Natural History of Congenital Generalized Lipodystrophy: A Nationwide Study From Turkey

Context: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. Objective: We aimed to study natural history and disease burden of various subtypes of CGL. Design: We attempted to ascertain nearly all patients with CGL in Turkey. Setting: This was a nationwide study. Patients or Other Participants: Participants included 33 patients (22 families) with CGL and 30 healthy controls. Main Outcome Measure(s): We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. Results: Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. Conclusions: CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

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Molecular and clinical findings of Turkish patients with hereditary fructose intolerance

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0303 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Mehmet Gunduz ◽

Özlem Ünal-Uzun ◽

Nevra Koç ◽

Serdar Ceylaner ◽

Eda Özaydın ◽

...

Keyword(s):

Clinical Symptoms ◽

Autosomal Recessive Disorder ◽

Molecular Genetic Analysis ◽

Clinical Findings ◽

Compound Heterozygous ◽

Novel Mutations ◽

Hereditary Fructose Intolerance ◽

Study Results ◽

Fructose Intolerance ◽

Aldolase B

Abstract Objectives Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by a deficiency in aldolase B that can result in hypoglycemia, nausea, vomiting, abdominal pain, liver and kidney dysfunction, coma, and even death. This study aims to represent the clinical features and molecular genetic analysis data of the patients diagnosed with HFI in our study population. Methods The medical records of the 26 patients with HFI were evaluated retrospectively. Age, gender, clinical findings, metabolic crises, and the results of molecular analyses were recorded. Results The patients with HFI had a good prognosis and the aversion to sugar-containing foods was the main complaint. Seven different variants were identified in the Aldolase B (ALDOB) gene in HFI patients. The most frequent mutations were p.Ala150Pro, p.Ala175Asp had a prevalence of 61 and 30%, respectively, in agreement with the literature and other known variants were found with minor frequencies c.360-363del4(3.8%), p.Asn335Lys(3.8%), and three novel mutations c.113-1_15del4 (3.8%), p.Ala338Val(7.6%), and p.Asp156His(3.8%) were identified at a heterozygous, homozygous, or compound heterozygous level. Conclusions This study results revealed three novel mutations in patients with HFI. On the basis of age of presentation, clinical symptoms, and metabolic crisis, there was no clear-cut genotype-phenotype correlation. This article also demonstrates the importance of screening suspected infants in cases of acute liver failure for prompt diagnosis and treatment of HFI.

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Identification of transcobalamin deficiency with two novel mutations in the TCN2 gene in a Chinese girl with abnormal immunity: a case report

BMC Pediatrics ◽

10.1186/s12887-020-02357-6 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Shihong Zhan ◽

Fangfang Cheng ◽

Hailong He ◽

Shaoyan Hu ◽

Xing Feng

Keyword(s):

Case Report ◽

Severe Combined Immunodeficiency ◽

Failure To Thrive ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Novel Mutations ◽

Targeted Next Generation Sequencing ◽

Chinese Girl ◽

Immunodeficiency Disease ◽

Compound Heterozygous Variants

Abstract Background Transcobalamin (TC) transports vitamin B12 from blood into cells. TC II deficiency is a rare autosomal recessive disorder. It is characterized by failure to thrive, diarrhoea, pallor, anaemia, pancytopenia or agammaglobulinemia. It is usually confirmed by molecular analysis of the TCN2 gene. We report a 2-month-old girl with two novel mutations, which were first reported in humans. Case presentation We present a 2-month-old Chinese girl with pancytopenia, severe combined immunodeficiency disease, and megaloblastic anaemia. Targeted next-generation sequencing (NGS) was performed, which detected compound heterozygous variants in exon 7 of the TCN2 gene (Mutation 1: c.1033 C > T; Mutation 2: c.1017-1031delinsGTAACAGAGATGGTT). These mutations result in stop codons in TCN2. The c.1033C > T mutation causes a stop at codon 345 (p.Gln345Ter), and the c.1017-1031delinsGTAACAGAGATGGTT mutation causes a stop at codon 340 (p.Leu340Ter). After being diagnosed, she was treated with intramuscular 1 mg hydroxycobalamin (OH-Cbl) every day for 2 months. The CBC value returned to normal after half a month. The peripheral blood lymphocyte subsets and immunoglobulin recovered after 2 months. Then, the dosage of OH-Cbl was gradually reduced. Conclusions TC II deficiency is a serious complication that requires lifelong treatment. Its diagnosis is difficult due to the lack of clearly identifiable symptoms. Genetic testing should be performed as early as possible if this disease is suspected. The specific observations of this case report make a considerable contribution to the literature and provide a reference for the diagnosis and treatment of future cases.

