Familial adult myoclonic epilepsy (FAME): clinical features, molecular characteristics, pathophysiological aspects and diagnostic 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.

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Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.652027 ◽

2021 ◽

Vol 8 ◽

Author(s):

Michelle M. Monasky ◽

Emanuele Micaglio ◽

Emanuela T. Locati ◽

Carlo Pappone

Keyword(s):

Genetic Testing ◽

Risk Stratification ◽

Brugada Syndrome ◽

Autosomal Dominant Disorder ◽

Second Stage ◽

Whole Exome ◽

Diagnostic Work ◽

Electrocardiogram Ecg ◽

Work Up ◽

Current Guidelines

The evolution of the current dogma surrounding Brugada syndrome (BrS) has led to a significant debate about the real usefulness of genetic testing in this syndrome. Since BrS is defined by a particular electrocardiogram (ECG) pattern, after ruling out certain possible causes, this disease has come to be defined more for what it is not than for what it is. Extensive research is required to understand the effects of specific individual variants, including modifiers, rather than necessarily grouping together, for example, “all SCN5A variants” when trying to determine genotype-phenotype relationships, because not all variants within a particular gene act similarly. Genetic testing, including whole exome or whole genome testing, and family segregation analysis should always be performed when possible, as this is necessary to advance our understanding of the genetics of this condition. All considered, BrS should no longer be considered a pure autosomal dominant disorder, but an oligogenic condition. Less common patterns of inheritance, such as recessive, X–linked, or mitochondrial may exist. Genetic testing, in our opinion, should not be used for diagnostic purposes. However, variants in SCN5A can have a prognostic value. Patients should be diagnosed and treated per the current guidelines, after an arrhythmologic examination, based on the presence of the specific BrS ECG pattern. The genotype characterization should come in a second stage, particularly in order to guide the familial diagnostic work-up. In families in which an SCN5A pathogenic variant is found, genetic testing could possibly contribute to the prognostic risk stratification.

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Clinical Features of Patients With Negative Results From Traditional Diagnostic Work-up and Crohn??s Disease Findings From Capsule Endoscopy

Journal of Clinical Gastroenterology ◽

10.1097/00004836-200609000-00006 ◽

2006 ◽

Vol 40 (8) ◽

pp. 692-696 ◽

Cited By ~ 21

Author(s):

Julio Valle ◽

Mariano Alc??ntara ◽

Mar??a Jos?? P??rez-Grueso ◽

Javier Navajas ◽

Concepci??n Mu??oz-Rosas ◽

...

Keyword(s):

Clinical Features ◽

Capsule Endoscopy ◽

Negative Results ◽

Diagnostic Work ◽

Work Up ◽

Diagnostic Work Up

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Prevalence, Characteristics, and Patterns of Health Care Use for Chronic Headache in Two Areas of Italy. Results of A Questionnaire Interview in General Practice

Cephalalgia ◽

10.1046/j.1468-2982.2003.00523.x ◽

2003 ◽

Vol 23 (3) ◽

pp. 175-182 ◽

Cited By ~ 8

Author(s):

E Beghi ◽

ML Monticelli ◽

L Amoruso ◽

MM Zarrelli

Keyword(s):

Health Care ◽

General Practice ◽

Clinical Features ◽

Chronic Headache ◽

Health Care Use ◽

Treatment Modalities ◽

Ihs Criteria ◽

Diagnostic Work ◽

Work Up ◽

Diagnostic Work Up

We set out to define the prevalence, clinical features and severity of chronic headache among the affiliates of two groups of general practitioners (GPs) and to illustrate the diagnostic and therapeutic modalities employed. A semistructured questionnaire was completed for 2291 children and adults, seen at office or home consultations over a 6-month period by 44 GPs in two areas of Northern Italy (Varese and Sondrio) and Southern Italy (San Giovanni Rotondo), to assess the presence and the clinical features of chronic headache, the severity of the disease (i.e. the degree of interference with work and daily living activities), the diagnostic work-up, and the main treatment modalities. GPs attempted the classification of headache according to the International Headache Society (IHS) criteria. The sample comprised 910 men and 1381 women aged 2-92 years; 39% of cases reported chronic headache (Varese/Sondrio 40%; San Giovanni Rotondo 38%; men 28%; women 47%). Headache was mostly present for >10 years, with one to three attacks/month lasting 4-24 h. Headache was mild in 18% of cases, moderate in 29%, severe in 24%, and very severe in 29%. Diagnostic assessment and treatment varied in the study areas. Diagnostic work-up, hospital admissions, referral to headache centres, and treatment modalities tended to be correlated with headache severity. The GPs could not classify headache using the IHS categories in 27% of cases (Varese/Sondrio 11%; San Giovanni Rotondo 78%). An inverse correlation was found between case classification and use of subsidiary diagnostic and therapeutic aids. Chronic headache is common among individuals seen in general practice. The patterns of health care use tend to be correlated to its severity. A better knowledge of the IHS criteria may be directly related to lower management costs.

