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The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs ∗ 33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as "tightjunctionopathies.", Competing Interests: Declaration of interests J.R.L. has stock ownership in 23andMe and is a paid consultant for the Regeneron Genetics Center., (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 ( VARS1 ) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1 . We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations., Competing Interests: Conflict of interest All authors declare lack of conflict of interest in relation to this report., (© TÜBİTAK.)

Background: Goltz syndrome (GS) is a X-linked disorder defined by defects of mesodermal- and ectodermal-derived structures and caused by PORCN mutations. Features include striated skin-pigmentation, ocular and skeletal malformations and supernumerary or hypoplastic nipples. Generally, GS is associated with in utero lethality in males and most of the reported male patients show mosaicism (only three non-mosaic surviving males have been described so far). Also, precise descriptions of neurological deficits in GS are rare and less severe phenotypes might not only be caused by mosaicism but also by less pathogenic mutations suggesting the need of a molecular genetics and functional work-up of these rare variants., Results: We report two cases: one girl suffering from typical skin and skeletal abnormalities, developmental delay, microcephaly, thin corpus callosum, periventricular gliosis and drug-resistant epilepsy caused by a PORCN nonsense-mutation (c.283C > T, p.Arg95Ter). Presence of these combined neurological features indicates that CNS-vulnerability might be a guiding symptom in the diagnosis of GS patients. The other patient is a boy with a supernumerary nipple and skeletal anomalies but also, developmental delay, microcephaly, cerebral atrophy with delayed myelination and drug-resistant epilepsy as predominant features. Skin abnormalities were not observed. Genotyping revealed a novel PORCN missense-mutation (c.847G > C, p.Asp283His) absent in the Genome Aggregation Database (gnomAD) but also identified in his asymptomatic mother. Given that non-random X-chromosome inactivation was excluded in the mother, fibroblasts of the index had been analyzed for PORCN protein-abundance and -distribution, vulnerability against additional ER-stress burden as well as for protein secretion revealing changes., Conclusions: Our combined findings may suggest incomplete penetrance for the p.Asp283His variant and provide novel insights into the molecular etiology of GS by adding impaired ER-function and altered protein secretion to the list of pathophysiological processes resulting in the clinical manifestation of GS., (© 2022. The Author(s).)

Background: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only., Objectives: To fully characterize, both phenotypically and genotypically, NDUFA12 -related mitochondrial disease., Methods: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature., Results: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities ( n  = 6), optic atrophy ( n  = 2), or was unremarkable ( n  = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel., Conclusions: Our case series expands phenotype-genotype correlations in NDUFA12 -associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy., Competing Interests: Biological samples from pedigree C were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA) and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Biological samples from pedigree D were collected as part of the project RAC# 2121053. Francesca Magrinelli is supported by the Edmond J. Safra Foundation and by the research grant “Fondo Gianesini” in collaboration with UniCredit Foundation and University of Verona, Italy. Robert W. Taylor is supported by the Wellcome Centre for Mitochondrial Research (203,105/Z/16/Z), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), Mitochondrial Disease Patient Cohort (UK) (G0800674), the UK NIHR Biomedical Research Centre for Aging and Age‐related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, The Lily Foundation, the Pathology Society and the UK NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children. Kailash P. Bhatia has received grant support from Wellcome/MRC, NIHR, Parkinson's UK and EU Horizon 2020. Tobias B. Haack was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—418081722, 433158657. Kate Sargeant thanks the UK NHS Specialist Commissioners, which funds the “Rare Mitochondrial Disease Service for Adults and Children” in Oxford for their support. The views expressed are those of the author(s) and not necessarily those of the NHS or the UK Department of Health and Social Care. Rita Horvath is a Wellcome Trust Investigator (109,915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20,014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Henry Houlden is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). The authors declare that there are no conflicts of interest relevant to this work., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Microtubules help building the cytoskeleton of neurons and other cells. Several components of the gamma-tubulin (γ-tubulin) complex have been previously reported in human neurodevelopmental diseases. We describe two siblings from a consanguineous Turkish family with dysmorphic features, developmental delay, brain malformation, and epilepsy carrying a homozygous mutation (p.Glu311Lys) in TUBGCP2 encoding the γ-tubulin complex 2 (GCP2) protein. This variant is predicted to disrupt the electrostatic interaction of GCP2 with GCP3. In primary fibroblasts carrying the variant, we observed a faint delocalization of γ-tubulin during the cell cycle but normal GCP2 protein levels. Through mass spectrometry, we observed dysregulation of multiple proteins involved in the assembly and organization of the cytoskeleton and the extracellular matrix, controlling cellular adhesion and of proteins crucial for neuronal homeostasis including axon guidance. In summary, our functional and proteomic studies link TUBGCP2 and the γ-tubulin complex to the development of the central nervous system in humans., Competing Interests: The authors have no conflicts of interest, and the publication has not been submitted to any other journal., (© 2020 The Author(s).)

