Dominant SCN2A Mutation Causes Familial Episodic Ataxia and Impairment of Speech Development

2018 ◽  
Vol 49 (06) ◽  
pp. 379-384 ◽  
Author(s):  
Kerstin Becker ◽  
Peter Herkenrath ◽  
Christoph Düchting ◽  
Friederike Körber ◽  
Pablo Landgraf ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Index Patient ◽  
Speech Development ◽  
Episodic Ataxia ◽  
Cerebellar Hemisphere ◽  
First Episode ◽  
Whole Exome ◽  
Neurologic Disorders ◽  
Left Cerebellar Hemisphere ◽  
Impaired Speech

AbstractMutations in SCN2A are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by SCN2A-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in SCN2A (NM_021007, c.4949T > C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of SCN2A-associated neurologic disorders, emphasizing that SCN2A mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.

scholarly journals Clinical Application of Whole Exome Sequencing to Identify Rare but Remediable Neurologic Disorders

2020 ◽  
Vol 9 (11) ◽  
pp. 3724
Author(s):  
Min-Jee Kim ◽  
Mi-Sun Yum ◽  
Go Hun Seo ◽  
Yena Lee ◽  
Han Na Jang ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Intractable Epilepsy ◽  
Episodic Ataxia ◽  
Treatment Modalities ◽  
Congenital Myasthenic Syndrome ◽  
Early Application ◽  
Whole Exome ◽  
Neurologic Disorders

Background: The aim of this study was to describe the application of whole exome sequencing (WES) in the accurate genetic diagnosis and personalized treatment of extremely rare neurogenetic disorders. Methods: From 2017 to 2019, children with neurodevelopmental symptoms were evaluated using WES in the pediatric neurology clinic and medical genetics center. The clinical presentation, laboratory findings including the genetic results from WES, and diagnosis-based treatment and outcomes of the four patients are discussed. Results: A total of 376 children with neurodevelopmental symptom were evaluated by WES, and four patients (1.1%) were diagnosed with treatable neurologic disorders. Patient 1 (Pt 1) showed global muscle hypotonia, dysmorphic facial features, and multiple anomalies beginning in the perinatal period. Pt 1 was diagnosed with congenital myasthenic syndrome 22 of PREPL deficiency. Pt 2 presented with hypotonia and developmental arrest and was diagnosed with autosomal recessive dopa-responsive dystonia due to TH deficiency. Pt 3, who suffered from intractable epilepsy and progressive cognitive decline, was diagnosed with epileptic encephalopathy 47 with a heterozygous FGF12 mutation. Pt 4 presented with motor delay and episodic ataxia and was diagnosed with episodic ataxia type II (heterozygous CACNA1A mutation). The patients’ major neurologic symptoms were remarkably relieved with pyridostigmine (Pt 1), levodopa (Pt 2), sodium channel blocker (Pt 3), and acetazolamide (Pt 4), and most patients regained developmental milestones in the follow-up period (0.4 to 3 years). Conclusions: The early application of WES helps in the identification of extremely rare genetic diseases, for which effective treatment modalities exist. Ultimately, WES resulted in optimal clinical outcomes of affected patients.

Spontaneous Catheter Separation from the Implanted Venous Port and Its Migration to the Venous Heart: Clinical Case

2018 ◽  
Vol 5 (2) ◽  
pp. 127-132 ◽  
Author(s):  
Lyudmila V. Olkhova ◽  
Vladimir E. Popov
Keyword(s):  
Clinical Case ◽  
Care Delivery ◽  
Venous Access ◽  
Cerebellar Hemisphere ◽  
Clinical State ◽  
Venous Port ◽  
Silicone Catheter ◽  
Oncological Diseases ◽  
Left Cerebellar Hemisphere ◽  
Port Systems

Background. Currently, vascular access is one of the most important aspects in specific and accompanying treatment of cancer patients regardless of their age and sex. Partially implanted venous catheters previously described by Hickman were widely applied all over the world. The introduction of completely implanted venous port-systems revolutionized health care delivery and improved the quality of life in patients with oncological diseases. A fully implanted venous port consists of a silicone catheter which distal tip is connected to a port tank implanted subcutaneously. Such a design allows providing safe and multiple adequate vascular accesses regardless of the patient’s clinical state.Case Report. We present a clinical case of a 10-year-old patient diagnosed with medulloblastoma of the cerebellopontine angle and the left cerebellar hemisphere. The case described spontaneous detachment of an implanted venous port catheter and its migration to the venous heart in a patient who underwent chemotherapy by venous access provided through implantation of the venous port.Conclusion. Our clinical case demonstrated a rare and potentially extremely dangerous noninfectious complication associated with the use of venous port-systems. Implanted systems require washing 1–2 times per month with heparinized solutions or solutions containing taurolidine when they are not used. Periodic chest radiographs can reveal integrity alterations of the system. Any implanted system should be removed when it is not used, or it should be monitored on a regular basis.

