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The Journal of Nutrition Oct 2020The metabolism of sulfur-containing amino acids (SAAs) requires an orchestrated interplay among several dozen enzymes and transporters, and an adequate dietary intake of... (Review)
Review
The metabolism of sulfur-containing amino acids (SAAs) requires an orchestrated interplay among several dozen enzymes and transporters, and an adequate dietary intake of methionine (Met), cysteine (Cys), and B vitamins. Known human genetic disorders are due to defects in Met demethylation, homocysteine (Hcy) remethylation, or cobalamin and folate metabolism, in Hcy transsulfuration, and Cys and hydrogen sulfide (H2S) catabolism. These disorders may manifest between the newborn period and late adulthood by a combination of neuropsychiatric abnormalities, thromboembolism, megaloblastic anemia, hepatopathy, myopathy, and bone and connective tissue abnormalities. Biochemical features include metabolite deficiencies (e.g. Met, S-adenosylmethionine (AdoMet), intermediates in 1-carbon metabolism, Cys, or glutathione) and/or their accumulation (e.g. S-adenosylhomocysteine, Hcy, H2S, or sulfite). Treatment should be started as early as possible and may include a low-protein/low-Met diet with Cys-enriched amino acid supplements, pharmacological doses of B vitamins, betaine to stimulate Hcy remethylation, the provision of N-acetylcysteine or AdoMet, or experimental approaches such as liver transplantation or enzyme replacement therapy. In several disorders, patients are exposed to long-term markedly elevated Met concentrations. Although these conditions may inform on Met toxicity, interpretation is difficult due to the presence of additional metabolic changes. Two disorders seem to exhibit Met-associated toxicity in the brain. An increased risk of demyelination in patients with Met adenosyltransferase I/III (MATI/III) deficiency due to biallelic mutations in the MATIA gene has been attributed to very high blood Met concentrations (typically >800 μmol/L) and possibly also to decreased liver AdoMet synthesis. An excessively high Met concentration in some patients with cystathionine β-synthase deficiency has been associated with encephalopathy and brain edema, and direct toxicity of Met has been postulated. In summary, studies in patients with various disorders of SAA metabolism showed complex metabolic changes with distant cellular consequences, most of which are not attributable to direct Met toxicity.
Topics: Amino Acids, Sulfur; Animals; Brain Diseases; Cysteine; Glutathione; Homocysteine; Homocystinuria; Humans; Hydrogen Sulfide; Liver; Metabolic Diseases; Metabolism, Inborn Errors; Methionine; Methionine Adenosyltransferase; Methylation; S-Adenosylmethionine; Sulfites; Sulfur; Sulfur Compounds
PubMed: 33000152
DOI: 10.1093/jn/nxaa134 -
Endokrynologia Polska 2019The aim of the study was to determine the frequency of occurrence of antibodies participating in the development of endocrine diseases in patients with autoimmune...
INTRODUCTION
The aim of the study was to determine the frequency of occurrence of antibodies participating in the development of endocrine diseases in patients with autoimmune haematopoietic disease, thus documenting the potential suitability of specific diagnostic and screening tests.
MATERIAL AND METHODS
The study group consisted of 124 persons (men and women) with newly diagnosed pernicious anaemia (PA) and a control group (C) of 41 healthy people. Antibodies against: intrinsic factor (IFAb), gastric parietal cells (APCA), thyroid peroxidase (TPOAb), thyroglobulin (TgAb), adrenal cortex (AdrenalAb), and pituitary anterior lobe (PituitaryAb) were determined in the blood.
RESULTS
1. The risk of the presence of antibodies against endocrine glands in patients with PA can be classified in order: TPOAb and/or TgAb - 41.1%, TPOAb - 36.3%, TgAb - 25.0%, TPOAb and TgAb - 20.2%, AdrenalAb - 1.6%, PituitaryAb - 0.8%. 2. TPOAb and/or TgAb (mainly TPOAb) are more frequently present in patients with PA, who have IFAb and/or APCA. This correlation is most evident in patients with simultaneous occurrence of IFAb and APCA. 3. Among patients with PA, the simultaneous presence of antibodies IFAb and/or APCA with TPOAb and/or TgAb antibodies is most likely in women over 45 years of age. 4. In group C, 12% had at least one of two antithyroid antibodies (TgAb twice as often as TPOAb), and 2.4% had both. AdrenalAb and PituitaryAb are not found in healthy persons.
