[show abstract][hide abstract] ABSTRACT: The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15-base pair deletion mutation in a regulatory element of GPR56 that selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including "Broca's area," the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.
[show abstract][hide abstract] ABSTRACT: Intellectual disability (ID) has a prevalence of 3% and is classified according to its severity. An underlying etiology cannot be determined in 75-80% in mild ID, and in 20-50% of severe ID. After it has been shown that copy number variations involving short DNA segments may cause ID, genome-wide SNP microarrays are being used as a tool for detecting submicroscopic copy number changes and uniparental disomy. This study was performed to investigate the presence of copy number changes in patients with ID of unidentified etiology. Affymetrix® 6.0 SNP microarray platform was used for analysis of 100 patients and their healthy parents, and data were evaluated using various databases and literature. Etiological diagnoses were made in 12 patients (12%). Homozygous deletion in NRXN1 gene and duplication in IL1RAPL1 gene were detected for the first time. Two separate patients had deletions in FOXP2 and UBE2A genes, respectively, for which only few patients have recently been reported. Interstitial and subtelomeric copy number changes were described in 6 patients, in whom routine cytogenetic tools revealed normal results. In one patient uniparental disomy type of Angelman syndrome was diagnosed. SNP microarrays constitute a screening test able to detect very small genomic changes, with a high etiological yield even in patients already evaluated using traditional cytogenetic tools, offer analysis for uniparental disomy and homozygosity, and thereby are helpful in finding novel disease-causing genes: for these reasons they should be considered as a first-tier genetic screening test in the evaluation of patients with ID and autism.
European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 01/2014; · 2.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
The American Journal of Human Genetics 12/2013; · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate the health-related quality of life (HRQoL) in adolescents with psychogenic nonepileptic seizures (PNESs) and to identify factors affecting the quality of life in these patients. Thirty-four adolescents with PNESs were compared to 30 adolescents without any psychiatric disorder. The Schedule for Affective Disorders and Schizophrenia for School-Age Children, Present and Lifetime Version (K-SADS-PL) was applied to determine comorbid psychiatric disorders in the study group and to rule out any psychiatric disorder in the control group. The Pediatric Quality-of-Life Inventory (PedsQL) was used to assess the HRQoL. Physical HRQoL and psychosocial HRQoL, including emotional and school functioning, were found to be significantly lower in adolescents with PNESs. In the group with PNESs, the physical HRQoL and total HRQoL of adolescents with somatoform disorders other than PNESs and the emotional functioning of adolescents with major depressive disorder were worse than those of the adolescents without these comorbid psychiatric disorders. Seizure frequency and the duration of symptoms were not correlated with HRQoL scores. Treatment strategies in adolescents with PNESs should regard comorbid unexplained somatic symptoms and psychiatric disorders in addition to the reduction or cessation of seizures.
[show abstract][hide abstract] ABSTRACT: The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background.
Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue.
Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7.
These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.
Journal of Medical Genetics 06/2012; 49(6):391-9. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypophosphatasia (HPP) is an inborn error of metabolism characterized by defective bone mineralization caused by a deficiency in alkaline phosphatase (ALP) activity due to mutations in the tissue-nonspecific ALP (TNALP) gene. The clinical expression of the disease is variable. Six forms of HPP are identified according to age at presentation and clinical features. Patients with the infantile form are normal at birth. First symptoms appear within the first 6 months of life. Along with skeletal findings, HPP patients may present with hypercalcemia, seizures, pseudotumor cerebri, and pulmonary insufficiency. Seizures in HPP are refractory to conventional antiepileptic drugs, but are responsive to pyridoxine. Herein, we report a case of HPP who presented with pyridoxine-responsive seizures in the early neonatal period and was found to have hypercalcemia, skeletal demineralization and increased intracranial pressure.
Journal of Clinical Research in Pediatric Endocrinology 03/2012; 4(1):34-8.
[show abstract][hide abstract] ABSTRACT: The aim of this study is to find out mutations of Turkish GM1 gangliosidosis patients and to make genotype-phenotype correlations.
β-galactosidase activities were measured by using fluorometric substrate. Mutation screening of 16 exons of β-galactosidase gene and mutation detection were done by PCR-SSCP and DNA sequencing, respectively.
Four new mutations, c.188_189insT in exon 2, c.569_570insA in exon 6, p.K142Q in exon 4, p.G190D in exon 6, and one known mutation p.P549L in exon 15, were identified in the β-galactosidase gene in 5 Turkish patients. Mutations in exons 4 and 6 are in the active site and mutation in exon is in the galactose-binding domain of the β-galactosidase gene.
This is the first mutational analysis performed in Turkish GM1 gangliosidosis patients and shows the molecular heterogeneity of the disease in Turkish population. All identified mutations result in severe enzyme deficiency and infantile phenotype.
[show abstract][hide abstract] ABSTRACT: Conversion disorder (CD) in children remains a major challenge both in pediatric and mental health clinics and is still a prevalent psychiatric disorder in developing countries. The authors describe a 10-year-old boy with the complaints of inability to walk, speak or eat, excessive drooling, urinary and fecal incontinence, disturbance from light and sound, and expression of needs only by eye movements. The patient diagnosed with CD was followed by the Department of Child and Adolescent Psychiatry with play therapy, individual psychotherapy and family therapy. At the end of three months, the patient was discharged. This is one of the most challenging cases of CD in children. The most important aim of the treatment is to understand the need for conversion symptoms and to constitute a healthy psychological environment for the child rather than to remove the physical symptoms.
