ABSTRACT
POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.
Subject(s)
Autistic Disorder , Epilepsy , Intellectual Disability , Humans , Child , Intellectual Disability/genetics , Autistic Disorder/genetics , Phenotype , Epilepsy/genetics , Mutation, Missense/genetics , Developmental Disabilities/genetics , POU Domain Factors/geneticsABSTRACT
POU3F3 proteins are eukaryotic transcription factors and contribute to the processes in the development of brain and kidney. Pathogenic POU3F3 variants cause a neurodevelopmental disorder called Snijders Blok-Fisher syndrome (SNIBFIS). This article reports a new SNIBFIS case harboring a novel heterozygous c.1018_1019delCAinsTT (p.Gln340Leu) variant in the POU3F3 gene. This variant affects the α2 helix of POU-S domain and is predicted to be "pathogenic" by multiple in-silico tools. The proband had severe intellectual disability, hypotonia, autistic features, sleep disturbances, and dysmorphic features. The association with epilepsy and hemangioma like two of the three previously reported patients with mutations in the POU-S domain was also a remarkable finding to understand the importance of POU-S domain. This clinical report also highlights the interest of reinterpretation of molecular data and brings a new perspective to the genotype-phenotype relationship in "Snijders Blok-Fisher syndrome".
Subject(s)
Developmental Disabilities/genetics , Epilepsy/genetics , Hemangioma/genetics , POU Domain Factors/genetics , Brain/growth & development , Brain/pathology , Developmental Disabilities/complications , Developmental Disabilities/diagnosis , Developmental Disabilities/pathology , Epilepsy/complications , Epilepsy/diagnosis , Epilepsy/pathology , Genetic Association Studies , Hemangioma/complications , Hemangioma/diagnosis , Hemangioma/pathology , Humans , Kidney/growth & development , Kidney/pathology , POU Domain Factors/ultrastructure , Protein Conformation, alpha-Helical/geneticsABSTRACT
Phosphomannomutase 2 deficiency (PMM2-CDG) is an autosomal recessive congenital disorder of glycosylation, characterized by multisystem phenotypes, mostly including neurological involvement. In Turkey, due to high rates of consanguinity, many patients with autosomal recessive disorders have homozygous variants and these diseases are more common, compared to Europe. However, published reports of PMM2-CDG from Turkey are scarce. Here, we describe clinical and molecular characteristics of PMM2-CDG patients diagnosed in three centers in Turkey, using data obtained retrospectively from hospital records. We also analyzed an in-house exome database of 1,313 individuals for PMM2 variants and estimated allele, carrier and disease frequencies, using the Hardy-Weinberg law. Eleven patients were identified from 10 families, displaying similar characteristics to previous publications, with the exception of the first report of epilepsia partialis continua and increased prevalence of sensorineural hearing loss. p.Val231Met was the most common variant, and was homozygous in four patients. This novel genotype results in a neurological phenotype with subclinical visceral involvement. Exome database analysis showed an estimated prevalence of 1:286,726 for PMM2-CDG, which is much lower than expected (1:20,000 in Europe) because of the lack of predominance of the common European p.Asp141His allele, associated with a severe phenotype (allele frequency of 1:2,622 compared to 1:252 in gnomAD). These data suggest that prevalence, phenotypes and genotypes of PMM2-CDG in Turkey differ significantly from those in Europe: Milder phenotypes may be more common, but the disease itself rarer, requiring a higher clinical suspicion for diagnosis. The association of sensorineural hearing loss with PMM2-CDG warrants further study.
