OBJECTIVE:SCN1A variants are the primary genetic cause of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy characterized by early-onset prolonged seizures and progressive neurodevelopmental impairment. Early molecular diagnosis may influence treatment decisions and clinical outcomes. To characterize the molecular spectrum of SCN1A variants and describe the associated clinical and therapeutic features in children with suspected DS. METHODS:This retrospective study included children evaluated between 2018 and 2020 with clinical suspicion of DS or febrile seizures with epilepsy who were referred for SCN1A genetic testing. Next-generation sequencing was used to detect sequence variants, complemented by multiplex ligation-dependent probe amplification for copy number analysis. A total of 60 patients were screened, and 18 patients carrying pathogenic or likely pathogenic SCN1A variants and fulfilling clinical criteria for DS were included. RESULTS:Eighteen patients were identified with heterozygous pathogenic or likely pathogenic SCN1A variants, including 6 novel variants. Segregation analysis demonstrated that all 15 tested patients had de novo variants. Seizure onset ranged from 2.5 to 8 months, predominantly before 6 months of age. Several patients were exposed to sodium channel-blocking agents prior to molecular confirmation, with seizure aggravation and subsequent treatment modification. All patients required multiple anti-seizure medications and showed varying degrees of neurodevelopmental impairment. CONCLUSION:SCN1A-confirmed DS is associated with substantial seizure burden and neurodevelopmental morbidity. Delayed molecular diagnosis may lead to inappropriate treatment exposure and seizure worsening. Early genetic testing in infants with early-onset seizures may improve treatment selection and clinical outcomes.

Objective: Pathologies occurring in Transport Protein Particles (TRAPP) involved in vesicular traffic are rare diseases called TRAPPopathies. The aim of this study was to present a case series of TRAPPopathies, to describe the clinical and molecular findings, and additionally to review our cases together with other cases reported from Turkiye. Materials and Methods: Patients with neurological findings such as microcephaly, epilepsy, muscular dystrophy, and intellectual disability who were referred to Bezmialem Vak & imath;f University, Faculty of Medicine, Department of Medical Genetics between March 2018 and March 2020 were reviewed for this study. Patients with pathogenic variants in genes with TRAPP complex family with known phenotype or not yet associated any human disease were included in the study. Clinical, radiological, and molecular findings obtained by whole exome sequences of cases were re-evaluated. Results: Molecular analysis revealed homozygous c.454+3A>G p.(?) variant in TRAPPC4 (NM_016146.5) gene in Case 1 with neuromotor retardation, intractable seizures, postnatal microcephaly, and cerebral-cerebellar atrophy, homozygous novel c.57C>G p.(Try19Ter) variant in TRAPPC6B (NM_001079537.1) in Case 2 with epilepsy, postnatal microcephaly, severe neuromotor retardation, and autism, and homozygous c.2938G>A p.(Gly980Arg) variant in TRAPPC11 (NM_021942.5) gene in Case 3 with muscular dystrophy, cataract, neuromotor retardation, and microcephaly. Conclusion: This study showed that newly identified genes in TRAPPopathies are responsible for microcephaly, developmental delay, epilepsy, intellectual disability, cerebral-cerebellar atrophy, and autism. Although the genes in the TRAPP family work independently of each other, the diseases in this group are called TRAPPopathies because their phenotypes overlap. The aim of our study was to discuss the clinical findings and to summarize the mutation profile of the genes in the TRAPP family in Turkiye.

Objective: Tay-Sachs disease is a fatal inherited lysosomal storage disease that mostly has an early infantile onset. We presented a case series of Tay-Sachs disease, describe the clinical and molecular findings, and compare the genetic spectrum with previously reported mutations from Turkiye.Methods: Patients with Tay-Sachs disease who were referred to the Istanbul University, Istanbul Faculty of Medicine, Department of Medical Genetics between January 2016 and December 2021 were included in this study. The diagnosis was confirmed by determining the level of serum 0-hexosaminidase activity and the detection of a biallelic related variant upon Sanger sequencing of the HEXA gene. The clinical and molecular findings of nine cases were re-evaluated. Results: Three disease-causing variants in the HEXA gene including c.78G>A (p.(Trp26Ter)) in three cases, c.1177C>T (p.(Arg393Ter)) in two cases, and c.1100_1111del (p.(Gly367_Tyr370del)) in three cases were determined. Moreover, a novel c.786C>G (p.(His262Gln)) variant was detected in one case. All of the stated variants were identified in the homozygous state.Conclusion: Our study both reassessed and expanded the known mutation spectrum of Tay-Sachs disease in Turkiye. Given the expanding horizon of newborn screening and population carrier testing, understanding the spectrum of population-specific disease-causing variants will facilitate early diagnosis of patients and carriers.

Purpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants.Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm-and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies.Results: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global develop-mental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involve-ment (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. Conclusion: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.(c) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Background The trafficking protein particle (TRAPP) complex subunit 9 (C9) protein is a member of TRAPP-II complexes and regulates vesicle trafficking. Biallelic mutations in the TRAPPC9 gene are responsible for intellectual disability with expanded developmental delay, epilepsy, microcephaly, and brain atrophy. TRAPPC9-related disease list is still expanding, however, the functional effects of only a limited fraction of these have been studied. Methods In a patient with a pathological variant in TRAPPC9, clinical examination and cranial imaging findings were evaluated. Whole-exome sequencing, followed by Sanger sequencing was performed to detect and verify the variant. To confirm the functional effect of the mutation; variant mRNA and protein expression levels were evaluated by qRT-PCR and Western blotting. Immunostaining for TRAPPC9 and lipid droplet accumulation were examined. Results We have identified a novel homozygous c.696C>G (p.Phe232Leu) pathogenic variant in TRAPPC9 (NM_031466.6) gene as a cause of severe developmental delay. Functional characterization of the TRAPPC9 variant resulted in decreased mRNA and protein expression. The intracellular findings showed that TRAPPC9 protein build-up around the nucleus in mutant type while there was no specific accumulation in the control cell line. This disrupted protein pattern affected the amount of neutral lipid-carrying vesicles and their homogenous distribution at a decreasing level. Conclusion Biallelic variants in the TRAPPC9 gene have been reported as the underlying cause of intellectual disability. This study provides functional evidence of the novel variant in TRAPPC9 We demonstrated that the loss of function variant exclusively targeting TRAPPC9 may explicate the neurological findings through vesicle trafficking.

BACKGROUND:Krabbe disease is a rare lysosomal storage disorder with a neurodegenerative course that occurs because of the deficiency of the beta-galactocerebrosidase (GALC) enzyme activity. The genetic basis of Krabbe disease consists of biallelic mutations in the GALC gene, but the genetic spectrum in the Turkish population is poorly defined. We aimed to present a Turkish case-series with infantile-onset Krabbe disease, define the clinical and molecular findings and compare the genetic spectrum with the mutations previously reported in the literature.METHODS:Six cases, who were referred to our clinic between 2015-2019, with a definite diagnosis of infantileonset Krabbe disease were included in the study. The family history, clinical information, biochemical and radiological examinations of the patients were screened and evaluated. All encoded exons and exon-intron regions of the GALC gene were sequenced using next generation sequencing technology. Multiplex ligationdependent probe amplification analysis was used for deletion type mutations that could not be detected by sequence analysis.RESULTS:GALC gene sequence analysis revealed four known mutations including c.1394C > T (p.Thr465Ile), c.411_413delTAA (p.Lys139del), c.820G > C (p.Glu274Gln), and 30 kilobase deletion mutation among the exons 11-17 (IVS10del30kbp). Moreover, the c.1623G > A (p.Trp541Ter) variant, which was not previously reported in the literature, was detected in two cases.CONCLUSIONS:We believe that the demonstration of the genetic spectrum of infantile-onset Krabbe disease in Turkish patients will be an important contribution to the GALC mutation data in our country. More importantly, two novel variants were defined. This knowledge may enable early detection and treatment with the advent of a carrier or newborn screening tests.

The appropriate treatment of pediatric mandibular condyle fractures is subject to much debate and concern among surgeons, with improper treatment potentially resulting in a number of adverse outcomes. Such outcomes include the disruption of mandible growth, decreased posterior facial height, facial asymmetry, and temporomandibular joint ankylosis. Several surgical and nonsurgical approaches to these fractures have been described in the literature; however, each one carries its own risk of various complications. In this study, the authors illustrate a new atraumatic approach for mild to moderately displaced subcondylar fractures, with least possible complications and unexpected outcomes. In this study, 6 patients (2 female and 4 male) with unilateral medially displaced condylar base and neck fractures, angulated between 30 and 45 degrees, were treated using a novel intraoral approach. The follow-up period varied from 12 to 18 months. All patients achieved normal occlusion and had painless functioning of the temporomandibular joint with proper mouth opening (>35 mm) without any recurrence at long term follow up. This minimally invasive approach could eliminate the possibility of major complications and be considered a safe and feasible surgical technique for certain cases of pediatric mandibular condyle fracture.

