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IEEE Reviews in Biomedical Engineering 2023The main reason why therapeutic schemes fail in Glioblastoma lies on its own peculiarities as a cancer and on our failure to fully decipher them. Fast tumor evolution,... (Review)
Review
The main reason why therapeutic schemes fail in Glioblastoma lies on its own peculiarities as a cancer and on our failure to fully decipher them. Fast tumor evolution, invasiveness and incomplete surgical resection contribute to disease recurrence, therapy resistance and high mortality. More faithful models must be developed to address Glioblastoma biology and better clinical guidance. Research studies are discussed in this review that: i) improve understanding and assessment of the growth mechanisms of Glioblastoma and ii) develop preclinical models (in vitro-in vivo-in silico) that mimic patient's tumor (phenocopying) in order to provide better prediction of response to therapies.
Topics: Humans; Glioblastoma
PubMed: 34506292
DOI: 10.1109/RBME.2021.3111744 -
Cell Metabolism Mar 2023A recent report by Yang et al. in Cell demonstrates that faithful DNA double-strand breaks and repair cycles phenocopy many aspects of aging in mice. Whether this...
A recent report by Yang et al. in Cell demonstrates that faithful DNA double-strand breaks and repair cycles phenocopy many aspects of aging in mice. Whether this progeroid phenotype is caused by a loss of epigenetic information remains to be conclusively determined.
Topics: Animals; Mice; DNA Repair; DNA Breaks, Double-Stranded; Aging
PubMed: 36889279
DOI: 10.1016/j.cmet.2023.02.012 -
Seminars in Neurology Feb 2023Chorea is a hyperkinetic movement disorder with a multitude of potential etiologies, both acquired and inherited. Although the differential diagnosis for new-onset...
Chorea is a hyperkinetic movement disorder with a multitude of potential etiologies, both acquired and inherited. Although the differential diagnosis for new-onset chorea is extensive, there are often clues in the history, exam, and basic testing that can help to narrow the options. Evaluation for treatable or reversible causes should take priority, as rapid diagnosis can lead to more favorable outcomes. While Huntington's disease is most common genetic cause of chorea, multiple phenocopies also exist and should be considered if Huntington gene testing is negative. The decision of what additional genetic testing to pursue should be based on both clinical and epidemiological factors. The following review provides an overview of the many possible etiologies as well as a practical approach for a patient presenting with new-onset chorea.
Topics: Humans; Chorea; Huntington Disease; Genetic Testing; Diagnosis, Differential; Phenotype
PubMed: 36882120
DOI: 10.1055/s-0043-1763506 -
Journal of Neurology Jul 2021CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6... (Review)
Review
OBJECTIVES
CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG is applied to study their episodic manifestations, but findings in the intervals did not gain attention up to date.
METHODS
We analyzed repeated EEG recordings performed between 1994 and 2019 in a large cohort of genetically confirmed CACNA1A patients. EEG findings were compared with those of CACNA1A-negative phenocopies. A review of the related literature was performed.
RESULTS
85 EEG recordings from 38 patients (19 EA2, 14 FHM1, 5 SCA6) were analyzed. Baseline EEG was abnormal in 55% of cases (12 EA2, 9 FHM1). The most common finding was a lateralized intermittent slowing, mainly affecting the temporal region. Slowing was more pronounced after a recent attack but was consistently detected in the majority of patients also during the follow-up. Interictal epileptic discharges (IEDs) were detected in eight patients (7 EA2,1 FHM1). EEG abnormalities and especially IEDs were significantly associated with younger age at examination (16 ± 9 vs 43 ± 21 years in those without epileptic changes, p = 0.003) and with earlier onset of disease (1 (1-2) vs 12 (5-45) years, p = 0.0009). EEG findings in CACNA1A-negative phenocopies (n = 15) were largely unremarkable (p = 0.03 in the comparison with CACNA1A patients).
CONCLUSIONS
EEG abnormalities between attacks are highly prevalent in episodic CACNA1A disorders and especially associated with younger age at examination and earlier disease onset. Our findings underpin an age-dependent effect of CACNA1A variants, with a more severe impairment when P/Q channel dysfunction manifests early in life.
Topics: Calcium Channels; Epilepsy; Humans; Migraine with Aura; Phenotype; Spinocerebellar Ataxias
PubMed: 33544220
DOI: 10.1007/s00415-021-10415-x -
Allergy, Asthma, and Clinical... Jan 2024Inborn errors of immunity (IEIs) are a group of conditions whereby parts of the immune system are missing or dysfunctional. Once thought to primarily be a pediatric... (Review)
Review
Inborn errors of immunity (IEIs) are a group of conditions whereby parts of the immune system are missing or dysfunctional. Once thought to primarily be a pediatric disorder, it is now estimated that more than 50% of worldwide incident IEI cases are accounted for by adults. Delayed diagnosis, late symptom onset, and IEI phenocopies can all lead to adult-onset recognition of IEIs. Lack of awareness regarding the diversity of IEI manifestations in adults contributes to diagnostic and treatment delays. Prompt referral to immunology is critical so that patients can receive a precise molecular diagnosis and targeted therapy when available. This article serves as a primer on IEIs in adulthood, highlighting the pathophysiology, epidemiology and clinical features. We present clinical vignettes of three key IEIs to assist clinicians in building illness scripts on their presentations. We provide a framework for the laboratory evaluation of IEIs and their initial treatment, with the aim of improving recognition and management of these conditions.
