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Current Opinion in Cardiology Sep 2023The aim of this study was to review imaging of myocardial hypertrophy in hypertrophic cardiomyopathy (HCM) and its phenocopies. The introduction of cardiac myosin... (Review)
Review
PURPOSE OF REVIEW
The aim of this study was to review imaging of myocardial hypertrophy in hypertrophic cardiomyopathy (HCM) and its phenocopies. The introduction of cardiac myosin inhibitors in HCM has emphasized the need for careful evaluation of the underlying cause of myocardial hypertrophy.
RECENT FINDINGS
Advances in imaging of myocardial hypertrophy have focused on improving precision, diagnosis, and predicting prognosis. From improved assessment of myocardial mass and function, to assessing myocardial fibrosis without the use of gadolinium, imaging continues to be the primary tool in understanding myocardial hypertrophy and its downstream effects. Advances in differentiating athlete's heart from HCM are noted, and the increasing rate of diagnosis in cardiac amyloidosis using noninvasive approaches is especially highlighted due to the implications on treatment approach. Finally, recent data on Fabry disease are shared as well as differentiating other phenocopies from HCM.
SUMMARY
Imaging hypertrophy in HCM and ruling out other phenocopies is central to the care of patients with HCM. This space will continue to rapidly evolve, as disease-modifying therapies are under investigation and being advanced to the clinic.
Topics: Humans; Diagnosis, Differential; Cardiomyopathy, Hypertrophic; Cardiomegaly; Magnetic Resonance Imaging, Cine; Contrast Media; Fibrosis
PubMed: 37421401
DOI: 10.1097/HCO.0000000000001070 -
Journal of Geriatric Psychiatry and... May 2021The relatively recent identification of a subgroup of patients with apparent behavioral variant frontotemporal dementia (bvFTD) that fails to progress with time has led... (Review)
Review
OBJECTIVES
The relatively recent identification of a subgroup of patients with apparent behavioral variant frontotemporal dementia (bvFTD) that fails to progress with time has led to a reevaluation of our understanding of bvFTD, and a growing body of research that attempts to characterize the mimic or "phenocopy" syndrome. In this article, we review the literature relating to the phenocopy syndrome, focusing in particular on distinguishing characteristics and potential etiologies.
METHODS
Published articles were identified via a systematic search of PubMed and Embase. Observational and interventional studies, case reports, and case series were sought for inclusion.
RESULTS
While bvFTD and the phenocopy syndrome are clinically indistinguishable at initial presentation, the presence or absence of characteristic changes on neuroimaging predicts 2 very different illness trajectories. The etiology for the phenocopy presentation remains uncertain. It is likely that the syndrome represents a heterogenous assortment of clinical frontal syndromes encompassing atypical neurodegenerative, psychiatric, psychological, and as yet unknown neuropsychiatric causes.
CONCLUSIONS
Although the prognosis of the phenocopy syndrome is generally held to be more favorable than that of bvFTD, patients and families are subject to major disruption in their relationships and social and occupational functioning. Early recognition is crucial to facilitate timely interventions aimed at maintaining relationships, roles, and quality of life of those affected.
Topics: Frontotemporal Dementia; Humans; Neuroimaging; Neuropsychological Tests; Quality of Life; Syndrome
PubMed: 32436433
DOI: 10.1177/0891988720924708 -
Kidney International Reports Nov 2021
PubMed: 34805625
DOI: 10.1016/j.ekir.2021.09.012 -
Frontiers in Immunology 2021Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many... (Review)
Review
Elucidating links between genotype and phenotype in patients with rare inborn errors of immunity (IEIs) provides insights into mechanisms of immune regulation. In many autosomal dominant IEIs, however, variation in expressivity and penetrance result in complex genotype-phenotype relations, while some autosomal recessive IEIs are so rare that it is difficult to draw firm conclusions. Phenocopies arise when an environmental or non-genetic factor replicates a phenotype conferred by a specific genotype. Phenocopies can result from therapeutic antibodies or autoantibodies that target a protein to replicate aspects of the phenotype conferred by mutations in the gene encoding the same protein. Here, we consider IEIs arising from rare genetic variants in and and compare clinical and laboratory manifestations arising as drug-induced phenocopies (immune related adverse events, IRAEs) in cancer patients treated with immune checkpoint inhibitors (ICI) and identify outstanding questions regarding mechanism of disease.