Objective: Obesity is known to affect thyroid function. Recently, waist-height ratio (WHtR) has been considered as a useful marker of subclinical hypothyroidism in obese cases, but its relation with thyroid autoimmunity still remains unclear. We evaluated the effect of body fat mass, WHtR, and metabolic parameters on thyroid autoantibody levels in children with obesity. Methods: This was a cross-sectional study carried out with an obese [n=56, male/female (M/F): 29/26] and a healthy group (n=38, M/F: 19/19). All subjects underwent anthropometric measurements, laboratory investigations for thyroid function tests, thyroid peroxidase (TPO-ab) and thyroglobulin-antibodies (Tg-ab), transaminases, blood glucose, insulin levels, and lipids after overnight fasting; homeostatic model assessment for insulin resistance (HOMA-IR) was calculated for assessment of insulin resistance. Fat mass was estimated by multiple frequency bioimpedance analysis in the obese group, which was further divided into two subgroups according to the median of WHtR. All parameters were compared between the groups/subgroups. Results: In the obese group, weight, height, body mass index (BMI), free triiodothyronine, thyrotropin, TPO-ab, insulin, low density lipoprotein-cholesterol, total cholesterol, alanine aminotransferase levels, and HOMA-IR were significantly higher than the controls group (p<0.05 for all). Median of WHtR was 0.6 in the obese group. In the “WHtR >0.6” subgroup (n=28), weight, BMI, fat mass, TPO-ab, Tg-ab, insulin and triglyceride levels were higher than WHtR ≤0.6 subgroup (p<0.05). A positive correlation was obtained between Tg-ab and WHtR (rho=0.28, p=0.041). Conclusion: Euthyroid children with obesity and a WHtR >0.6 are likely to have higher thyroid antibody levels, and Tg-ab levels have a positive correlation with WHtR, which reveals an association of central adiposity with thyroid autoantibody levels in these cases.

Objective This study aimed to investigate the relationship between autism spectrum disorder (ASD) and vitamin D levels in children and adolescents. Methods We measured serum 25-hydroxyvitamin D (25-OHD) levels in 1529 patients with ASD aged 3 to 18 years, without any additional chronic diseases. Levels of 25-OHD were compared according to sex, age (<11 or ≥11 years), and birth season. Additionally, laboratory parameters (calcium, phosphorus, alkaline phosphatase, and 25-OHD) of 100 selected patients with ASD were compared with those of the healthy control group. Results Vitamin D deficiency or insufficiency was found in approximately 95% of all patients. Levels of 25-OHD in adolescent patients with ASD aged 11 to 18 years were significantly lower than those in patients aged younger than 11 years. In the 100 selected patients with ASD, mean serum 25-OHD levels were significantly lower and alkaline phosphatase levels were higher compared with those in healthy children. Conclusion Our study suggests a relationship between vitamin D and ASD in children. Monitoring vitamin D levels is crucial in autistic children, especially adolescents, to take protective measures and treat this condition early.

Amac: Polikistik over sendromu tanisi alan ergen kizlarin basvurudaki klinik, metabolik ve endokrin bulgularini degerlendirmeyi amacladik. Gerec-Yontemler : Ocak 2008-Aralik 2012 tarihleri arasinda Rotterdam tani olcutlerine gore tanilandirilan 53 olgunun yakinmalari, adet duzenleri, fizik baki bulgulari (antropometrik olcumler, Ferriman Gallwey skoru, akantozis nigrikans varligi), bazal/uyarilmis adrenal androjen, aclik glukoz/insulin degerleri, kan yag ve lipoprotein duzeyleri, pelvik ultrasonografi bulgulari kaydedildi. Yasa gore vucut kitle indeksi (VKI) %95 ve uzeri olgular sisman olarak tanimlandi. Oligo/amenore, hiperandrojenizm ve ultrasonografide polikistik over bulgularinin hepsinin bulundugu hastalar klasik grup olarak adlandirildi. Kan trigliserit duzeyi yasa gore %97 degerinden fazla ise yuksek olarak nitelendirildi; HOMA-IR degeri ≥ 3,82 olgularda insulin direnci var kabul edildi. Bulgular: Ortalama basvuru yasi 15±1,5 yildi. En sik yakinma adet duzensizligiydi (%49,1). Adet duzeni ayrintili sorgulandigindaysa olgularin %60,4’unde oligo/amenore oldugu goruldu. Olgularin  %43,4’u sismandi. Akantozis nigrikans (%37,7) olan olgularda sismanlik daha sikti (p=0.010). Hirsutizm %41,5 olguda orta-agir (Ferriman Gallwey skoru≥16) olarak belirlendi: orta-agir olgularda oligo/amenore daha sikti (p=0,007). Insulin direnci %39,6 olguda (%81 obez) vardi ve akantozis nigrikans saptananlarda daha sikti (p=0,001). Trigliserit yuksekligi 49 olgudan 7’sinde saptandi; bu olgularin hepsinde insulin direnci de mevcuttu (p=0,033). Serum trigliserit duzeyi ile HOMA-IR degeri arasinda korelasyon saptandi (r:0,415). Polikistik over bulgusu olgularin % 96,2’sinde belirlendi. Klasik grupta diger gruba gore oligo/amenore, hirsutizm, akantozis nigrikans, trigliserit yuksekligi anlamli (p<0.005), total testosteron duzeyi anlamliliga yakin yuksekti (p=0.056). Sonuc: Polikistik over sendromu tanisinda adet duzeni ayrintili olarak sorgulanmalidir. Akantozis nigrikans saptanan olgular insulin direnci acisindan irdelenmeli, insulin direnci varliginda trigliserit yuksekligi arastirilmalidir.

