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Praxis Der Kinderpsychologie Und... Mar 2024How Does the Kaufman Assessment Battery for Children-II Stand the Test of Clinical Practice? Findings in 7- To 12-Year-Old Children Reliability and validity of the...
How Does the Kaufman Assessment Battery for Children-II Stand the Test of Clinical Practice? Findings in 7- To 12-Year-Old Children Reliability and validity of the KABC-II were investigated in 646 children aged 7 to 12 years who had been assessed in four social pediatric centers and one pediatric clinic in Germany due to developmental, behavioral, or emotional disorders.The reliability of the global scales Fluid-Crystallized-Index (FCI) and Mental Processing Index (MPI) proved to be very high in all age groups, with values ≥ .96. Reliability values for the scales were above .85 for Sequential/ Gsm and Delayed Recall, and above .90 for the other scales. Relatively higher test scores were found for Learning/Glr in children with intellectual disability than in other scales. Findings for discriminative validity for clinical diagnostic groups and educational backgrounds were as expected, with the lowest intelligence scores for children with intellectual disabilities.The correlation between FCI and the full scale IQ of the SON-R 2.-7 was .73 in a longitudinal subsample. Divergent validity for behavioral variables was confirmed in a subsample by low and nonsignificant correlations with the CBCL/6-18R. With some limitations, psychometric data indicate the suitability of the KABC-II for individual clinical assessment.
Topics: Child; Humans; Reproducibility of Results; Intelligence Tests; Psychometrics; Cognition; Intellectual Disability
PubMed: 38634389
DOI: 10.13109/prkk.2024.73.3.253 -
Journal of Medical Genetics Jul 2023KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function...
BACKGROUND
KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving cause KBG syndrome, but no genotype-phenotype correlation has been reported.
METHODS
67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature.
RESULTS
Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions.
CONCLUSION
We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.
Topics: Male; Humans; Intellectual Disability; Abnormalities, Multiple; Bone Diseases, Developmental; Tooth Abnormalities; Facies; Autism Spectrum Disorder; DNA Copy Number Variations; Repressor Proteins; Chromosome Deletion; Phenotype; Transcription Factors
PubMed: 36446582
DOI: 10.1136/jmg-2022-108632 -
Annals of Neurology Aug 2023Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with...
OBJECTIVE
Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.
METHODS
Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells.
RESULTS
The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.
INTERPRETATION
We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
Topics: Humans; HEK293 Cells; Neuroblastoma; Phenotype; Genotype; Intellectual Disability; Potassium Channels, Sodium-Activated
PubMed: 37062836
DOI: 10.1002/ana.26662 -
The Journal of Clinical Endocrinology... Aug 2023Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by...
CONTEXT
Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish.
OBJECTIVE
The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders.
METHODS
We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers.
RESULTS
Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common.
CONCLUSION
Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.
Topics: Humans; Intellectual Disability; Hyperostosis, Cortical, Congenital; Phenotype; Electrolytes; Hypoparathyroidism
PubMed: 36916904
DOI: 10.1210/clinem/dgad147 -
Scientific Reports Sep 2023To compare the anterior segment indices between mentally retarded and normal children. The current study was conducted as a cohort. In this study, 73 mentally retarded...
