scholarly journals Early-onset COQ8B (ADCK4) glomerulopathy in a child with isolated proteinuria: a case report and literature review

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Shu-bo Zhai ◽  
Li Zhang ◽  
Bai-chao Sun ◽  
Yan Zhang ◽  
Qing-shan Ma
Keyword(s):  
Literature Review ◽  
Early Onset ◽  
Clinical Manifestations ◽  
Vital Signs ◽  
Disease Stage ◽  
Compound Heterozygous ◽  
Asian Populations ◽  
Laboratory Test Results ◽  
Compound Heterozygous Variants ◽  
Isolated Proteinuria

Abstract Background Herein, a 3-year-old boy presented with hidden-onset isolated proteinuria was reported. The disease was induced by COQ8B (previously termed ADCK4) compound heterozygous variants, including c.[271C > T] and c.[737G > A], which were inherited from his father and mother, respectively. Case presentation The patient visited our clinic due to non-nephrotic range proteinuria for 3 months, but no obvious abnormality was detected in the vital signs or laboratory test results. Renal histopathology revealed mitochondrial nephropathy, which manifested as mild glomerular abnormalities under light microscope, together with mitochondrial proliferation and hypertrophy and crowded arrangement under electron microscope. As suggested by whole exome sequencing, the patient inherited the COQ8B compound heterozygous variants from both of his parents who showed normal phenotype. After literature review, it was confirmed that one of the variant site (c.[271C > T]) had not been reported among the East Asian populations so far. Conclusions Steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis are the most common phenotypes and renal histopathological manifestations of COQ8B variant. Nonetheless, our case shows that such variant may have hidden and mild clinical manifestations at the early onset. Therefore, early diagnosis will help to identify children at the early disease stage who have opportunity to benefit from oral coenzyme Q10 supplementation.

Kv7.3 Compound Heterozygous Variants in Early Onset Encephalopathy Reveal Additive Contribution of C-Terminal Residues to PIP2-Dependent K+ Channel Gating

2018 ◽  
Vol 55 (8) ◽  
pp. 7009-7024 ◽  
Author(s):  
Paolo Ambrosino ◽  
Elena Freri ◽  
Barbara Castellotti ◽  
Maria Virginia Soldovieri ◽  
Ilaria Mosca ◽  
...  
Keyword(s):  
Early Onset ◽  
Channel Gating ◽  
K Channel ◽  
Compound Heterozygous ◽  
Additive Contribution ◽  
Compound Heterozygous Variants

scholarly journals Recurrent respiratory viral diseases and chronic sequelae due to dominant negative IFIH1

2020 ◽  
Author(s):  
Christin L Deal ◽  
Timothy J Thauland ◽  
Rebecca Signer ◽  
Stanley F Nelson ◽  
Hane Lee ◽  
...  
Keyword(s):  
Viral Infections ◽  
Respiratory Infections ◽  
Clinical Manifestations ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Negative Effect ◽  
Respiratory Viral Infections ◽  
Compound Heterozygous Variants

Viral respiratory infections are the most common childhood infection worldwide. However, even common pathogens can have significant consequences in the context of patients with primary immunodeficiency diseases. More than half or viral infections annually are due to rhinovirus/enterovirus strains. Most clinical manifestations of viral infection are mild. However 3% of cases result in hospitalization in patients who have no other known risk factors. These patients may have an inborn error of immunity, a genetic susceptibility to viral infections. Here we present the case of an adult male who suffered respiratory viral infections his whole life and developed chronic, inflammatory damage to sinuses and lungs as a consequence. Genomic sequencing identified compound heterozygous variants in the IFIH1 gene, encoding the protein Melanoma Differentiation Association Protein 5 (MDA5), a RIG-I-like cytoplasmic sensor of RNA intracellular infections. We show a dominant negative effect on these variants on the level of interferon-induced expression of MDA5 protein. This work supports that loss-of-function variants in IFIH1 affect the sensing of viral infections. Underlying genomic variants may dictate the point at which recurrent, respiratory viral infections leave commonplace experience and incur lasting damage.

scholarly journals Establishment of Routine Clinical Indicators-Based Nomograms for Predicting the Mortality in Patients with COVID-19