Subject(s)
Congenital Disorders of Glycosylation/epidemiology , Congenital Disorders of Glycosylation/pathology , Mutation , Phosphotransferases (Phosphomutases)/deficiency , Child , Child, Preschool , Congenital Disorders of Glycosylation/genetics , Female , Genotype , Glycosylation , Humans , Infant , Male , Phenotype , Phosphotransferases (Phosphomutases)/genetics , Prevalence , Retrospective Studies , Turkey/epidemiologyABSTRACT
Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
Subject(s)
Brain Diseases/diagnosis , Brain Diseases/genetics , Epilepsy/diagnosis , Kv1.2 Potassium Channel/genetics , Animals , Brain Diseases/complications , Epilepsy/complications , Epilepsy/genetics , Genetic Association Studies , Mutation , Oocytes/physiology , Phenotype , XenopusABSTRACT
BACKGROUND: Results of epidemiologic studies have determined several risk factors for asthma in school-age children. OBJECTIVE: To examine whether parental and perinatal risk factors, along with infantile feeding patterns, were associated with asthma in children with grass pollen allergy and allergic rhinitis. METHODS: We retrospectively analyzed the data of our cohort, which consisted of children with allergic rhinitis. Only children with grass pollen sensitization were enrolled. A detailed questionnaire regarding demographic features and perinatal events was given to the parents. RESULTS: A total of 293 children (200 boys [68.3%]; with median age, 10.2 years [interquartile range {IQR}, 7.4-13.0 years]) were included. A total of 109 children (37.2%) had accompanying asthma. The median age of onset of rhinitis symptoms was earlier (5.3 years [IQR, 4.0-8.0 years] versus 7.0 years [IQR, 5.0-10.0 years]; p = 0.001), histories of prematurity (16.7 versus 6.5%; p = 0.006), preeclampsia (5.5 versus 0%; p = 0.001), neonatal intensive care unit admission (15.1 versus 6.0%; p = 0.01), phototherapy (17.9 versus 7.1%; p = 0.004), early formula feeding (58.7 versus 41.2%; p = 0.006), and parental asthma (25.0 versus 11.4%; p = 0.002) were more frequent in children with asthma. Multivariate logistic regression analysis revealed prematurity (odds ratio [OR] 2.78 [95% confidence interval [CI],1.24-6.24]; p = 0.013), history of formula feeding (OR 1.81 [95% CI, 1.09-3.01]; p = 0.022), and parental asthma (OR 2.37 [95% CI, 1.22-4.63]; p = 0.011) were associated with asthma in school-age children with grass pollen-induced allergic rhinitis. CONCLUSION: Close monitoring of patients with these risk factors may help with an earlier diagnosis of asthma and prompt initiation of therapeutic interventions in children with allergic rhinitis and who were sensitized to grass pollen.
Subject(s)
Asthma/epidemiology , Premature Birth/epidemiology , Prenatal Exposure Delayed Effects/epidemiology , Rhinitis, Allergic, Seasonal/epidemiology , Rhinitis, Allergic/epidemiology , Adolescent , Age of Onset , Allergens/immunology , Antigens, Plant/immunology , Child , Female , Humans , Immunization , Male , Pollen/immunology , Pregnancy , Retrospective Studies , Risk FactorsABSTRACT
BACKGROUND: Childhood obesity leads to many complications including impaired respiratory function. There are various anthropometric parameters related to obesity. OBJECTIVE: To investigate the correlation between anthropometric indices and pulmonary function test results in children without asthma. METHODS: Children without any respiratory disorders were enrolled in this study. Anthropometric measurements, such as height, weight, neck circumference (NC), and waist circumference, were obtained from the enrollees and body mass index was calculated. Afterward, pulmonary function tests were performed using spirometry. RESULTS: A total of 178 children (106 boys, 59.5%) with a mean age of 9.7 years were included the study. NC was above the 90th percentile in 65 children. Importantly, pulmonary parameters, such as forced expiratory volume during the first second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC), were lower in subjects with a large NC. Similarly, waist circumference was above the 90th percentile in 67 children, and FEV1/FVC was significantly lower in children with a large waist circumference. Moreover, there was a statistically significant negative correlation among FEV1, FEV1/FVC, and body mass index SD score. Also, multivariable linear regression analysis showed that an NC above the 90th percentile was associated with lower FEV1 and FEV1/FVC values. CONCLUSION: We identified NC as a novel anthropometric index that is strongly correlated with respiratory functions in children. Therefore, close monitoring of respiratory symptoms, particularly in children with obesity and a large NC, could help with early and prompt determination of respiratory complications of obesity.
