Clinical and molecular characterization of myotonia congenita using whole-exome sequencing in Egyptian patients.

BACKGROUND: Myotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle excitability and encodes voltage-gated chloride channels (CLC-1). While, there are no data regarding the clinical and molecular characterization of myotonia in Egyptian patients. METHODS: Herein, we report seven Egyptian MC patients from six unrelated families. Following the clinical diagnosis, whole-exome sequencing (WES) was performed for genetic diagnosis. Various in silico prediction tools were utilized to interpret variant pathogenicity. The candidate variants were then validated using Sanger sequencing technique. RESULTS: In total, seven cases were recruited. The ages at the examination were ranged from eight months to nineteen years. Clinical manifestations included warm-up phenomenon, hand grip, and percussion myotonia. Electromyography was performed in all patients and revealed myotonic discharges. Molecular genetic analysis revealed five different variants. Of them, we identified two novel variants in the CLCN1 gene ( c.1583G > C; p.Gly528Ala and c.2203_2216del;p.Thr735ValfsTer57) and three known variants in the CLCN1 and SCN4A gene. According to in silico tools, the identified novel variants were predicted to have deleterious effects. CONCLUSIONS: As the first study to apply WES among Egyptian MC patients, our findings reported two novel heterozygous variants that expand the CLCN1 mutational spectrum for MC diagnosis. These results further confirm that genetic testing is essential for early diagnosis of MC, which affects follow-up treatment and prognostic assessment in clinical practice.

Congenital leptin and leptin receptor deficiencies in nine new families: identification of six novel variants and review of literature.

Early childhood obesity is a real public health problem worldwide. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Measurement of serum leptin levels is helpful in the diagnosis of congenital leptin and leptin receptor deficiencies which are considered important rare causes of early childhood obesity. The main aim of this study was to investigate the frequency of LEP, LEPR, and MC4R gene variants among a cohort of Egyptian patients with severe early onset obesity. The current cross-sectional study included 30 children who developed obesity during the first year of life with BMI > 2SD (for age and sex). The studied patients were subjected to full medical history taking, anthropometric measurements, serum leptin and insulin assays, and genetic testing of LEP, LEPR and MC4R. Disease causing variants in LEP and LEPR were identified in 10/30 patients with a detection rate of 30%. Eight different homozygous variants (two pathogenic, three likely pathogenic, and three variants of uncertain significant) were identified in the two genes, including six previously unreported LEPR variants. Of them, a new frameshift variant in LEPR gene (c.1045delT, p.S349Lfs*22) was recurrent in two unrelated families and seems to have a founder effect in our population. In conclusion, we reported ten new patients with leptin and leptin receptor deficiencies and identified six novel LEPR variants expanding the mutational spectrum of this rare disorder. Furthermore, the diagnosis of these patients helped us in genetic counseling and patients' managements specially with the availability of drugs for LEP and LEPR deficiencies.

Prevalence and risk factors of disabilities among Egyptian preschool children: a community-based population study.