CONCLUSIONS
In patients with PA, a screening for autoimmune thyroid disease is justified, which should first involve the determination of TPOAb (further TgAb) in the blood. The assessment of antithyroid antibodies should be recommended primarily to patients with PA, who have IFAb and/or APCA, and in particular those with concurrent IFAb and APCA.
Topics: Adult; Age Factors; Anemia, Pernicious; Antibodies; Autoantibodies; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Intrinsic Factor; Iodide Peroxidase; Male; Middle Aged; Parietal Cells, Gastric; Thyroglobulin
PubMed: 30648728
DOI: 10.5603/EP.a2018.0086 -
Discovery Medicine Mar 2015Pernicious anemia (PA) is an entity initially described in 1849 as a condition that consisted of pallor, weakness, and progressive health decline. Since then several... (Review)
Review
Pernicious anemia (PA) is an entity initially described in 1849 as a condition that consisted of pallor, weakness, and progressive health decline. Since then several advances led to the conclusion that PA is an autoimmune disease characterized by the deficient absorption of dietary cobalamin. It is currently recognized as the most common cause of cobalamin deficiency worldwide. We hereby review the current understanding of the disease and its neurological, hematological, and biochemical manifestations with emphasis on the diagnostic approach, treatment, and monitoring strategies. We propose an algorithm for the diagnostic approach considering the current performance and limitations of the available diagnostic tools for evaluation of cobalamin status and the presence of autoimmune chronic atrophic gastritis (CAG). Patients with PA require lifelong treatment with cobalamin replacement therapy. The current widely available treatment can be provided through enteral or parenteral cobalamin supplements, with comparable efficacy and tolerability.
Topics: Aged; Algorithms; Anemia, Pernicious; Autoimmune Diseases; Decision Support Systems, Clinical; Dietary Supplements; Female; Humans; Male; Methylmalonic Acid; Middle Aged; Sex Factors; Treatment Outcome; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 25828519
DOI: No ID Found -
Clinica Chimica Acta; International... May 2021Thiamine-responsive megaloblastic anemia (TRMA), caused by SLC19A2 loss-of-function variants, is characterized by the triad of megaloblastic anemia, progressive...
BACKGROUND AND AIMS
Thiamine-responsive megaloblastic anemia (TRMA), caused by SLC19A2 loss-of-function variants, is characterized by the triad of megaloblastic anemia, progressive sensorineural deafness, and non-type 1 diabetes mellitus. Here, we present the case of a Chinese infant with two novel variants segregating in compound heterozygous form in SLC19A2 and reviewed genotype-phenotype associations (GPAs) in patients with TRMA.
MATERIALS AND METHODS
Whole-exome sequencing was performed to establish a genetic diagnosis. The clinical manifestations and genetic variants were collected by performing a literature review. The bioinformatics software SIFT, PolyPhen2, and Mutation Taster was applied to predict variant effects and analyze GPAs.
RESULTS
Two novel variants segregating in compound heterozygous form in SLC19A2 (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) was identified. Thiamine supplementation corrected anemia and diabetes mellitus but did not improve the hearing defect. In the literature, 183 patients with TRMA with 74 variants in SLC19A2 have been reported, with high incidence in the Middle East, South Asia, and the northern Mediterranean. Patients with biallelic premature termination codon variants presented with more severe phenotypes, and truncating sites on extracellular domains was a protective factor for the hemoglobin level at diagnosis.
CONCLUSION
Two novel compound heterozygous variants (NM_006996.2: exon2:c.336_363del:p.W112fs; exon2:c.358G>T:p.G120X) were identified, and GPAs in TRMA indicated the predictability of clinical manifestations.
Topics: Anemia, Megaloblastic; Asia; Diabetes Mellitus; Genetic Association Studies; Hearing Loss, Sensorineural; Humans; Infant; Membrane Transport Proteins; Thiamine; Thiamine Deficiency
PubMed: 33571483
DOI: 10.1016/j.cca.2021.01.025 -
BMC Cancer May 2024Observational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly...
BACKGROUND
Observational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis.
METHODS
The European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests.
RESULTS
Our study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P' < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P'> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P'< 0.05), while prostate cancer shows an implied reverse causal relationship(P'> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy.
CONCLUSIONS
PA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.