Subject(s)
Body Weights and Measures , Lung/physiology , Neck/anatomy & histology , Adolescent , Body Mass Index , Child , Child, Preschool , Female , Humans , Lung/physiopathology , Male , Obesity/epidemiology , Respiratory Function TestsABSTRACT
BACKGROUND: Obesity is a well-established risk factor for asthma. Previous studies have reported that central obesity is associated with asthma. OBJECTIVE: To investigate the association between fat distribution, which is determined by anthropometric measures, including neck circumference (NC), and asthma in school-aged children. METHODS: Children diagnosed as having asthma were enrolled along with controls who were admitted to our outpatient department with allergic symptoms, such as rhinitis, urticaria and atopic dermatitis. Anthropometric measures, including height, weight, NC, waist circumference, and hip circumference, were obtained. Skin prick tests, blood eosinophil counts, and serum total IgE level measurements were performed. RESULTS: A total of 196 children (92 male [46.9%]) were included. Asthma was present in 102 patients (52.1%). Ninety-one of the patients (46.4%) were overweight, and 45 patients (22.9%) were obese. The NC of children with asthma was significantly higher than that of children in the control group. Grades defined according to NC percentiles were also significantly different between groups. In children with asthma, the prevalence of children with an NC higher than the 90th percentile (grade 6) was more frequent when compared with controls. The median NC of obese-overweight children with asthma was significantly higher compared with obese-overweight controls without asthma. Results of multivariable logistic regression analysis revealed that the presence of an NC in the greater than 90th percentile was associated with asthma in obese-overweight children. CONCLUSION: This study found that NC, which is a simple anthropometric measure, is associated with asthma in obese children.
Subject(s)
Asthma/diagnosis , Neck/anatomy & histology , Obesity/diagnosis , Allergens/immunology , Asthma/blood , Body Weights and Measures , Child , Eosinophils/immunology , Female , Humans , Immunoglobulin E/blood , Leukocyte Count , Male , Obesity/blood , Skin TestsABSTRACT
AIM: The objective of our study was to investigate nerve conduction in normoglycemic obese children. METHODS: A total of 60 children with obesity (30 female and 30 male) and 30 healthy children (15 female and 15 male) were enrolled in the study. Insulin resistance (IR) and other metabolic disturbances were investigated and nerve conduction was measured in all participants. Obese children were divided into groups according to the presence of IR. All results were compared between these subgroups. RESULTS: The nerve conduction velocity (NCV) of motor median nerves in the IR+ group was significantly higher than that in the IR- group and lower than that in the control group. The NCV of the motor peroneal nerve in the IR+ group was significantly lower than that in the IR- group. The sensory nerve action potential (SNAP) of the sensory median nerve was significantly lower in the IR+ group compared to that in the IR- group. The sensory sural nerve's SNAP was significantly lower in the IR+ group than that in the control group. CONCLUSION: Nerve conduction tests may help to detect early pathologies in peripheral nerves and to decrease morbidities in obese children.
Subject(s)
Insulin Resistance/physiology , Neural Conduction/physiology , Obesity/complications , Adolescent , Child , Electromyography , Female , Humans , MaleABSTRACT
Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by a distinctive mid-hindbrain malformation. JS is part of a group of disorders called ciliopathies based on their overlapping phenotypes and common underlying pathophysiology linked to primary cilium dysfunction. Biallelic mutations in one of 28 genes, all encoding proteins localizing to the primary cilium or basal body, can cause JS. Despite this large number of genes, the genetic cause can currently be determined in about 62% of individuals with JS. To identify novel JS genes, we performed whole exome sequencing on 35 individuals with JS and found biallelic rare deleterious variants (RDVs) in KIAA0586, encoding a centrosomal protein required for ciliogenesis, in one individual. Targeted next-generation sequencing in a large JS cohort identified biallelic RDVs in eight additional families for an estimated prevalence of 2.5% (9/366 JS families). All affected individuals displayed JS phenotypes toward the mild end of the spectrum.
Subject(s)
Cell Cycle Proteins/genetics , Cerebellum/abnormalities , Mutation , Retina/abnormalities , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Adolescent , Adult , Alternative Splicing , Brain/pathology , Child , Child, Preschool , DNA Mutational Analysis , Eye Abnormalities/diagnosis , Eye Abnormalities/genetics , Gene Order , Genetic Association Studies , Humans , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Magnetic Resonance Imaging , Phenotype , Young AdultABSTRACT
BACKGROUND: Obesity is an established risk factor for asthma in children. Measures of central obesity are reported to be more associated with the severity of asthma in adults. The aim of the study was to investigate the association between fat distribution, which is determined by anthropometric measures including neck circumference (NC) and asthma severity in children. METHODS: Children with asthma who were followed in our pediatric allergy unit were consecutively recruited. Asthma severity was graded according to GINA guidelines. Children whose asthma was controlled with Step 1 or 2 treatment options formed Group 1 (mild asthma), whereas children who needed Step 3, 4, or 5 treatment options formed Group 2 (moderate-to-severe asthma). Anthropometric measures including height, weight, NC, waist circumference, and hip circumference were obtained. RESULTS: A total of 127 children (82 male, 64.6%) with a median age of 8.3 (6.4-11.3) years were included. Atopy was present in 77 (60.6%) patients. 91 patients (71.6) were in the mild asthma group. NC of children with severe asthma was significantly wider than children with mild asthma (29.0 cm (27.0-32.0) vs. 28.0 (26.0-30.0), p = 0.019). The prevalence of children with NC higher than 90th percentile was also more frequent in children with severe asthma (15 [41.7%] vs. 21 [23.1%]). Result of multivariable logistic regression analysis revealed that presence of NC >90th percentile was associated with severe asthma in children (odds ratio; [95% confidence interval] (2.52 [1.05-6.01]; p = 0.038). CONCLUSIONS: Neck circumference, which is a simple anthropometric tool, is associated with asthma severity in children.