BACKGROUND: Child disability has significant implications on their well-being and healthcare systems. AIM: This survey aimed to assess the magnitude of seven types of disability among Egyptian children aged 1 < 6 years and their socio-demographic, epidemiological, and perinatal predictors. METHODS: A national population-based cross-sectional household survey targeting 21,316 children from eight governorates was conducted. The screening questionnaire was derived from the WHO ten-question survey tool validated for identifying seven disability categories. RESULTS: The percentage of children with at least one disability was 8.1% as follows: speech/communication (4.4%), Mobility/physical (2.5%), Seizures (2.2%), Comprehension (1.7%), Intellectual impairment (1.4%), Visual (0.3%) and Hearing (0.2%). Age was not found to affect the odds of disability except for visual disability (significantly increased with age (AOR = 1.4, 95% CI:1.1-1.7). Male sex also increased the odds of all disabilities except visual, hearing, and seizures. Convulsions after birth significantly increased the odds of disability as follows: hearing (AOR = 8.1, 95% CI: 2.2-30.5), intellectual impairment (AOR = 4.2, 95% CI: 2.5-6.9), and mobility/physical (AOR = 3.4, 95% CI: 2.3-5.0). Preterm delivery and being kept in an incubator for more than two days after birth increased the odds for visual disability (AOR = 3.7, 95% CI: 1.1-12.1 & AOR = 3.7, 95% CI: 1.7-7.9 respectively). Cyanosis increased the odds of seizures (AOR = 4.7, 95% CI: 2.2-10.3). Low birth weight also increased the odds for all disability domains except for visual and hearing. Maternal health problems during pregnancy increased the odds for all types of disability except hearing and seizures. Higher paternal education decreased the odds for all disabilities by at least 30% except for vision and hearing. CONCLUSION: The study found a high prevalence of disability among Egyptian children aged 1-6 years. It identified a number of modifiable risk factors for disability. The practice of early screening for disability is encouraged to provide early interventions when needed.

National screening for Egyptian children aged 1 year up to 12 years at high risk of Autism and its determinants: a step for determining what ASD surveillance needs.

This study aimed to provide a national estimate of the prevalence of the high risk of autism spectrum disorder (ASD) and their determinants. A national screening survey was conducted for 41,640 Egyptian children aged 1 to 12 years in two phases. Tools used were Vineland's Adaptive Behavior Scales, Modified Checklist for Autism in Toddlers, Gilliam Autism Rating scale, and Denver II Developmental screening test. The overall prevalence of children at high risk of ASD was 3.3% (95% CI:3.1%-3.5%). Children living without mothers in homes, suffered from convulsions (AOR = 3.67; 95%CI:2.8-4.8), a history of cyanosis after birth (AOR = 1.87; 95% CI:1.35-2.59) or history of LBW babies (AOR = 1.53; 95% CI:1.23-1.89) carried higher odds of being at high risk of ASD.

Screening and determinant of suspected developmental delays among Egyptian preschool-aged children: a cross-sectional national community-based study.

BACKGROUND: Early childhood life is critical for optimal development and is the foundation of future well-being. Genetic, sociocultural, and environmental factors are important determinants of child development. AIM: The objectives were to screen for suspected developmental delays (DDs) among Egyptian preschool children, and to explore the determinants of these delays based on sociodemographic, epidemiological, maternal, and child perinatal risk factors. METHODS: A national Egyptian cross-sectional developmental screening of a representative sample of preschool children (21,316 children) aged 12 to 71 months. The Revised Denver Prescreening Developmental Questionnaire (R-PDQ) followed by the Denver Developmental Screening Test, 2nd edition (DDST) was used. RESULTS: Each screened child manifested at least one of six developmental categories. Either typical development, gross motor delay (GM), fine motor adaptive delay (FMA), Language delay (L), Personal-social delay (PS), or multiple DDs. The prevalence of preschool children with at least one DD was 6.4%, while 4.5% had multiple DDs. Developmental language delay was the most prevalent, affecting 4.2% of children. The least affected domain was GM (1.9% of children). Boys were more likely to have DD than girls. Children in urban communities were more likely to have at least one DD than those in rural areas (OR = 1.28, 95%CI: 1.14-1.42), and children of middle social class than of low or high social class (OR = 1.49, 95%CI: 1.30-1.70 & OR = 1.40, 95%CI: 1.23-1.59 respectively). The strong perinatal predictors for at least one DD were children with a history of postnatal convulsions (OR = 2.68, 95%CI: 1.97-3.64), low birth weight (OR = 2.06, 95%CI: 1.69-2.52), or history of postnatal cyanosis (OR = 1.77, 95%CI: 1.26-2.49) and mothers had any health problem during pregnancy (OR = 1.73, 95%CI: 1.44-2.07). Higher paternal and maternal education decreased the odds of having any DD by 43% (OR = 0.57, 95% CI: 0.47-0.68) and 31% (OR = 0.69, 95%CI: 0.58-0.82) respectively. CONCLUSION: This study demonstrates a considerable attempt to assess the types and the prevalence of DD among preschool children in Egypt. Perinatal factors are among the most common determinants of DD in preschool children and the majority could be preventable risk factors.

