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Prilozi (Makedonska Akademija Na... Dec 2023Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a genetically and clinically heterogeneous disorder with four described subtypes. Autosomal...
Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a genetically and clinically heterogeneous disorder with four described subtypes. Autosomal recessive syndrome of cerebellar ataxia, mental retardation, and disequilibrium type 4 (CAMRQ4) is caused by mutations in the gene. We report an 8-year-old boy with choreoathetosis, hypotonia, without the ability to keep his head up and profound mental retardation. There was quadrupedal locomotion, as well. MRI of the brain revealed a hypotrophy of the corpus callosum, diffuse white matter reduction, widespread delayed myelination and ventriculomegaly. Trio whole-exome sequencing revealed compound heterozygosity in the gene consisting of a known variant c.1756C>T (p.Arg586*) inherited from the mother and a novel variant c.691_701delCTGATGAAGTT (p.Leu231fs) inherited from the father. CAMRQ type 4 has been found in about 50 patients. To the best of our knowledge, this is the first reported patient with CAMRQ4 with these gene variants. The clinical presentation is severe.
Topics: Male; Humans; Child; Cerebellar Ataxia; Intellectual Disability; Brain; Mutation
PubMed: 38109455
DOI: 10.2478/prilozi-2023-0051 -
Molecular Genetics and Metabolism Nov 2023Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include... (Review)
Review
Creatine transporter deficiency (CTD), caused by pathogenic variants in SLC6A8, is the second most common cause of X-linked intellectual disability. Symptoms include intellectual disability, epilepsy, and behavioral disorders and are caused by reduced cerebral creatine levels. Targeted treatment with oral supplementation is available, however the treatment efficacy is still being investigated. There are clinical and theoretical indications that heterozygous females with CTD respond better to supplementation treatment than hemizygous males. Unfortunately, heterozygous females with CTD often have more subtle and uncharacteristic clinical and biochemical phenotypes, rendering diagnosis more difficult. We report a new female case who presented with learning disabilities and seizures. After determining the diagnosis with molecular genetic testing confirmed by proton magnetic resonance spectroscopy (H-MRS), the patient was treated with supplementation treatment including creatine, arginine, and glycine. After 28 months of treatment, the patient showed prominent clinical improvement and increased creatine levels in the brain. Furthermore, we provide a review of the 32 female cases reported in the current literature including a description of phenotypes, genotypes, diagnostic approaches, and effects of supplementation treatment. Based on this, we find that supplementation treatment should be tested in heterozygous female patients with CTD, and a prospective treatment underlines the importance of diagnosing these patients. The diagnosis should be suspected in a broad clinical spectrum of female patients and can only be made by molecular genetic testing. H-MRS of cerebral creatine levels is essential for establishing the diagnosis in females, and especially valuable when assessing variants of unknown significance.
Topics: Male; Humans; Female; Intellectual Disability; Creatine; Brain Diseases, Metabolic, Inborn; Mental Retardation, X-Linked; Plasma Membrane Neurotransmitter Transport Proteins; Nerve Tissue Proteins
PubMed: 37708665
DOI: 10.1016/j.ymgme.2023.107694 -
Psychiatria Danubina Dec 2023Intellectual Abilities, as defined in the twelfth edition of the classification manual of the American Association on Intellectual and Developmental Disabilities, are a...
Intellectual Abilities, as defined in the twelfth edition of the classification manual of the American Association on Intellectual and Developmental Disabilities, are a fundamental part of the rehabilitation process, also understood as functional rehabilitation or the rehabilitation of specific more or less complex functions, in a paradoxical game of mirrors even in the rehabilitation of intellectual functions themselves. Intellectual Disability changes the rules of the game, all the more radically the more severe it is, exacerbating the importance of multidimensional assessment of residual abilities and impaired functions on the basis of which to define realistic goals and choose the tools of rehabilitation and the ways of implementing therapeutic programs in a team effort that consists of the professionals, family and care givers, as well as the disabled person to the extent that he or she is able to actively participate in conducting his or her own rehabilitation.
Topics: Humans; Male; Female; Disabled Persons; Intellectual Disability; Cognition; Medicine
PubMed: 37994074
DOI: No ID Found -
Genetics in Medicine : Official Journal... Jul 2023The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.
PURPOSE
The study aimed to clinically and molecularly characterize the neurodevelopmental disorder associated with heterozygous de novo variants in CNOT9.
METHODS
Individuals were clinically examined. Variants were identified using exome or genome sequencing. These variants were evaluated using in silico predictions, and their functional relevance was further assessed by molecular models and research in the literature. The variants have been classified according to the criteria of the American College of Medical Genetics.
