scholarly journals 10. Cerebral hyaline astrocytic inclusions in treatment-resistant epilepsy and global developmental delay

2015 ◽  
Vol 42 (S2) ◽  
pp. S4-S5
Author(s):  
M. Signaevski ◽  
C. Sanguansermsri ◽  
M. Connolly ◽  
LN. Hazrati ◽  
C. Dunham
Keyword(s):  
Developmental Delay ◽  
Resection Margin ◽  
Seizure Activity ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Treatment Resistant ◽  
Partial Deletion ◽  
Brain Anomalies ◽  
Epileptic Spasms ◽  
Patients With Epilepsy

Cerebral hyaline astrocytic inclusions (HAI) have been observed in a subset of patients with epilepsy, structural brain anomalies, and developmental delay. We present a case of a 2.5-year-old male with epilepsy and global developmental delay. Chromosomal microarray detected a copy loss at 22q13 that resulted in a partial deletion of SHANK3 gene. The EEGs revealed seizure activity arising from left frontal central region. Invasive video electrocorticography captured clusters of epileptic spasms, all originating from left antero-lateral frontal lobe rostral to the motor cortex. We utilized routine histology to identify the inclusions and mapped their distribution in the resected portion of the cortex against electrocorticographic data. Histologic analysis revealed the presence of HAI in the posterio-medial portion of the resected cortex, which corresponded to the site of seizure generalization. HAI were present at the resection margin. Immunohistochemistry was largely non-contributory. HAI is a rare but emerging entity that is associated with epilepsy. To our knowledge, the distribution of inclusions in HAI has never been mapped to electrophysiologic data. In our case, seizure generalization correlated with the inclusions distribution. This suggests that the inclusions may: 1) play a role in epileptogenesis; or, 2) be a biomarker of disease distribution. Finally, the presence of the HAI at the resection margin may foreshadow future seizure activity in this patient.

scholarly journals Phenotypes in Children With SYNGAP1 Encephalopathy in China

2021 ◽  
Vol 15 ◽  
Author(s):  
Huiting Zhang ◽  
Liu Yang ◽  
Jing Duan ◽  
Qi Zeng ◽  
Li Chen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Behavioral Problems ◽  
Disease Onset ◽  
Gene Mutations ◽  
Global Developmental Delay ◽  
Clinical Trial Registry ◽  
Neurodevelopmental Delay ◽  
Epileptic Spasms ◽  
Registration Number ◽  
Drug Resistant Epilepsy

Objective: We aimed to explore the associated clinical phenotype and the natural history of patients with SYNGAP1 gene variations during early childhood and to identify their genotype–phenotype correlations.Methods: This study used a cohort of 13 patients with epilepsy and developmental disorder due to SYNGAP1 mutations, namely, 7 patients from Shenzhen Children’s Hospital between September 2014 and January 2020 and 6 patients from previously published studies. Their clinical data were studied.Results: A total of 13 children with SYNGAP1 gene variants (eight boys and five girls) were identified. The age of disease onset was in infancy. Mutations were located between exons 8 and 15; most were frameshift or truncated mutations. Four mutation sites (c.924G > A, c.1532-2_1532del, c.1747_1755dup, and c.1735_1738del) had not been reported before. All patients had global developmental delay within the first year of life, and intellectual impairment became gradually apparent. Some of them developed behavioral problems. The developmental delay occurred before the onset of seizures. All seven patients in our cohort presented with epilepsy; myoclonic seizures, absence seizures, and epileptic spasms were the most common seizure types. Abnormal electroencephalograms were identified from five patients before the onset of their seizures. All patients suffered from drug-resistance seizures. However, comorbidities such as behavioral problems were less frequently observed.Conclusion: The most common age of disease onset in SYNGAP1 gene mutations is in infancy, while neurodevelopmental delay and epilepsy are the major phenotypes. They have a higher percentage of drug-resistant epilepsy and epileptic spasms than those in previous reports. We should give attention to the patients with abnormal EEGs without seizures and think about the suitable time of the anti-seizure medications for them. We have not found the genotype–phenotype correlation.Trial registration: Chinese Clinical Trial Registry, Registration number: ChiCTR2100049289 (https://www.chictr.org.cn/listbycreater.aspx).

scholarly journals Relationship between Clinical Parameters and Chromosomal Microarray Data in Infants with Developmental Delay

Healthcare ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 305
Author(s):  
Zeeihn Lee ◽  
Byung Joo Lee ◽  
Sungwon Park ◽  
Donghwi Park
Keyword(s):  
Developmental Delay ◽  
Diagnostic Yield ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Chromosomal Microarray ◽  
Clinical Parameters ◽  
Brain Anomalies ◽  
Pathogenic Cnvs ◽  
Clinical Records ◽  
The Relationship