Subject(s)
Adiposity , Asthma/etiology , Neck/pathology , Pediatric Obesity/complications , Age Factors , Anthropometry , Asthma/diagnosis , Child , Cross-Sectional Studies , Female , Humans , Logistic Models , Male , Multivariate Analysis , Odds Ratio , Pediatric Obesity/pathology , Predictive Value of Tests , Risk Assessment , Risk Factors , Severity of Illness IndexABSTRACT
Patients with Albright hereditary osteodystrophy (AHO) phenotype are usually seen in pediatric endocrinology policlinics when they are evaluated for short stature and/or obesity. Brachydactyly mental retardation syndrome (BDMR, OMIM #600430) is a rare genetic disorder caused by aberrations of chromosomal region 2q37 and characterized with AHO-like phenotype without any hormone resistance. Diagnosis of BDMR is based on the detection of the deletion on the long arm of chromosome 2. Diagnosis can usually be made with karyotype analysis but sometimes chromosomal deletion can only be detected by fluorescent in situ hybridization (FISH) screening. We report a patient with the AHO phenotype whose karyotype was normal but who was diagnosed with BDMR with FISH analysis showing 2q deletion. In pediatric endocrinology practice, in patients with AHO phenotype but without parathormone (PTH) resistance, BDMR should be considered. For the diagnosis of BDMR, the subtelomeric region of chromosome 2 should be screened for deletion by FISH analysis even in patients with normal karyotypes.
Subject(s)
Brachydactyly/genetics , Intellectual Disability/genetics , Pseudopseudohypoparathyroidism/diagnosis , Child , Diagnosis, Differential , Female , Humans , Pseudopseudohypoparathyroidism/geneticsABSTRACT
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.
ABSTRACT
We report a five-year-old girl presenting with dysphagia, dysarthria, drooling, and generalized tonic convulsions in whom the final diagnosis was acquired epileptiform opercular syndrome. Levetiracetam monotherapy at a dosage of 40 mg/kg/day improved the clinical findings, and seizures were controlled at the end of the first month of treatment. Six months after the initial diagnosis, she presented with speech deterioration and dysarthria. At this time, although sleep and awake electroencephalography (EEG) were normal, FDG-PET showed hypometabolic and hypermetabolic regions in the anterior/inferior and anterior regions of the right frontal lobe, respectively. By increasing before levetiracetam dosage to 50 mg/kg/day, the clinical findings resolved and the patient is still seizure free. Acquired epileptiform opercular syndrome is a rare epileptic disorder in which the seizures are resistant to conventional antiepileptic drugs. Levetiracetam may be an effective antiepileptic drug in controlling seizures and other clinical findings in acquired opercular epileptiform syndrome. Hypometabolic and hypermetabolic regions in FDG-PET study may be due to ongoing seizure activity or impaired glucose metabolism in this disorder.
Subject(s)
Anticonvulsants/therapeutic use , Deglutition Disorders , Dysarthria , Epilepsy, Generalized , Piracetam/analogs & derivatives , Sialorrhea , Child, Preschool , Deglutition Disorders/complications , Deglutition Disorders/diagnostic imaging , Deglutition Disorders/drug therapy , Dysarthria/complications , Dysarthria/diagnostic imaging , Dysarthria/drug therapy , Electroencephalography , Epilepsy, Generalized/complications , Epilepsy, Generalized/diagnostic imaging , Epilepsy, Generalized/drug therapy , Female , Fluorodeoxyglucose F18 , Humans , Levetiracetam , Piracetam/therapeutic use , Positron-Emission Tomography , Sialorrhea/complications , Sialorrhea/diagnostic imaging , Sialorrhea/drug therapyABSTRACT
BACKGROUND: METTL5 gene is one of the members of methyltransferase superfamily and biallelic variants cause intellectual disability syndrome (ID) with microcephaly. This article reports three new cases with METTL5 related ID syndrome in a consanguineous family. CASE: Afghanistan descent family was affected by a novel homozygous c.362A > G (p.Asp121Gly) METTL5 gene variant. This variant is predicted to be `pathogenic` by multiple in-silico tools. Patients had dysmorphic and neurodevelopmental features including intellectual disability, microcephaly, poor/absent speech, delayed walking, aggressive behavior, large/posteriorly rotated ears, broad nasal base and short stature, which seem to be the cardinal findings of the designated syndrome. CONCLUSIONS: While the data reported in these individuals indicate characteristic clinical features of METTL5 related ID syndrome, further investigations and study of additional cases are needed to improve the understanding of disease pathogenesis, and management.
