scholarly journals Infantile Alexander disease with late onset infantile spasms and hypsarrhythmia

2019 ◽  
Vol 22 (2) ◽  
pp. 77-82
Author(s):  
J Paprocka ◽  
B Rzepka-Migut ◽  
N Rzepka ◽  
A Jezela-Stanek ◽  
E Morava
Keyword(s):  
Autosomal Dominant ◽  
Clinical Presentation ◽  
De Novo ◽  
Late Onset ◽  
Alexander Disease ◽  
Heterozygous Mutation ◽  
Type I ◽  
Infantile Form ◽  
Epileptic Spasms ◽  
Electroencephalogram Eeg

AbstractAlexander disease (AxD) is a rare autosomal dominant leukodystrophy with three clinical subtypes: infantile, juvenile and adult. Forms differ by age of symptoms occurrence and the clinical presentation. Although recent data suggest considering only two subtypes: type I (infantile onset with lesions extending to the cerebral hemispheres); type II (adult onset with primary involvement of subtentorial structures). Dominant mutations in the glial fibrillary acidic protein (GFAP) gene in AxD cause dysfunction of astrocytes (a type III intermediate filament). The authors discuss the clinical picture of a boy with infantile form of AxD confirmed by the presence of de novo heterozygous mutation c.236G>A in the GFAP gene and without striking symptoms such as macrocephaly and with exceptional late-onset epileptic spasms with hypsarrhyth- mia on electroencephalogram (EEG).

Search for mutations of the interferon-induced transmembrane protein 5 (IFITM5) gene in patients with osteogenesis imperfecta

2019 ◽  
pp. 21-29
Author(s):  
А.Р. Зарипова ◽  
Л.Р. Нургалиева ◽  
А.В. Тюрин ◽  
И.Р. Минниахметов ◽  
Р.И. Хусаинова
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Transmembrane Protein ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Heterozygous Mutation ◽  
Type I ◽  
New Genes ◽  
Wide Range ◽  
Type V

Проведено исследование гена интерферон индуцированного трансмембранного белка 5 (IFITM5) у 99 пациентов с несовершенным остеогенезом (НО) из 86 неродственных семей. НО - клинически и генетически гетерогенное наследственное заболевание соединительной ткани, основное клиническое проявление которого - множественные переломы, начиная с неонатального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам НО относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушения роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. НО встречается как у мужчин, так и у женщин. До сих пор не определена степень генетической гетерогенности заболевания. На сегодняшний день известно 20 генов, вовлеченных в патогенез НО, и исследователи разных стран продолжают искать новые гены. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-сцепленные мутации в широком спектре генов, кодирующих белки, которые участвуют в синтезе коллагена I типа, его процессинге, секреции и посттрансляционной модификации, а также в белках, которые регулируют дифференцировку и активность костеобразующих клеток, вызывают НО. Мутации в гене IFITM5, также называемом BRIL (bone-restricted IFITM-like protein), участвующем в формировании остеобластов, приводят к развитию НО типа V. До 5% пациентов имеют НО типа V, который характеризуется образованием гиперпластического каллуса после переломов, кальцификацией межкостной мембраны предплечья и сетчатым рисунком ламелирования, наблюдаемого при гистологическом исследовании кости. В 2012 г. гетерозиготная мутация (c.-14C> T) в 5’-нетранслируемой области (UTR) гена IFITM5 была идентифицирована как основная причина НО V типа. В представленной работе проведен анализ гена IFITM5 и идентифицирована мутация c.-14C>T, возникшая de novo, у одного пациента с НО, которому впоследствии был установлен V тип заболевания. Также выявлены три известных полиморфных варианта: rs57285449; c.80G>C (p.Gly27Ala) и rs2293745; c.187-45C>T и rs755971385 c.279G>A (p.Thr93=) и один ранее не описанный вариант: c.128G>A (p.Ser43Asn) AGC>AAC (S/D), которые не являются патогенными. В статье уделяется внимание особенностям клинических проявлений НО V типа и рекомендуется определение мутации c.-14C>T в гене IFITM5 при подозрении на данную форму заболевания. A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

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.