Amaç: Polikistik over sendromu tanısı alan ergen kızların başvurudaki klinik, metabolik ve endokrin bulgularını değerlendirmeyi amaçladık.Gereç-Yöntemler: Ocak 2008-Aralık 2012 tarihleri arasında Rotterdam tanı ölçütlerine göre tanılandırılan 53 olgunun yakınmaları, adet düzenleri, fizik bakı bulguları (antropometrik ölçümler, Ferriman Gallwey skoru, akantozis nigrikans varlığı), bazal/uyarılmış adrenal androjen, açlık glukoz/insülin değerleri, kan yağ ve lipoprotein düzeyleri, pelvik ultrasonografi bulguları kaydedildi. Yaşa göre vücut kitle indeksi (VKİ) %95 ve üzeri olgular şişman olarak tanımlandı. Oligo/amenore, hiperandrojenizm ve ultrasonografide polikistik over bulgularının hepsinin bulunduğu hastalar klasik grup olarak adlandırıldı. Kan trigliserit düzeyi yaşa göre %97 değerinden fazla ise yüksek olarak nitelendirildi; HOMA-IR değeri ≥ 3,82 olgularda insülin direnci var kabul edildi.Bulgular: Ortalama başvuru yaşı 15±1,5 yıldı. En sık yakınma adet düzensizliğiydi (%49,1). Adet düzeni ayrıntılı sorgulandığındaysa olguların %60,4’ünde oligo/amenore olduğu görüldü. Olguların %43,4’ü şişmandı. Akantozis nigrikans (%37,7) olan olgularda şişmanlık daha sıktı (p=0.010). Hirsutizm %41,5 olguda orta-ağır (Ferriman Gallwey skoru≥16) olarak belirlendi: orta-ağır olgularda oligo/amenore daha sıktı (p=0,007). İnsülin direnci %39,6 olguda (%81 obez) vardı ve akantozis nigrikans saptananlarda daha sıktı (p=0,001). Trigliserit yüksekliği 49 olgudan 7’sinde saptandı; bu olguların hepsinde insülin direnci de mevcuttu (p=0,033). Serum trigliserit düzeyi ile HOMA-IR değeri arasında korelasyon saptandı (r:0,415). Polikistik over bulgusu olguların % 96,2’sinde belirlendi. Klasik grupta diğer gruba göre oligo/amenore, hirsutizm, akantozis nigrikans, trigliserit yüksekliği anlamlı (p<0.005), total testosteron düzeyi anlamlılığa yakın yüksekti (p=0.056). Sonuç: Polikistik over sendromu tanısında adet düzeni ayrıntılı olarak sorgulanmalıdır. Akantozis nigrikans saptanan olgular insülin direnci açısından irdelenmeli, insülin direnci varlığında trigliserit yüksekliği araştırılmalıdır.

The medical records of 2283 patients with ventricular septal defect (VSD) were reviewed to determine spontaneous closure, left ventricular-to-right atrial shunt, subaortic ridge, and aortic valve prolapse. One thousand eight hundred and twenty-three patients had been followed 1 month to 26 years (median 4 years) by echocardiography. Most of 460 patients could not be followed due to transportation of the institution. VSD was perimembranous in 68.8% (1255), trabecular muscular in 21.7% (395), muscular outlet in 6% (109), muscular inlet in 2.6% (48), and doubly committed subarterial in 0.9% (16). Defect size was classified in 66.8% (1218) as small, in 15.7% (286) as moderate, and in 17.5% (319) as large. VSD closed spontaneously in 18.8% (343 of 1823 patients) by ages 40 days to 24.9 years (median, 1.8 years). One hundred fifty-seven of 1255 perimembranous defects (12.5%) and 167 of 395 trabecular muscular defects (42%) closed spontaneously (p < 0.001). Defect size became small in 306 (16.8%) of patients with VSD at a median of 2.5 years. Aneurysmal transformation was detected in 32.9% (600), left ventricular-to-right atrial shunt in 9.7% (176), subaortic ridge in 2.6% (48) of 1823 patients who were followed. In 381 (20.9%) of the 1823 patients, the VSD had been closed by a surgical or transcatheter technique. Surgery is required in one-fifth of patients with subaortic ridge or aortic valve prolapse. In conclusion, isolated VSDs are usually benign abnormalities that tend to shrink and close spontaneously.