To compare the anterior segment indices between mentally retarded and normal children. The current study was conducted as a cohort. In this study, 73 mentally retarded and 76 normal children were selected from normal school and special schools for mentally retarded children using random cluster sampling method. Mental retardation in children was confirmed by a psychologist. Optometry examinations including visual acuity and refraction were performed for all participants, and ultimately, corneal imaging measurements were taken by Pentacam. The mean age of mentally retarded and normal children was of 13.30 ± 1.83 and 13.05 ± 1.82 years, respectively (P = 0.180). A multiple generalized estimating equations model demonstrated that there is a significant association between central corneal thickness (CCT) (coef = 1.011, P < 0.001), corneal diameter (CD) (coef = 0.444, P = 0.046), anterior chamber depth (ACD) (coef = 0.23), P < 0.001) and index of vertical asymmetry (IVA) (coef = 0.12, P < 0.001) and mental retardation. Cerebral palsy children had higher keratoconus index (KI), central keratoconus index (CKI), index of height asymmetry(IHA), and index of height decentration (IHD) compared to those without cerebral palsy (P < 0.05). Children with moderate mental retardation had higher index of surface variance (ISV), IVA, IHA, and IHD than those with mild mental retardation (P < 0.05). The mean and standard deviation of CCT, CD, ACD and IVA index in mentally retarded children were 535.3 ± 46.68 micron, 11.87 ± 0.42 mm, 3.29 ± 0.24 mm and 0.25 ± 0.18 mm, respectively. These indices in the normal group were 525.53 ± 47.52 micron, 11.84 ± 0.38 mm, 3.15 ± 0.28 mm and 0.17 ± 0.05 mm, respectively. The findings of this study showed that some anterior segment indices were different in mentally retarded compared to normal children. Moreover, some keratoconus indicators were worse in cerebral palsy children and children with higher grade mental retardation. So, it is important to consider keratoconus screening in these children.
Topics: Humans; Child; Adolescent; Persons with Mental Disabilities; Intellectual Disability; Cerebral Palsy; Keratoconus; Physical Examination
PubMed: 37666932
DOI: 10.1038/s41598-023-41827-6 -
Developmental Medicine and Child... Dec 2023Epidemiological approaches have played an important role in creating better understanding of developmental disabilities by delineating their frequency in populations and... (Review)
Review
Epidemiological approaches have played an important role in creating better understanding of developmental disabilities by delineating their frequency in populations and changes in their frequency over time, by identifying etiological factors, and by documenting pathways to prevention. Both cerebral palsy (CP) and mild intellectual disability are declining in frequency in high-income countries. The diagnosis of autism spectrum disorder has increased in recent decades, but much of this increase is a result of changing approaches to ascertainment and recording. Epidemiological studies have found that most CP is not of birth-asphyxial origin, that most febrile seizures do not pose a major risk for epilepsy, and that folic acid deficiency may contribute to developmental disabilities apart from its effect on neural tube defects. Epidemiological research has shown that an important fraction of neural tube defects and virtually all cases of Reye syndrome are preventable, and recent trials have shown ways to prevent CP. Early psychoeducational interventions in children at risk for mild intellectual disability are an effective and valuable societal investment. Very large population-based studies starting in pregnancy have been launched in Norway, Denmark, and Japan in recent years and these and other population studies promise to continue the epidemiological contribution to a better understanding of developmental disabilities.
Topics: Child; Pregnancy; Female; Humans; Developmental Disabilities; Autism Spectrum Disorder; Intellectual Disability; Neural Tube Defects; Cerebral Palsy
PubMed: 37149891
DOI: 10.1111/dmcn.15633 -
Epilepsy & Behavior : E&B May 2024PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by... (Review)
Review
PCDH19 clustering epilepsy (PCDH19-CE) is an X-linked epilepsy disorder associated with intellectual disability (ID) and behavioral disturbances, which is caused by PCDH19 gene variants. PCDH19 pathogenic variant leads to epilepsy in heterozygous females, not in hemizygous males and the inheritance pattern is unusual. The hypothesis of cellular interference was described as a key pathogenic mechanism. According to that, males do not develop the disease because of the uniform expression of PCDH19 (variant or wild type) unless they have a somatic variation. We conducted a literature review on PCDH19-CE pathophysiology and concluded that other significant mechanisms could contribute to pathogenesis including: asymmetric cell division and heterochrony, female-related allopregnanolone deficiency, altered steroid gene expression, decreased Gamma-aminobutyric acid receptor A (GABAA) function, and blood-brain barrier (BBB) dysfunction. Being aware of these mechanisms helps us when we should decide which therapeutic option is more suitable for which patient.