Topics: CTLA-4 Antigen; Genetic Association Studies; Genetic Diseases, Inborn; Genetic Predisposition to Disease; Genetic Variation; Haploinsufficiency; Humans; Immune System Diseases; Immunologic Deficiency Syndromes; Loss of Function Mutation; Phenotype; Programmed Cell Death 1 Receptor
PubMed: 35154081
DOI: 10.3389/fimmu.2021.806043 -
Neuroscience Oct 2020Genetic neurodevelopmental disorders - that often include epilepsy as part of their phenotype - are a heterogeneous and clinically challenging spectrum of disorders in... (Review)
Review
Genetic neurodevelopmental disorders - that often include epilepsy as part of their phenotype - are a heterogeneous and clinically challenging spectrum of disorders in children. Although seizures often contribute significantly to morbidity in these affected populations, the mechanisms of epileptogenesis in these conditions remain poorly understood. Different model systems have been developed to aid in unraveling these mechanisms, which include a number of specific mutant mouse lines which genocopy specific general types of mutations present in patients. These mouse models have not only allowed for assessments of behavioral and electrographic seizure phenotypes to be ascertained, but also have allowed effects on the neurodevelopmental alterations and cognitive impairments associated with these disorders to be examined. In addition, these models play a role in advancing our understanding of these epileptic processes and developing preclinical therapeutics. The concordance of seizure phenotypes - in a select group of rare, genetic, neurodevelopmental disorders and epileptic encephalopathies - found between human patients and their model counterparts will be summarized. This review aims to assess whether models of Rett syndrome, CDKL5 deficiency disorder, Fragile-X syndrome, Dravet syndrome, and Ohtahara syndrome phenocopy the seizures seen in human patients.
Topics: Animals; Epilepsy; Epileptic Syndromes; Humans; Mice; Mutation; Neurodevelopmental Disorders; Protein Serine-Threonine Kinases; Seizures; Spasms, Infantile
PubMed: 32059984
DOI: 10.1016/j.neuroscience.2020.01.041 -
The Journal of Clinical Investigation Dec 2023Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates...
Foxp3-expressing Tregs employ multiple suppressive mechanisms to curtail conventional T cell (Tconv) responses and establish tissue homeostasis. How Foxp3 coordinates Treg contact-dependent suppressive function is not fully resolved. In this issue of the JCI, Wang and colleagues revealed that Foxp3-mediated inhibition of ryanodine receptor 2 (RyR2) led to strong Treg-DC interactions and enhanced immunosuppression. RyR2 depletion in Tconvs phenocopied this effect and equipped Tconvs with Treg-like suppressive function in multiple inflammatory or autoimmune contexts. This study provides molecular and therapeutic insights underlying how cell-cell contact limits immune reactivity.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Ryanodine Receptor Calcium Release Channel; Mice, Inbred C57BL; Immunosuppression Therapy; Forkhead Transcription Factors
PubMed: 38099491
DOI: 10.1172/JCI172986 -
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 -
Current Cardiology Reports Nov 2022We describe the most common phenocopies of hypertrophic cardiomyopathy, their pathogenesis, and clinical presentation highlighting similarities and differences. We also... (Review)
Review
PURPOSE OF REVIEW
We describe the most common phenocopies of hypertrophic cardiomyopathy, their pathogenesis, and clinical presentation highlighting similarities and differences. We also suggest a step-by-step diagnostic work-up that can guide in differential diagnosis and management.
RECENT FINDINGS
In the last years, a wider application of genetic testing and the advances in cardiac imaging have significantly changed the diagnostic approach to HCM phenocopies. Different prognosis and management, with an increasing availability of disease-specific therapies, make differential diagnosis mandatory. The HCM phenotype can be the cardiac manifestation of different inherited and acquired disorders presenting different etiology, prognosis, and treatment. Differential diagnosis requires a cardiomyopathic mindset allowing to recognize red flags throughout the diagnostic work-up starting from clinical and family history and ending with advanced imaging and genetic testing. Different prognosis and management, with an increasing availability of disease-specific therapies make differential diagnosis mandatory.
Topics: Humans; Cardiomyopathy, Hypertrophic
PubMed: 36053410
DOI: 10.1007/s11886-022-01778-2 -
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 -
Seminars in Immunology May 2023Inborn errors of immunity (IEI) are a diverse group of monogenic disorders of the immune system due to germline variants in genes important for the immune response. Over... (Review)
Review
Inborn errors of immunity (IEI) are a diverse group of monogenic disorders of the immune system due to germline variants in genes important for the immune response. Over the past decade there has been increasing recognition that acquired somatic variants present in a subset of cells can also lead to immune disorders or 'phenocopies' of IEI. Discovery of somatic mosaicism causing IEI has largely arisen from investigation of seemingly sporadic cases of IEI with predominant symptoms of autoinflammation and/or autoimmunity in which germline disease-causing variants are not detected. Disease-causing somatic mosaicism has been identified in genes that also cause germline IEI, such as FAS, and in genes without significant corresponding germline disease, such as UBA1 and TLR8. There are challenges in detecting low-level somatic variants, and it is likely that the extent of the somatic mosaicism causing IEI is largely uncharted. Here we review the field of somatic mosaicism leading to IEI and discuss challenges and methods for somatic variant detection, including diagnostic approaches for molecular diagnoses of patients.
Topics: Humans; Mosaicism; Autoimmunity; Phenotype
PubMed: 37062181
DOI: 10.1016/j.smim.2023.101761