scholarly journals Teenage-onset progressive myoclonic epilepsy due to a familial C9orf72 repeat expansion

Neurology ◽  
2018 ◽  
Vol 90 (8) ◽  
pp. e658-e663 ◽  
Author(s):  
Jelle van den Ameele ◽  
Ivana Jedlickova ◽  
Anna Pristoupilova ◽  
Anne Sieben ◽  
Sara Van Mossevelde ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Brain Biopsy ◽  
Repeat Expansion ◽  
Causative Mutation ◽  
Cytoplasmic Inclusions ◽  
Whole Exome ◽  
The Family ◽  
Repeat Expansions ◽  
Neuronal Cytoplasmic Inclusions ◽  
Progressive Myoclonic Epilepsy

BackgroundThe progressive myoclonic epilepsies (PME) are a heterogeneous group of disorders in which a specific diagnosis cannot be made in a subset of patients, despite exhaustive investigation. C9orf72 repeat expansions are emerging as an important causal factor in several adult-onset neurodegenerative disorders, in particular frontotemporal lobar degeneration and amyotrophic lateral sclerosis. An association with PME has not been reported previously.ObjectiveTo identify the causative mutation in a Belgian family where the proband had genetically unexplained PME.ResultsWe report a 33-year old woman who had epilepsy since the age of 15 and then developed progressive cognitive deterioration and multifocal myoclonus at the age of 18. The family history suggested autosomal dominant inheritance of psychiatric disorders, epilepsy, and dementia. Thorough workup for PME including whole exome sequencing did not reveal an underlying cause, but a C9orf72 repeat expansion was found in our patient and affected relatives. Brain biopsy confirmed the presence of characteristic p62-positive neuronal cytoplasmic inclusions.ConclusionC9orf72 mutation analysis should be considered in patients with PME and psychiatric disorders or dementia, even when the onset is in late childhood or adolescence.

scholarly journals Recurrent homozygous damaging mutation in TMX2, encoding a protein disulfide isomerase, in four families with microlissencephaly

2019 ◽  
Vol 57 (4) ◽  
pp. 274-282 ◽  
Author(s):  
Shereen Georges Ghosh ◽  
Lu Wang ◽  
Martin W Breuss ◽  
Joshua D Green ◽  
Valentina Stanley ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Transmembrane Protein ◽  
Repeat Expansion ◽  
Global Developmental Delay ◽  
Disulfide Isomerase ◽  
Whole Exome ◽  
Brain Malformations ◽  
Repeat Expansions ◽  
Protein Disulfide

BackgroundProtein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.MethodsEight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.ResultsAn identical homozygous variant in TMX2 (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While TMX2 is an activator of cellular C9ORF72 repeat expansion toxicity, patients showed no evidence of C9ORF72 repeat expansions.ConclusionThe TMX2 c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of C9ORF72 expansions. TMX2 is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

scholarly journals Germline variant in REXO2 is a novel candidate gene in familial pheochromocytoma

2020 ◽  
Vol 102 ◽  
Author(s):  
Yael Laitman ◽  
Shay Tzur ◽  
Ruben Attali ◽  
Amit Tirosh ◽  
Eitan Friedman
Keyword(s):  
Allelic Imbalance ◽  
Chromosomal Region ◽  
Cancer Susceptibility ◽  
Functional Studies ◽  
Cancer Susceptibility Genes ◽  
Whole Exome ◽  
Familial Pheochromocytoma ◽  
The Family ◽  
Recombination Processes

Abstract Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.

scholarly journals REscan: inferring repeat expansions and structural variation in paired-end short read sequencing data

2020 ◽  
Author(s):  
Russell Lewis McLaughlin
Keyword(s):  
Structural Variation ◽  
Sequence Data ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Sequencing Data ◽  
Short Read ◽  
Short Read Sequencing ◽  
Repeat Expansions ◽  
Paired End Sequencing

