0
selected
-
1.
Inherited conditions resulting in nephrolithiasis.
Hoppe, B, Martin-Higueras, C
Current opinion in pediatrics. 2020;(2):273-283
Abstract
PURPOSE OF REVIEW Prevalence of pediatric urolithiasis is increasing, which is definitively visible in increasing numbers of presentations in emergency or outpatient clinics. In pediatric patients, a genetic or metabolic disease has to be excluded, so that adequate treatment can be installed as early as possible. Only then either recurrent stone events and chronic or even end-stage kidney disease can be prevented. RECENT FINDINGS The genetic background of mostly monogenic kidney stone diseases was unravelled recently. In hypercalcuria, for example, the commonly used definition of idiopathic hypercalciuria was adopted to the genetic background, here three autosomal recessive hereditary forms of CYP24A1, SLC34A1 and SLC34A3 associated nephrocalcinosis/urolithiasis with elevated 1.25-dihydroxy-vitamin D3 (1.25-dihydroxy-vitamin D3) (calcitriol) levels. In addition either activating or inactivating mutations of the calcium-sensing receptor gene lead either to hypocalcemic hypercalciuria or hypercalcemic hypocalciuria. In primary hyperoxaluria, a third gene defect was unravelled explaining most of the so far unclassified patients. In addition, these findings lead to new treatment options, which are currently evaluated in phase III studies. SUMMARY Kidney stones are not the disease itself, but only its first symptom. The underlying disease has to be diagnosed in every pediatric patient with the first stone event.
-
2.
Rare genetic E196A mutation in a patient with Creutzfeldt-Jakob disease: a case report and literature.
Wu, X, Cui, Z, Guomin, X, Wang, H, Zhang, X, Li, Z, Sun, Q, Qi, F
Prion. 2020;(1):143-148
-
-
Free full text
-
Abstract
Genetic Creutzfeldt-Jakob disease (gCJD) is characterized by mutations in the PRNP gene and represents approximately 10-15% of the human prion diseases. Here, we report a 42-year-old Chinese man who was diagnosed with gCJD. The patient had a rare mutation in codon 196 (E196A) of PRNP leading to an exchange of amino acid from glutamic acid (E) to alanine (A). The polymorphism of codon 129 in the patient was methionine homozygote. His mother and daughter are asymptomatic carriers of the same mutation. The clinical manifestations were similar to those of sporadic CJD. 14-3-3 protein was positive in cerebrospinal fluid, and there were sharp slow complex waves in electroencephalography and ribbon-like signals on magnetic resonance imaging (MRI). The main complaints of patient changed from visual space and visual colour to psychotic symptoms with enhanced high signal intensity on the occipital and frontal cortices on MRI. We compared the clinical characteristics of the current patient with those of previously reported Chinese patients with other gCJD of E196A mutation to summarize the common features of E196A gCJD.
-
3.
Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis with Cooccurrent SF3B1 and MPL Gene Mutations: A Case Report and Brief Review of the Literature.
Park, CH, Yun, JW, Kim, HY, Lee, KO, Kim, SH, Kim, HJ
Laboratory medicine. 2020;(3):315-319
Abstract
BACKGROUND Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a new disease entity in the current WHO classification. Genetically, 60%-90% of cases have mutations in SF3B1, strongly associated with RS, and more than half of them cooccur with JAK2 V617F. This report describes the rare case of MDS/MPN-RS-T with SF3B1 mutation cooccurring with an MPL mutation. METHODS We report a 79-year-old man who was referred because of generalized edema. Peripheral blood testing showed macrocytic anemia and thrombocytosis, and bone marrow analysis demonstrated dyserythropoiesis with RS and increased megakaryocytes. A molecular study was performed to detect SF3B1 mutations and recurrent mutations in MPN disease (JAK2 V617F/exon 12, CALR gene exon 9, and MPL gene exon 10 mutations). RESULTS The molecular study revealed SF3B1 K666T and MPL W515R mutations, while BCR-ABL1 or JAK2 V617F/exon 12 and CALR mutations were all negative. CONCLUSION This is a rare case of concomitant SF3B1 and MPL mutations in MDS/MPN-RS-T.
-
4.
Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review.
Palmieri, F, Scarcia, P, Monné, M
Biomolecules. 2020;(4)
Abstract
In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.
-
5.
Beyond cholesterol metabolism: The pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9). Genetics, mutations, expression, and perspective for long-term inhibition.
Cesaro, A, Bianconi, V, Gragnano, F, Moscarella, E, Fimiani, F, Monda, E, Scudiero, O, Limongelli, G, Pirro, M, Calabrò, P
BioFactors (Oxford, England). 2020;(3):367-380
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has a crucial role in lipid metabolism, particularly due to its function in low-density lipoprotein receptor degradation. Gain-of-function genetic mutations of PCSK9 result in autosomal dominant familial hypercholesterolemia, characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and clinical signs of early atherosclerosis. In recent years, PCSK9 has become an important therapeutic target for cholesterol-lowering therapy. Particularly, its inhibition with monoclonal antibodies has shown excellent efficacy in decreasing LDL-C and reducing cardiovascular events. However, PCSK9, first identified in the brain, seems to be a ubiquitous protein with different tissue-specific functions also independent of cholesterol metabolism. Accordingly, it appears to be involved in the immune response, haemostasis, glucose metabolism, neuronal survival, and several other biological functions. This review provides a comprehensive overview of the genetics, biochemical structure, expression, and function of PCSK9 and discusses the potential implications of its long-term pharmacological inhibition.
-
6.
