurogenetic disorders, including Canavan disease, metachromatic leukodystrophy, neuronal ceroid lipofuscinosis, mucopolysaccharidosis III, spinal muscular atrophy, and aromatic l-amino acid decarboxylase deficiency. Of these diseases, only spinal muscular atrophy has a viral-mediated gene replacement therapy approved for marketing. Despite significant progress in therapy development, many challenges remain. Surmounting these challenges is critical to advancing the current status of viral-mediated gene replacement therapy for pediatric central nervous system neurogenetic disorders.

Adaptive behavior in infants and toddlers with Down syndrome and fragile X syndrome.

Individuals with Down syndrome (DS) experience deficits across all domains of adaptive functioning, however little is known about the emergence and age-related changes of these impairments compared to other neurogenetic disorders with similar intellectual disability impairments, such as fragile X syndrome (FXS). Adaptive behavior is key for optimal functioning in these populations. Participants aged 5-45 months comprised three age-matched groups, DS (n = 64), FXS (n = 69), and typically developing controls (TD; n = 69). Adaptive behavior was measured on the Vineland Adaptive Behavior Scales-II. Regressions were used to examine adaptive behavior in a cross-sectional design across age. DS infants and toddlers evidenced deficits across all areas of adaptive behaviors compared to the age-matched TD group, with clear impairments present in the first year of life. Motor skills were the area of greatest weakness in children with DS with significant impairment evident at 12 months of age that remained low through 3 years. Compared to age-matched children with FXS, children with DS showed initially lower standard scores at 12 months of age, but slower declines in standard scores across age, resulting in less impaired functioning at 36 months. This is the first study to compare adaptive behavior in infants and toddlers with DS to FXS, and demonstrate the phenotypic specificity of adaptive profiles in this diagnostic group. These findings provide evidence that adaptive behavior should be a major target of intervention in children with FXS and DS, and that these differences are potentially driven by unique etiologies attributable to each disorder.

Comparing the broad socio-cognitive profile of youth with Williams syndrome and 22q11.2 deletion syndrome.

BACKGROUND: Numerous studies have assessed the socio-cognitive profile in Williams syndrome (WS) and, independently, in 22q11.2 deletion syndrome (22q11.2DS). Yet, a cross-syndrome comparison of these abilities between individuals with these two syndromes with known social deficits has not been conducted. METHODS: Eighty-two children participated in four study groups: WS (n = 18), 22q112.DS (n = 24), age-matched individuals with idiopathic developmental disability (IDD; n = 20) and typically developing (TD) controls (n = 20). Participants completed four socio-cognitive tests: facial emotion recognition, mental state attribution, differentiating real from apparent emotions and trait inference based on motives and actions-outcomes. RESULTS: The current findings demonstrate that children with WS were better in labelling happy faces compared with children with 22q11.2DS, partially reflecting their exaggerated social drive. In the false belief task, however, the WS and IDD groups performed poorly compared with the 22q11.2DS group, possibly due to their difficulty to interpret subtle social cues. When asked to identify the gap between real-negative vs. apparent-positive emotions, the 22q11.2DS group performed similarly to TD children but better than the WS group, possibly due to their anxious personality and their innate bias towards negatively valence cues. Finally, individuals with WS were more willing to become friends with a story character even when the character's motives were negative, reflecting their difficulty to avoid potentially harmful real-life situations. CONCLUSIONS: Overall, our multi-facet socio-cognitive battery uncovered strengths and weaknesses in social cognition that are syndrome-specific, shared among the genetic syndromes, or common to the three clinical groups compared with healthy controls. Our findings underscore the need to devise age-specific and condition-specific assessment tools and intervention programs towards improving these children's socio-cognitive deficits.

Treatment of Neurogenetic Developmental Conditions: From 2016 into the Future.

BACKGROUND: Neurogenetic developmental conditions represent a heterogeneous group of rare inherited disorders with neurological manifestation during development. Treatments for these conditions have largely been supportive; however, a number of treatments are emerging which target the underlying physiology and offer great potential. Our aim was to present a state-of-the-art overview of the current and potential causal treatments available or under development for neurogenetic developmental conditions. METHODS: In this review, we focus on the following neurogenetic developmental conditions: (1) inborn errors of metabolism causing neurogenetic developmental conditions, (2) fragile X syndrome, (3) Rett syndrome, (4) tuberous sclerosis complex, 5) Down syndrome and other neurogenetic developmental conditions. RESULTS: A large group of inborn errors of metabolism leads to neurodevelopmental disability, affecting the central nervous system during infancy or childhood and can present with comorbidities such as intellectual developmental disability, epilepsy, atypical cerebral palsy, autism spectrum disorder, behavioral and psychiatric disturbances, for which causal treatments are discussed. CONCLUSIONS: The advent of these new disease-modifying therapies has the potential to reverse the underlying neural mechanisms of these debilitating conditions, which may provide prospect to affected individuals.

Joint Attention and Early Social Developmental Cascades in Neurogenetic Disorders.

This review examines what is known about joint attention and early social development in three neurogenetic syndromes: Down syndrome, Williams syndrome, and fragile X syndrome. In addition, the potential cascading effects of joint attention on subsequent social development, especially social interaction and social cognition are proposed. The potential issues and complexities associated with conducting prospective, longitudinal studies of infant social development in neurogenetic disorders are discussed.

Myoclonus in childhood-onset neurogenetic disorders: The importance of early identification and treatment.

BACKGROUND: In clinical practice, myoclonus in childhood-onset neurogenetic disorders frequently remains unrecognized, because it is often overshadowed by other neurological features. Since treatment can lead to significant functional improvement, accurate phenotyping is essential. To demonstrate the importance of early identification and treatment, we report on four patients with various childhood-onset neurogenetic disorders suffering from myoclonus. METHODS: We evaluated four patients with established childhood-onset neurogenetic disorders and involuntary jerky movements, who visited our young-onset movement disorder outpatient clinic. RESULTS: We present the clinical data of four patients (aged 8-21 years) with childhood-onset neurogenetic disorders, including ataxia-telangiectasia, Coffin-Lowry syndrome and epileptic encephalopathy due to SCN1A mutations. All four suffered from jerky movements that hampered normal daily activities and that had gone unrecognized for several years. The presence of multifocal myoclonus was confirmed by polymyography. In all patients, treatment resulted in marked improvement of both myoclonus and overall functioning. CONCLUSION: These cases highlight the relevance of actively searching for myoclonus in childhood-onset neurogenetic disorders, even when a molecular diagnosis has already been established. To further improve the awareness and recognition of myoclonus in children, we provide a list of childhood-onset neurogenetic disorders with myoclonus as important associated feature.