Topics: Humans; Mendelian Randomization Analysis; Anemia, Pernicious; Male; Stomach Neoplasms; Neoplasms; Testicular Neoplasms; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Prostatic Neoplasms; Female
PubMed: 38741062
DOI: 10.1186/s12885-024-12354-y -
Advances in Nutrition (Bethesda, Md.) Jul 2018There is clear evidence that proton-pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and metformin can reduce serum vitamin B-12 concentrations by inhibiting the... (Review)
Review
There is clear evidence that proton-pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and metformin can reduce serum vitamin B-12 concentrations by inhibiting the absorption of the vitamin. However, it is unclear if the effects of these drugs on serum vitamin B-12 are associated with increased risk of biochemical or functional deficiency (as is indicated by elevated blood concentrations of homocysteine and methylmalonic acid) or clinical deficiency (including megaloblastic anemia and neurologic disorders such as peripheral neuropathy and cognitive dysfunction). This review provides an overview of vitamin B-12 absorption and biochemistry and the mechanisms by which PPIs, H2RAs, and metformin affect these functions. It also summarizes the literature relating the use of these drugs to the risk of vitamin B-12 deficiency. Also discussed is that strategies for assessing vitamin B-12 status and diagnosing vitamin B-12 deficiency have evolved in recent years beyond solely measuring serum total vitamin B-12. Multiple analyte testing, a strategy in which ≥2 of 4 biomarkers of vitamin B-12 status-serum total vitamin B-12, holotranscobalamin, homocysteine, and methylmalonic acid-are measured, increases sensitivity and specificity for diagnosing vitamin B-12 deficiency. It is concluded that randomized controlled trials are now needed that use the strategy of multiple analyte testing to determine if PPIs, H2RAs, and metformin do indeed increase the risk of vitamin B-12 deficiency. Until these studies are conducted, a reasonable recommendation for physicians and their patients who are taking these drugs is to monitor vitamin B-12 status and to provide vitamin B-12 supplements if altered blood biomarkers or clinical signs consistent with low or deficient vitamin B-12 status develop.
Topics: Histamine H2 Antagonists; Homocysteine; Humans; Metformin; Methylmalonic Acid; Nutritional Status; Proton Pump Inhibitors; Risk Factors; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 30032223
DOI: 10.1093/advances/nmy023 -
Frontiers in Medicine 2021Aplastic anemia (AA), megaloblastic anemia (MA), and myelodysplastic syndrome (MDS) were common anemic diseases. Sometimes it was difficult to distinguish patients with...
Measurement for the Area of Red Blood Cells From Microscopic Images Based on Image Processing Technology and Its Applications in Aplastic Anemia, Megaloblastic Anemia, and Myelodysplastic Syndrome.
BACKGROUND
Aplastic anemia (AA), megaloblastic anemia (MA), and myelodysplastic syndrome (MDS) were common anemic diseases. Sometimes it was difficult to distinguish patients with these diseases.
METHODS
In this article, we proposed one measurement method for the area of red blood cells (RBCs) from microscopic images based on image processing technology and analyzed the differences of the area in 25 patients with AA, 64 patients with MA, and 68 patients with MDS.
RESULTS
The area of RBCs was 44.19 ± 3.88, 42.09 ± 5.35, 52.87 ± 7.68, and 45.75 ± 8.07 μm in normal subjects, patients with AA, MA, and MDS, respectively. The coefficients of variation were 8.78%, 10.05%, 14.53%, and 14.00%, respectively, in these groups. The area of RBCs in patients with MA was significantly higher than normal subjects ( < 0.001). Compared with patients with AA and MDS, the area of RBCs in patients with MA was also significantly higher ( < 0.001). The results of correlation analysis between the area of RBCs and mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), MCH concentration (MCHC), and red cell distribution width showed no significant correlations ( > 0.05). The area under the curve (AUC) results of the Receiver Operating Characteristic (ROC) curves of RBCs area were 0.421, 0.580, and 0.850, respectively, in patients with AA ( = 0.337), MDS ( = 0.237), and MA ( < 0.001).
CONCLUSION
Identifying the area of RBCs in peripheral blood smears based on the image processing technology could achieve rapid and efficient diagnostic support for patients with MDS and MA, especially for patients with MA and in combination with MCV. However, a larger sample study is needed to find the cutoff area values.
PubMed: 35145978
DOI: 10.3389/fmed.2021.796920 -
Italian Journal of Pediatrics Nov 2023Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune...