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Epidemiology, clinical features and diagnostic work-up of cystic neoplasms of the pancreas: Interim analysis of the prospective PANCY survey

Digestive and Liver Disease ◽

10.1016/j.dld.2020.02.003 ◽

2020 ◽

Vol 52 (5) ◽

pp. 547-554 ◽

Cited By ~ 1

Author(s):

Raffaele Pezzilli ◽

Elisabetta Buscarini ◽

Tommaso Pollini ◽

Deborah Bonamini ◽

Giovanni Marchegiani ◽

...

Keyword(s):

Clinical Features ◽

Interim Analysis ◽

Cystic Neoplasms ◽

Diagnostic Work ◽

Work Up ◽

Diagnostic Work Up

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Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Nature Communications ◽

10.1038/s41467-019-12763-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 31

Author(s):

Rahel T. Florian ◽

◽

Florian Kraft ◽

Elsa Leitão ◽

Sabine Kaya ◽

...

Keyword(s):

Blood Cells ◽

Repeat Expansion ◽

Myoclonic Epilepsy ◽

Genomic Rearrangements ◽

Nanopore Sequencing ◽

Considerable Variability ◽

Single Dna Molecules ◽

Molecular Combing ◽

Repeat Expansions ◽

Type 3

Abstract Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

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Waardenburg syndrome: a rare genetic disorder in four generations of a family

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20194766 ◽

2019 ◽

Vol 6 (6) ◽

pp. 2733 ◽

Cited By ~ 1

Author(s):

Charusheela Korday ◽

Baraturam Bhaisara ◽

Dhara Shah ◽

Srinivas Shinde ◽

N. S. K. Vasu ◽

...

Keyword(s):

Genetic Disorder ◽

Sensorineural Deafness ◽

Female Child ◽

Waardenburg Syndrome ◽

Autosomal Dominant Disorder ◽

The Family ◽

Appropriate For Gestational Age ◽

Work Up

Waardenburg Syndrome (WS) is a rare autosomal dominant disorder manifesting with sensorineural deafness, pigmentation defects of the skin, hair and iris and various defects of neural crest derived tissues. A primigravida mother delivered a full term, appropriate for gestational age, 2530 gm female child, by emergency LSCS. Baby was admitted in the NICU in view of features suggestive of Waardenburg syndrome, like white forelock of hair, broad nasal root and hypopigmented patches on the skin for further work up and management. Several members in the family were affected in the last 4 consecutive generations. Our baby was feeding well and discharged home after an uneventful hospital stay. Early diagnosis, detection of findings of hearing loss and the characteristic ophthalmic findings as well as regular follow up is necessary to enable the patient to lead a better quality of life.

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Overhydrated stomatocytosis associated with a complex RHAG genotype including a novel de novo mutation

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205018 ◽

2018 ◽

Vol 71 (7) ◽

pp. 648-652 ◽

Cited By ~ 5

Author(s):

Manu Jamwal ◽

Anu Aggarwal ◽

Man Updesh Singh Sachdeva ◽

Prashant Sharma ◽

Pankaj Malhotra ◽

...

Keyword(s):

