A clinical and experimental study of adult hereditary spherocytosis in the Chinese population.

Hereditary spherocytosis (HS) is often misdiagnosed due to lack of specific diagnostic methods. Our study summarized clinical characteristics and described the diagnostic workflow for mild and moderate HS in Chinese individuals, using data from 20 adults, 8 of whom presented a familial history for HS. We used scanning electron microscopy (SEM) to diagnose HS. We observed reduced eosin maleimide fluorescence activity (5.50 mean channel fluorescence (MCF) units) in the 10 cases of HS, which differed significantly when compared with 10 normal adults (15.50 units), iron deficiency anemia (15.50 MCF units), and megaloblastic anemia (12.00 MCF units) values (P < .05). Next generation sequencing results revealed that 9 out of 10 patients were found to have mutations in the spectrin alpha chain (SPTB), anchor protein (ANK1), and SLC4A1 genes. These mutations were not reported in the Human Gene Mutation Database (HGMD), 1000 human genome, ExAC, and dbSNP147 databases. Splenectomy proved to be beneficial in alleviating HS symptoms in 10 cases. It was found that for the diagnosis of HS, SEM and next generation gene sequencing method proved to be more ideal than red blood cell membrane protein analysis using sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blotting.

A Novel Mutation of SLC19A2 in a Chinese Zhuang Ethnic Family with Thiamine-Responsive Megaloblastic Anemia.

BACKGROUND/AIMS: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. METHODS: We study a Chinese Zhuang ethnicity family with thiamine-responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1-3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband's and his brother's clinical data. Computer analysis and prediction of the protein conformation of mutant THTR-1. The relative concentration of thiamine pyrophosphate in the proband's whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). RESULTS: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband's whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. CONCLUSIONS: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband.

Dysplasia features of myelodysplastic syndrome in ethnically Chinese people.

OBJECTIVE: It was our aim to study the diagnostic significances of various dysplasia characteristics in myelodysplastic syndrome (MDS). METHODS: We analyzed 160 cases of primary MDS and a control group including 28 cases of paroxysmal nocturnal hemoglobinuria (PNH), 104 cases of idiopathic thrombocytopenic purpura (ITP), 53 cases of non-severe aplastic anemia (NSAA), 40 cases of megaloblastic anemia and 50 cases of infectious and autoimmune diseases. Peripheral blood smears and bone marrow morphology were reviewed. RESULTS: There was no significant difference in the occurrence rates of a variety of dysplasias in three lineages among MDS, megaloblastic anemia and PNH; however, changes in qualities and quantities in three lineages between NSAA and MDS were significantly different. ITP and MDS showed statistical differences in multiple changes in myeloid and erythroid cells. Significant differences also existed in multiple changes in erythroid series and megakaryocytes between infectious and autoimmune diseases and MDS. Morphological abnormalities highly related with MDS included multinucleated erythroblasts, ringed sideroblasts, poikilocytosis and gigantocytes, pseudo-Pelger neutrophils, ring-shaped nucleus, and micromegakaryocytes. CONCLUSIONS: It is difficult to discriminate megaloblastic anemia and PNH from MDS by means of cell morphology. Different dysplasias of MDS have specific diagnostic values.

Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations.

Thiamine-responsive megaloblastic anemia (TRMA) is a rare disorder typically characterized by megaloblastic anemia, non-type I diabetes and sensorineural deafness. It is caused by various mutations in the SLC19A2 gene that impair the encoded thiamine transporter. So far, only 70 affected individuals mainly from consanguineous families of Middle and Far Eastern origin with a wide spectrum of signs and symptoms, variable onset of disease, and primarily homozygote mutations in SLC19A2 have been reported. We present the first genuine central European descendent with combined heterozygote mutations in SLC19A2, an Austrian boy suffering from pancytopenia and non-type I diabetes. Both manifestations resolved completely under continuous oral thiamine supplementation. Our observation underlines that despite its rarity, TRMA must be considered as an important differential diagnosis in native central European patients with suggestive signs and symptoms. An early molecular genetic verification of the diagnosis provides a sound basis for a successful and simple treatment that helps to prevent severe sequelae.

Pregnancy- and lactation-related folate deficiency in South Africa--a case for folate food fortification.

OBJECTIVE: Characterisation of patients presenting with megaloblastic anaemia according to clinical, sociological, haematological and aetiological aspects of their disease, and use of these findings to increase awareness among clinicians and to make recommendations regarding changes in national health policy. METHODS: This study included 104 patients presenting with megaloblastic anaemia to a large referral hospital over a 1-year period. Data were collected and analysed in terms of age, gender, parity, gravidity, duration of lactation, socio-economic status, geographical origins, diet, previous haematinic treatment, clinical presentation and haematological measurements. RESULTS: The most common cause of megaloblastic anaemia was pernicious anaemia or probable pernicious anaemia (50%), followed by pregnancy- and lactation-related folate deficiency (32%); of these patients, the majority (28) presented postpartum while lactating; 5 patients were in the immediate puerperal period of 6 weeks, and a further 16 were seen during the first year and 7 during the second year following delivery. Only 4 patients were pregnant, and it is noteworthy that 2 of these were still lactating at 34 weeks' gestation. CONCLUSION: Pregnancy- and lactation-related folate deficiency up to 2 years after delivery remains a common cause of megaloblastic anaemia in South Africa. Certain communities in rural South Africa have recently been shown to have high incidences of both neural tube defects and folate deficiency. The fortification of a staple food (e.g. maize or flour) with folic acid is feasible, inexpensive, safe and likely to be beneficial. This practice should reduce the prevalences of megaloblastic anaemia in fertile women, neural tube defects, other congenital abnormalities, intra-uterine growth retardation, prematurity and possibly cardiovascular disease. There is urgent need for a national policy in this regard.

Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.

Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.