Abstract Motivation Repeat expansions are an important class of genetic variation in neurological diseases. However, the identification of novel repeat expansions using conventional sequencing methods is a challenge due to their typical lengths relative to short sequence reads and difficulty in producing accurate and unique alignments for repetitive sequence. However, this latter property can be harnessed in paired-end sequencing data to infer the possible locations of repeat expansions and other structural variation. Results This article presents REscan, a command-line utility that infers repeat expansion loci from paired-end short read sequencing data by reporting the proportion of reads orientated towards a locus that do not have an adequately mapped mate. A high REscan statistic relative to a population of data suggests a repeat expansion locus for experimental follow-up. This approach is validated using genome sequence data for 259 cases of amyotrophic lateral sclerosis, of which 24 are positive for a large repeat expansion in C9orf72, showing that REscan statistics readily discriminate repeat expansion carriers from non-carriers. Availabilityand implementation C source code at https://github.com/rlmcl/rescan (GNU General Public Licence v3).

Identification of a novel causative mutation in KRT1 in diffuse palmoplantar keratoderma, facilitated by whole-exome sequencing

2021 ◽  
Vol 31 (2) ◽  
pp. 264-265
Author(s):  
So Takeuchi ◽  
Takuya Takeichi ◽  
Yasutoshi Ito ◽  
Kana Tanahashi ◽  
Yoshinao Muro ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Causative Mutation ◽  
Palmoplantar Keratoderma ◽  
Whole Exome

Family environment of eating disordered patients with and without self-injurious behaviors

2004 ◽  
Vol 19 (8) ◽  
pp. 494-498 ◽  
Author(s):  
Laurence Claes ◽  
Walter Vandereycken ◽  
Hans Vertommen
Keyword(s):  
Psychiatric Disorders ◽  
Family Environment ◽  
Interaction Effect ◽  
Significant Interaction ◽  
Family Context ◽  
Hair Pulling ◽  
Significant Interaction Effect ◽  
Eating Disordered ◽  
Significant Difference ◽  
The Family

AbstractObjective.– The family environment is known to be an important contributor to the course of psychiatric disorders. In this study, we examined the family context of eating disordered (ED) patients with and without self-injurious behaviors (SIB).Method.– A Dutch adaptation of the Family Environment Scale ‘Sci Eng 57(9-B):1997;5927’ was completed by 131 ED patients of whom 47% showed at least one form of SIB (e.g., cutting, burning, hair pulling, etc.).Results– Results showed a significant difference in family environment between patients with and without SIB. The family environment of self-injuring ED patients was less cohesive, expressive and socially oriented, and more conflictual and disorganized than the family environment of those without SIB. No significant differences in perceived family environment were found with respect to the number or form of SIB and the subtype of ED. Neither did we find a significant interaction effect between ED subtype and presence/absence of SIB.

scholarly journals Familial adult myoclonic epilepsy (FAME): clinical features, molecular characteristics, pathophysiological aspects and diagnostic work-up

2021 ◽  
Vol 33 (4) ◽  
pp. 311-318
Author(s):  
Lorenz Peters ◽  
Christel Depienne ◽  
Stephan Klebe
Keyword(s):  
Clinical Features ◽  
Neurological Disorders ◽  
Genetic Disorder ◽  
Repeat Expansion ◽  
Myoclonic Epilepsy ◽  
Molecular Characteristics ◽  
Autosomal Dominant Disorder ◽  
Repeat Expansions ◽  
Diagnostic Work ◽  
Work Up

Abstract Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3′ end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains mainly unsolved.

scholarly journals Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

2021 ◽  
Vol 67 (1) ◽  
pp. 111-116
Author(s):  
Kirill Zagorodnev ◽  
Aleksandr Romanko ◽  
Uliy Gorgul ◽  
Aleksandr Ivantsov ◽  
Anna Sokolenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Hereditary Breast Cancer ◽  
Germ Line ◽  
Genetic Diagnosis ◽  
Clinical Signs ◽  
Causative Mutation ◽  
Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia

2008 ◽  
Vol 116 (2) ◽  
pp. 193-203 ◽  
Author(s):  
Fumiaki Mori ◽  
Kunikazu Tanji ◽  
Hai-Xin Zhang ◽  
Yasushi Nishihira ◽  
Chun-Feng Tan ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Maturation Process ◽  
Cytoplasmic Inclusions ◽  
Neuronal Cytoplasmic Inclusions ◽  
Lateral Sclerosis