Blepharophimosis-ptosis-intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum.

Blepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.

Rubinstein-Taybi syndrome in diverse populations.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

Study of C677T variant of methylene tetrahydrofolate reductase gene in autistic spectrum disorder Egyptian children.

BACKGROUND: Autism spectrum disorders (ASD) is a heterogeneous neurodevelopmental disease, various articles reported that dysfunctional folate-methionine pathway enzymes might assume a paramount part in the pathophysiology of autism. Methylene tetrahydrofolate reductase (MTHFR) is a basic catalyst for this pathway, also MTHFR gene C677T variant accounted as a risk factor of autism. OBJECTIVE: The present study aimed to investigate the association of MTHFR gene rs1801133(C677T) variant among Egyptian autistic children. METHODS: The study included 78 autistic children, and 80 matched healthy control children. Full clinical and radiological examinations were conducted. MTHFR genetic variant, rs1801133(C677T) was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods followed by direct sequencing technique. RESULTS: MTHFR (C677T) allele frequency was found to be higher significantly in ASD cases compared with nonautistic children. Also, we had a higher distribution of combined CT + TT genotypes among autistic patients with consanguinity and family history of psychological disease. In Gastrointestinal tract (GIT) and sleep disorders showed a higher distribution of hetero CT genotype as well as combined CT + TT genotypes. CONCLUSION: This study demonstrated a role of MTHFR gene (C667T) variant with the increased risk for ASD.

Williams-Beuren syndrome in diverse populations.

Williams-Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P-value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.

Potential biomarkers of ASD a target for future treatments: oxidative stress, chemokines, apoptotic, and methylation capacity.

OBJECTIVES: The study aimed to assess the effect of these biomarkers on a sample of children with autism spectrum disorder (ASD) to help in early diagnosis and intervention. METHODS: A total of 71 autistic patients and 65 normal controls were enrolled in this study. Their ages ranged from 5 to 11 years (mean ± SD 7.47 ± 3.81). Childhood Autism Rating Scale (CARS) was assessed for all patients and controls. Assessment of oxidative stress, monocyte chemoattractant protein-1, B-cell lymphoma 2, S-adenosylhomocysteine (SAH), and apelin was performed. RESULTS: Oxidative stress (oxidized low-density lipoprotein and malonaldehyde) increased while antioxidant paraoxonase (PON) decreased. Monocyte chemoattractant protein-1, B-cell lymphoma 2, and S-adenosylhomocysteine (SAH) were all elevated whereas, apelin was downregulated. CONCLUSIONS: It is important to note that many factors that may contribute to ASD including genetic factors. To open the door for novel treatment strategies, it is still necessary to precisely understand how oxidative stress, chemokines, apoptosis, and methylation capability affect the metabolism of people with ASD.

Screening and evaluation of TBX20 and CITED2 mutations in children with congenital cardiac septal defects: Correlation with cardiac troponin T and caspase-3.