Subject(s)
Intellectual Disability , Microcephaly , Humans , Intellectual Disability/genetics , Microcephaly/genetics , Siblings , Exome , Pedigree , Syndrome , Speech Disorders , PhenotypeABSTRACT
Human mitochondrial disease exhibits large variation of clinical phenotypes, even in patients with the same causative gene defect. We illustrate this heterogeneity by confronting clinical and biochemical data of two patients with the uncommon pathogenic homoplasmic NC_012920.1(MT-ATP6):m.9035T>C variant in MT-ATP6. Patient 1 presented as a toddler with severe motor and speech delay and spastic ataxia without extra-neurologic involvement. Patient 2 presented in adolescence with ataxia and ophthalmoplegia without cognitive or motor impairment. Respiratory chain complex activities were normal in cultured skin fibroblasts from both patients when calculated as ratios over citrate synthase activity. Native gels found presence of subcomplexes of complex V in fibroblast and/or skeletal muscle. Bioenergetic measurements in fibroblasts from both patients detected reduced spare respiratory capacities and altered extracellular acidification rates, revealing a switch from mitochondrial respiration to glycolysis to uphold ATP production. Thus, in contrast to the differing disease presentation, biochemical evidence of mitochondrial deficiency turned out quite similar. We conclude that biochemical analysis remains a valuable tool to confirm the genetic diagnosis of mitochondrial disease, especially in patients with new gene variants or atypical clinical presentation.
Subject(s)
Mitochondrial Diseases , Mitochondrial Proton-Translocating ATPases , Adolescent , Ataxia/genetics , Genotype , Humans , Infant , Mitochondrial Diseases/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mutation/genetics , PhenotypeABSTRACT
BACKGROUND: Little is known about the relationship between sensory processing and motor development in very preterm infants. The purpose of this study was to explore the relationship of motor development with sensory processing among such infants with developmental delay and those who had typical development at the ages of 8 and 12 months. METHODS: This prospective case-control study included 61 preterm infants (31 males, 30 females, mean gestational age: 29.1 weeks). The infants had a gestational age of 32 weeks or less and a current corrected age of 8 months, and they had spent at least 15 days in the neonatal intensive care unit. Motor development was assessed with the Neuro-sensory Motor Developmental Assessment (NSMDA), and sensory processing was evaluated with the Test of Sensory Functions in Infants (TSFI). RESULTS: There were very strong positive correlations between the gross and fine motor scores of the NSMDA and the TSFI`s subdomain scores and total scores (r=0.85-0.93, p < 0.001). There were also very strong negative correlations between the functional level according to the NSMDA and the subdomain scores and total scores of the TSFI (r=-0.89-0.94, p < 0.001). CONCLUSIONS: The results show that sensory processing and motor development are related parts of the development of very preterm infants. In the early rehabilitation process, therapists should comprehensively take motor and sensory development into consideration.
Subject(s)
Child Development , Infant, Extremely Premature , Case-Control Studies , Female , Gestational Age , Humans , Infant , Infant, Newborn , Male , Perception , SensationABSTRACT
Autosomal recessive cerebellar ataxias (ARCA) are characterized by the abnormal structure of the cerebellum and spinal cord. Spinocerebellar ataxia type 18 (MIM 616204), one of the ARCA, is caused by the loss-of-function mutations of the GRID2 gene due to deletions. Missense mutations in the GRID2 cause ataxia with the gain-of-function mechanism. We report a homozygous GRID2 duplication in childhood-onset ataxia in two siblings. The clinical exome sequencing was performed on one of the siblings. No disease-causing mutations were reported as a result of the clinical exome test. Chromosomal microarray analysis was performed on the entire family using Affymetrix Optima® chips. Chromosomal microarray analysis showed a ~ 121-kb homozygous duplication of GRID2 (arr[GRCh37]4q22.2(94426536_94613158) × 4), including exon 14, in both siblings. Previously, GRID2 has been associated with an autosomal recessive (loss-of-function) and autosomal semi-dominant (gain-of-function) forms of ataxia. To the best of our knowledge, this is the first study to identify a homozygous duplication of GRID2 causing loss of function of the GluRD2 protein. These findings provide us with the conclusion that copy number variation analyses should be in the diagnostic process of autosomal recessive ataxia types.