scholarly journals A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

2021 ◽  
Author(s):  
Qing Li ◽  
Chengfeng Wang ◽  
Wei Li ◽  
Zaiqiang Zhang ◽  
Shanshan Wang ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Skin Biopsy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Collagen Type Iv ◽  
Lacunar Infarcts ◽  
Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

scholarly journals A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110065
Author(s):  
Nesrin Şenbil ◽  
Zeynep Arslan ◽  
Derya Beyza Sayın Kocakap ◽  
Yasemin Bilgili
Keyword(s):  
Corpus Callosum ◽  
Autosomal Dominant ◽  
Genetic Disorder ◽  
Gene Mutations ◽  
Hirschsprung Disease ◽  
Agenesis Of Corpus Callosum ◽  
Whole Exome ◽  
Congenital Cardiac Anomalies ◽  
History Of ◽  
Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

Utility of indocyanine green in the detection of radiologically silent hemangioblastomas: case report

2021 ◽  
pp. 1-7
Author(s):  
Alice Senta Ryba ◽  
Juan Sales-Llopis ◽  
Stefan Wolfsberger ◽  
Aki Laakso ◽  
Roy Thomas Daniel ◽  
...  
Keyword(s):  
Indocyanine Green ◽  
Histological Analysis ◽  
Complete Resection ◽  
Fluorescent Imaging ◽  
Cerebellar Hemisphere ◽  
Potential Applications ◽  
Left Cerebellar Hemisphere ◽  
Future Treatments ◽  
Cerebellar Mass ◽  
Suboccipital Approach

Hemangioblastomas (HBs) are rare, benign, hypervascularized tumors. Fluorescent imaging with indocyanine green (ICG) can visualize tumor angioarchitecture. The authors report a case of multiple HBs involving two radiologically silent lesions only detected intraoperatively by ICG fluorescence. A 26-year-old woman presented with a cystic cerebellar mass on the tentorial surface of the left cerebellar hemisphere on MRI. A left paramedian suboccipital approach was performed to remove the mural nodule with the aid of ICG injection. The first injection, applied just prior to removing the nodule, highlighted the tumor and vessels. After resection, two new lesions, invisible on the preoperative MRI, surprisingly enhanced on fluorescent imaging 35 minutes after the ICG bolus. Both silent lesions were removed. Histological analysis of all three lesions revealed they were positive for HB. The main goal of this report is to hypothesize possible explanations about the mechanism that led to the behavior of the two silent lesions. Intraoperative ICG videoangiography was useful to understand the 3D angioarchitecture and HB flow patterns to perform a safe and complete resection in this case. Understanding the HB ultrastructure and pathophysiological mechanisms, in conjunction with the properties of ICG, may expand potential applications for their diagnosis and future treatments.

scholarly journals A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Bing-Bing Guo ◽  
Jie-Yuan Jin ◽  
Zhuang-Zhuang Yuan ◽  
Lei Zeng ◽  
Rong Xiang
Keyword(s):  
Extracellular Matrix ◽  
Cartilage Oligomeric Matrix Protein ◽  
Matrix Protein ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Structure Model ◽  
Whole Exome ◽  
Nucleotide Mutation

Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.

scholarly journals Prenatal Diagnosis of Holt–Oram Syndrome With a Novel Mutation of TBX5 Gene: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Guan-nan He ◽  
Xue-yan Wang ◽  
Min Kang ◽  
Xi-min Chen ◽  
Na Xi ◽  
...  
Keyword(s):  
Septal Defect ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Splice Donor ◽  
Autosomal Dominant Disorder ◽  
Cubitus Valgus ◽  
Case Presentation ◽  
Whole Exome ◽  
The Right ◽  
Tbx5 Gene

Background: Holt–Oram syndrome (HOS) is an autosomal dominant disorder caused by mutations of TBX5 gene.Case presentation: We report a fetus with HOS diagnosed sonographically at 23 weeks of gestation. The fetal parents are non-consanguineous. The fetus exhibited short radius and ulna, inability to supinate the hands, absence of the right thumb, and heart ventricular septal defect (VSD), while the fetal father exhibited VSD and short radius and ulna only. Fetal brother had cubitus valgus and thumb adduction, except for VSD, short radius and ulna. The pregnancy was terminated. Whole-exome sequencing (WES) revealed a novel mutation in the TBX5 (c.510+1G>A) in the fetus inherited from the father. The variant (c.510+1G>A) occurs at splice donor and may alter TBX5 gene function by impact on splicing. It was not previously reported in China.Conclusion: Our case reported a novel mutation in TBX5, which expanded the known genetic variants associated with HOS.