Haemolytic Anaemia ◽

In Silico ◽

De Novo ◽

In Silico Analysis ◽

De Novo Mutation ◽

Heterozygous Mutation ◽

Autosomal Dominant Disorder ◽

Family Screening ◽

Diagnostic Work ◽

Work Up

Overhydrated stomatocytosis is a rare autosomal dominant disorder known to cause variably severe haemolytic anaemia due to heterozygous mutations in the RHAG gene. We report a 26-year-old man with recurring jaundice, splenohepatomegaly and mild chronic haemolytic anaemia with significant stomatocytosis. Extensive haemolytic work-up including flow cytometry for eosin-5′-maleimide and CD47 expression levels was carried out. Targeted resequencing revealed two probably causative heterozygous mutations in RHAG (Leu336Ser and Ile149Met) and one heterozygous mutation in ANK1 (Glu1046Lys). RHAG involvement was confirmed by decreased RhAG macrocomplex component indicated by the reduced CD47 expression on erythrocytes. In silico analysis concordantly flagged RHAG:Leu336Ser and ANK1:Glu1046Lys as likely deleterious mutation, whereas RHAG:Ile149Met was reported as likely neutral by PROVEAN. Family screening by Sanger sequencing revealed RHAG:Leu336Ser in a mother and ANK1:Glu1046Lys in a father who were both asymptomatic, excluding them as causative dominant events, thus establishing RHAG:Ile149Met, novel de novo mutation as probably causative. This case illustrates the importance of family screening in interpreting next-generation sequencing (NGS) data, as in silico analysis alone can be misleading. Erudite generation of diagnostic possibilities based on a thorough baseline clinical and laboratory work-up remains as important as ever, even as NGS brings about a paradigm shift in the diagnostic work-up of rare haemolytic anaemias.

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Whole genome sequencing for diagnosis of neurological repeat expansion disorders

10.1101/2020.11.06.371716 ◽

2020 ◽

Author(s):

Kristina Ibanez ◽

James Polke ◽

Tanner Hagelstrom ◽

Egor Dolzhenko ◽

Dorota Pasko ◽

...

Keyword(s):

Family History ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Neurological Disorders ◽

Repeat Expansion ◽

Whole Genome ◽

Dna Repeats ◽

Paediatric Patients ◽

Health And Social Care ◽

Repeat Expansions

ABSTRACTBackgroundRepeat expansion (RE) disorders affect ~1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in under diagnosis of atypical clinical presentations, especially in paediatric patients without a prior positive family history. Whole genome sequencing (WGS) is emerging as a first-line test for rare genetic disorders, but until recently REs were thought to be undetectable by this approach.MethodsWGS pipelines for RE disorder detection were deployed by the 100,000 Genomes Project and Illumina Clinical Services Laboratory. Performance was retrospectively assessed across the 13 most common neurological RE loci using 793 samples with prior orthogonal testing (182 with expanded alleles and 611 with alleles within normal size) and prospectively interrogated in 13,331 patients with suspected genetic neurological disorders.FindingsWGS RE detection showed minimum 97·3% sensitivity and 99·6% specificity across all 13 disease-associated loci. Applying the pipeline to patients from the 100,000 Genomes Project identified pathogenic repeat expansions which were confirmed in 69 patients, including seven paediatric patients with no reported family history of RE disorders, with a 0.09% false positive rate.InterpretationWe show here for the first time that WGS enables the detection of causative repeat expansions with high sensitivity and specificity, and that it can be used to resolve previously undiagnosed neurological disorders. This includes children with no prior suspicion of a RE disorder. These findings are leading to diagnostic implementation of this analytical pipeline in the NHS Genomic Medicine Centres in England.FundingMedical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, Illumina Inc

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Rapidly progressive glomerulonephritis as presenting feature of systemic lupus erythematosus in a Bangladeshi male patient: a rare case report

BIRDEM Medical Journal ◽

10.3329/birdem.v10i2.47748 ◽

2020 ◽

Vol 10 (2) ◽

pp. 137-138

Author(s):

Samiha Haque ◽

Ishrat Jahan ◽

Tufayel Ahmed Chowdhury ◽

Muhammad Abdur Rahim ◽

Mehruba Alam Ananna ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Venous Pressure ◽

Rapidly Progressive Glomerulonephritis ◽

Initial Response ◽

Systemic Lupus ◽

Renal Manifestation ◽

Rare Case Report ◽

Diagnostic Work ◽

Work Up

Rapidly progressive glomerulonephritis is one of the most dramatic and tragic presentations of lupus nephritis (LN) or renal manifestation of systemic lupus erythematosus (SLE). A 35-year-old Bangladeshi gentleman presented with worsening oedema, scanty, high colored, frothy urine and deteriorating renal function. He had puffy face, anaemia, oedema, normal jugular venous pressure (JVP), high blood pressure (150/90 mm Hg), ascites and bilateral pleural effusions. Diagnostic work-up confirmed SLE with class IV LN. His initial response to specific therapy showed improvement Birdem Med J 2020; 10(2): 137-138

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