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A Case Report of Germline Compound Heterozygous Mutations in the BRCA1 Gene of an Ovarian and Breast Cancer Patient

International Journal of Molecular Sciences ◽

10.3390/ijms22020889 ◽

2021 ◽

Vol 22 (2) ◽

pp. 889

Author(s):

Ava Kwong ◽

Cecilia Y. S. Ho ◽

Vivian Y. Shin ◽

Chun Hang Au ◽

Tsun Leung Chan ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Brca1 Gene ◽

Pathogenic Mutation ◽

Compound Heterozygous ◽

Strong Family History ◽

Breast And Ovarian Cancer ◽

Pathogenic Mutations ◽

Increased Risk ◽

History Of

The germline carrier of the BRCA1 pathogenic mutation has been well proven to confer an increased risk of breast and ovarian cancer. Despite BRCA1 biallelic pathogenic mutations being extremely rare, they have been reported to be embryonically lethal or to cause Fanconi anemia (FA). Here we describe a patient who was a 48-year-old female identified with biallelic pathogenic mutations of the BRCA1 gene, with no or very subtle FA-features. She was diagnosed with ovarian cancer and breast cancer at the ages of 43 and 44 and had a strong family history of breast and gynecological cancers.

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Atypical Clinical Presentation of Persistent Müllerian Duct Syndrome in Siblings

Sexual Development ◽

10.1159/000512844 ◽

2021 ◽

pp. 1-6

Author(s):

Evgenia Globa ◽

Nataliya Zelinska ◽

Nina Siryk ◽

Anu Bashamboo ◽

Kenneth McElreavey

Keyword(s):

Genetic Diagnosis ◽

Autosomal Recessive Disorder ◽

Normal Male ◽

Compound Heterozygous ◽

Mullerian Duct ◽

Müllerian Duct ◽

Persistent Müllerian Duct Syndrome ◽

Persistent Mullerian Duct Syndrome ◽

Bilateral Cryptorchidism ◽

Duct Syndrome

Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder characterized by the lack of regression of the derivatives of the Müllerian ducts in males. Boys with this condition usually present with unilateral or bilateral cryptorchidism, inguinal hernias, and reproductive disorders with normal male genitalia. Variants in the AMH or AMHR2 genes are responsible for the development of this syndrome. The genetic diagnosis and surgery in PMDS is challenging for both the endocrinologist and the urologist. Here, we describe the management of 2 siblings from 1 family who presented with bilateral cryptorchidism and hypospadias at birth. One child had testis located in the pelvis in the position of normal ovaries, while the other child had testis which were located in the inguinal canals (bilateral inguinal cryptorchidism). Exome sequencing revealed a compound heterozygous variant in the AMHR2 gene c.1388G>A, p.R463H and c.1412G>A p.R471H. To our knowledge, hypospadias has not been described in association with PMDS.

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Potential of Beetroot and Blackcurrant Compounds to Improve Metabolic Syndrome Risk Factors

Metabolites ◽

10.3390/metabo11060338 ◽

2021 ◽

Vol 11 (6) ◽

pp. 338

Author(s):

Cameron Haswell ◽

Ajmol Ali ◽

Rachel Page ◽

Roger Hurst ◽

Kay Rutherfurd-Markwick

Keyword(s):

Quality Of Life ◽

Diabetes Mellitus ◽

Risk Factors ◽

Metabolic Syndrome ◽

Metabolic Abnormalities ◽

Dietary Nitrate ◽

Increased Risk ◽

High Concentrations

Metabolic syndrome (MetS) is a group of metabolic abnormalities, which together lead to increased risk of coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM), as well as reduced quality of life. Dietary nitrate, betalains and anthocyanins may improve risk factors for MetS and reduce the risk of development of CHD and T2DM. Beetroot is a rich source of dietary nitrate, and anthocyanins are present in high concentrations in blackcurrants. This narrative review considers the efficacy of beetroot and blackcurrant compounds as potential agents to improve MetS risk factors, which could lead to decreased risk of CHD and T2DM. Further research is needed to establish the mechanisms through which these outcomes may occur, and chronic supplementation studies in humans may corroborate promising findings from animal models and acute human trials.

