Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions.

BACKGROUND: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. METHODS: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. RESULTS: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. CONCLUSIONS: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.

[Treatment of sleep disorders in neurodevelopmental disorders]. / Abordaje de los trastornos del sueño en los trastornos del neurodesarrollo.

Sleep disorders are common in children and affect neurological development with important cognitive, emotional and behavioral repercussions. There is a high prevalence of sleep disorders (SD) in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Sleep disorders in pediatric population have a prevalence of 6-25%, while in children with NDD this number rises to 50-80%. In NDDs, higher rates of difficulties in falling asleep, nocturnal awakenings and daytime sleepiness are observed. Disturbances in the circadian rhythm as well as respiratory sleep disorders are also observed. Consequently, there is a decrease in alertness for daytime activities with increased behavioral disorders, emotional problems and academic difficulties associated with executive and memory dysfunctions. Sleep assessment has to be a systemic part in the clinical evaluation of children with NDDs, so as to give a convenient diagnosis and treatment in each case, allowing to improve the quality of life of children and their families.

Los trastornos del sueño son frecuentes en niños y afectan al desarrollo neurológico, con importante repercusión cognitiva, emocional y conductual. Existe una alta prevalencia de trastornos del sueño (TS) en los trastornos del neurodesarrollo (TND), como trastorno del espectro autista (TEA) y trastorno por déficit de atención con hiperactividad (TDAH). Los TS en población pediátrica tienen una prevalencia del 6-25%, mientras que en los niños con TND esta cifra asciende al 50-80%. En los TND se observa un incremento de las dificultades para conciliar el sueño, de los despertares nocturnos y de la somnolencia diurna. Así mismo, presentan alteraciones del ritmo circadiano y trastornos respiratorios del sueño. Como consecuencia se produce una reducción de la alerta para las actividades diarias con incremento de trastornos conductuales, problemas emocionales y dificultades académicas asociadas a disfunciones ejecutivas y de memoria. La evaluación del sueño debe formar parte sistemática en la valoración clínica de los niños con TND, con el fin de realizar un diagnóstico y un tratamiento adecuados a cada caso, permitiendo mejorar la calidad de vida del niño y de su familia.

Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

Sleep and Circadian Disturbances in Children With Neurodevelopmental Disorders.

Sleep problems are highly prevalent in those with neurodevelopmental disorders (NDDs). We propose this is secondary to multiple factors that directly and indirectly negatively impact sleep and circadian processes in those with NDDs, which in turn, further perturbs development, resulting in a "developmental and sleep/circadian-related encephalopathy." In this review, we discuss select NDDs with known or suspected sleep and circadian phenotypes. We also highlight important considerations when evaluating and treating sleep and circadian disorders in these populations.

Using urine FTIR spectra to screen autism spectrum disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder caused by multiple factors, lacking clear biomarkers. Diagnosing ASD still relies on behavioural and developmental signs and usually requires lengthy observation periods, all of which are demanding for both clinicians and parents. Although many studies have revealed valuable knowledge in this field, no clearly defined, practical, and widely acceptable diagnostic tool exists. In this study, 26 children with ASD (ASD+), aged 3-5 years, and 26 sex and age-matched controls are studied to investigate the diagnostic potential of the Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy. The urine FTIR spectrum results show a downward trend in the 3000-2600/cm region for ASD+ children when compared to the typically developing (TD) children of the same age. The average area of this region is 25% less in ASD+ level 3 children, 29% less in ASD+ level 2 children, and 16% less in ASD+ level 1 children compared to that of the TD children. Principal component analysis was applied to the two groups using the entire spectrum window and five peaks were identified for further analysis. The correlation between the peaks and natural urine components is validated by artificial urine solutions. Less-than-normal levels of uric acid, phosphate groups, and ammonium ([Formula: see text]) can be listed as probable causes. This study shows that ATR-FTIR can serve as a practical and non-invasive method to screen ASD using the high-frequency region of the urine spectrum.