When tumor doesn't read textbook. Third case of TTF1 and p40 co-expression in the same tumour cells in a non-small cell carcinoma. A potential new entity to consider?
Spinelli, M, Khorshad, J, Viola, P
Pathologica. 2019;(2):58-61
Abstract
INTRODUCTION The 2011 WHO Classification for lung adenocarcinoma enlightened the need for a wise use of immunohistochemistry to preserve tissue for both diagnosis and molecular studies. The current recommendation is to use a panel comprising TTF1 and p40 to classify tumors with no clear squamous or glandular differentiation as many studies have showed the higher specificity of p40 over p63 as marker of squamous differentiation. However, the co-expression of both markers opens a new scenario with subsequent classification and potentially treatment issues. MATERIALS AND METHODS We report a case of a non-small lung cell carcinoma (NSCLC) with coexistent expression of TTF1 and p40 in the same tumour cells. To our knowledge, this peculiar immunohistochemical profile is very rare, and thus a review of the clinical and molecular features including molecular variances of the tumour was performed. Review of the pertinent literature was also carried out. RESULTS Two additional articles describing unusual cases of NSCLC with coexistent expression of TTF1 and p40 were found and compared to our case. Interestingly, they all carried out aberrant mutation in TP53 oncogene and were of advance stage. CONCLUSION The positivity for both "squamous" and "adenocarcinomatous" markers and mutations of TP53 could be the expression of a not fully recognized variant of NSCLC with possible implications for classification, diagnosis and therapy.
-
7.
Diseases caused by mutations in luteinizing hormone/chorionic gonadotropin receptor.
Qiao, J, Han, B
Progress in molecular biology and translational science. 2019;:69-89
Abstract
Accumulating evidence showed that the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is an essential regulator of sexual development and reproduction from zebrafish to human. Activating and inactivating mutations of LHCGR gene have been identified from patients of different phenotypes. Familial male-limited precocious puberty, Leydig cell hypoplasia, and empty follicle syndrome are caused by LHCGR mutations. More than 50 mutations have been reported from subjects of different ethnic backgrounds. Functional analyses of the mutant LHCGR revealed multiple defects, including cell surface expression, ligand binding, and signaling. The difference of the two native ligands and signaling pathway activated by LHCGR are illustrated. Potential therapeutic implications from the analyses of the naturally occurring LHCGR mutations, such as pharmacological chaperones, are highlighted.
-
8.
Irregularities in genetic variation and mutation rates with environmental stresses.
Ferenci, T
Environmental microbiology. 2019;(11):3979-3988
Abstract
The appearance of new mutations is determined by the equilibrium between DNA error formation and repair. In bacteria like Escherichia coli, stresses are thought shift this balance towards increased mutagenesis. Recent findings, however, suggest a very uneven relationship between stress and mutations. Only a subset of stressful environments increase the net rate of mutation and different forms of nutritional stress (such as oxygen, carbon or phosphorus limitations) result in markedly different mutation rates after similar reductions in growth rate. Moreover, different stresses result in altered mutational spectra, with some increasing transposition and others increasing indel formation. Single-base substitution rates are lower with some stresses than in unstressed bacteria. Indeed, changes to the mix of mutations with stress are more widespread than a marked increase in net mutation rate. Much remains to be learned on how environments have unique mutational signatures and why some stresses are more mutagenic than others. Even beyond stress-induced genetic variation, the fundamental unresolved question in the stress-mutation relationship is the adaptive value of different types of mutations and mutation rates; is transposition, for example, more advantageous under anaerobic conditions? It remains to be investigated whether stress-specific genetic variation impacts on evolvability differentially in distinct environments.
-
9.
[Sitosterolemia (phytosterolemia)].
Lütjohann, D
Der Internist. 2019;(8):871-877
Abstract
Sitosterolemia or phytosterolemia is a rare autosomal recessive hereditary lipid storage disorder. It is caused by homozygous or compound heterozygous mutations in one of the two ABCG5 and ABCG8 genes encoding the intestinal and hepatic heterodimer ABCG5 (sterolin 1)/ABCG8 (sterolin 2) efflux transporters. These mutations lead to intestinal hyperabsorption and reduced hepatic secretion of cholesterol and plant sterols with subsequent accumulation of phytosterols and cholesterol in plasma and deposition in tissue (xanthoma). Phytosterols are found mainly in vegetable oils, margarine, nuts, grains, soybeans and avocados. Patients with sitosterolemia show extreme phenotypic heterogeneity from almost asymptomatic individuals to those with combined severe hypercholesterolemia at a young age, leading to increased atherosclerosis and premature cardiac death. Early abnormalities include hemolytic anemia with stomatocytosis, macrothrombocytopenia and splenomegaly. In addition to strict avoidance of phytosterol-containing foods, the use of the sterol absorption inhibitor ezetimibe, possibly in combination with the bile acid-binding resin cholestyramine, is the most effective treatment option.
-
10.
Diseases associated with mutations in CNGA3: Genotype-phenotype correlation and diagnostic guideline.
Sun, W, Zhang, Q
Progress in molecular biology and translational science. 2019;:1-27
Abstract
Along with the molecular and functional characterization of CNGA3, knowledge about diseases associated with CNGA3 mutations has made great progress. So far, CNGA3 mutations are not only one of the most common causes of achromatopsia and cone dystrophy or cone-rod dystrophy but also one of the most commonly mutated genes among various forms of retinopathy. Understanding the clinical characteristics of CNGA3-associated retinal diseases may help clinical practice of infants or children with related diseases. Recognizing the importance of CNGA3 in inherited retinal diseases may enhance related research in searching for functional restoration or repair of CNGA3 defects.