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Biallelic novel mutations of the COL27A1 gene in a patient with Steel syndrome

Human Genome Variation ◽

10.1038/s41439-021-00149-7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Jong Seop Kim ◽

Hyoungseok Jeon ◽

Hyeran Lee ◽

Jung Min Ko ◽

Yonghwan Kim ◽

...

Keyword(s):

Hip Dysplasia ◽

Large Deletion ◽

Compound Heterozygous ◽

Radial Head Dislocation ◽

Sequencing Data ◽

Novel Mutations ◽

Exome Sequencing Data ◽

Whole Exome ◽

Whole Exome Sequencing Data ◽

Carpal Coalition

AbstractAn 11-year-old Korean boy presented with short stature, hip dysplasia, radial head dislocation, carpal coalition, genu valgum, and fixed patellar dislocation and was clinically diagnosed with Steel syndrome. Scrutinizing the trio whole-exome sequencing data revealed novel compound heterozygous mutations of COL27A1 (c.[4229_4233dup]; [3718_5436del], p.[Gly1412Argfs*157];[Gly1240_Lys1812del]) in the proband, which were inherited from heterozygous parents. The maternal mutation was a large deletion encompassing exons 38–60, which was challenging to detect.

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Observational study of thrombosis and bleeding in COVID-19 VV ECMO patients

The International Journal of Artificial Organs ◽

10.1177/0391398821989065 ◽

2021 ◽

pp. 039139882198906

Author(s):

Brianda Ripoll ◽

Antonio Rubino ◽

Martin Besser ◽

Chinmay Patvardhan ◽

William Thomas ◽

...

Keyword(s):

Intensive Care ◽

Ct Scan ◽

Thrombotic Event ◽

Area Under The Curve ◽

Whole Body ◽

Bleeding Events ◽

Heparin Resistance ◽

Increased Risk ◽

Thrombotic Complications ◽

Clinically Significant

Introduction: COVID-19 has been associated with increased risk of thrombosis, heparin resistance and coagulopathy in critically ill patients admitted to intensive care. We report the incidence of thrombotic and bleeding events in a single center cohort of 30 consecutive patients with COVID-19 supported by veno-venous extracorporeal oxygenation (ECMO) and who had a whole body Computed Tomography Scanner (CT) on admission. Methodology: All patients were initially admitted to other hospitals and later assessed and retrieved by our ECMO team. ECMO was initiated in the referral center and all patients admitted through our CT scan before settling in our intensive care unit. Clinical management was guided by our institutional ECMO guidelines, established since 2011 and applied to at least 40 patients every year. Results: We diagnosed a thrombotic event in 13 patients on the initial CT scan. Two of these 13 patients subsequently developed further thrombotic complications. Five of those 13 patients had a subsequent clinically significant major bleeding. In addition, two patients presented with isolated intracranial bleeds. Of the 11 patients who did not have baseline thrombotic events, one had a subsequent oropharyngeal hemorrhage. When analyzed by ROC analysis, the area under the curve for % time in intended anticoagulation range did not predict thrombosis or bleeding during the ECMO run (0.36 (95% CI 0.10–0.62); and 0.51 (95% CI 0.25–0.78); respectively). Conclusion: We observed a high prevalence of VTE and a significant number of hemorrhages in these severely ill patients with COVID-19 requiring veno-venous ECMO support.

