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Frontiers in Genetics 2023Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may...
Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the gene. Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria.
PubMed: 36999056
DOI: 10.3389/fgene.2023.1135267 -
Journal of Thrombosis and Haemostasis :... Sep 2022The diagnosis of immune thrombocytopenia (ITP) is one of exclusion. Although guidelines recommend against routine bone marrow examination (BME) at time of ITP diagnosis,...
BACKGROUND
The diagnosis of immune thrombocytopenia (ITP) is one of exclusion. Although guidelines recommend against routine bone marrow examination (BME) at time of ITP diagnosis, the role of BME in relapsed/refractory ITP is unclear.
OBJECTIVES
To examine the frequency and predictors of BME in relapsed/refractory ITP.
PATIENTS/METHODS
This multicenter retrospective cohort study included adults with ITP who received second-line therapy in Alberta, Canada from 2012 to 2019. We calculated the frequency of BME and rate of abnormal marrow findings. Logistic regression was performed to assess predictors of BME and predictors of bone marrow pathology.
RESULTS
Of 324 patients with presumed ITP, 181 (56%) underwent BME. We observed a marked decline in the rates of BME among patients >60 years over the past decade, but not in patients younger than age 60 years. On multivariable logistic regression, older age (adjusted OR [aOR] 1.03, p = .0001), anemia (aOR 2.5, p = .01), splenomegaly (aOR 3.2, p = .01), splenectomy (aOR 2.4, p = .02), and lack of splenectomy response (aOR 3.4, p = .04) were significant predictors of BME. Abnormal marrow findings were found in eight (2% of overall cohort; 4% of BME): four myelodysplastic syndrome, one aplastic anemia, one chronic lymphocytic leukemia, one metastatic cancer, and one megaloblastic anemia. Seven (88%) underwent BME for bicytopenias/pancytopenias. Macrocytosis (aOR 9.6, p = .03) and rural residence (aOR 6.7, p = .02) were independent predictors of abnormal bone marrow findings.
CONCLUSIONS
Although routine BME is frequently performed in relapsed/refractory ITP, abnormal findings are rare. Future prospective studies are needed to help identify a subgroup of relapsed/refractory ITP who may benefit from BME.
Topics: Adult; Anemia, Aplastic; Bone Marrow Examination; Humans; Middle Aged; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Thrombocytopenia
PubMed: 35751575
DOI: 10.1111/jth.15802 -
Journal of Family Medicine and Primary... Feb 2021Pancytopenia is a triage of anemia, leukopenia, and thrombocytopenia. The etiology causing pancytopenia varies depending upon factors such as age, sex, occupation, and...
BACKGROUND
Pancytopenia is a triage of anemia, leukopenia, and thrombocytopenia. The etiology causing pancytopenia varies depending upon factors such as age, sex, occupation, and geographical distribution. Unfortunately, the major treatises of hematology have not given emphasis on the hemorrhagic manifestation of different etiologies causing pancytopenia.
OBJECTIVE
This observational study was carried out with the aim to identify hemorrhagic manifestation in patients with pancytopenia in eastern India.
DESIGN
This study was conducted over a period of two years at the Department of Medicine of a tertiary care teaching institute in eastern India. All the patients with features of anemia, thrombocytopenia, or leukopenia were screened for pancytopenia and a total of 214 cases were selected. Patients were divided into two groups as patients with age more than 14 years constitute group one and the patients less than 14 years constitute the second group. A detailed physical examination, hematological, and biochemical investigation was done to ascertain the hemorrhagic manifestations in pancytopenia patients.
RESULTS
In the groups, the most common cause of hemorrhagic manifestation in patients with pancytopenia was aplastic anemic, leukemia, myelodysplastic syndrome, and myelofibrosis. No bleeding manifestation was seen in patients with megaloblastic anemia, kala-azar, hypersplenism, and other causes of pancytopenia.
CONCLUSIONS
Patients with pancytopenia caused by aplastic anemia, acute leukemia, and myelodysplastic syndrome have more chances of bleeding manifestation as compared with pancytopenia caused by megaloblastic anemia, kala-azar, or hypersplenism.
PubMed: 34041080
DOI: 10.4103/jfmpc.jfmpc_1117_20 -
Nutrients Jun 2023Vitamin B (B) is an essential cofactor of two important biochemical pathways, the degradation of methylmalonic acid and the synthesis of methionine from homocysteine.... (Review)
Review
Vitamin B (B) is an essential cofactor of two important biochemical pathways, the degradation of methylmalonic acid and the synthesis of methionine from homocysteine. Methionine is an important donor of methyl groups for numerous biochemical reactions, including DNA synthesis and gene regulation. Besides hematological abnormalities (megaloblastic anemia or even pancytopenia), a deficiency in B may cause neurological symptoms, including symptoms resembling diabetic neuropathy. Although extensively studied, the underlining molecular mechanism for the development of diabetic peripheral neuropathy (DPN) is still unclear. Most studies have found a contribution of oxidative stress in the development of DPN. Detailed immunohistochemical investigations in sural nerve biopsies obtained from diabetic patients with DPN point to an activation of inflammatory pathways induced via elevated advanced glycation end products (AGE), ultimately resulting in increased oxidative stress. Similar results have been found in patients with B deficiency, indicating that the observed neural changes in patients with DPN might be caused by cellular B deficiency. Since novel results show that B exerts intrinsic antioxidative activity in vitro and in vivo, B may act as an intracellular, particularly as an intramitochondrial, antioxidant, independent from its classical, well-known cofactor function. These novel findings may provide a rationale for the use of B for the treatment of DPN, even in subclinical early states.
Topics: Humans; Vitamin B 12; Diabetic Neuropathies; Vitamin B 12 Deficiency; Antioxidants; Methionine; Vitamins; Diabetes Mellitus
PubMed: 37299560
DOI: 10.3390/nu15112597 -
Cureus Nov 2023We present a 29-year-old man admitted to our hospital with fatigue for two months of duration and recent palpitations, lightheadedness, blurred vision and nausea. Workup...
We present a 29-year-old man admitted to our hospital with fatigue for two months of duration and recent palpitations, lightheadedness, blurred vision and nausea. Workup showed pancytopenia with severe macrocytic anemia, laboratory and blood smear features of hemolysis, low reticulocyte percentage and a negative direct Coombs test. B12 and folate levels were normal. As bone marrow aspirate was suggestive of megaloblastic anemia and upper endoscopy showed atrophic gastritis, we ordered homocysteine (elevated) and intrinsic factor (IF) antibodies (positive). The workup led to the diagnosis of pernicious anemia with spuriously normal B12 levels. Replacement therapy allowed a rapid recovery. We highlight that the presence of IF antibodies can interfere with the competitive binding assays commonly used to measure B12 levels.
PubMed: 38106734
DOI: 10.7759/cureus.48937 -
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 -
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 -
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