2020 ◽  
Author(s):  
Jialin He ◽  
Caiping Song ◽  
En Liu ◽  
Xi Liu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Clinical Manifestations ◽  
Vital Signs ◽  
Multivariate Logistic Regression Analysis ◽  
Hospital Death ◽  
Multivariate Logistic Regression ◽  
Clinical Indicators ◽  
Risk Of Death ◽  
Laboratory Test Results ◽  
Better Than

Abstract Background: The aim of the study was to establish and validate nomograms to predict the mortality risk of patients with COVID-19 using routine clinical indicators. Method: This retrospective study included a development cohort enrolled 2119 hospitalized COVID-19 patients and a validation cohort included 1504 COVID-19 patients. The demographics, clinical manifestations, vital signs and laboratory test results of the patients at admission and outcome of in-hospital death were recorded. The independent factors associated with death were identified by a forward stepwise multivariate logistic regression analysis and used to construct two prognostic nomograms. The models were then tested in an external dataset. Results: Nomogram 1 is a full model included nine factors identified in the multivariate logistic regression and nomogram 2 is built by selecting four factors from nine to perform as a reduced model. Nomogram 1 and nomogram 2 established showed better performance in discrimination and calibration than the MuLBSTA score in training. In validation, Nomogram 1 performed better than nomogram 2 for calibration. Conclusion: Nomograms we established performed better than the MuLBSTA score. We recommend the application of nomogram 1 in general hospital which provide robust prognostic performance but more cumbersome; nomogram 2 in mobile cabin hospitals which depend on less laboratory examinations and more convenient. Both nomograms can help clinicians in identifying patients at risk of death with routine clinical indicators at admission, which may reduce the overall mortality of COVID-19.

scholarly journals Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Aliaa H. Abdelhakim ◽  
Avinash V. Dharmadhikari ◽  
Sara D. Ragi ◽  
Jose Ronaldo Lima de Carvalho ◽  
Christine L. Xu ◽  
...  
Keyword(s):  
Coenzyme Q ◽  
Clinical Manifestations ◽  
Missense Variant ◽  
Neurological Involvement ◽  
Cone Dystrophy ◽  
Compound Heterozygous ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Compound Heterozygous Variants ◽  
End Stage

Abstract Background Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes).

scholarly journals COG5 variants lead to complex early onset retinal degeneration, upregulation of PERK and DNA damage

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Sami Tabbarah ◽  
Erika Tavares ◽  
Jason Charish ◽  
Ajoy Vincent ◽  
Andrew Paterson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Retinal Degeneration ◽  
Skeletal Dysplasia ◽  
Early Onset ◽  
Protein Misfolding ◽  
Cultured Cells ◽  
Retinal Dystrophy ◽  
Compound Heterozygous ◽  
Cog Complex ◽  
Compound Heterozygous Variants

AbstractLeber congenital amaurosis (LCA), a form of autosomal recessive severe early-onset retinal degeneration, is an important cause of childhood blindness. This may be associated with systemic features or not. Here we identified COG5 compound-heterozygous variants in patients affected with a complex LCA phenotype associated with microcephaly and skeletal dysplasia. COG5 is a component of the COG complex, which facilitates retrograde Golgi trafficking; if disrupted this can result in protein misfolding. To date, variants in COG5 have been associated with a distinct congenital disorder of glycosylation (type IIi) and with a variant of Friedreich’s ataxia. We show that COG5 variants can also result in fragmentation of the Golgi apparatus and upregulation of the UPR modulator, PKR-like endoplasmic reticulum kinase (PERK). In addition, upregulation of PERK induces DNA damage in cultured cells and in murine retina. This study identifies a novel role for COG5 in maintaining ER protein homeostasis and that disruption of that role results in activation of PERK and early-onset retinal degeneration, microcephaly and skeletal dysplasia. These results also highlight the importance of the UPR pathway in early-onset retinal dystrophy and as potential therapeutic targets for patients.

scholarly journals Inherited Variants in SCARB1 Cause Severe Early-Onset Coronary Artery Disease