Congenital cardiac septal defect (CCSD) is the main type of congenital heart disease and owns a very high mortality rate among newborns. CCSD is controlled by specific transcription factors, including T-box transcription factor 20 (TBX20) and Cbp/P300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2) which are key molecular actors in heart development. Here, we screened for mutations in TBX20 and CITED2 genes in Egyptian children with CCSD and assessed their association with CCSD susceptibility and with cardiac troponin T (cTnT) and the apoptotic marker caspase-3 as biochemical markers for CCSD. Thirty unrelated newborns and children affected with CCSD and 30 matched healthy controls with no personal history of cardiac diseases were recruited. Selection criteria were children (<18 years) with any age diagnosed with CCSD using ECHO. Mutational analysis and genotyping were done using PCR-Sanger DNA sequencing technique. Serum cTnT and caspase-3 were analyzed using ELISA. Sequencing analysis identified 2 TBX20 variants (c.766T>C and c.39T>C) in the CCSD and control groups and 2 CITED2 variants (c.12T>C and c.9C>T) in one CCSD patient, while were absent in controls. In silico analysis identified TBX20 c.766T>C (rs3999941) as a missense (F256L) pathogenic variant and the other three variants as synonymous and benign. Compared with controls, TBX20 c.766T>C TC genotype and minor C allele were candidate high-risk factors for CCSD. Besides, serum cTnT and caspase-3 were dramatically elevated in CCSD children compared to controls. TBX20 c.766T>C TC genotype was associated with high cTnT in CCSD children. Conclusively, we advocate TBX20 c.766T>C variant as a potential genetic marker for CCSD which might associate with high cTnT levels. CITED2 genetic variants might have rare incidence among Egyptian CCSD children. Serum cTnT and caspase-3 are useful markers for ascertaining CCSD in children. These data could be exploited in prenatal genetic counseling, pre-implantation genotyping, and therapy of CCSD.

Clinical and molecular study of Egyptian patients with Treacher Collins syndrome.

Treacher Collins syndrome (TCS) is a rare disorder of craniofacial development following different patterns of inheritance. To date, mutations in four genes ( TCOF1, POLR1D, POLR1C , and POLR1B ) have been found to cause the condition. The molecular defect remains unidentified in a significant proportion of patients. In the current study, whole exome sequencing including analysis of copy number variants was applied for genetic testing of eight Egyptian patients with typical TCS phenotype, representing the first molecular analysis of TCS patients in Egypt as well as in Arab countries. Five heterozygous frameshift mutations were reported, including four variants in the TCOF1 gene (c.3676_3694delinsCTCTGG, c.3984_3985delGA, c.4366_4369delGAAA, and c.3388delC) and one variant in the POLR1D gene (c.60dupA). Four variants were novel extending the disease mutation spectrum. In three affected individuals, no variants of interest were identified in genes associated with TCS or clinically overlapping conditions. Additionally, no relevant variant was detected in genes encoding other subunits of RNA polymerase (pol) I. Molecular analysis is important to provide accurate genetic counseling. It would also contribute to reduced disease incidence. Further studies should be designed to investigate other possible etiologies when no pathogenic variants were revealed in either of the known genes.

Efficacy of Laser Acupuncture for Children With Autism Spectrum Disorder: Clinical, Molecular, and Biochemical Study.

BACKGROUND: Low-level laser acupuncture (LLLA) biostimulation could contribute to improving the symptoms and communication of children manifesting autism spectrum disorder (ASD). Photobiomodulation might influence the level of brain-derived neurotrophic factor (BDNF) and miR-320 expression. The aim was to investigate the influence of LLLA biostimulation on the severity, language abilities, BDNF levels, and miR-320 in a sample of children with ASD. METHODS: The participants with ASD (N = 30) were randomly divided equally into groups: Group I received LLLA therapy twice a week for 12 sessions and Group II did not receive it. Assessments of the severity, language abilities, BDNF level by enzyme-linked immunosorbent assay, and miR-320 expression by reverse transcriptase quantitative polymerase chain reaction were performed before and after the intervention. A comparison between ASD cases (N = 30) before starting the therapy and neurotypical children (N = 15) regarding miR-320 expression was performed. RESULTS: Following the intervention, the severity of ASD was reduced and language performance was elevated in both groups. The improvement in Group I was higher with (P = 0.002; 0.03). The plasma BDNF level was reduced only in Group I (P < 0.001). The expression level of miR-320 in Group I did not show a change (P = 0.641). A significant difference in miR-320 expression between children with ASD and the neurotypical group (P = 0.000) was observed. CONCLUSION: This study introduces LLLA therapy as a safe and promising therapeutic procedure for improving the core manifestations and communication abilities and for modulating BDNF levels in children with ASD. The reduced expression of miR-320 showed a good diagnostic value in children with ASD.