P01-331-Family functioning of adolescents with a major depressive disorder – a comparative study

2011 ◽  
Vol 26 (S2) ◽  
pp. 333-333
Author(s):  
M.L. Perereira ◽  
D.L. Nunes Peçanha ◽  
I.A. Santos Bordin
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Family Functioning ◽  
Psychiatric Disorders ◽  
Family Income ◽  
Well Being ◽  
Occupational Activity ◽  
Major Depressive ◽  
The Family ◽  
Depressive Episodes

IntroductionPsychiatric disorders occur in a complex context of human relations in its social and psychological aspects. Family functioning is closely related to physical and psychological well-being of family members and its impairment affects the family as a whole.ObjectivesTo evaluate family functioning in two groups of adolescents (13–18 years): cases (with major depressive disorder) and controls (with no DSM-IV psychiatric disorders based on the Brazilian version of the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime/K-SADS-PL).MethodFamilies of cases (N = 9) and controls (N = 9) were matched by adolescent's age, gender and education, number and age of siblings, parental marital status and occupational activity, and family income. An experienced systemic family therapist applied the Structured Family Interview to each family. Nine dimensions of family functioning were evaluated: communication, rules, roles, leadership, conflict, aggressiveness, affect, individuation and integration. Session transcripts were independently evaluated by two other systemic family therapists blind to the family case-control category.ResultsRaters scored all interview items using a standardized coding system (overall agreement = 83.5%). Cases exhibited lower mean scores in seven family dimensions, specially affect (p = 0.0078). Differences were not found regarding rules and leadership.ConclusionDifficulty in expressing affect in parent-child relationships was the main characteristic of families with a depressive adolescent. Improvement of family functioning can contribute to minimize the negative influence of psychosocial and family factors on the reoccurrence, and severity of depressive episodes among depressed adolescents.

Diagnostic Brain Biopsy

Neurosurgery ◽  
1979 ◽  
Vol 4 (2) ◽  
pp. 129-136 ◽  
Author(s):  
Howard H. Kaufman ◽  
Louis W. Catalano
Keyword(s):  
New York ◽  
Biopsy Specimen ◽  
Brain Biopsy ◽  
Definitive Diagnosis ◽  
Consecutive Series ◽  
Progressive Dementia ◽  
Biopsy Material ◽  
Institutional Level ◽  
Suitable Material ◽  
The Family

Abstract A consecutive series of 50 diagnostic cerebral biopsies carried out over a 12-year period (1960 to 1972) at The Neurological Institute of New York is reported. The goal of the biopsy was to acquire a definitive diagnosis to aid the patient, counsel the family, and advance scientific knowledge. General indications for biopsy were either chronic bilateral cerebral findings associated with progressive dementia or profound retardation or acute unilateral cerebral findings, usually associated with signs of meningoencephalitis. Four patients were not suitable for analysis, leaving 46 patients to be surveyed. Diagnostic neuropathological features were judged to be present in 17 specimens (37%). Abnormal but not diagnostic pathological changes were found in 22 specimens (48%). Thus, 39 specimens (85%) displayed some abnormality. No apparent neuropathological changes were present in 7 specimens (15%). These findings correspond favorably with the results of others and suggest that a certain “irreducible minimum” of normal biopsies occurs with the techniques utilized. Fourteen (30%) of the patients were known to be alive at the conclusion of the study. Twenty-two patients (48%) had died, but necropsy findings were available for only 10 of these. Except in 2 cases in which biopsies had been normal, no discrepancy was noted between the basic neuropathological changes found at necropsy and those of the biopsy specimen. One death could be directly attributed to the procedure, and total morbidity and mortality was approximately 13%. The authors recommend that any biopsy program should be organized at an institutional level to take into account the patient's special illness and the capabilities of that institution. In addition, suitable material must be forwarded to appropriate experts who have the knowledge and facility to make full use of biopsy material.

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