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Seizure May 2024People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM)...
INTRODUCTION
People with Intellectual Disabilities (PwID) are twenty times more likely than general population to have epilepsy. Guidance for prescribing antiseizure medication (ASM) to PwID is driven by trials excluding them. Levetiracetam (LEV) is a first-line ASM in the UK. Concerns exist regarding LEV's behavioural and psychological adverse effects, particularly in PwID. There is no high-quality evidence comparing effectiveness and adverse effects in PwID to those without, prescribed LEV.
METHODS
Pooled casenote data for patients prescribed LEV (2000-2020) at 18 UK NHS Trusts were analysed. Demographics, starting and maximum dose, adverse effects, dropouts and seizure frequency between ID (mild vs. moderate-profound (M/P)) and general population for a 12-month period were compared. Descriptive analysis, Mann-Whitney, Fisher's exact and logistic regression methods were employed.
RESULTS
173 PwID (mild 53 M/P 120) were compared to 200 without ID. Mean start and maximum dose were similar across all groups. PwID (Mild & M/P) were less likely to withdraw from treatment (P = 0.036). No difference was found between ID and non-ID or between ID groups (Mild vs M/P) in LEV's efficacy i.e. >50 % seizure reduction. Significant association emerged between ID severity and psychiatric adverse effects (P = 0.035). More irritability (14.2 %) and aggression (10.8 %) were reported in M/P PwID.
CONCLUSION
PwID and epilepsy have high rates of premature mortality, comorbidities, treatment resistance and polypharmacy but remain poorly researched for ASM use. This is the largest studied cohort of PwID trialled on LEV compared to general population controls. Findings support prescribing of LEV for PwID as a first-line ASM.
PubMed: 38897161
DOI: 10.1016/j.seizure.2024.05.010 -
Journal of Clinical Immunology Jun 2024Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who...
Patients with chromosome 18q deletion syndrome generally experience hypogammaglobulinemia. Herein, we describe two patients with chromosome 18q deletion syndrome who presented with late-onset combined immune deficiency (LOCID), which has not been previously reported. Patient 1 was a 29-year-old male with 18q deletion syndrome, who was being managed for severe motor and intellectual disabilities at the Yamabiko Medical Welfare Center for 26 years. Although the patient had few infections, he developed Pneumocystis pneumonia at the age of 28. Patient 2, a 48-year-old female with intellectual disability and congenital malformations, was referred to Tokyo Medical and Dental University Hospital with abnormal bilateral lung shadows detected on her chest radiography. Computed tomography showed multiple lymphadenopathies and pneumonia. A lymph node biopsy of the inguinal region revealed granulomatous lymphadenitis, and a chromosomal examination revealed 18q deletion. Array-based genomic hybridization analysis revealed deletion at 18q21.32-q22.3 for patient 1 and at 18q21.33-qter for patient 2. Immune status work-up of the two patients revealed panhypogammaglobulinemia, decreased number of memory B cells and naïve CD4 and/or CD8 cells, reduced response on the carboxyfluorescein diacetate succinimidyl ester T-cell division test, and low levels of T-cell receptor recombination excision circles and Ig κ-deleting recombination excision circles. Consequently, both patients were diagnosed with LOCID. Although patients with 18q deletion syndrome generally experience humoral immunodeficiency, the disease can be further complicated by cell-mediated immunodeficiency, causing combined immunodeficiency. Therefore, patients with 18q deletion syndrome should be regularly tested for cellular/humoral immunocompetence.
Topics: Humans; Chromosome Deletion; Male; Female; Chromosomes, Human, Pair 18; Chromosome Disorders; Adult; Middle Aged; Age of Onset; Severe Combined Immunodeficiency; Intellectual Disability; Immunologic Deficiency Syndromes
PubMed: 38896123
DOI: 10.1007/s10875-024-01751-4 -
Frontiers in Pharmacology 2024Patients with mutations that alter the function of the sodium channel present with a range of clinical features, including mild to severe seizures, developmental delay,...
Patients with mutations that alter the function of the sodium channel present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in associated epilepsy, Atkin et al. conducted an screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%-90% decrease in seizure frequency in three patients with -associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with mutations.
PubMed: 38895634
DOI: 10.3389/fphar.2024.1397225 -
BioRxiv : the Preprint Server For... Jun 2024is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors....
is a high confidence risk gene for autism spectrum disorder that encodes a subunit of a chromatin remodeling complex expressed in neuronal progenitors. Haploinsufficiency causes a broad range of social, behavioral, and intellectual disability phenotypes, including Coffin-Siris syndrome. Recent work using transgenic mouse models suggests pathology is due to deficits in proliferation, survival, and synaptic development of cortical neurons. However, there is conflicting evidence regarding the relative roles of excitatory projection neurons and inhibitory interneurons in generating abnormal cognitive and behavioral phenotypes. Here, we conditionally knocked out either one or both copies of from excitatory projection neuron progenitors and systematically investigated the effects on intrinsic membrane properties, synaptic physiology, social behavior, and seizure susceptibility. We found that disrupting expression in excitatory neurons alters their membrane properties, including hyperpolarizing action potential threshold; however, these changes depend on neuronal subtype. Using paired whole-cell recordings, we found increased synaptic connectivity rate between projection neurons. Furthermore, we found reduced strength of excitatory synapses to parvalbumin (PV)-expression inhibitory interneurons. These data suggest an increase in the ratio of excitation to inhibition. However, the strength of inhibitory synapses from PV interneurons to excitatory neurons was enhanced, which may rebalance this ratio. Indeed, haploinsufficiency in projection neurons was insufficient to cause social deficits and seizure phenotypes observed in a preclinical germline haploinsufficient mouse model. Our data suggest that while excitatory projection neurons likely contribute to autistic phenotypes, pathology in these cells is not the primary cause.