Prenatal diagnosis of Apert syndrome

2018 ◽  
Author(s):  
N.P. Veropotvelyan , D.I. Laylo , T.V. Usenko
Keyword(s):  
Prenatal Diagnosis ◽  
Autosomal Dominant ◽  
De Novo ◽  
The Other ◽  
Lower Limbs ◽  
Apert Syndrome ◽  
Type I ◽  
Autosomal Dominant Disorder ◽  
Nasal Bridge ◽  
Skull Shape

Apert syndrome is a rare monogenic autosomal dominant disorder characterized by severe craniosynostosis, hypoplastic mediofacial structures and symmetric syndactyly of the upper and lower limbs. De novo case with Apert synclrome fetus was detected prenatally at 19–20 weeks of gestation when echography showed next pathognomic signs: an abnormal skull shape, frontal bossing, mild pachygyria, severe hypertelorism bilateral exophthalmos, deep nasal bridge, short upturned nose, prognathia, long filtrum, mild microgenia and ful syndactyly of the feet and hands. Differential diagnosis with other acrocephalosyndactyly types was performed. It is considered, that this is the earliest term of this syndrom prenatal diagnosis in a low risk pregnancies with unimpaired family history. By the parents desire this pregnancy was terminated and subsequent autopsy confirmed the diagnosis of Apert syndrome (acrocephalosyndactyly — type I) one of the hands looks like mitten the other one has the bucket shape.

Studies on the Genetic Mutations of Hereditary Fibrinogen Disorder

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4954-4954
Author(s):  
Rong-Fu Zhou ◽  
Zhou Na ◽  
OuYang Jian
Keyword(s):  
De Novo ◽  
Conflicts Of Interest ◽  
Genetic Mutations ◽  
Heterozygous Mutation ◽  
Homologous Sequence ◽  
Type I ◽  
Type Ii ◽  
Restriction Digestion ◽  
Pcr Products ◽  
The Stability

Abstract Hereditary fibrinogen disorder is a rare kind of bleeding disease, which divided into two types. Type I is a kind of quantity disorder, including afibrinogenemia and hypofibrinogenemia. Type II is a kind of quality disorder, including dysfibrinogenemia. Fibrinogen is a kind of hexameric glycoprotein and consists of two pairs of three chains, which are Aα, Bβ and γchain. FGA、FGB and FGG code for the relevant glycoprotein. The mutations on these genes are responsible for this disorder. In this study, the levels of fibrinogen antigen of 12 cases with low fibrinogen activity were firstly detected. The results showed that one case had low level, and the patient definded as hypofibrinogenemia, and other 11 cases had normal level, thus these patients identified as dysfibrinogenemia. All exons and their flanks of FGA , FGB and FGG were amplified by PCR. THe PCR products were sequenced directly and blasted to normal sequence of corresponding gene to find the mutation. The result showed that among 11 cases with dysfibrinogenemia, five harbored Aα Arg16His heterozygous mutation and one of those also possessed a de novo γAsp185Asn heterozygous mutation ; one Aα Arg16Cys heterozygous mutation; four γArg275Cys heterozygous mutation and one γArg275His heterozygous mutation.The patient with hypofibrinogenemia harbored Aα Cys36Arg heterozygous mutation. Endonuclease restriction digestion was performed to exclude genetic polymorphism for the γAsp185Asn mutation. In molecular modeling, the hydrogen bonds were changed in the mutational variant of γ185Asn. Besides, a new site of glycosylation might appear after the mutation, which might lead to destroy the stability of molecular structure. The alignment of homologous sequence between different species suggested that γAsp185 was a highly conservative site. In a word, the above mutations might be the causes of dysfibrinogenemia or hypofibrinogenemia for these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A

2021 ◽  
Author(s):  
Alice Lepelley ◽  
Erika Della Mina ◽  
Erika Van Nieuwenhove ◽  
Lise Waumans ◽  
Sylvie Fraitag ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
De Novo ◽  
Mitochondrial Protein ◽  
Dominant Negative ◽  
Heterozygous Mutation ◽  
Type I ◽  
Interferon Signaling ◽  
Immune System Activation ◽  
Neurological Phenotype ◽  
System Activation

AbstractMitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype, and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A, and recorded up-regulated ISG expression and interferon alpha protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.SummaryDominant-negative mutations in ATAD3A, a ubiquitously expressed mitochondrial protein, cause mitochondrial DNA-dependent up-regulation of type I interferon signaling in the context of neurological disease and autoimmunity, thereby defining a novel type I interferonopathy.

