- Genetic defects of thiamine transport and metabolism: a review of clinical phenotypes, genetics and functional studies. [Review]
- JIJ Inherit Metab Dis 2019 May 16
- Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria and peroxisomes. Curre…
Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anaemia and sensory-neural hearing loss, whereas SLC19A3, SLC25A19 and TPK1-related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free-thiamine in CSF and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anaemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free-thiamine in the CSF of SLC19A3 patients. Herein we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans. This article is protected by copyright. All rights reserved.
- Neurological disorders in vitamin B12 deficiency. [Review]
- TATer Arkh 2019 May 16; 91(4):122-129
- The review discusses thesteps of vitamin B12 metabolism and its role in maintaining of neurological functions. The term "vitamin B12 (cobalamin)" refers to several substances (cobalamins) of a very s…
The review discusses thesteps of vitamin B12 metabolism and its role in maintaining of neurological functions. The term "vitamin B12 (cobalamin)" refers to several substances (cobalamins) of a very similar structure. Cobalamin enters the body with animal products. On the peripherу cobalamin circulates only in binding with proteins transcobalamin I and II (complex cobalamin-transcobalamin II is designated as "holotranscobalamin"). Holotranscobalamin is absorbed by different cells, whereas transcobalamin I-binded vitamin B12 - only by liver and kidneys. Two forms of cobalamin were identified as coenzymes of cellular reactions which are methylcobalamin (in cytoplasm) and hydroxyadenosylcobalamin (in mitochondria). The main causes of cobalamin deficiency are related to inadequate intake of animal products, autoimmune gastritis, pancreatic insufficiency, terminal ileum disease, syndrome of intestinal bacterial overgrowth. Relative deficiency may be seen in excessive binding of vitamin B12 to transcobalamin I. Cobalamin deficiency most significantly affects functions of blood, nervous system and inflammatory response. Anemia occurs in 13-15% of cases; macrocytosis is an early sign. The average size of neutrophils and monocytes is the most sensitive marker of megaloblastic hematopoiesis. The demands in vitamin B12 are particularly high in nervous tissue. Hypovitaminosis is accompanied by pathological lesions both in white and gray brain matter. Several types of neurological manifestations are described: subacute combined degeneration of spinal cord (funicular myelinosis), sensomotor polyneuropathy, optic nerve neuropathy, cognitive disorders. The whole range of neuropsychiatric disorders with vitamin B12 deficiency has not been studied well enough. Due to certain diagnostic difficulties they are often regarded as "cryptogenic", "reactive", "vascular» origin. Normal or decreased total plasma cobalamin level could not a reliable marker of vitamin deficiency. In difficult cases the content of holotranscobalamin, methylmalonic acid / homocysteine, and folate in the blood serum should be investigated besides carefully analysis of clinical manifestations.
- Reversible dementia, psychotic symptoms and epilepsy in a patient with vitamin B12 deficiency. [Journal Article]
- BCBMJ Case Rep 2019 May 14; 12(5)
- Vitamin B12 deficiency is a common condition, typically associated with megaloblastic anaemia, glossitis and neuropsychiatric symptoms. We report the case of a patient presenting with progressive cog…
Vitamin B12 deficiency is a common condition, typically associated with megaloblastic anaemia, glossitis and neuropsychiatric symptoms. We report the case of a patient presenting with progressive cognitive and functional deterioration, psychosis and seizures, later found to be secondary to pernicious anaemia. Importantly, the diagnosis of pernicious anaemia was only established 5 years after symptom onset and was overlooked even when the patient was under medical care, in part due to the lack of classic neurological and haematological signs associated with the condition. The patient had a remarkable neuropsychiatric recovery after vitamin replacement and psychopharmacological management. We discuss similar presentations of vitamin B12 deficiency found in the literature, symptom reversibility and the importance of its early recognition and treatment.