Acute cerebellitis is one of the most common cerebellar disorders and occurs due to para-infectious, post-infectious, or post-vaccination cerebellar inflammation. Herpes simplex virus-1 (HSV-1) is known as a common infectious cause of sporadic encephalitis. Cerebellar involvement of HSV-1 is rare and almost always associated with meningoencephalitis. To date, HSV-1 has been identified as the cause of acute isolated cerebellitis in only two patients. Here we report another case of isolated acute cerebellitis caused by HSV-1 in a 20-month-old boy.

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

Objective: This study presents the neurologic phenotypes of 2 brothers with a novel homozygous COL4A1 mutation that was identified in a large Turkish consanguineous cohort of neurogenetic diseases., Methods: Whole-exome sequencing and bioinformatic analysis of consanguineous families with children affected by early-onset, neurogenetic disorders was performed using the RD-Connect Genome-Phenome Analysis Platform. We also performed clinical, EEG, and neuroimaging analyses in unaffected siblings and parents., Results: We have identified a homozygous missense mutation in COL4A1 (p.Gly1278Ser, NM_001845.5:c.3832G>T) in 2 siblings affected by small vessel brain disease with periventricular leukoencephalopathy and ocular defects. Presenting symptoms included mild weakness, hemiparetic gait, pyramidal findings, and seizures, whereas their intellectual and behavioral functions were normal. Both parents and 5 of the siblings (3 boys and 2 girls) were heterozygous for the variant. They did not show any clinical or laboratory signs of small vessel disease., Conclusions: COL4A1 has previously been associated with dominant small vessel disease of the brain and other organs, manifesting with high penetrance in heterozygous mutation carriers. Our findings provide evidence that COL4A1 -related encephalopathy can be inherited in an autosomal recessive manner, which is important for counseling, prognosis, and treatment. Genotype-phenotype correlations remain to be established., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The aim of this study is to analyze the epidemiology of the clinical and genetic features of childhood-onset limb-girdle muscular dystrophies (LGMD) in the Aegean part of Turkey. In total fifty-six pediatric cases with LGMD followed in four different pediatric neurology departments in the Aegean region of Turkey were evaluated. Among them, LGMD2C was the most common followed by LGMD2A, LGMD2D, and LGMD2F with equal frequencies. In twenty-eight patients (50%) the diagnosis could be confirmed by genetic analysis, where SGCG proved to be disease-causing in most of the cases. About half of the patients were diagnosed with whole exome or targeted gene sequencing. A positive correlation between muscle biopsy and genetic findings were observed in 11% of the patients. We report one novel frameshifting mutation in TTN . Knowledge on frequencies of childhood-onset limb-girdle muscular dystrophies and related genes in Turkey will lead to a prompt diagnosis of these neuromuscular disorders.

Non-ketotic hyperglycinemia (NKH) is a rare inborn error of metabolism and is caused by a glycine cleavage system deficiency. Eighty-five percent of patients present with the neonatal type of NKH, the infants initially develop lethargy, seizures, and episodes of apnea, and most often death. Between 60-90% of cases are caused by mutations in the glycine decarboxylase (GLDC). We believed that more mutation reports especially for rare disease as NKH help to evaluate the genotype-phenotype relationship in patients with GLDC. In this study, we describe a case of a neonate admitted to intensive care unit with hypotonia, respiratory failure, lethargy, poor feeding. Due to the history of 2 non-ketotic hyperglycinemia diagnosed male siblings, molecular prenatal diagnosis in patient was performed and a novel c.2963G>A (Arg998Gln) homozygous mutation within the GLDC gene has been detected. We aimed to contribute to mutation knowledge pool of GLDC gene with a novel mutation.

Aicardi syndrome (AS) is an X-linked inherited disorder characterized by infantile spasms, chorioretinal lacunae, and agenesis or hypogenesis of the corpus callosum. The syndrome is more frequently seen in females but is observed in XXY male patients. Central nervous system, ocular, and costovertebral malformations may also seen in AS. Eye findings are of a considerable diagnostic importance; the chorioretinal lacunae are pathognomonic for AS and are generally bilateral. The outcome of the disease is generally severe, with a high mortality rate and poor developmental outcome. It is not clear which characteristics of the syndrome are related to a good prognosis in terms of psychomotor development, epileptic seizures, and survival. The purpose of this report was to demonstrate the spectrum of the clinical findings and the course of AS in two Turkish patients with different ocular and cranial MRI findings.