Subject(s)
Exons/genetics , Gene Duplication/genetics , Homozygote , Receptors, Glutamate/genetics , Spinocerebellar Degenerations/diagnostic imaging , Spinocerebellar Degenerations/genetics , Adolescent , Child, Preschool , Female , Humans , Pedigree , SiblingsABSTRACT
Kabuki syndrome (KS) is a disease characterized by distinctive facial features, skeletal anomalies and delay in neuromotor development. KS 1 is an autosomal dominant condition caused by mutations in the KMT2D gene, whereas KS 2 is an X-linked disorder caused by mutations in the KDM6A gene. In the majority of KS patients who present with hypoglycemia, KDM6A is the defective gene. A 9-month old girl was admitted to our emergency department due to a seizure. On physical examination, hypotonia, mild facial dysmorphism, brachydactyly of the 5th finger, prominent finger pads and pansystolic murmur were detected. A fasting glucose tolerance test was performed the next day due to her history of hypoglycemia, but she had convulsions at the fifth hour of the test. Her serum glucose was 24 mg/dL, insulin 1.94 mIU/L, C-peptide 0.94 ng/mL, growth hormone 11 ng/mL, anti-insulin antibody 4.2 IU/mL, cortisol 19.8 µg/dL, and adrenocorticotropic hormone 9.3 pg/mL. A diagnosis of hyperinsulinemic hypoglycemia was considered. Given the abnormalities, genetic analysis for congenital hyperinsulinism, including the genes causing KS was performed. A heterozygous frameshift mutation (c.2579del, p.Leu860Argfs*70) was detected in the KMT2D gene. Epilepsy and other neurological symptoms may be seen in KS patients and in some of these the neurological symptoms are the result of hypoglycemia. In such cases, the detection and prevention of hypoglycemia can help prevent the progression of neurological symptoms. We suggest considering the diagnosis of KS for patients with hypoglycemia and dysmorphic features, even if the patient does not manifest all features of KS.
Subject(s)
Abnormalities, Multiple/diagnosis , Congenital Hyperinsulinism/diagnosis , DNA-Binding Proteins/genetics , Face/abnormalities , Hematologic Diseases/diagnosis , Neoplasm Proteins/genetics , Vestibular Diseases/diagnosis , Abnormalities, Multiple/genetics , Congenital Hyperinsulinism/genetics , Female , Hematologic Diseases/genetics , Humans , Infant , Vestibular Diseases/geneticsSubject(s)
Insect Bites and Stings/complications , Torticollis/etiology , Child, Preschool , Humans , MaleABSTRACT
AIM: To investigate the relationship between motor and sensory development in the first 4 months of life in preterm infants born at 32 gestational weeks and below. MATERIAL AND METHODS: The study consisted of 56 high-risk infants with a corrected age of 1 month who were born at 32 gestational weeks and stayed in the neonatal intensive care unit for at least 15 days. Neuro Sensory Motor Developmental Assessment and Infant Sensory Profile-2 were used for evaluation. These assessments were applied to preterm infants at the 1st and 4th months. The results of assessments were analyzed using the Wilcoxon test. The relationship between the results of motor and sensory assessments was analyzed using Spearman's correlation test. RESULTS: The mean gestational age of the infants was 29.58±2.09 weeks, their birth weights were 1233.87±251.22 grams, and their duration of stay in the neonatal intensive care unit was 26.48±9.58 days. There was a statistically significant difference between the Neuro Sensory Motor Developmental Assessment and Infant Sensory Profile-2 scores between the 1st and 4th months (p<0.05). It was found that there was a risk in terms of sensory development in 86-91% of the preterm infants at the 1st month and in 69-85% at the 4th month. There was moderate-strong degree of significant relationship between motor and sensory development. CONCLUSION: Considering the findings of our study, preterm infants are at risk for motor and sensory development. There is, therefore, a need for future research to investigate the effect of early sensory-based intervention approaches on preterm infants.