2021 ◽  
Author(s):  
Sara N Koenig ◽  
Holly C Sucharski ◽  
Elizabeth Jose ◽  
Emma K Dudley ◽  
Francesca Madiai ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Early Onset ◽  
Null Allele ◽  
Mendelian Inheritance ◽  
Paternal Allele ◽  
Compound Heterozygous ◽  
Atherosclerotic Cardiovascular Disease ◽  
Artery Disease ◽  
Compound Heterozygous Variants

Rationale: Coronary artery disease (CAD) is a pervasive and critical healthcare problem. Elevated high density lipoprotein-associated cholesterol (HDL-C) is associated with improved atherosclerotic cardiovascular disease (ASCVD) outcomes on a population level, but clinical trials aimed at HDL-C elevation have not succeeded in improving ASCVD event risk. Nevertheless, human variants in the HDL receptor, encoded by SCARB1, are associated with dyslipidemia, suggesting that HDL metabolism, not HDL-C, is a suitable target for therapy. However, variants in SCARB1 have never been directly attributed to CAD by Mendelian inheritance. Objective: To determine if compound heterozygous variants in SCARB1 cause disease in two brothers with severe, early-onset CAD. Methods and Results: Using whole exome sequencing, we have identified rare, compound heterozygous variants in SCARB1 that segregate with severe, premature CAD, following patterns of Mendelian inheritance. Using induced pluripotent stem cell-derived hepatocyte-like cells (iPSC-HLCs) from the proband, we discovered the maternal variant (c.754_755delinsC) to be the first identified SCARB1 null allele, characterized by the absence of RNA and protein expression. Further, we demonstrate that the variant on the paternal allele (c.956G>T (p.G319V)) results in decreased cholesterol uptake, decreased SR-BI:HDL binding, and increased affinity for SR-BI dimerization. Finally, we generated a p.G319V knock-in mouse model that displays nearly 100% homozygous lethality and elevated plasma cholesterol in heterozygous animals, confirming pathogenicity of this variant. Conclusions: In summary, our data provide the first molecular mechanism to show the Mendelian inheritance of CAD as a result of human SCARB1 variants. The rarity of these variants supports pathogenicity in this family. Furthermore, SR-BI p.G319V, which has previously been reported benign in the context of heterozygosity, was uniquely presented alongside a null allele, demonstrating the disease-contributing capability of loss-of-function SCARB1 variants within the population.

scholarly journals POLR3A-related hypomyelinating leukodystrophy: case report and literature review

2020 ◽  
Vol 11 (4) ◽  
pp. 48-54
Author(s):  
A. F. Murtazina ◽  
T. V. Markova ◽  
A. A. Orlova ◽  
O. P. Ryzhkova ◽  
O. A. Shchagina ◽  
...  
Keyword(s):  
Case Report ◽  
Hypogonadotropic Hypogonadism ◽  
Molecular Genetic ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Permanent Teeth ◽  
Diagnostic Process ◽  
Compound Heterozygous ◽  
Compound Heterozygous Variants ◽  
First Year Of Life

Hypomyelinating leukodystrophies (HL) is a group of genetically heterogeneous neurodegenerative disorders characterized by a lack of brain myelin deposition. One of the most common autosomal recessive HL is HL type 7 caused by mutations in the POLR3A gene. We reported the first clinical case of a Russian patient with HL type 7.Proband is a 7‑year‑old patient with HL type 7. The diagnosis was confirmed by genealogy, neurological examination, brain magnetic resonance imaging and molecular genetic testing. Two compound‑heterozygous variants in the POLR3A gene were revealed in the patient. Each variant was described earlier in patients with variable clinical manifestations of neurodegenerative diseases. The peculiarities of clinical manifestations in our patient were the manifestation of the disease in the first year of life, the predominance of cerebellar symptoms, a movement limitation of the jaw, leading to worsening of dysarthria, a delay in the formation of permanent teeth and short stature. The course of the disease was moderate that could be explained by different effect of the variants in the POLR3A gene.POLR3A‑related disease is a group of clinically heterogeneous disorders manifesting from early childhood to adulthood and characterized by isolated spastic ataxia or ataxia combined with oligodontia and hypogonadotropic hypogonadism, isolated or complicated spastic paraplegia, as well as a combination of ataxia with extrapyramidal symptoms. Our case report demonstrates the complexity of diagnostic process in the absence of a peculiar clinical picture and specific changes in brain imaging.

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