scholarly journals MOLECULAR-GENETIC ASPECTS OF KABUKI MAKEUP SYNDROME. Review

2021 ◽  
Vol 17 (3) ◽  
pp. 93-97
Author(s):  
I.V. Lastivka ◽  
V.V. Antsupva ◽  
A.H. Babintseva ◽  
M.D. Unhurian ◽  
I.A. Ushko
Keyword(s):  
Clinical Case ◽  
Autosomal Dominant ◽  
De Novo ◽  
Molecular Genetic ◽  
Pathogenic Mutation ◽  
Molecular Genetic Analysis ◽  
Current Data ◽  
Type I ◽  
Pathogenic Mutations

Relevance. Kabuki Makeup Syndrome (KS) is a rare monogenic genetic disease characterized by multiple malformations. The phenotype includes specific facial features, skeletal and dermatoglyphic abnormalities, mental retardation, short stature. Most cases are associated with de novo mutations in the KMT2D and KMD6A genes. However, in 25% of patients with KS, the genetic basis remains unknown, which indicates the genetic heterogeneity of the disease and encourages further accumulation of clinical experience in KS. The article summarizes current data on the molecular geneticі aspects of the development of Kabuki Makeup Syndrome and describes its own clinical case of Kabuki Makeup Syndrome Type I. Objective: to summarize the data on modern molecular-genetic aspects of the development of Kabuki makeup syndrome on the example of a clinical case. Materials and methods. Analysis of scientific publications in the international electronic scientometric database Scopus, PubMed by keywords. Search depth – 15 years (2007-2021). The clinical case of Kabuki Makeup Syndrome from our own practice. Clinical and genealogical, molecular-genetic, cytogenetic, instrumental research methods. Results. According to current data, the development of Kabuki Makeup Syndrome is due to mutations in the KMT2D (MLL2) gene, which belongs to the genes that control embryogenesis. KMT2D functions as a promoter of the expression of other genes and the KDM6A gene; encodes a large multidomain protein that interacts with the SET1/COMPASS complex. KDM6A is a cofactor physically associated with the KMT2D-COMPASS complex and exhibits demethylase activity in histone 3. Gene mutations KMT2D and KDM6A associated with KS lead to a lack of functioning of the corresponding enzyme, which leads to impaired methylation of histones and active genes in many organs and tissues of the body. Depending on the type of mutation in the KMT2D and KMD6A genes, there are two types of Kabuki Makeup Syndrome. KS type 1 with autosomal dominant type of inheritance due to pathogenic mutations in the KMT2D gene in a heterozygous state on chromosome 12q13.12. 70% of patients have KS1. Type 2 KS is an X-linked disease that develops as a result of a heterozygous pathogenic mutation in the KDM6 gene. In most cases, KS mutations are sporadic, but families with parent-to-child transmission have been described. In patients with phenotypic signs of KS pathogenic mutations are detected in 75% of cases. Pathogenic mutations in the KMT2D gene can be detected in mosaic form, and the carrier can pass this mutation on to offspring. Pathogenic mutations have not been described in phenotypically healthy people. Here is our own observation. The girl with a combined congenital heart defect and multiple stigmas of dysembryogenesis was born at 36 weeks with a weight of 2930, 49 cm long, on the Apgar scale 8/8 points from the third planned pregnancy in parents who already had an older healthy boy. In connection with multiple malformations, the girl underwent a syndromic diagnosis using the program "Face2gene"; Kabuki Makeup Syndrome is suspected. Molecular genetic analysis revealed a pathogenic mutation (c.11884C>T) (p.Gln3962*) in the KMT2D gene, which is associated with autosomal dominant Kabuki Makeup Syndrome of type 1 (MedGen UID: 893727). Conclusions. Kabuki Makeup Syndrome has clinical and molecular polymorphisms. Most of the registered KMT2D mutations occur de novo and occur in episodic cases. The described case demonstrates the molecular-positive Kabuki Makeup Syndrome of type I. The identified variant c.11884C>T(p.Gln3962*) in the KMT2D gene is associated with the autosomal dominant Kabuki Makeup Syndrome (MedGen UID: 893727). Verification of the diagnosis of the disease and prevention of KS in siblings is based on the results of molecular genetic analysis. The prognosis of this disease depends on the severity of heart disease and intellectual impairment. Early diagnosis determines the type and timing of therapeutic interventions, is crucial for medical and genetic counseling of the family.

