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Kidney Research and Clinical Practice Mar 2020Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in children, and a considerable number of patients progress to end-stage renal... (Review)
Review
Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in children, and a considerable number of patients progress to end-stage renal disease. SRNS is a highly heterogeneous disorder, both clinically and genetically, and more than 50 monogenic causes of SRNS, including isolated and syndromic forms, have been identified. Recent large-cohort studies indicate that at least 30% of childhood-onset SRNS cases are genetic. The benefits of definitive molecular diagnosis by genetic testing include the avoidance of unnecessary and potentially harmful diagnostic procedures (e.g., kidney biopsy) and treatment (e.g., steroid and immunosuppressants), detection of rare and potentially treatable mutations (e.g., coenzyme Q10 biosynthesis pathway defect), prediction of prognosis (e.g., posttransplant recurrence), and providing precise genetic counseling. Furthermore, the identification of novel disease-causing genes could provide new insights into the pathogenic mechanisms of SRNS. Therefore, whenever accessible and affordable, genetic testing is recommended for all pediatric patients with SRNS, and should certainly be performed in patients with a higher probability of genetic predisposition based on genotype-phenotype correlation data. The genetic testing approach should be determined for each patient, and clinicians should, therefore, be aware of the advantages and disadvantages of methods currently available, which include Sanger sequencing, gene panel testing, and whole-exome or whole-genome sequencing. Importantly, the need for precise and thorough phenotyping by clinicians, even in the era of genomics, cannot be overemphasized. This review provides an update on recent advances in genetic studies, a suggested approach for the genetic testing of pediatric patients with SRNS.
PubMed: 32155690
DOI: 10.23876/j.krcp.20.001 -
Journal of Clinical Medicine May 2021Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric... (Review)
Review
Hypertrophic cardiomyopathy (HCM) and primary restrictive cardiomyopathy (RCM) have a similar genetic background as they are both caused mainly by variants in sarcomeric genes. These "sarcomeric cardiomyopathies" also share diastolic dysfunction as the prevalent pathophysiological mechanism. Starting from the observation that patients with HCM and primary RCM may coexist in the same family, a characteristic pathophysiological profile of HCM with restrictive physiology has been recently described and supports the hypothesis that familiar forms of primary RCM may represent a part of the phenotypic spectrum of HCM rather than a different genetic cardiomyopathy. To further complicate this scenario some infiltrative (amyloidosis) and storage diseases (Fabry disease and glycogen storage diseases) may show either a hypertrophic or restrictive phenotype according to left ventricular wall thickness and filling pattern. Establishing a correct etiological diagnosis among HCM, primary RCM, and hypertrophic or restrictive phenocopies is of paramount importance for cascade family screening and therapy.
PubMed: 34062949
DOI: 10.3390/jcm10091954 -
Journal of Arrhythmia Feb 2021We illustrate the case Brugada Type 1 pattern on electrocardiogram in a setting of hyperkalemia, changes which were reversible following normalization of serum potassium...
We illustrate the case Brugada Type 1 pattern on electrocardiogram in a setting of hyperkalemia, changes which were reversible following normalization of serum potassium levels. Although Brugada Type 1 syndrome is associated with sudden cardiac death, a quick search for alternate reversible pathology is essential to timely management and avoid unnecessary cardiac intervention.
PubMed: 33664911
DOI: 10.1002/joa3.12498 -
Journal of Neuroinflammation Jul 2019This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative... (Review)
Review
This article describes pathogenic concepts and factors, in particular glycolipid abnormalities, that create cell dysfunction and synaptic loss in neurodegenerative diseases. By phenocopying lysosomal storage disorders, such as Gaucher disease and related disorders, age- and dose-dependent changes in glycolipid cell metabolism can lead to Parkinson's disease and related dementias. Recent results show that perturbation of sphingolipid metabolism can precede or is a part of abnormal protein handling in both genetic and idiopathic Parkinson's disease and Lewy body dementia. In aging and genetic predisposition with lipid disturbance, α-synuclein's normal vesicular and synaptic role may be detrimentally shifted toward accommodating and binding such lipids. Specific neuronal glycolipid, protein, and vesicular interactions create potential pathophysiology that is amplified by astroglial and microglial immune mechanisms resulting in neurodegeneration. This perspective provides a new logic for therapeutic interventions that do not focus on protein aggregation, but rather provides a guide to the complex biology and the common sequence of events that lead to age-dependent neurodegenerative disorders.
Topics: Animals; Brain; Humans; Inflammation; Nerve Degeneration; Neurons; Parkinson Disease; alpha-Synuclein; tau Proteins
PubMed: 31331333
DOI: 10.1186/s12974-019-1532-2 -
JACC. Clinical Electrophysiology Sep 2017
Topics: Aged; Brugada Syndrome; Electrocardiography; Humans; Hyperkalemia; Male; Prognosis
PubMed: 29759712
DOI: 10.1016/j.jacep.2016.12.012 -
Annals of Noninvasive Electrocardiology... Oct 2012Brugada syndrome is a channelopathy characterized on ECG by coved ST-segment elevation (≥2 mm) in the right precordial leads and is associated with an increased risk... (Review)
Review
Brugada syndrome is a channelopathy characterized on ECG by coved ST-segment elevation (≥2 mm) in the right precordial leads and is associated with an increased risk of malignant ventricular arrhythmias. The term Brugada phenocopy is proposed to describe conditions that induce Brugada-like ECG manifestations in patients without true Brugada syndrome. An extensive review of the literature identified case reports that were classified according to their suspected etiological mechanism. Future directions to learn more about these intriguing cases is discussed.