BACKGROUND
Individuals with thiamine-responsive megaloblastic anemia (TRMA) mainly manifest macrocytic anemia, sensorineural deafness, ocular complications, and nonautoimmune diabetes. Macrocytic anemia and diabetes may be responsive to high-dosage thiamine treatment, in contrast to sensorineural deafness. Little is known about the efficacy of thiamine treatment on ocular manifestations.
CASES PRESENTATION
Our objective is to report data from four Italian TRMA patients: in Cases 1, 2 and 3, the diagnosis of TRMA was made at 9, 14 and 27 months. In 3 out of 4 subjects, thiamine therapy allowed both normalization of hyperglycemia, with consequent insulin suspension, and macrocytic anemia. In all Cases, thiamine therapy did not resolve the clinical manifestation of deafness. In Cases 2 and 3, follow-up showed no blindness, unlike Case 4, in which treatment was started for megaloblastic anemia at age 7 but was increased to high doses only at age 25, when the genetic diagnosis of TRMA was performed.
CONCLUSIONS
Early institution of high-dose thiamine supplementation seems to prevent the development of retinal changes and optic atrophy in TRMA patients. The spectrum of clinical manifestations is broad, and it is important to describe known Cases to gain a better understanding of this rare disease.
Topics: Humans; Child; Adult; Diabetes Mellitus; Hearing Loss, Sensorineural; Thiamine; Anemia, Megaloblastic; Early Diagnosis; Deafness
PubMed: 38037112
DOI: 10.1186/s13052-023-01553-1 -
Genetics in Medicine : Official Journal... Feb 2019Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was to...
PURPOSE
Lesch-Nyhan disease is an inherited metabolic disorder characterized by overproduction of uric acid and neurobehavioral abnormalities. The purpose of this study was to describe macrocytic erythrocytes as another common aspect of the phenotype.
METHODS
The results of 257 complete blood counts from 65 patients over a 23-year period were collected from 2 reference centers where many patients are seen regularly.
RESULTS
Macrocytic erythrocytes occurred in 81-92% of subjects with Lesch-Nyhan disease or its neurological variants. After excluding cases with iron deficiency because it might pseudonormalize erythrocyte volumes, macrocytosis occurred in 97% of subjects. Macrocytic erythrocytes were sometimes accompanied by mild anemia, and rarely by severe anemia.
CONCLUSION
These results establish macrocytic erythrocytes as a very common aspect of the clinical phenotype of Lesch-Nyhan disease and its neurological variants. Macrocytosis is so characteristic that its absence should prompt suspicion of a secondary process, such as iron deficiency. Because macrocytosis is uncommon in unaffected children, it can also be used as a clue for early diagnosis in children with neurodevelopmental delay. Better recognition of this characteristic feature of the disorder will also help to prevent unnecessary diagnostic testing and unnecessary attempts to treat it with folate or B12 supplements.
Topics: Adolescent; Adult; Anemia, Macrocytic; Child; Child, Preschool; Humans; Infant; Lesch-Nyhan Syndrome; Longitudinal Studies; Male; Phenotype; Young Adult
PubMed: 29875418
DOI: 10.1038/s41436-018-0053-1 -
Clinical Medicine Insights. Case Reports 2023Bardet-Biedl syndrome (BBS) also known as Laurence-Moon-Bardet-Biedl syndrome one of the rarely reported genetic disorder characterized by an intellectual disability,...
BACKGROUND
Bardet-Biedl syndrome (BBS) also known as Laurence-Moon-Bardet-Biedl syndrome one of the rarely reported genetic disorder characterized by an intellectual disability, limb, kidney abnormalities, obesity, and Rod-cone dystrophy. Other associated condition includes diabetes mellitus, hypertension, hypogonadism, facial dysmorphism, and congenital heart defects. This case highlights megaloblastic anemia associated with BBS.
CASE PRESENTATION
A 16-year-old female patient who had a moon face, truncal obesity, polydactyly, low IQ, and visual impairment presented with the complaint of shortness of breath and easy fatiguability. She had bilateral retinal pigmentosa in her eyes and her laboratory evaluation and bone marrow biopsy revealed megaloblastic anemia secondary to vitamin B12 deficiency. She received injectable vitamin B12, folate, and red cell contrate transfusion. Her symptoms improved and she was discharged with oral medication.
CONCLUSION
Megaloblastic anemia in BBS is rarely reported, further research is needed to find the exact cause that is necessary for proper management and better outcome.
PubMed: 37588947
DOI: 10.1177/11795476231193896