RESULTS
We report on 7 individuals carrying de novo missense variants in CNOT9, p.(Arg46Gly), p.(Pro131Leu), and p.(Arg227His), and, recurrent in 4 unrelated individuals, p.(Arg292Trp). All affected persons have developmental delay/intellectual disability, with 5 of them showing seizures. Other symptoms include muscular hypotonia, facial dysmorphism, and behavioral abnormalities. Molecular modeling predicted that the variants are damaging and would lead to reduced protein stability or impaired recognition of interaction partners. Functional analyses in previous studies showed a pathogenic effect of p.(Pro131Leu) and p.(Arg227His).
CONCLUSION
We propose CNOT9 as a novel gene for neurodevelopmental disorder and epilepsy.
Topics: Humans; Epilepsy; Intellectual Disability; Mutation, Missense; Neurodevelopmental Disorders; Phenotype; Seizures
PubMed: 37092538
DOI: 10.1016/j.gim.2023.100859 -
American Journal of Human Genetics Mar 2024Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause...
Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. Here, we identify loss-of-function (LoF) variation in ZFHX3 as a cause for syndromic intellectual disability (ID). ZFHX3 is a zinc-finger homeodomain transcription factor involved in various biological processes, including cell differentiation and tumorigenesis. We describe 42 individuals with protein-truncating variants (PTVs) or (partial) deletions of ZFHX3, exhibiting variable intellectual disability and autism spectrum disorder, recurrent facial features, relative short stature, brachydactyly, and, rarely, cleft palate. ZFHX3 LoF associates with a specific methylation profile in whole blood extracted DNA. Nuclear abundance of ZFHX3 increases during human brain development and neuronal differentiation. ZFHX3 was found to interact with the chromatin remodeling BRG1/Brm-associated factor complex and the cleavage and polyadenylation complex, suggesting a function in chromatin remodeling and mRNA processing. Furthermore, ChIP-seq for ZFHX3 revealed that it predominantly binds promoters of genes involved in nervous system development. We conclude that loss-of-function variants in ZFHX3 are a cause of syndromic ID associating with a specific DNA methylation profile.
Topics: Humans; Intellectual Disability; Autism Spectrum Disorder; Haploinsufficiency; Neurodevelopmental Disorders; Brain; Homeodomain Proteins
PubMed: 38412861
DOI: 10.1016/j.ajhg.2024.01.013 -
Journal of Applied Research in... Sep 2023People with intellectual disabilities are more likely to experience sleep problems, which can affect quality of life, physical health, mental health and well-being. (Review)
Review
BACKGROUND
People with intellectual disabilities are more likely to experience sleep problems, which can affect quality of life, physical health, mental health and well-being.
METHODS
An integrative literature review was conducted to investigate what is known about behavioural sleep disturbances in people with an intellectual disability. The search used the following databases: Scopus, PsycInfo and Cinahl, to find papers published since 2015.
RESULTS
Within intellectual disability research, sleep appears as a common issue due to its high prevalence, negative relationships with an individual's physical and mental health, their quality of life, and impact of sleep problems on family or carers. The growing evidence base appears to support the use of behavioural, lifestyle and pharmacological interventions to improve sleep in people with an intellectual disability.
CONCLUSION
A wide array of literature provides evidence that people with intellectual disabilities are affected by and need support with their sleep.
Topics: Humans; Child; Adult; Intellectual Disability; Quality of Life; Mental Health; Sleep Wake Disorders; Problem Behavior
PubMed: 37177858
DOI: 10.1111/jar.13116 -
American Journal of Medical Genetics.... Nov 20233q29 deletion syndrome (3q29del) is a rare genomic disorder caused by a 1.6 Mb deletion (hg19, chr3:195725000-197350000). 3q29del is associated with neurodevelopmental...
3q29 deletion syndrome (3q29del) is a rare genomic disorder caused by a 1.6 Mb deletion (hg19, chr3:195725000-197350000). 3q29del is associated with neurodevelopmental and psychiatric phenotypes, including an astonishing >40-fold increased risk for schizophrenia, but medical phenotypes are less well-described. We used the online 3q29 registry of 206 individuals (3q29deletion.org) to recruit 57 individuals with 3q29del (56.14% male) and requested information about musculoskeletal phenotypes with a custom questionnaire. 85.96% of participants with 3q29del reported at least one musculoskeletal phenotype. Congenital anomalies were most common (70.18%), with pes planus (40.35%), pectus excavatum (22.81%), and pectus carinatum (5.26%) significantly elevated relative to the pediatric general population. 49.12% of participants reported fatigue after 30 min or less of activity. Bone fractures (8.77%) were significantly elevated relative to the pediatric general population. Participants commonly report receiving medical care for musculoskeletal complaints (71.93%), indicating that these phenotypes impact quality of life for individuals with 3q29del. This is the most comprehensive description of musculoskeletal phenotypes in 3q29del to date, suggests ideas for clinical evaluation, and expands our understanding of the phenotypic spectrum of this syndrome.