Major Surgery, Brain Injury, and Neurodevelopmental Outcomes in Very Preterm Infants.

OBJECTIVES: We determined whether (1) major surgery is associated with an increased risk for brain injury and adverse neurodevelopment and (2) brain injury modifies associations between major surgery and neurodevelopment in very preterm infants. METHODS: Prospectively enrolled infants across 3 tertiary neonatal intensive care units underwent early-life and/or term-equivalent age MRI to detect moderate-severe brain injury. Eighteen-month neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development, third edition. Multivariable logistic and linear regressions were used to determine associations of major surgery with brain injury and neurodevelopment, adjusting for clinical confounders. RESULTS: There were 294 infants in this study. Major surgery was associated with brain injury (odds ratio 2.54, 95% CI 1.12-5.75, p = 0.03) and poorer motor outcomes (ß = -7.92, 95% CI -12.21 to -3.64, p < 0.001), adjusting for clinical confounders. Brain injury x major surgery interaction significantly predicted motor scores (p = 0.04): Lowest motor scores were in infants who required major surgery and had brain injury. DISCUSSION: There is an increased risk for brain injury and adverse motor outcomes in very preterm infants who require major surgery, which may be a marker of clinical illness severity. Routine brain MRI to detect brain injury and close neurodevelopmental surveillance should be considered in this subgroup of infants.

Refining of the electroclinical phenotype in familial and sporadic cases of CSNK2B-related Neurodevelopmental Syndrome.

CSNK2B encodes a regulatory subunit of casein kinase II, which is highly expressed in the brain. Heterozygous pathogenic variants in CSNK2B are associated with Poirier-Bienvenu neurodevelopmental syndrome (POBINDS) (OMIM #618732), characterized by facial dysmorphisms, seizures, intellectual disability, and behavioral disturbances. We report ten new patients with CSNK2B-related Neurodevelopmental Syndrome associated with heterozygous variants of CSNK2B. In three patients, a pathogenic variant was inherited from an affected parent. We describe both molecular and clinical features, focusing on epileptic and neurodevelopmental phenotypes. The median age at follow-up was 8.5 years (range 21 months-42 years). All patients had epilepsy, with onset at a median age of 10.5 months range 6 days-10 years). Seizures were both focal and generalized and were resistant to anti-seizure medications in two out of ten patients. Six patients had mild to moderate cognitive delays, whereas four patients had no cognitive disability. Although all previously reported patients had a de novo CSNK2B pathogenic variant, here we report, for the first time, two familial cases of CSNK2B-related Neurodevelopmental Syndrome. We confirmed the highly variable expressivity of the disease among both interfamilial and intrafamilial cases. Furthermore, this study provides information about the long-term outcome in adult patients and underlines the importance of detailed family history collection before performing genetic testing in patients with epilepsy and neurodevelopmental disorders.

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease.

Here, we describe the process of development of the methodology for an international multicenter natural history study of alternating hemiplegia of childhood as a prototype disease for rare neurodevelopmental disorders. We describe a systematic multistep approach in which we first identified the relevant questions about alternating hemiplegia of childhood natural history and expected challenges. Then, based on our experience with alternating hemiplegia of childhood and on pragmatic literature searches, we identified solutions to determine appropriate methods to address these questions. Specifically, these solutions included development and standardization of alternating hemiplegia of childhood-specific spell video-library, spell calendars, adoption of tailored methodologies for prospective measurement of nonparoxysmal and paroxysmal manifestations, unified data collection protocols, centralized data platform, adoption of specialized analysis methods including, among others, Cohen kappa, interclass correlation coefficient, linear mixed effects models, principal component, propensity score, and ambidirectional analyses. Similar approaches can, potentially, benefit in the study of other rare pediatric neurodevelopmental disorders.

Amblyopia treatment outcomes in patients with neurodevelopmental disorders.