New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects.

Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2-Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and drug-like estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski's rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended.

A Novel Truncating Mutation in PAX1 Gene Causes Otofaciocervical Syndrome Without Immunodeficiency.

Otofaciocervical syndrome (OTFCS) is a rare genetic disorder of both autosomal recessive and autosomal dominant patterns of inheritance. It is caused by biallelic or monoallelic mutations in PAX1 or EYA1 genes, respectively. Here, we report an OTFCS2 female patient of 1st consanguineous healthy parents. She manifested facial dysmorphism, hearing loss, intellectual disability (ID), and delayed language development (DLD) as the main clinical phenotype. The novel homozygous variant c.1212dup (p.Gly405Argfs*51) in the PAX1 gene was identified by whole exome sequencing (WES), and family segregation confirmed the heterozygous status of the mutation in the parents using the Sanger sequencing. The study recorded a novel PAX1 variant representing the sixth report of OTFCS2 worldwide and the first Egyptian study expanding the geographic area where the disorder was confined.

First LIPA Mutational Analysis in Egyptian Patients Reveals One Novel Variant: Wolman Disease.

Lysosomal acid lipase (LAL) is a necessary enzyme for the hydrolysis of both triglycerides (TGs) and cholesteryl esters (CEs) in the lysosome. Deficiency of this enzyme encoded by the lipase A (LIPA) gene leads to LAL deficiency (LAL-D). A severe disease subtype of LAL-D is known as Wolman disease (WD), present with diarrhea, hepatosplenomegaly, and adrenal calcification. Untreated patients do not survive more than a year. The aim of this study was to assess the clinical and molecular characterizations of WD patients in Egypt. A total of seven patients (from five unrelated Egyptian families) were screened by targeted next-generation sequencing (NGS), and the co-segregation of causative variants was analyzed using Sanger sequencing. Furthermore, multiple in silico analyses were performed to assess the pathogenicity of the candidate variants. Overall, we identified three diseases causing variants harbored in the LIPA gene. One of these variants is a novel missense variant (NM_000235.4: c.1122 T > G; p. His374Gln), which was classified as a likely pathogenic variant. All variants were predicted to be disease causing using in silico analyses. Our findings expand the spectrum of variants involved in WD which may help to investigate phenotype-genotype correlation and assist genetic counseling. To the best of our knowledge, this is the first clinico-genetic study carried out on Egyptian patients affected with WD.

Sialic acid and anti-ganglioside M1 antibodies are invaluable biomarkers correlated with the severity of autism spectrum disorder.

BACKGROUND: Autism spectrum disorders (ASD) are devastating neurodevelopmental disorders that showed global increased prevalence. They are characterized by impairment of social communication and stereotyped patterns. OBJECTIVE: This study aimed at measuring the levels of total sialic acid (SA) and anti-ganglioside M1 (anti- GM1) IgG antibodies as essential biomarkers in a cohort of children with ASD to identify their diagnostic yield as well as their correlation with the severity of autistic behaviors. METHODS: The demographic characteristics, anthropometric measurements, and clinical data were recorded. The levels of total plasma SA and serum anti-GM1 IgG antibodies levels were measured in 100 children with ASD and 100 healthy controls. The severity of ASD-related symptoms was assessed by using the Childhood Autism Rating Scale (CARS). RESULTS: Children with ASD had significantly higher levels of both SA and anti-GM1 antibodies than healthy controls (p < 0.001). SA showed a statistically significant moderate diagnostic performance while anti-GM1 antibody showed a statistically significant high diagnostic in differentiating severe from mild to moderate autism. Moreover, both SA and anti-GM1 antibodies levels were significantly correlated to the severity of ASD symptoms (p < 0.001). CONCLUSION: The significantly increased levels of SA and anti-GM1 antibodies in children with ASD and their correlation with autism-related symptoms suggest their possible etiopathogenic role in autism as one of the pediatric autoimmune neuropsychiatric disorders. However, further large-scale studies are still needed to explore their possible bidirectional relationship as biomarkers for autism.

