BK K
+
channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the
KCNMA1
gene and cell- and tissue-selective β subunits (
KCNMB1-4
...). Mutations in
KCNMA1
are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating. In this study, we report the functional effect of G124R, a novel
KCNMB2
mutation obtained from whole-exome sequencing of a patient diagnosed with autism spectrum disorder. Residue G124, located in the extracellular loop between TM1 and TM2, is conserved across species, and the G124R missense mutation is predicted deleterious with computational tools. To investigate the pathogenicity potential, BK channels were co-expressed with β2
WT
and β2
G124R
subunits in HEK293T cells. BK/β2 currents were assessed from inside-out patches under physiological K
+
conditions (140/6 mM K
+
and 10 μM Ca
2+
) during activation and inactivation (voltage-dependence and kinetics). Using β2 subunits lacking inactivation (β2IR) revealed that currents from BK/β2IR
G124R
channels activated 2-fold faster and deactivated 2-fold slower compared with currents from BK/β2IR
WT
channels, with no change in the voltage-dependence of activation (V
1/2
). Despite the changes in the BK channel opening and closing, BK/β2
G124R
inactivation rates (τ
inact
and τ
recovery
), and the V
1/2
of inactivation, were unaltered compared with BK/β2
WT
channels under standard steady-state voltage protocols. Action potential-evoked current was also unchanged. Thus, the mutant phenotype suggests the β2
G124R
TM1-TM2 extracellular loop could regulate BK channel activation and deactivation kinetics. However, additional evidence is needed to validate pathogenicity for this patient-associated variant in
KCNMB
2.
•
KCNMA1
channelopathy is a neurobehavioral disorder associated with seizures, dyskinesia, and intellectual disability.
•
KCNMB2
encodes an accessory β subunit that confers inactivation to the
KCNMA1
pore-forming α subunit BK channel.
•
The
KCNMB2
-G124R variant, identified in an autistic individual, affects BK/β2 channel activation but not inactivation.
The impact of ADHD on reading Sánchez-Carmona, Alberto J; Albert, Jacobo; López-Martín, Sara ...
Medicina,
04/2023, Volume:
83 Suppl 2
Journal Article
Peer reviewed
Beyond the frequent coexistence of attention deficit hyperactivity disorder (ADHD) and reading disorder (dyslexia), the present review aims to examine the available empirical evidence on how ADHD ...negatively impacts on learning to read. Existing data suggest that the presence of the disorder (especially inattention symptoms), may affect i) the correct acquisition of reading, either directly or through its influence on the precursors to reading; ii) decoding skills themselves (reading accuracy and fluency), both directly and indirectly through its influence on cognitive processes such as distractibility or executive functions; and iii) reading comprehension, probably indirectly through the executive and verbal memory difficulties characteristic of ADHD. These findings have important implications for better characterizing and intervening on reading difficulties in ADHD, whether clinical or subclinical.
. COL18A1 gene mutations have been associated with Knobloch syndrome, which is characterized by ocular and brain abnormalities. Here we report a 4.5 years-old male child with autism and two ...novel COL18A1 mutations (NM_030582.4: c.1883_1891dup and c.1787C>T). Hypermetropic astigmatism, but not brain migration disorders, was observed. However, an asymmetric pattern of cerebellar perfusion and a smaller arcuate fascicle were found. Low levels of collagen XVIII were also observed in the patient´s serum. Thus, biallelic loss-of-function mutations in COL18A1 may be a new cause of autism without the brain malformations typically reported in patients with Knobloch syndrome.