scholarly journals West Syndrome Is an Exceptional Presentation of Pyridoxine- and Pyridoxal Phosphate-Dependent Epilepsy: Data From a French Cohort and Review of the Literature

2021 ◽  
Vol 9 ◽  
Author(s):  
Marc Gibaud ◽  
Magalie Barth ◽  
Jérémie Lefranc ◽  
Karine Mention ◽  
Nathalie Villeneuve ◽  
...  
Keyword(s):  
Pyridoxal Phosphate ◽  
Clinical Presentation ◽  
De Novo ◽  
West Syndrome ◽  
Therapeutic Trial ◽  
Review Of The Literature ◽  
Focal Seizures ◽  
Epileptic Spasms ◽  
French Cohort

Objective: To characterize the electro-clinical presentation of patients with pyridoxine-dependent epilepsy (PDE) and pyridoxal phosphate (PLP)-dependent epilepsy in order to determine whether some of them could be diagnosed as de novo West syndrome, i. e., West syndrome that starts after the age of 2 months without other types of seizures (focal seizures for instance) before the onset of epileptic spasms.Methods: We analyzed data from an unpublished cohort of 28 genetically confirmed cases of PDE with antiquitine (ATQ) deficiency and performed a review of the literature looking for description of West syndrome in patients with either PDE with ATQ deficiency or PLP-dependent epilepsy with Pyridox(am)ine phosphate oxidase (PNPO) deficiency.Results: Of the 28 cases from the ATQ deficiency French cohort, 5 had spasms. In four cases, spasms were associated with other types of seizures (myoclonus, focal seizures). In the last case, seizures started on the day of birth. None of these cases corresponded to de novo West syndrome. The review of the literature found only one case of PNPO deficiency presenting as de novo West syndrome and no case of ATQ deficiency.Significance: The presentation of PDE- and PLP-dependent epilepsy as de novo West syndrome is so exceptional that it probably does not justify a systematic trial of pyridoxine or PLP. We propose considering a therapeutic trial with these vitamins in West syndrome if spasms are associated with other seizure types or start before the age of 2 months.

scholarly journals Enhanced cGAS-STING–dependent interferon signaling associated with mutations in ATAD3A

2021 ◽  
Vol 218 (10) ◽  
Author(s):  
Alice Lepelley ◽  
Erika Della Mina ◽  
Erika Van Nieuwenhove ◽  
Lise Waumans ◽  
Sylvie Fraitag ◽  
...  
Keyword(s):  
De Novo ◽  
Dominant Negative ◽  
Heterozygous Mutation ◽  
Interferon Α ◽  
Type I ◽  
Interferon Signaling ◽  
Immune System Activation ◽  
Neurological Phenotype ◽  
System Activation ◽  
Mitochondrial Membrane Protein

Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain–containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.

Jansky-Bielschowsky syndrome, a lysosomal disease: First diagnosed cash in Oman

1992 ◽  
Vol 50 (1) ◽  
pp. 632-633
Author(s):  
Line Buhl ◽  
David Muirhead
Keyword(s):  
Mental Retardation ◽  
Clinical Picture ◽  
Neurological Disorder ◽  
Clinical Presentation ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Infantile Form ◽  
Lysosomal Disease ◽  
Juvenile Form ◽  
Progressive Encephalopathy ◽  
Lysosomal Diseases

There are four lysosomal diseases of which the neuronal ceroid lipofuscinosis is the rarest. The clinical presentation and their characteric abnormal ultrastructure subdivide them into four types. These are known as the Infantile form (Santavuori-Haltia), Late infantile form (Jansky-Bielschowsky), Juvenile form (Batten-Spielmeyer-Voght) and the Adult form (Kuph's).An 8 year old Omani girl presented wth myclonic jerks since the age of 4 years, with progressive encephalopathy, mental retardation, ataxia and loss of vision. An ophthalmoscopy was performed followed by rectal suction biopsies (fig. 1). A previous sibling had died of an undiagnosed neurological disorder with a similar clinical picture.

Sign in / Sign up

Export Citation Format

Share Document