Topics: Humans; Epilepsy; Protocadherins; Cadherins; Intellectual Disability; Female; Male; Clinical Relevance
PubMed: 38521028
DOI: 10.1016/j.yebeh.2024.109730 -
Human Genomics Jul 2023This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS).... (Review)
Review
This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome's variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000-7000 men and 1 in 4000-6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene's promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS's variable expressivity by regulating the pathophysiological mechanisms related to the syndrome's behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.
Topics: Male; Humans; Female; Fragile X Syndrome; Autism Spectrum Disorder; DNA Methylation; Mosaicism; Biological Variation, Population; Fragile X Mental Retardation Protein
PubMed: 37420260
DOI: 10.1186/s40246-023-00507-2 -
Genetics in Medicine : Official Journal... Sep 2023The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals...
PURPOSE
The "NALCN channelosome" is an ion channel complex that consists of multiple proteins, including NALCN, UNC79, UNC80, and FAM155A. Only a small number of individuals with a neurodevelopmental syndrome have been reported with disease causing variants in NALCN and UNC80. However, no pathogenic UNC79 variants have been reported, and in vivo function of UNC79 in humans is largely unknown.
METHODS
We used international gene-matching efforts to identify patients harboring ultrarare heterozygous loss-of-function UNC79 variants and no other putative responsible genes. We used genetic manipulations in Drosophila and mice to test potential causal relationships between UNC79 variants and the pathology.
RESULTS
We found 6 unrelated and affected patients with UNC79 variants. Five patients presented with overlapping neurodevelopmental features, including mild to moderate intellectual disability and a mild developmental delay, whereas a single patient reportedly had normal cognitive and motor development but was diagnosed with epilepsy and autistic features. All displayed behavioral issues and 4 patients had epilepsy. Drosophila with UNC79 knocked down displayed induced seizure-like phenotype. Mice with a heterozygous loss-of-function variant have a developmental delay in body weight compared with wild type. In addition, they have impaired ability in learning and memory.
CONCLUSION
Our results demonstrate that heterozygous loss-of-function UNC79 variants are associated with neurologic pathologies.
Topics: Animals; Humans; Mice; Drosophila; Epilepsy; Intellectual Disability; Neurodevelopmental Disorders; Phenotype; Membrane Proteins
PubMed: 37183800
DOI: 10.1016/j.gim.2023.100894 -
Genetics in Medicine : Official Journal... Jul 2023LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to...
PURPOSE
LHX2 encodes the LIM homeobox 2 transcription factor (LHX2), which is highly expressed in brain and well conserved across species, but it has not been clearly linked to neurodevelopmental disorders (NDDs) to date.
METHODS
Through international collaboration, we identified 19 individuals from 18 families with variable neurodevelopmental phenotypes, carrying a small chromosomal deletion, likely gene-disrupting or missense variants in LHX2. Functional consequences of missense variants were investigated in cellular systems.
RESULTS
Affected individuals presented with developmental and/or behavioral abnormalities, autism spectrum disorder, variable intellectual disability, and microcephaly. We observed nucleolar accumulation for 2 missense variants located within the DNA-binding HOX domain, impaired interaction with co-factor LDB1 for another variant located in the protein-protein interaction-mediating LIM domain, and impaired transcriptional activation by luciferase assay for 4 missense variants.
CONCLUSION
We implicate LHX2 haploinsufficiency by deletion and likely gene-disrupting variants as causative for a variable NDD. Our findings suggest a loss-of-function mechanism also for likely pathogenic LHX2 missense variants. Together, our observations underscore the importance of LHX2 in the nervous system and for variable neurodevelopmental phenotypes.
Topics: Humans; LIM-Homeodomain Proteins; Autism Spectrum Disorder; Haploinsufficiency; Neurodevelopmental Disorders; Transcription Factors; Intellectual Disability
PubMed: 37057675
DOI: 10.1016/j.gim.2023.100839