Chromosomal microarray (CMA) is considered a first-tier test for genetic analysis as it can be used to examine gene copy number variations (CNVs) throughout the entire genome, with enhanced sensitivity for detecting submicroscopic deletions and duplications. However, its cost can represent a heavy burden. Moreover, the diagnostic yield of CMA in infants with developmental delay (DD) was reported to be less than 10%. Therefore, we aimed to investigate the relationship between CMA results and clinical features and risk factors of DD. The study included 59 infants with DD who were recruited between August 2019 and February 2020 during a visit to the outpatient clinic of a rehabilitation department. We reviewed the clinical records of the infants regarding gender, age, body weight at birth, delivery method, brain imaging data, perinatal history, and parent-related clinical parameters, such as mother and father age at birth. The infants were categorized according to CMA results, and differences in clinical parameters were evaluated. Except for brain anomalies, there was no statistically significant differences between infants who had pathogenic and variants of unknown significance (VOUS)-likely pathogenic CNVs groups compared with those within the VOUS-likely no sub-classification, VOUS-likely benign, benign, and normal CNVs groups. The incidence of brain anomalies was significantly higher within infants with pathogenic and VOUS-likely pathogenic CNVs groups (p < 0.05). Our study suggests that infants with DD who present dysmorphism or brain anomaly may benefit from early CMA analysis, for adequate diagnosis and timely treatment. Further studies are warranted to confirm the relationship between DD clinical parameters and CMA results.

The Fault in Their Stars—Accumulating Astrocytic Inclusions Associated With Clusters of Epileptic Spasms in Children With Global Developmental Delay

2017 ◽  
Vol 73 ◽  
pp. 92-97.e3 ◽  
Author(s):  
Robyn Whitney ◽  
Sameer AlMehmadi ◽  
Bláthnaid McCoy ◽  
Ivanna Yau ◽  
Ayako Ochi ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Global Developmental Delay ◽  
Epileptic Spasms

scholarly journals Genome sequencing demonstrates high diagnostic yield in children with undiagnosed global developmental delay/intellectual disability: a prospective study

2021 ◽  
Author(s):  
Yu Sun ◽  
Jing Peng ◽  
Desheng Liang ◽  
Xiantao Ye ◽  
Na Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Genome Sequencing ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Chromosomal Microarray Analysis ◽  
High Diagnostic Yield ◽  
Wide Range

Genome sequencing(GS) has been applied in the diagnosis of global developmental delay(GDD)/intellectual disability(ID). However, the performance in those with inconclusive results from chromosomal microarray analysis(CMA) and exome sequencing(ES) is unknown. We recruited 100 pediatric GDD/ID patients from multiple sites in China from February 2018 to August 2020 for GS. Patients have received at least one genomic diagnostic test prior to enrollment. Reanalysis of CMA/ES data was performed. The yield of GS was calculated and explanations for missed diagnoses by CMA/ES were investigated. Clinical utility was assessed by interviewing the parents by phone. The overall diagnostic yield of GS was 23%. Seven families could have been solved with reanalysis of ES data. 13 families were missed by previous CMA/ES due to improper method. Three remained unsolved after ES reanalysis due to allele dropout, complex variants missed by ES, and a CNV in untranslated regions. Follow-up of the diagnosed families revealed that nine families experienced changes in clinical management, including identification of targeted treatments, cessation of unnecessary treatment, and considerations for family planning. GS demonstrated high diagnostic yield and clinical utility in this cohort of undiagnosed GDD/ID patients, detecting a wide range of variant types of different sizes in a single workflow.

scholarly journals SAT-081 Hidden in Plain Sight: Rethinking Our Approach to Allan-Herndon-Dudley Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alyssa M Dye ◽  
Grace Bazan Nelson ◽  
Alicia Marie Diaz-Thomas
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Brain Mri ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Neurological Manifestations ◽  
Free T4 ◽  
Phase 2 Trial ◽  
Whole Exome

