COL4A1-related autosomal recessive encephalopathy in 2 Turkish children.

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

Parieto-occipital encephalomalacia in children; clinical and electrophysiological features of twenty-seven cases

Context: Brain injuries occurring at a particular time may cause damages in well-defined regions of brain. Perinatal hypoxic ischemic encephalopathy and hypoglycemia are some of the most common types of brain injuries. Neonatal hypoglycemia can cause abnormal myelination in parietal and occipital lobes resulting in parieto-occipital encephalomalacia. There is a small number of studies about clinical and electroencephalographic (EEG) features of children with parieto-occipital encephalomalacia. They might have important neurologic sequelae such as cortical visual loss, seizures, and psychomotor retardation. Aims: We aimed to evaluate the causes of parieto-occipital encephalomalacia and evaluate the clinical and electrophysiological features of children with parieto-occipital encephalomalacia. Settings and Design: We evaluated clinical features and EEGs of 27 children with parieto-occipital encephalomalacia. Statistical Analysis Used: Descriptive statistics were used. Results: Hospitalization during the neonatal period was the most common cause (88.9%) of parieto-occipital brain injury. Eleven patients (40.7%) had a history of neonatal hypoglycemia. Twenty-three patients (85.2%) had epilepsy and nine of the epileptic patients (39%) had refractory seizures. Most of the patients had bilateral (50%) epileptic discharges originating from temporal, parietal, and occipital lobes (56.2%). However, some patients had frontal sharp waves and some had continuous spike and wave discharges during sleep. Visual abnormalities were evident in 15 (55.6%) patients. Twenty-two (81.5%) had psychomotor retardation. Fine motor skills, social contact and language development were impaired more than gross motor skills. Conclusions: In our study, most of the patients with parieto-occipital encephalomalacia had an eventful perinatal history. Epilepsy, psychomotor retardation, and visual problems were common neurologic complications

Genetic Landscape Of Congenital Myasthenic Syndromes From Turkey: Novel Mutations And Clinical Insights

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis. Here, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, referred over a 5-year period (2011-2016) to the Child Neurology Department of Dokuz Eylul University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven congenital myasthenic syndromes originating from Turkey. In total, the authors identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n = 15; 35%) were the most common type, followed by synaptic basal-lamina associated (n = 14; 33%) and presynaptic syndromes (n = 10; 23%). The authors had only 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n = 1; 2%). Knowledge on congenital myasthenic syndromes and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.Wo

Dropped head congenital muscular dystrophy caused by de novo mutations in LMNA

Background: Dropped head syndrome is an easily recognizable clinical presentation of Laurin A/C-related congenital muscular dystrophy. Patients usually present in the first year of life with profound neck muscle weakness, dropped head, and elevated serum creative kinase. Case description: Two patients exhibited head drop during infancy although they were able to sit independently. Later they developed progressive axial and limb-girdle weakness. Creatine kinase levels were elevated and muscle biopsies of both patients showed severe dystrophic changes. The distinctive clinical hallmark of the dropped head led us to the diagnosis of Lamin A/C-related congenital muscular dystrophy, with a pathogenic de novo mutation p.Glu3ldel in the head domain of the Lamin A/C gene in both patients. Remarkably, one patient also had a central involvement with white matter changes on brain magnetic resonance imaging. Conclusion: Lamin A/C-related dropped-head syndrome is a rapidly progressive congenital muscular dystrophy and may lead to loss of ambulation, respiratory insufficiency, and cardiac complications. Thus, the genetic diagnosis of dropped-head syndrome as L-CMD and the implicated clinical care protocols are of vital importance for these patients. This disease may be underdiagnosed, as only a few genetically confirmed cases have been reported. (C) 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate

Lack of IL7R alpha expression in T cells is a hallmark of T-cell immunodeficiency in Schimke immuno-osseous dysplasia (SIOD)

Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive, fatal childhood disorder associated with skeletal dysplasia, renal dysfunction, and T-cell immunodeficiency. This disease is linked to biallelic loss-of-function mutations of the SMARCAL1 gene. Although recurrent infection, due to T-cell deficiency, is a leading cause of morbidity and mortality, the etiology of the T-cell immunodeficiency is unclear. Here, we demonstrate that the T cells of SIOD patients have undetectable levels of protein and mRNA for the IL-7 receptor alpha chain (IL7R alpha) and are unresponsive to stimulation with IL-7, indicating a loss of functional receptor. No pathogenic mutations were detected in the exons of IL7R in these patients; however, CpG sites in the IL7R promoter were hypermethylated in SIOD T cells. We propose therefore that the lack of IL7R alpha expression, associated with hypermethylation of the IL7R promoter, in T cells and possibly their earlier progenitors, restricts T-cell development in SIOD patients. (C) 2015 Elsevier Inc. All rights reserved

Erratum: Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome (The American Journal of Human Genetics (2018) 103(3) (431–439)(S0002929718302374)(10.1016/j.ajhg.2018.07.010))

(The American Journal of Human Genetics 103, 431–439; September 6, 2018) In the original version of this article, author Tracy Dixon-Salazar's name was incomplete. It now appears correctly here and online. The authors regret the error

Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome

ADP-ribosylation, the addition of poly-ADP ribose (PAR) onto proteins, is a response signal to cellular challenges, such as excitotoxicity or oxidative stress. This process is catalyzed by a group of enzymes referred to as poly(ADP-ribose) polymerases (PARPs). Because the accumulation of proteins with this modification results in cell death, its negative regulation restores cellular homeostasis: a process mediated by poly-ADP ribose glycohydrolases (PARGs) and ADP-ribosylhydrolase proteins (ARHs). Using linkage analysis and exome or genome sequencing, we identified recessive inactivating mutations in ADPRHL2 in six families. Affected individuals exhibited a pediatric-onset neurodegenerative disorder with progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. Loss of the Drosophila paralog Parg showed lethality in response to oxidative challenge that was rescued by human ADPRHL2, suggesting functional conservation. Pharmacological inhibition of PARP also rescued the phenotype, suggesting the possibility of postnatal treatment for this genetic condition

Picturing asthma in Turkey: results from the Turkish adult asthma registry

Introduction: National data on asthma characteristics and the factors associated with uncontrolled asthma seem to be necessary for every country. For this purpose, we developed the Turkish Adult Asthma Registry for patients with asthma aiming to take a snapshot of our patients, thereby assigning the unmet needs and niche areas of intervention. Methods: Case entries were performed between March 2018 and March 2022. A web-based application was used to record data. Study outcomes were demographic features, disease characteristics, asthma control levels, and phenotypes. Results: The registry included 2053 patients from 36 study centers in Turkey. Female subjects dominated the group (n = 1535, 74.8%). The majority of the patients had allergic (n = 1158, 65.3%) and eosinophilic (n = 1174, 57.2%) asthma. Six hundred nineteen (32.2%) of the patients had obese asthma. Severe asthma existed in 670 (32.6%) patients. Majority of cases were on step 3–5 treatment (n: 1525; 88.1%). Uncontrolled asthma was associated with low educational level, severe asthma attacks in the last year, low FEV1, existence of chronic rhinosinusitis and living in particular regions. Conclusion: The picture of this registry showed a dominancy of middle-aged obese women with moderate-to-severe asthma. We also determined particular strategic targets such as low educational level, severe asthma attacks, low FEV1, and chronic rhinosinusitis to decrease uncontrolled asthma in our country. Moreover, some regional strategies may also be needed as uncontrolled asthma is higher in certain regions. We believe that these data will guide authorities to reestablish national asthma programs to improve asthma service delivery