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Mevalonate Kinase-Associated Diseases: Hunting for Phenotype–Genotype Correlation

Journal of Clinical Medicine ◽

10.3390/jcm10081552 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1552

Author(s):

Guilaine Boursier ◽

Cécile Rittore ◽

Florian Milhavet ◽

Laurence Cuisset ◽

Isabelle Touitou

Keyword(s):

Severe Disease ◽

Compound Heterozygous ◽

Mevalonate Kinase ◽

Kinase Gene ◽

New Associations ◽

Associated Diseases ◽

Ocular Symptoms ◽

Disseminated Superficial Actinic Porokeratosis ◽

Increased Risk ◽

Genotype Correlation

Mevalonate kinase-associated diseases (MKAD) are caused by pathogenic mutations in the mevalonate kinase gene (MVK) and encompass several phenotypically different rare and hereditary autoinflammatory conditions. The most serious is a recessive systemic metabolic disease called mevalonic aciduria, and the most recently recognized is disseminated superficial actinic porokeratosis, a dominant disease limited to the skin. To evaluate a possible correlation between genotypes and (1) the different MKAD clinical subtypes or (2) the occurrence of severe manifestations, data were reviewed for all patients with MVK variants described in the literature (N = 346), as well as those referred to our center (N = 51). The genotypes including p.(Val377Ile) (homozygous or compound heterozygous) were more frequent in mild systemic forms but were also sometimes encountered with severe disease. We confirmed that amyloidosis was more prevalent in patients compound heterozygous for p.(Ile268Thr) and p.(Val377Ile) than in others and revealed new associations. Patients homozygous for p.(Leu264Phe), p.(Ala334Thr) or compound heterozygous for p.(His20Pro) and p.(Ala334Thr) had increased risk of severe neurological or ocular symptoms. All patients homozygous for p.(Leu264Phe) had a cataract. The variants associated with porokeratosis were relatively specific and more frequently caused a frameshift than in patients with other clinical forms (26% vs. 6%). We provide practical recommendations focusing on phenotype–genotype correlation in MKAD that could be helpful for prophylactic management.

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Rare Variants in Autophagy and Non-Autophagy Genes in Late-Onset Pompe Disease: Suggestions of Their Disease-Modifying Role in Two Italian Families

International Journal of Molecular Sciences ◽

10.3390/ijms22073625 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3625

Author(s):

Filomena Napolitano ◽

Giorgia Bruno ◽

Chiara Terracciano ◽

Giuseppina Franzese ◽

Nicole Piera Palomba ◽

...

Keyword(s):

Pompe Disease ◽

Rare Variants ◽

Clinical Symptoms ◽

Late Onset ◽

Respiratory Muscles ◽

Autosomal Recessive Disorder ◽

Compound Heterozygous ◽

Enzyme Replacement ◽

Whole Exome ◽

Clinical Pictures

Pompe disease is an autosomal recessive disorder caused by a deficiency in the enzyme acid alpha-glucosidase. The late-onset form of Pompe disease (LOPD) is characterized by a slowly progressing proximal muscle weakness, often involving respiratory muscles. In LOPD, the levels of GAA enzyme activity and the severity of the clinical pictures may be highly variable among individuals, even in those who harbour the same combination of GAA mutations. The result is an unpredictable genotype–phenotype correlation. The purpose of this study was to identify the genetic factors responsible for the progression, severity and drug response in LOPD. We report here on a detailed clinical, morphological and genetic study, including a whole exome sequencing (WES) analysis of 11 adult LOPD siblings belonging to two Italian families carrying compound heterozygous GAA mutations. We disclosed a heterogeneous pattern of myopathic impairment, associated, among others, with cardiac defects, intracranial vessels abnormality, osteoporosis, vitamin D deficiency, obesity and adverse response to enzyme replacement therapy (ERT). We identified deleterious variants in the genes involved in autophagy, immunity and bone metabolism, which contributed to the severity of the clinical symptoms observed in the LOPD patients. This study emphasizes the multisystem nature of LOPD and highlights the polygenic nature of the complex phenotype disclosed in these patients.

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Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E654-E667 ◽

Cited By ~ 70

Author(s):

Dake Qi ◽

Brian Rodrigues

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Glucose Utilization ◽

Experimental Studies ◽

Cardiac Metabolism ◽

Multiple Organ ◽

Whole Body ◽

Metabolic Abnormalities ◽

Organ Systems ◽

Per Se

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in “lipotoxicity”. In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.

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