PubMed: 38895205
DOI: 10.1101/2024.06.04.597344 -
Frontiers in Cell and Developmental... 2024[This corrects the article DOI: 10.3389/fcell.2022.934662.].
[This corrects the article DOI: 10.3389/fcell.2022.934662.].
PubMed: 38895159
DOI: 10.3389/fcell.2024.1416720 -
Iranian Journal of Public Health Feb 2024Hearing loss is the second most common disease after mental retardation in Iran. Autosomal recessive non-syndromic hearing loss (ARNSHL) is an extreme and highly...
BACKGROUND
Hearing loss is the second most common disease after mental retardation in Iran. Autosomal recessive non-syndromic hearing loss (ARNSHL) is an extreme and highly heterogeneous disease, for which more than 70 genes have been identified. Considering the frequency of family marriage as well as the importance of ARNSHL in Iran, we evaluated the genetic factors involved in this type of deafness.
METHODS
We performed the whole exome sequencing (WES) of eight Iranian subjects with severe nonsyndromic hearing loss selected from 110 well-characterized subjects with non-syndromic hearing loss from 2017-2019. The patients with mutated and genes were excluded from the study.
RESULTS
The use of the whole exome sequencing method revealed 10 different mutations in 7 genes, including c.1234G>T), (c.45DelC, c.466T>C), (c.12528-2A>C, c.16226-16227insAGTC), (c.7454delG), (c.3570+2T>C), (c.992G>A), (c.2359G>T, c.2353A>C). Seven new variants were observed in seven families including (c.1234G>T), (c.45DelC), (c.12528-2A>C), (c.7454delG), (c.16226-16227insAGTC), (c.3570+2T>C).
CONCLUSION
The causal mutation of ARNSHL was found in all patients using the WES. Meta-analysis studies can help to identify common mutations causing deafness in any population to facilitate identification of carriers and subjects with deafness.
PubMed: 38894825
DOI: 10.18502/ijph.v53i2.14930 -
Diagnostics (Basel, Switzerland) Jun 2024Hearing impairment among adults with intellectual disability (ID) is notably prevalent yet frequently underdiagnosed due, in part, to the challenges associated with...
Hearing impairment among adults with intellectual disability (ID) is notably prevalent yet frequently underdiagnosed due, in part, to the challenges associated with traditional hearing screening methods in this population. This study explores the effectiveness of the Digit-in-Noise (DIN) test as a viable alternative for hearing screening within natural settings and with familiar personnel. A total of 16 Hebrew-speaking adults with ID were recruited from supported employment programs, 10 of whom completed the study. The DIN test, which was administered in a daily environment using a simple digital device, evaluated the speech recognition threshold in noise. Results indicated that while some participants performed comparably to typically developing individuals, others showed varying levels of hearing thresholds, suggesting diverse auditory capabilities within the ID population. This pilot study confirms that the DIN test can be feasibly integrated into routine care settings, offering a friendly and accessible method for assessing hearing abilities in adults with ID. The findings advocate for the broader adoption of and potential modifications to the DIN Test to enhance its applicability and inclusiveness, thereby improving diagnostic accuracy and subsequent auditory care for this underserved population.
PubMed: 38893727
DOI: 10.3390/diagnostics14111202 -
International Journal of Molecular... Jun 2024Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene,...
Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.
Topics: Humans; Phosphorylation; Receptor, Serotonin, 5-HT1A; HEK293 Cells; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Cell Line, Tumor; Repressor Proteins; Gene Expression Regulation; DNA-Binding Proteins
PubMed: 38892382
DOI: 10.3390/ijms25116194 -
International Journal of Molecular... May 2024Heterozygous mutations in the gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as "intellectual developmental disorder with...
Heterozygous mutations in the gene (OMIM#605515) are responsible for a well-characterized neurodevelopmental syndrome known as "intellectual developmental disorder with language impairment with or without autistic features" (OMIM#613670) or FOXP1 syndrome for short. The main features of the condition are global developmental delay/intellectual disability; speech impairment in all individuals, regardless of their level of cognitive abilities; behavioral abnormalities; congenital anomalies, including subtle dysmorphic features; and strabismus, brain, cardiac, and urogenital abnormalities. Here, we present two siblings with a de novo heterozygous variant, namely, a four-year-old boy and 14-month-old girl. Both children have significantly delayed early psychomotor development, hypotonia, and very similar, slightly dysmorphic facial features. A lack of expressive speech was the leading symptom in the case of the four-year-old boy. We performed whole-exome sequencing on the male patient, which identified a pathogenic heterozygous c.1541G>A (p.Arg514His) mutation. His sister's targeted mutation analysis also showed the same heterozygous variant. Segregation analysis revealed the de novo origin of the mutation, suggesting the presence of parental gonadal mosaicism. To the best of our knowledge, this is the first report of gonadal mosaicism in -related neurodevelopmental disorders in the medical literature.
Topics: Humans; Forkhead Transcription Factors; Male; Mosaicism; Female; Child, Preschool; Neurodevelopmental Disorders; Infant; Repressor Proteins; Mutation; Exome Sequencing; Heterozygote
PubMed: 38891897
DOI: 10.3390/ijms25115709