- StatPearls: Myelophthisic Anemia [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Anemia is the reduction in the level of hemoglobin, red blood cells (RBCs) or hematocrit below their lower normal range. There are different types and causes of anemia. Anemia subdivides into microcy…
Anemia is the reduction in the level of hemoglobin, red blood cells (RBCs) or hematocrit below their lower normal range. There are different types and causes of anemia. Anemia subdivides into microcytic, macrocytic and normocytic variants. Myelophthisic anemia categorizes under the normocytic variety of anemia. Normocytic anemia has the mean corpuscular volume (MCV) within the normal range of 80 to 100 fL. Other types of normocytic anemia apart from myelophthisic anemia include aplastic anemia, anemia of chronic disease and anemia of renal disease. Microcytic anemia is anemia with MCV below 80 fL, and they include sideroblastic anemia, iron deficiency anemia and thalassemia. The macrocytic anemias have MCV greater than 100 fL, and they include megaloblastic anemia and non-megaloblastic anemia. Anemia can be asymptomatic or can present with mild to severe symptoms. Severe symptoms can be devastating since it can limit the functional capacity of the individual in carrying out even basic activities of daily living. A recent article by Kassebaum NJ et al. reported that about 27% of the world population is affected by anemia with iron deficiency anemia being the most common subtype implicated. Anemia considerably affects morbidity and mortality, and thereby there is the utmost relevance in making a timely diagnosis and undertaking effective treatment of the same. Myelophthisic anemia is anemia characterized by the presence of immature erythrocytes in the peripheral blood due to the infiltration (crowding out) of the bone marrow by abnormal tissue. It is of a hypo-proliferative variant of anemia because it results from inadequate production of red blood cells from the bone marrow. Hypo-proliferative anemia is different from other forms of anemia since the reticulocyte count is usually low compared to anemia caused by increased blood loss or peripheral destruction wherein the reticulocyte count mostly increases. Other causes of hypo-proliferative anemia include nutritional deficiencies, toxin exposures, endocrine abnormalities, hematologic malignancies, and bone marrow failure syndromes.  This article will be focusing on myelophthisic anemia, and its epidemiology, etiology, pathophysiology, complications, evaluations, and management.
- StatPearls: Pernicious Anemia [BOOK]
- BOOKStatPearls Publishing: Treasure Island (FL)
- Pernicious anemia (PA) is megaloblastic anemia which results from a deficiency in cobalamin (vitamin B12) due to a deficit of intrinsic factor (IF). Intrinsic factor is a glycoprotein which binds cob…
Pernicious anemia (PA) is megaloblastic anemia which results from a deficiency in cobalamin (vitamin B12) due to a deficit of intrinsic factor (IF). Intrinsic factor is a glycoprotein which binds cobalamin and therefore enables its absorption at the terminal ileum. Pernicious anemia is often described as an autoimmune disorder due to the findings of gastric autoantibodies directed against both IF and parietal cells. Pernicious anemia also correlates with other autoimmune disease and as well as a genetic disease. The clinical presentation of pernicious anemia is multifarious and insidious in onset. Symptoms may include fatigue, pallor, paresthesia, incontinence, psychosis and generalized weakness. The diagnosis is problematic secondary to the restricted availability of diagnostic tools. Treatment aims at repletion of therapeutic doses of vitamin B12 either through intramuscular injections or orally. When the disease remains undiagnosed and untreated for an extended period, it may lead to neurological complications and even fatal anemia. The present article exposes the epidemiology, pathogenesis, clinical presentation, evaluation, and treatment of pernicious anemia.
- [Hyperpigmentation due to Vitamin B12 Deficiency]. [Journal Article]
- BNBrain Nerve 2019; 71(4):364-367
- Vitamin B12 deficiency is associated with mucocutaneous symptoms, such as glossitis and hyperpigmentation, as well as megaloblastic anemia and neuropathy. These are reversible conditions, and the sym…
Vitamin B12 deficiency is associated with mucocutaneous symptoms, such as glossitis and hyperpigmentation, as well as megaloblastic anemia and neuropathy. These are reversible conditions, and the symptoms improve with early detection and treatment. Whenever anemia is encountered in routine practice, vitamin B12 deficiency should be considered and the presence of skin symptoms should be investigated.
- Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing. [Journal Article]
- MGMol Genet Metab Rep 2019; 19:100465
- CONCLUSIONS: Our findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.
- 50 Years Ago in The Journal of Pediatrics: Thiamine-Responsive Megaloblastic Anemia. [Journal Article]
- JPedJ Pediatr 2019; 207:53
- Etiology and clinico-hematological profile of pancytopenia: experience of a Mexican Tertiary Care Center and review of the literature. [Review]
- HHematology 2019; 24(1):399-404
- CONCLUSIONS: We found a complex picture of pancytopenia in Mexico and compared it with what is reported elsewhere in the literature.The sociocultural context in which the patients develop helps narrowing the possible etiology of pancytopenia, and therefore hasten the diagnostic process. Of all the studies available, bone marrow aspiration seems the most useful.
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- Deoxyuracil in DNA and disease: Genomic signal or managed situation? [Review]
- DRDNA Repair (Amst) 2019; 77:36-44
- Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its re…
Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its repair are known to cause genomic instability by inducing DNA strand breaks leading to apoptosis, but there is emerging evidence that uracil incorporation may also result in broader modifications of gene expression, including: changes in transcriptional stalling, strand break-mediated transcriptional upregulation, and direct promoter inhibition. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, dUTPase, and DNA repair. There is evidence that the nuclear localization of the enzymes in these pathways in mammalian cells may modify and/or control the levels of uracil accumulation into nuclear DNA. Uracil sequencing technologies demonstrate that uracil in DNA is not distributed stochastically across the genome, but instead shows patterns of enrichment. Nuclear localization of the enzymes that modify uracil in DNA may serve to change these patterns of enrichment in a tissue-specific manner, and thereby signal the genome in response to metabolic and/or nutritional state of the cell.