Abstract Background: Allan-Herndon-Dudley (AHD) is a rare X-linked disorder with neurological manifestations secondary to a mutation in monocarboxylate transporter 8, a protein that transports T3 into nerve cells in the brain. AHD is characterized by increased serum free T3, decreased serum free T4 and normal serum TSH levels as well as the severe neurological manifestations including global developmental delay, hypotonia, and joint contractures (1). A phase 2 trial using triodyothyroacetic acid has shown promise in treating this disorder (2). We report on three children who were diagnosed by whole exome sequencing after presenting with neurological manifestations. Clinical Cases: Patient 1 presented at 4 months to the neurology clinic for seizures. He had a normal newborn screen. Worsening developmental delays and central hypotonia prompted a brain MRI that revealed delayed myelination for age. At 6 months a chromosomal microarray and metabolic work-up were performed and were nondiagnostic. Whole exome sequencing was obtained at the age of 4.5 years revealing a mutation in the SLC16A2 gene (p.Ser210Tyr). Thyroid studies were consistent with the diagnosis. Patient 2 presented to neurology at 9 months for developmental delay. A brain MRI was obtained which was within normal limits. At 14 months an acylcarnitine profile was obtained which indicated a possible CPT1 deficiency, which did not fit his clinical picture. Chromosomal microarray as well as work-up for inborn errors of metabolism were performed and were nondiagnostic. Thyroid studies were obtained which showed low free T4 with normal TSH. Whole exome sequencing was obtained at the age of 2.5 years, which revealed a mutation in SLC16A2 (p.R371C). Patient 3 presented as sibling of patient 2 with known AHD syndrome. Testing for SLC16A2 was performed at the age of 5 months and returned positive for same mutation as sibling (p.R371C). Conclusion: Allan-Herndon-Dudley syndrome is a rare neurological disease secondary to a mutation in the T3 transporter protein to nervous tissue. A high index of suspicion as well as thyroid studies should be obtained in patients presenting with central hypotonia and global developmental delay with normal newborn screens, particularly in states that use TSH as a screening test. This is especially important as treatments are becoming available that may help prevent neurological devastation seen in these patients. References: 1. Dumitrescu AM, Fu J, Dempsey MA, Refetoff S. MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993 2. Groeneweg S, Peeters RP, Moran C, et al. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(9):695-706.

scholarly journals 239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype

2021 ◽  
pp. 1-6
Author(s):  
Konstantina Kosma ◽  
Konstantinos Varvagiannis ◽  
Anastasios Mitrakos ◽  
Maria Tsipi ◽  
Joanne Traeger-Synodinos ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Common Mechanism ◽  
Facial Dysmorphism ◽  
Gi Symptoms

Pathogenic <i>KMT2E</i> variants underly O&apos;Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning <i>KMT2E</i> suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning <i>KMT2E</i> and <i>LHFPL3</i>. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jayalakshmi Narayan Bhat ◽  
Brittany Mock ◽  
Aqeel Alaqeel ◽  
Aditya Dewoolkar ◽  
Ricardo Gomez
Keyword(s):  
Parathyroid Hormone ◽  
Developmental Delay ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Potential Contribution ◽  
Unbalanced Translocation ◽  
Genetic Syndrome ◽  
Severe Hypercalcemia ◽  
Vitamin D Levels ◽  
Duplication Syndrome

Abstract Objectives We report an uncommon case of severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8 with 2p duplication. After ruling out all the possible etiologies of hypercalcemia, we speculated a potential contribution of 2p duplication involving 225 genes. Case presentation An 11-month old female infant with global developmental delay, failure to thrive (FTT), hypotonia, amblyopia, constipation, and recent onset emesis was admitted to the hospital after an incidental diagnosis of severe hypercalcemia. Labs revealed normal serum phosphate, serum 25 (OH) vitamin D levels, and low serum parathyroid hormone (PTH) level. Elevated urinary calcium to creatinine ratio ruled out the possibility of hypocalciuric hypercalcemia. Endocrinological evaluations, including thyroid function test, Adrenocorticotropic hormone (ACTH), Cortisol, Insulin like growth factor 1 (IGF-1) were all normal. Transient elevation of parathyroid hormone related peptide (PTHrP) level was noted, but skeletal survey, chest X-ray and lab values including low 1,25 (OH)2 cholecalciferol, lactate dehydrogenase (LDH), uric acid (UA), erythrocyte sedimentation rate (ESR) excluded granulomatous diseases and malignancies. Further evaluation with chromosomal microarray (CMA) and whole exome gene sequencing (WES) showed an unbalanced chromosomal translocation with 2p duplication involving 225 genes. The infant showed an improvement with medical management. Conclusions 2p duplication syndrome is a rare syndrome characterized by developmental delay, feeding problems, FTT, hypotonia, constipation, and unusual facial features as noted in our case. However, hypercalcemia has been only reported once earlier in 2p duplication syndrome, which was the presenting feature of our case. We attributed this genetic syndrome as an underlying etiology for hypercalcemia after ruling out all the common potential causes of hypercalcemia.

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