The Turkish journal of pediatrics 01/2012; 54(4):413-8. · 0.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Neurometabolic diseases diagnosed by cerebrospinal fluid (CSF) examination are GLUT1 deficiency, serine-deficiency syndromes, glycine encephalopathy, cerebral folate deficiency, neonatal vitamin-responsive epileptic encephalopathies, disorders of monoamine metabolism, and y-amino butyric acid (GABA) metabolism. We retrospectively analyzed and compared the demographic, clinical, laboratory, and neuroimaging features of 62 patients in whom CSF examination was performed. Of the 62 patients, 16 (25.8%) had a final diagnosis, including succinic semialdehyde dehydrogenase (SSADH) deficiency (n=4), aromatic amino acid decarboxylase (AADC) deficiency (n=4), L-dopa-responsive dystonia (n=3), glycine encephalopathy (n=2), pyridoxal-phosphate-dependent seizures (n=l), cerebral folate deficiency (n=1), and serine biosynthesi defect (n=1). Parental consanguinity was present in all patients except one Positive yield of a diagnostic lumbar puncture (LP) for the diagnosis of inherited neurotransmitter metabolism disorder was 25.8% overall. Oculogyric crisis (50%), diurnal variation (81.8%) and consanguinity (93.8%) were the only statistically significant variables between patients with and without a specific diagnosis. It is challenging to diagnose neurotransmitter defects, since there is no ideal set of clinical symptoms. In our cohort, consanguinity, diurnal variation and abnormal ocular movements were the most significant findings associated with a diagnosis of a specific neurometabolic disorder based on CSF examination. Early diagnosis is of great importance not only for specific treatment, but also for genetic counseling and prenatal diagnosis.
The Turkish journal of pediatrics 01/2012; 54(1):52-8. · 0.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: To evaluate the nature of the molecular lesions in the alpha-galactosidase A gene of two patients having Fabry disease.
Enzyme analyses were done using 4-methylumbellyferyl alpha-galactoside as substrate. Single stranded conformational polymorphism analysis and DNA sequencing were performed following PCR amplification of seven exons of alpha-galactosidase A gene.
Two new mutations, M11V and R190X, were identified. The female patient with M11V mutation had rheumatologic symptoms, microalbuminuria. The male patient with R190X mutation had a classical phenotype. M11V mutation is in the signal sequence of the peptide and may affect the targeting of the ribosomes to ER. R190X mutation causes premature termination, and probably leads to degradation of the protein.
This is the first study in our country investigating the molecular aspects of Fabry disease. It provides the molecular basis for understanding the underlying mechanism of Fabry disease, allows prenatal diagnosis and provides genotype/phenotype correlations.
[show abstract][hide abstract] ABSTRACT: Megalencephalic Leukoencephalopathy with Subcortical Cysts (MLC) is a rare autosomal recessive disease presenting with increased head circumference at birth or in early infancy. MLC1 (MIM 605908) mutations are responsible for this disorder. In this study, we sequenced the entire coding region of the MLC1 gene in 13 patients and detected five novel nucleotide variations in six of them. Two of the novel variations created a missense amino acid change and the other three were located in the introns and were putative splice mutations. One novel missense variation was observed in two unrelated patients from the central Black Sea region, and the data suggested a founder haplotype for this novel variation. Similarly, three unrelated patients with the previously reported p.Thr118Arg mutation shared a common haplotype. These data suggest an Anatolian origin for these two mutations. As in the previous reports, it is not possible to correlate the clinical phenotype of the patients with the mutation spectra.
European journal of medical genetics 12/2010; 54(3):281-3. · 1.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5-Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4,000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. Magnetic resonance imaging and postmortem brain analysis supports important roles for WDR62 in the proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as in postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest it has central roles in many aspects of cerebral cortical development.
[show abstract][hide abstract] ABSTRACT: The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.
[show abstract][hide abstract] ABSTRACT: Background: Bilateral perisylvian polymicrogyria (BPP) is a well-recognized malformation of cortical development commonly associated with epilepsy, cognitive impairment, and oromotor apraxia. Reports have suggested the association of BPP with arthrogryposis multiplex congenita. We sought to investigate the clinical, electrophysiological, and neuroradiological features of this combined syndrome to determine if there are unique features that distinguish BPP with arthrogryposis from BPP alone. Methods: Cases of BPP with congenital arthrogryposis were identified from a large research database of individuals with polymicrogyria. Clinical features (including oromotor function, seizures, and joint contractures), MR brain imaging, and results of neuromuscular testing were reviewed. Results: Ten cases of BPP with congenital arthrogryposis were identified. Most cases had some degree of oromotor apraxia. Only a few had seizures, but a majority of cases were still young children. Electrophysiological studies provided evidence for lower motor neuron or peripheral nervous system involvement. On brain imaging, bilateral polymicrogyria (PMG) centered along the Sylvian fissures was seen, with variable extension frontally or parietally; no other cortical malformations were present. We did not identify obvious neuroimaging features that distinguish this syndrome from that of BPP without arthrogryposis. Conclusions: The clinical and neuroimaging features of the syndrome of BPP with congenital arthrogryposis appear similar to those seen in cases of isolated BPP without joint contractures, but electrophysiological studies often demonstrate coexistent lower motor neuron or peripheral nervous system pathology. These findings suggest that BPP with arthrogryposis may have a genetic etiology with effects at two levels of the neuraxis.