scholarly journals Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene

2002 ◽  
pp. 649-656 ◽  
Author(s):  
J Rutishauser ◽  
P Kopp ◽  
MB Gaskill ◽  
TJ Kotlar ◽  
GL Robertson
Keyword(s):  
Diabetes Insipidus ◽  
Autosomal Dominant ◽  
De Novo ◽  
Index Patient ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
Posterior Pituitary ◽  
Recurrent Mutations ◽  
Neurophysin Ii

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

scholarly journals Identification of a novel pathogenic missense mutation in PRPF31 using whole exome sequencing: a case report

2018 ◽  
Vol 103 (6) ◽  
pp. 761-767 ◽  
Author(s):  
Laura Bryant ◽  
Olga Lozynska ◽  
Anson Marsh ◽  
Tyler E Papp ◽  
Lucas van Gorder ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Whole Exome Sequencing ◽  
Protein Trafficking ◽  
Protein Misfolding ◽  
Autosomal Dominant ◽  
Null Alleles ◽  
Incomplete Penetrance ◽  
Missense Mutations ◽  
Whole Exome

BackgroundVariants in PRPF31, which encodes pre-mRNA processing factor 31 homolog, are known to cause autosomal-dominant retinitis pigmentosa (adRP) with incomplete penetrance. However, the majority of mutations cause null alleles, with only two proven pathogenic missense mutations. We identified a novel missense mutation in PRPF31 in a family with adRP.MethodsWe performed whole exome sequencing to identify possible pathogenic mutations in the proband of a family with adRP. Available affected family members had a full ophthalmological evaluation including kinetic and two-colour dark adapted static perimetry, electroretinography and multimodal imaging of the retina. Two patients had evaluations covering nearly 20 years. We carried out segregation analysis of the probable mutation, PRPF31 c.590T>C. We evaluated the cellular localisation of the PRPF31 variant (p.Leu197Pro) compared with the wildtype PRPF31 protein.ResultsPRPF31 c.590T>C segregated with the disease in this four-generation autosomal dominant pedigree. There was intrafamilial variability in disease severity. Nyctalopia and mid-peripheral scotomas presented from the second to the fourth decade of life. There was severe rod >cone dysfunction. Visual acuity (VA) was relatively intact and was maintained until later in life, although with marked interocular asymmetries. Laboratory studies showed that the mutant PRPF31 protein (p.Leu197Pro) does not localise to the nucleus, unlike the wildtype PRPF31 protein. Instead, mutant protein resulted in punctate localisation to the cytoplasm.Conclusionsc.590T>C is a novel pathogenic variant in PRPF31 causing adRP with incomplete penetrance. Disease may be due to protein misfolding and associated abnormal protein trafficking to the nucleus.

Cleft Palate

2018 ◽  
Author(s):  
Oksana A Jackson ◽  
Alison E Kaye ◽  
David W Low
Keyword(s):  
Cleft Palate ◽  
Normal Function ◽  
Speech Development ◽  
Velopharyngeal Insufficiency ◽  
Surgical Interventions ◽  
Feeding Difficulties ◽  
Oronasal Fistula ◽  
Cleft Palate Repair ◽  
Palate Repair ◽  
Impaired Speech

A cleft of the palate represents one of the most common congenital anomalies of the craniofacial region. Palatal clefting can occur in combination with a cleft of the lip and alveolus or as an isolated finding and can vary significantly in severity. The intact palate is a structure that separates the oral and nasal cavities, and the function of the palate is to close off the nasal cavity during deglutition and to regulate the flow of air between the nose and mouth during speech production. An unrepaired cleft palate can thus result in nasal regurgitation of food and liquid, early feeding difficulties, and impaired speech development. The goals of surgical repair are to restore palatal integrity by closing the cleft defect and repairing the musculature to allow for normal function during speech. The secondary goal of cleft palate repair is to minimize deleterious effects on growth of the palate and face, which can be impacted by standard surgical interventions. This review describes two of the most commonly performed cleft palate repair techniques in use today, as well as highlighting special anatomic considerations, summarizing perioperative care, and reviewing postoperative complications and their management. This review contains 11 figures, 2 videos, 3 tables and 63 references Key words: cleft, cleft team, Furlow, orofacial, oronasal fistula, palatoplasty, speech, submucous cleft, velopharyngeal insufficiency

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