PubMed: 38233962
DOI: 10.1186/s13223-023-00862-8 -
Current Opinion in Lipidology Apr 2020This review summarizes the current knowledge regarding autosomal recessive hypercholesterolemia (ARH) and provides new insight into the natural history and therapeutic... (Review)
Review
PURPOSE OF REVIEW
This review summarizes the current knowledge regarding autosomal recessive hypercholesterolemia (ARH) and provides new insight into the natural history and therapeutic management of this lipid disorder.
RECENT FINDINGS
Novel homozygous and compound heterozygous ARH-causing mutations have been reported in the literature, to date. The long-term follow-up of a cohort of ARH patients demonstrated that, despite intensive treatment with conventional lipid-lowering therapies, their low-density lipoprotein (LDL) cholesterol levels remain far from target and this translates into a poor cardiovascular prognosis. ARH is also associated with increased risk of developing aortic valve stenosis. However, lomitapide, a microsomal triglyceride transfers protein inhibitor, may represent a new opportunity for the effective treatment of ARH.
SUMMARY
ARH is an ultrarare disorder of LDL metabolism caused by mutations in the LDLRAP1 gene. It is inherited as a recessive trait and causative mutations, though heterogeneous, are all predicted to be loss-of-function. Recent investigations have demonstrated that ARH can be considered a phenocopy of homozygous familial hypercholesterolemia, where the risk of atherosclerotic cardiovascular diseases and aortic valve stenosis remains elevated despite conventional therapies. The combination of lomitapide with the conventional LDL-C-lowering medications appears to be a promising approach to treat this condition.
Topics: Animals; Anticholesteremic Agents; Benzimidazoles; Humans; Hypercholesterolemia; Lipid Metabolism; Lipoproteins, LDL; Mutation; Hyperlipoproteinemia Type III
PubMed: 32011344
DOI: 10.1097/MOL.0000000000000664 -
The Journal of Allergy and Clinical... Jan 2022Anticytokine autoantibodies can cause immunodeficiency or dysregulate immune responses. They may phenocopy genetically defined primary immunodeficiencies. We review... (Review)
Review
Anticytokine autoantibodies can cause immunodeficiency or dysregulate immune responses. They may phenocopy genetically defined primary immunodeficiencies. We review current anti-type 1 and anti-type 2 interferon; anti-IL-12/23, anti-IL-17, and anti-GM-CSF autoantibodies; HLA associations; disease associations; and mechanistically based treatment options. Suspecting the presence of these autoantibodies in patients and identifying them at the onset of symptoms should ameliorate disease and improve outcomes.
Topics: Autoantibodies; Autoimmunity; Cytokines; Humans
PubMed: 34998474
DOI: 10.1016/j.jaci.2021.11.016 -
International Journal of Molecular... Jul 2022Stargardt disease is the commonest juvenile macular dystrophy. It is caused by genetic mutations in the ABCA4 gene. Diagnosis is not always straightforward, and various... (Review)
Review
Stargardt disease is the commonest juvenile macular dystrophy. It is caused by genetic mutations in the ABCA4 gene. Diagnosis is not always straightforward, and various phenocopies exist. Late-onset disease can be misdiagnosed with age-related macular disease. A correct diagnosis is particularly critical because of emergent gene therapies. Stargardt disease is known to affect retinal pigment epithelium and photoreceptors. Many studies have also highlighted the importance of the choroid in the diagnosis, pathophysiology, and progression of the disease. The choroid is in an integral relationship with the retinal pigment epithelium and photoreceptors, and its possible involvement during the disease should be considered. The purpose of this review is to analyze the current diagnostic tools for choroidal evaluation and the extrapolation of useful data for ophthalmologists and researchers studying the disease.
Topics: ATP-Binding Cassette Transporters; Choroid; Fluorescein Angiography; Humans; Retinal Pigment Epithelium; Stargardt Disease; Tomography, Optical Coherence
PubMed: 35886953
DOI: 10.3390/ijms23147607 -
Heart Failure Reviews Sep 2023The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular... (Review)
Review
The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.
Topics: Humans; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Cardiomyopathies; Phenotype; Fabry Disease; Inflammation
PubMed: 37115472
DOI: 10.1007/s10741-023-10307-4 -
APMIS : Acta Pathologica,... Dec 2023Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent... (Review)
Review
Good's syndrome, an infrequent adult-onset immunodeficiency is characterized by the triad of thymoma, hypogammaglobulinemia, and increased susceptibility to recurrent infections. The clinical presentation is highly variable, with a spectrum ranging from recurrent bacterial and opportunistic infections to concomitant autoimmune diseases and, sometimes malignant pathologies. Due to heterogeneous clinical phenotypes and the lack of adequate diagnostic criteria, its recognition is often challenging, even delaying it by years. It is one of the most unusual, less studied form of the immune deficiency syndromes with a still unknown pathophysiology. It was initially considered a thymoma-associated variant of primary antibody deficiencies with a reduced or absent number of mature B cells, but it later emerged that significant defects of T cell-mediated immune functions are the underlying cause of opportunistic infections. On the basis of current evidence, Good's syndrome is evaluated as a distinct acquired form of combined immunodeficiency states and classified as a phenocopy of primary immunodeficiency diseases. Epigenetic and acquired genetic factors can play an ultimate role in its evolution.
Topics: Adult; Humans; Thymoma; Immunologic Deficiency Syndromes; Thymus Neoplasms; Primary Immunodeficiency Diseases; Opportunistic Infections
PubMed: 37729389
DOI: 10.1111/apm.13351