PURPOSE: To compare amblyopia treatment outcomes between patients with neurodevelopmental disorders and their typically developing peers. METHODS: Of 2,311 patients diagnosed with amblyopia between 2010 and 2014 at Boston Children's Hospital, 460 met inclusion criteria (age 2-12 with anisometropic, strabismic, or mixed amblyopia [interocular difference (IOD) ≥2 lines]). Treatment and visual outcomes were analyzed according to neurodevelopmental status: neurodevelopmental delay (DD) versus typical development (TD). RESULTS: The DD group (n = 54) and TD group (n = 406) were similar in demographics, amblyogenic risk factors, baseline visual measures, prescribed therapy, and adherence (P ≥ 0.10). Between-visit follow-up time was longer for the DD group (0.65 [0.42- 0.97] years) than for the TD group (0.5 [0.36-0.82] years; P = 0.023). IOD improved similarly in each group by the last visit (DD, -0.15 logMAR [-0.31 to -0.02]; TD, -0.2 logMAR [-0.38 to -0.1]; P = 0.09). Each group reached amblyopia resolution by the last visit at similar frequencies (DD, 23/54 [43%]; TD, 211/406 [52%]; P > 0.2). DD diagnosis did not independently influence amblyopia resolution (HR, 0.77; 95% CI, 0.53-1.12; P = 0.17), but each additional month of interval time between follow-up visits reduced the likelihood of resolution by 2.7% (HR, 0.67; 95% CI, 0.51-0.87; P = 0.003). CONCLUSIONS: Patients with DD and those with TD responded similarly to amblyopia therapy; however, follow-up intervals were longer in patients with DD and correlated with the likelihood of persistent amblyopia, suggesting that greater efforts at assuring follow-up may benefit patients with DD.

Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features.

Protein phosphatase 1 regulatory subunit 3F (PPP1R3F) is a member of the glycogen targeting subunits (GTSs), which belong to the large group of regulatory subunits of protein phosphatase 1 (PP1), a major eukaryotic serine/threonine protein phosphatase that regulates diverse cellular processes. Here, we describe the identification of hemizygous variants in PPP1R3F associated with a novel X-linked recessive neurodevelopmental disorder in 13 unrelated individuals. This disorder is characterized by developmental delay, mild intellectual disability, neurobehavioral issues such as autism spectrum disorder, seizures and other neurological findings including tone, gait and cerebellar abnormalities. PPP1R3F variants segregated with disease in affected hemizygous males that inherited the variants from their heterozygous carrier mothers. We show that PPP1R3F is predominantly expressed in brain astrocytes and localizes to the endoplasmic reticulum in cells. Glycogen content in PPP1R3F knockout astrocytoma cells appears to be more sensitive to fluxes in extracellular glucose levels than in wild-type cells, suggesting that PPP1R3F functions in maintaining steady brain glycogen levels under changing glucose conditions. We performed functional studies on nine of the identified variants and observed defects in PP1 binding, protein stability, subcellular localization and regulation of glycogen metabolism in most of them. Collectively, the genetic and molecular data indicate that deleterious variants in PPP1R3F are associated with a new X-linked disorder of glycogen metabolism, highlighting the critical role of GTSs in neurological development. This research expands our understanding of neurodevelopmental disorders and the role of PP1 in brain development and proper function.

Electroencephalographic (EEG) Biomarkers in Genetic Neurodevelopmental Disorders.