The Diagnostic Value of Whole-Exome Sequencing in a Spectrum of Rare Neurological Disorders Associated with Cerebellar Atrophy.

Several neurological disorders, neurodevelopmental disorders, and neurodegenerative disorders have a genetic element with various clinical presentations ranging from mild to severe presentation. Neurological disorders are rare multifactorial disorders characterized by dysfunction and degeneration of synapses, neurons, and glial cells which are essential for movement, coordination, muscle strength, sensation, and cognition. The cerebellum might be involved at any time, either during development and maturation or later in life. Herein, we describe a spectrum of NDDs and NDs in seven patients from six Egyptian families. The core clinical and radiological features of our patients included dysmorphic features, neurodevelopmental delay or regression, gait abnormalities, skeletal deformities, visual impairment, seizures, and cerebellar atrophy. Previously unreported clinical phenotypic findings were recorded. Whole-exome sequencing (WES) was performed followed by an in silico analysis of the detected genetic variants' effect on the protein structure. Three novel variants were identified in three genes MFSD8, AGTPBP1, and APTX, and other previously reported three variants have been detected in "TPP1, AGTPBP1, and PCDHGC4" genes. In this cohort, we described the detailed unique phenotypic characteristics given the identified genetic profile in patients with neurological "neurodevelopmental disorders and neurodegenerative disorders" disorders associated with cerebellar atrophy, hence expanding the mutational spectrum of such disorders.

National screening for developmental delays and their determinants among Egyptian school age children: A step towards implementing life skills programs.

AIM: This study aimed to estimate the national prevalence of developmental delays (DDs) and their determinants among Egyptian children aged 6 to 12 years. Such estimation is a prerequisite step toward the application of Life Skill Education (LSE) programs that will potentiate children's future capabilities. METHODS: Vineland Adaptive Behavior Scales" was used as a reliable and diagnostic test for DDs screening during this national cross sectional study. Gross motor (GM), fine motor (FM), daily living skills, communication, and socialization skills were assessed. The multivariate logistic regression analysis was used to identify factors associated with DDs. The Adjusted Odds Ratio (AOR) with a 95% Confidence Interval was estimated to indicate the strength of association. A p-value of <0.05 was used to declare statistical significance. RESULTS: Out of the 20324 surveyed school-aged children, 7.4% were found to have at least one delay. Communication deficits were the most common (6.4%) followed by delay in daily living skills (2.0%). The final model of logistic regression had a good fit for seven variables out of the sociodemographic, epidemiological characteristics, maternal and perinatal problems that were associated with a higher likelihood of at least one DD: Children suffering from any convulsions (AOR = 4.32; 95% CI: 3.18-5.88), male gender (AOR = 1.86; 95% CI: 1.65-2.09), birth weight less than 2.5 kg (AOR = 1.77; 95% CI: 1.40-2.24), history of maternal health problem during pregnancy (AOR = 1.64; 95% CI:1.34-2.01), children staying in an incubator for more than two days (AOR = 1.57, 95% CI: 1.29-1.91), having less educated fathers (AOR = 1.55, 95% CI: 1.24-1.95) and belonging to the middle social class (AOR = 1.40, 95% CI: 1.24-1.58). CONCLUSION: The identified types and determinants for each DD are allowing for the implementation of tailored programs for school children's life skills promotion for achieving the most sustainable effects on children's biological and psychological health and well-being.