Abstract Structural and functional brain studies on attention deficit/hyperactivity disorder (ADHD) have primarily examined anatomical abnormalities in the prefronto-striatal circuitry (especially, ...dorsal and lateral areas of the prefrontal cortex and dorsal striatum). There is, however, increased evidence that several temporal lobe regions could play an important role in ADHD. The present study used MRI-based measurements of cortical thickness to examine possible differences in both prefrontal and temporal lobe regions between medication-näive patients with ADHD ( N =50) and age- and sex-matched typically developing controls ( N =50). Subjects with ADHD exhibited significantly decreased cortical thickness in the right temporal pole and orbitofrontal cortex (OFC) relative to healthy comparison subjects. These differences remained significant after controlling for confounding effects of age, overall mean cortical thickness and comorbid externalizing conditions, such as oppositional defiant and conduct disorders. These results point to the involvement of the temporal pole and OFC in the neuropathology of ADHD. Moreover, present findings add evidence to the assumption that multiple brain regions and psychological processes are associated with ADHD.
Abstract Background: Striatal cholinergic dysfunction may be important in tics and attention-deficit/hyperactivity disorder (ADHD). Objective: The purpose of this study was to deter-mine the safety ...profile of donepezil and whether it improves chronic tics in young patients with comorbid ADHD. Methods: This 18-week (14 weeks of open treatment followed by a 4-week washout period), single-center, dose-escalating, prospective, open-label trial was conducted in patients aged 7 to 17 years with tics, including chronic motor or vocal tics and Tourette's syndrome, and ADHD. Patients were treated with once-daily oral donepezil doses of 2.5 mg for 2 weeks, 5 mg for the next 6 weeks, and 10 mg for the last 6 weeks, followed by a 4-week washout period. Pa-tients were evaluated using the Children's Global Assessment Scale; the Yale Global Tic Severity Scale (YGTSS); the Revised Conners' Parent Rating Scale; the Symbol and Digit Wisconsin Card Sorting Test; the Stroop black/white, color, and interference tests; the Rey Complex Figure Test; and the Children's Yale-Brown Obsessive Compulsive Scale at 4 visits: baseline, week 8 (5-mg dose), week 14 (10-mg dose), and week 18 (washout). Results: Seventeen males and 3 females (mean SD age, 11.3 1.9 years range, 8–14 years; tic duration, 5.3 1.9 years; ADHD duration, 6.5 1.7 years) were included in this study. Tics were significantly reduced at the 10-mg (week-14) donepezil visit compared with the baseline and washout visits based on the total mean (SD) tic score of the YGTSS (18.6 9.3 vs 12.2 11.0; P = 0.006). Fifty percent of patients withdrew and 65% experienced adverse events. Conclusions: These preliminary results suggest that donepezil significantly reduced tics in these children and adolescents with comorbid ADHD who completed the study. No significant improvement in the symptoms of comorbid ADHD was found with the use of donepezil 10 mg. Donepezil 5 and 10 mg were not well tolerated in these children and adolescents.
Selective Inhibitory Control in Middle Childhood Rincón-Pérez, Irene; Sánchez-Carmona, Alberto J.; Arroyo-Lozano, Susana ...
International journal of environmental research and public health,
06/2021, Volume:
18, Issue:
12
Journal Article
Peer reviewed
Open access
The main aim of this study was to investigate the development of selective inhibitory control in middle childhood, a critical period for the maturation of inhibition-related processes. To this end, ...64 children aged 6–7 and 56 children aged 10–11 performed a stimulus-selective stop-signal task, which allowed us to estimate not only the efficiency of response inhibition (the stop-signal reaction time or SSRT), but also the strategy adopted by participants to achieve task demands. We found that the adoption of a non-selective (global) strategy characterized by stopping indiscriminately to all stimuli decreased in older children, so that most of them were able to interrupt their ongoing responses selectively at the end of middle childhood. Moreover, compared to younger children, older children were more efficient in their ability to cancel an initiated response (indexed by a shorter SSRT), regardless of which strategy they used. Additionally, we found improvements in other forms of impulsivity, such as the control of premature responding (waiting impulsivity), and attentional-related processes, such as intra-individual variability and distractibility. The present results suggest that middle childhood represents a milestone in the development of crucial aspects of inhibitory control, including selective stopping.