Collectively, neurodevelopmental disorders are highly prevalent, but more than a third of neurodevelopmental disorders have an identifiable genetic etiology, each of which is individually rare. The genes associated with neurodevelopmental disorders are often involved in early brain development, neuronal signaling, or synaptic plasticity. Novel treatments for many genetic neurodevelopmental disorders are being developed, but disease-relevant clinical outcome assessments and biomarkers are limited. Electroencephalography (EEG) is a promising noninvasive potential biomarker of brain function. It has been used extensively in epileptic disorders, but its application in neurodevelopmental disorders needs further investigation. In this review, we explore the use of EEG in 3 of the most prevalent genetic neurodevelopmental disorders-Angelman syndrome, Rett syndrome, and fragile X syndrome. Quantitative analyses of EEGs, such as power spectral analysis or measures of connectivity, can quantify EEG signatures seen on qualitative review and potentially correlate with phenotypes. In both Angelman syndrome and Rett syndrome, increased delta power on spectral analysis has correlated with clinical markers of disease severity including developmental disability and seizure burden, whereas spectral power analysis on EEG in fragile X syndrome tends to demonstrate abnormalities in gamma power. Further studies are needed to establish reliable relationships between quantitative EEG biomarkers and clinical phenotypes in rare genetic neurodevelopmental disorders.

Excitatory/inhibitory balance in epilepsies and neurodevelopmental disorders: Depolarizing γ-aminobutyric acid as a common mechanism.

Epilepsy is one of the most common neurological disorders. Although many factors contribute to epileptogenesis, seizure generation is mostly linked to hyperexcitability due to alterations in excitatory/inhibitory (E/I) balance. The common hypothesis is that reduced inhibition, increased excitation, or both contribute to the etiology of epilepsy. Increasing evidence shows that this view is oversimplistic, and that increased inhibition through depolarizing γ-aminobutyric acid (GABA) similarly contributes to epileptogenisis. In early development, GABA signaling is depolarizing, inducing outward Cl- currents due to high intracellular Cl- concentrations. During maturation, the mechanisms of GABA action shift from depolarizing to hyperpolarizing, a critical event during brain development. Altered timing of this shift is associated with both neurodevelopmental disorders and epilepsy. Here, we consider the different ways that depolarizing GABA contributes to altered E/I balance and epileptogenesis, and discuss that alterations in depolarizing GABA could be a common denominator underlying seizure generation in neurodevelopmental disorders and epilepsies.

Common sleep disorders in children: assessment and treatment.

Pediatric sleep disorders are a common, mainly among children with pre-existing disabilities, neurological conditions, and neurodevelopmental disorders. The consequences are variable, and sleep disorders may be associated with deficits in neurocognitive performance and growth failure. Rising awareness about sleep disorders among pediatricians will improve the early diagnosis and management of these disorders. This review describes normal sleep patterns in infants and children and provide a recent update on common sleep disorders that improve the diagnosis and treatment of children with sleep disorders.

Maternal Epigenetic Dysregulation as a Possible Risk Factor for Neurodevelopmental Disorders.

Neurodevelopmental Disorders (NDs) are a heterogeneous group of disorders and are considered multifactorial diseases with both genetic and environmental components. Epigenetic dysregulation driven by adverse environmental factors has recently been documented in neurodevelopmental disorders as the possible etiological agent for their onset. However, most studies have focused on the epigenomes of the probands rather than on a possible epigenetic dysregulation arising in their mothers and influencing neurodevelopment during pregnancy. The aim of this research was to analyze the methylation profile of four well-known genes involved in neurodevelopment (BDNF, RELN, MTHFR and HTR1A) in the mothers of forty-five age-matched AS (Asperger Syndrome), ADHD (Attention Deficit Hyperactivity Disorder) and typically developing children. We found a significant increase of methylation at the promoter of the RELN and HTR1A genes in AS mothers compared to ADHD and healthy control mothers. For the MTHFR gene, promoter methylation was significantly higher in AS mothers compared to healthy control mothers only. The observed dysregulation in AS mothers could potentially contribute to the affected condition in their children deserving further investigation.

A Biallelic Truncating Variant in the TPR Domain of GEMIN5 Associated with Intellectual Disability and Cerebral Atrophy.