Topics: Adult; Aged; Aged, 80 and over; Brugada Syndrome; Electrocardiography; Female; Humans; Male; Middle Aged; Terminology as Topic
PubMed: 23094876
DOI: 10.1111/j.1542-474X.2012.00525.x -
Journal of Lipid Research Feb 2024Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes....
Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person's treatment according to the affected pathway.
Topics: Humans; Proprotein Convertase 9; Hypercholesterolemia; Cholesterol, LDL; Hyperlipoproteinemia Type II; Phenotype; Genetic Background; Receptors, LDL; Mutation
PubMed: 38122934
DOI: 10.1016/j.jlr.2023.100490 -
Journal of the American College of... Aug 2022The Brugada phenocopy represents electrocardiogram (ECG) changes nearly identical to the Brugada syndrome but without the congenital abnormality associated with lethal...
INTRODUCTION
The Brugada phenocopy represents electrocardiogram (ECG) changes nearly identical to the Brugada syndrome but without the congenital abnormality associated with lethal arrhythmias and normalizes with treatment of the underlying etiology. This case highlights the Brugada phenocopy in the setting of moderate hyperkalemia and severe hyponatremia from adrenal insufficiency that resolves with treatment of the underlying metabolic disturbance.
CASE REPORT
A 26-year-old man with no prior medical history presented to the emergency department with syncope, and his ECG revealed a Brugada-like pattern. The patient was found to have significant metabolic derangements, including severe hyponatremia (94 mEq/L), moderate hyperkalemia (6.1 mEq/L), severe hypochloremia (<60 mEq/L), acute kidney injury, and rhabdomyolysis. The patient was diagnosed with primary adrenal insufficiency, and electrolyte correction led to resolution of the Brugada phenocopy.
CONCLUSION
The Brugada phenocopy on ECG can occur with severe hyponatremia and moderate hyperkalemia and quickly resolves with electrolyte correction.
PubMed: 35978657
DOI: 10.1002/emp2.12800 -
Kardiologia Polska 2022From its initial description to the present day, left ventricular noncompaction cardiomyopathy has been the subject of numerous studies and publications. In question as...
From its initial description to the present day, left ventricular noncompaction cardiomyopathy has been the subject of numerous studies and publications. In question as a real cardiomyopathy, left ventricular noncompaction can appear in isolation or in association with other cardiac malformations, genetic syndromes, and neuromuscular disorders. As a genetically heterogeneous disorder, it can be sporadic or familial, with an autosomal dominant pattern with variable penetrance most frequently observed. Different diagnostic criteria have been described through the years, first by using echocardiogram and later on by cardiac magnetic resonance. The lack of universally accepted diagnostic criteria has led to the condition being over-diagnosed in the general population. Differential diagnosis between real cardiomyopathy, epiphenomenon (phenocopy in the setting of loading conditions or even other cardiomyopathies), and physiological hypertrabeculation, like in the athlete's heart must be considered. Clinically it can present as heart failure, ventricular arrhythmias, and even sudden death, but it can also be asymptomatic during familial screening. The main prognosis factors are left ventricular dilatation, dysfunction, and fibrosis. There is no specific treatment. Familial screening is recommended and special recommendations in the case of athletes must be taken into account. In the present article, we review the myth and reality concerning main and more recent aspects of left ventricular noncompaction.
PubMed: 35366003
DOI: 10.33963/KP.a2022.0089 -
Brain Communications 2020The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the... (Review)
Review
The genetic underpinnings of late-onset degenerative disease have typically been determined by screening families for the segregation of genetic variants with the disease trait in affected, but not unaffected, individuals. However, instances of intrafamilial etiological heterogeneity, where pathogenic variants in a culprit gene are not shared among all affected family members, continue to emerge and confound gene-discovery and genetic counselling efforts. Discordant intrafamilial cases lacking a mutation shared by other affected family members are described as disease phenocopies. This description often results in an over-simplified acceptance of an environmental cause of disease in the phenocopy cases, while the role of intrafamilial genetic heterogeneity, shared mutations or epigenetic aberrations in such families is often ignored. On a related note, it is now evident that the same disease-associated variant can be present in individuals exhibiting clinically distinct phenotypes, thereby genetically uniting seemingly unrelated syndromes to form a spectrum of disease. Herein, we discuss the intricacies of determining complex degenerative disease aetiology and suggest alternative mechanisms of disease transmission that may account for the apparent missing heritability of disease.
PubMed: 33134917
DOI: 10.1093/braincomms/fcaa120