Aim
Loss‐of‐function KCNMA1 variants cause Liang–Wang syndrome (MIM #618729), a newly identified multiple malformation syndrome with a broad spectrum of developmental and neurological phenotypes. ...However, the full spectrum of clinical features and underlying pathogenic mechanisms need full elucidation.
Methods
Exome sequencing was used to identify pathogenic variants. Patch‐clamp recordings were performed to access the effects of KCNMA1 variants on BK channels. Total and membrane protein expression levels of BK channels were characterized using Western blotting.
Results
We report identification and functional characterization of two new de novo loss‐of‐function KCNMA1 variants p.(A172T) and p.(A314T) with characteristics of Liang–Wang syndrome. Variant p.(A172T) is associated with developmental delay, cognitive impairment and ataxia. Mechanistically, p.(A172T) abolishes BK potassium current, inhibits Mg2+‐dependent gating, but shifts conductance‐voltage (G‐V) curves to more positive potentials when complexed with WT channels. Variant p.(A314T) is associated with developmental delay, intellectual disability, cognitive impairment, mild ataxia and generalized epilepsy; suppresses BK current amplitude; and shifts G‐V curves to more positive potentials when expressed with WT channels. In addition, two new patients with previously reported gain‐of‐function variants p.(N536H) and p.(N995S) are found to show epilepsy and paroxysmal dyskinesia as reported previously, but also exhibit additional symptoms of cognitive impairment and dysmorphic features. Furthermore, variants p.(A314T) and p.(N536H) reduced total and membrane levels of BK proteins.
Conclusion
Our findings identified two new loss‐of‐function mutations of KCNMA1 associated with Liang–Wang syndrome, expanded the spectrum of clinical features associated with gain‐of‐function KCNMA1 variants and emphasized the overlapping features shared by gain‐of‐function and loss‐of‐function mutations.
Abstract Several lines of evidence suggest that the dopamine transporter gene (DAT1) plays a crucial role in attention deficit hyperactivity disorder (ADHD). Concretely, recent data indicate that the ...10-repeat (10R) DAT1 allele may mediate neuropsychological functioning, response to methylphenidate, and even brain function and structure in children with ADHD. This study aimed to investigate the influence of 10R DAT1 on thickness of the prefrontal cortex in children and adolescents with ADHD. To this end, brain magnetic resonance images were acquired from 33 patients with homozygosity for the 10R allele and 30 patients with a single copy or no copy of the allele. The prefrontal cortex of each MRI scan was automatically parceled into regions of interest (ROIs) based on Brodmann areas (BA). The two groups were matched for age, gender, IQ, ADHD subtype, symptom severity, comorbidity and medication status. However, patients with two copies of the 10R allele exhibited significantly decreased cortical thickness in right BA 46 relative to patients with one or fewer copies of the allele. No other prefrontal ROI differed significantly between the two groups. Present findings suggest that cortical thickness of right lateral prefrontal cortex (BA 46) is influenced by the presence of the DAT1 10 repeat allele in children and adolescents with ADHD.
Intellectual disability (ID) is a neurological disorder arising from early neurodevelopmental defects. The underlying genetic and molecular mechanisms are complex, but are thought to involve, among ...others, alterations in genes implicated in axon guidance and/or neural circuit formation as demonstrated by studies on mouse models. Here, by combining exome sequencing with in silico analyses, we identified a patient affected by severe ID and cognitive regression, carrying a novel loss-of-function variant in the semaphorin 3E (
) gene, which encodes for a key secreted cue that controls mouse brain development. By performing ad hoc in vitro and ex vivo experiments, we found that the identified variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues. Further, we revealed SEMA3E expression during human brain development. Overall, our findings demonstrate the pathogenic impact of the identified
variant and provide evidence that clinical neurological features of the patient might be due to a defective SEMA3E signaling in the brain.
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders ...and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
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