GEMIN5 is a multifunctional RNA-binding protein required for the assembly of survival motor neurons. Several bi-allelic truncating and missense variants in this gene are reported to cause a neurodevelopmental disorder characterized by cerebellar atrophy, intellectual disability (ID), and motor dysfunction. Whole exome sequencing of a Pakistani consanguineous family with three brothers affected by ID, cerebral atrophy, mobility, and speech impairment revealed a novel homozygous 3bp-deletion NM_015465.5:c.3162_3164del that leads to the loss of NM_015465.5 (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) amino acid in one of the α-helixes of the tetratricopeptide repeats of GEMIN5. In silico 3D representations of the GEMIN5 dimerization domain show that this variant likely affects the orientation of the downstream sidechains out of the helix axis, which would affect the packing with neighboring helices. The phenotype of all affected siblings overlaps well with previously reported patients, suggesting that NM_015465.5: c.3162_3164del (NP_056280.2):p. (Asp1054_Ala1055delinsGlu) is a novel GEMIN5 pathogenic variant. Overall, our data expands the molecular and clinical phenotype of the recently described neurodevelopmental disorder with cerebellar atrophy and motor dysfunction (NEDCAM) syndrome.

Test-retest reliability of the assessment of time management skills (ATMS-S) in adults with neurodevelopmental disorders.

BACKGROUND: Time-management skills are essential in handling daily life, and adults with neurodevelopmental disorders often have difficulty with these skills. Therefore, interventions targeting such skills are common in occupational therapy. The Assessment of Time-Management Skills (ATMS) is a self-rated instrument for measuring time-management skills. AIM: This study aims to evaluate the test-retest reliability of the Swedish version of the ATMS (ATMS-S). MATERIALS AND METHODS: A total of 33 participants with neurodevelopmental disorders and difficulty with time management completed the test twice, approximately 1 week apart. The test-retest reliability for the three subscales in the ATMS-S was analyzed using intraclass correlation coefficients. The smallest detectable change was calculated to determine the precision of individual ATMS units. RESULTS AND CONCLUSION: The results showed overall moderate to good stability for the measures. The intraclass correlation coefficients were 0.79 (time management), 0.82 (organization and planning), and 0.50 (regulation of emotions) for the three subscales, and the smallest detectable changes were 9.5, 6.9, and 15.7 ATMS units for the respective subscales. These results suggest that the ATMS-S is a sufficiently stable tool for measuring time management and organization and planning skills in adults with neurodevelopmental disorders, but may be less reliable for measuring emotional regulation.

Prenatal Sex Hormone Exposure Is Associated with the Development of Autism Spectrum Disorder.

Sexual differentiation is a major developmental process. Sex differences resulting from sexual differentiation have attracted the attention of researchers. Unraveling what contributes to and underlies sex differences will provide valuable insights into the development of neurodevelopmental disorders that exhibit sex biases. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects an individual's social interaction and communication abilities, and its male preponderance has been consistently reported in clinical studies. The etiology of male preponderance remains unclear, but progress has been made in studying prenatal sex hormone exposure. The present review examined studies that focused on the association between prenatal testosterone exposure and ASD development, as well as sex-specific behaviors in individuals with ASD. This review also included studies on maternal immune activation-induced developmental abnormalities that also showed striking sex differences in offspring and discussed its possible interacting roles in ASD so as to present a potential approach for future studies on sex biases in ASD.

Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect?

Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.

Cluster Analysis of Clinical Features of Children Suspected to Have Neurodevelopmental Disorders.

Early identification of neurodevelopmental disabilities (NDDs) is critical to a good prognosis. Several factors such as overlapping diagnoses can complicate this process and thus delay access to services. This study sought to identify meaningful clinical profiles, beyond diagnostic labels, in 194 children with NDDs referred to an assessment clinic. Cluster analyses were applied to eight selected behavioral and cognitive variables. Results suggested a cluster structure in which three homogenous groups differed significantly from one another: children who presented either (1) heterogeneous diagnoses and ambiguous profiles, (2) a clinical profile closely aligned to a classic presentation of ASD, and (3) emotional and behavioral challenges. These distinct profiles may have implications for assessment and clinical practices.