Topics: Humans; Child; Male; Female; Developmental Disabilities; Chromosome Deletion; Quality of Life; Intellectual Disability; Phenotype; Syndrome
PubMed: 37691301
DOI: 10.1002/ajmg.a.63384 -
European Journal of Medical Genetics Jul 2023Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and...
Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.
Topics: Humans; DNA Copy Number Variations; Intellectual Disability; Nerve Tissue Proteins; Chromosome Disorders; Chromosome Deletion; Phenotype; Syndrome; Chromosomes, Human, Pair 22
PubMed: 37003575
DOI: 10.1016/j.ejmg.2023.104754 -
Nordic Journal of Psychiatry Oct 2023Mental health disorders are prevalent among individuals with intellectual disabilities (ID). However, there is a lack of research on the impact of concomitant autism...
OBJECTIVE
Mental health disorders are prevalent among individuals with intellectual disabilities (ID). However, there is a lack of research on the impact of concomitant autism spectrum disorders (ASD) or attention deficit hyperactivity disorder (ADHD) on the mental health within this population. We aimed to investigate the prevalence of mental health disorders and registered healthcare visits due to self-harm among individuals with ID.
METHOD
We used administrative data for all healthcare with at least one recorded diagnosis of mental health disorder or self-harm during 2007-2017 among people with a diagnosis of Down syndrome (DS; = 1298) and with ID without DS (IDnonDS; = 10,671) using the rest of the population in Stockholm Region ( = 2,048,488) for comparison.
RESULTS
The highest odds ratios for a mental health disorder were present in females with IDnonDS (9.01) followed by males with IDnonDS (8.50), compared to the general population. The ORs for self-harm among individuals with IDnonDS were high (8.00 for females and 6.60 for males). There were no registered cases of self-harm among individuals with DS. The prevalence of an anxiety or affective disorder was higher among individuals with ID including DS with concomitant ASD or ADHD. Neighbourhood socio-economic status was associated with a lower occurrence of mental health disorders and self-harm in wealthier areas for all outcomes and for all groups.
CONCLUSIONS
Self-harm and psychiatric comorbidities were common among individuals with ID without DS with an attenuated difference among those with concomitant ASD or ADHD, which calls for attention.
Topics: Male; Female; Humans; Intellectual Disability; Prevalence; Mood Disorders; Attention Deficit Disorder with Hyperactivity; Self-Injurious Behavior
PubMed: 37387438
DOI: 10.1080/08039488.2023.2228292 -
BMC Psychiatry Feb 2024Observational studies and diagnostic criteria have indicated that Attention Deficit Hyperactivity Disorder (ADHD) frequently comorbid with various psychiatric...
BACKGROUND
Observational studies and diagnostic criteria have indicated that Attention Deficit Hyperactivity Disorder (ADHD) frequently comorbid with various psychiatric disorders. Therefore, we conducted a Mendelian randomization (MR) study to explore this potential genetic association between ADHD and six psychiatric disorders.
METHODS
Using a two-sample Mendelian randomization (MR) design, this study systematically screened genetic instrumental variables (IVs) based on the genome-wide association studies (GWAS) of ADHD and six psychiatric disorders, with the inverse variance weighted (IVW) method as the primary approach.
RESULTS
The study revealed a positive and causal association between ADHD and the risk of ASD, with an odds ratio (OR) of 2.328 (95%CI: 1.241-4.368) in the IVW MR analysis. Additionally, ADHD showed a positive causal effect on an increased risk of schizophrenia, with an OR of 1.867 (95%CI: 1.260-2.767) in the IVW MR analysis. However, no causal effect of Tic disorder, Mental retardation, Mood disorders and Anxiety disorder with ADHD was found in the analysis mentioned above.
CONCLUSION
Our MR analysis provides robust evidence of the causal role of ADHD in increasing the risk of ASD and schizophrenia. However, ADHD is not associated with the risk of Tic Disorder, Mental Retardation, Mood Disorders and Anxiety Disorder. This suggests the need for increased attention to the co-occurrence of ADHD-ASD or ADHD-schizophrenia and the implementation of timely intervention and treatment.
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Genome-Wide Association Study; Intellectual Disability; Mendelian Randomization Analysis; Tic Disorders
PubMed: 38317064
DOI: 10.1186/s12888-024-05548-y