Thiamine responsive anaemia: a study of two further cases

Haworth, Catherine; Evans, D. I. K.; Mitra, J.; Wickramasinghe, S. N.

doi:10.1111/j.1365-2141.1982.tb01955.x

Cited by 52 publications

(30 citation statements)

References 10 publications

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“…A less frequently encountered triad of thiamine-responsive sideroblastic anemia, diabetes mellitus and sensorineural deafness was first recognized by Roger et al [3] in 1969, but Borgna-Pignatti et al [12] has recently suggested that the triad could be part of the wider spectrum of DIDMOAD syndrome, with both conditions resulting from a defect of thiamine metabolism. In our patients, the peripheral blood and bone marrow findings strikingly corresponded to thiamine-responsive anemia described in association with diabetes mellitus and sensorineural deafness [3][4][5][6][7][8][9][10][11][12]. A good response to therapy with thiamine, and in particular, the significant increase of hemoglobin level with brisk reticulocytosis confirms this diagnosis.…”

Section: Discussionsupporting

confidence: 48%

“…The akined but less common triad of thiamine responsive anemia, diabetes mellitus, and sensorineural deafness has been described so far in only 14 patients [3][4][5][6][7][8][9][10][11][12]. We describe two additional patients (sister and brother) both of whom presented with thiamine responsive anemia, diabetes mellitus, and sensorineural deafness.…”

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confidence: 99%

“…Thereafter, in 1938, Wolfram [2] described a family of eight siblings, four of whom had DM and OA; three of the four affected siblings subsequently developed neurosensory hearing losses; and later, two developed neurogenic bladders. Since then, over 100 cases of this syndrome have been described in the literature and analysis of multiple pedigrees revealed an autosomal recessive mode of inheritance [1,2].The akined but less common triad of thiamine responsive anemia, diabetes mellitus, and sensorineural deafness has been described so far in only 14 patients [3][4][5][6][7][8][9][10][11][12]. We describe two additional patients (sister and brother) both of whom presented with thiamine responsive anemia, diabetes mellitus, and sensorineural deafness.…”

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confidence: 99%

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Thiamine Dependent Anemia in Didmoad (Wolfram) Syndrome: Further Studies and Report of Two Additional Cases

Al-Fawaz

Al‐Herbish²,

Al-Jurayyan³

et al. 1992

Ann Saudi Med

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IM Al-Fawaz, AS Al-Herbish, NAM Al-Jurayyan, AM Abo-Bakr, Thiamine Dependent Anemia in Didmoad (Wolfram) Syndrome: Further Studies and Report of Two Additional Cases. 1992; 12(3): 309-312 The DIDMOAD syndrome includes diabetes mellitus (DM) and optic atrophy (OA), variously associated with diabetes insipidus (DI), sensorineural deafness (D), dilatation of the urinary tract, and other minor abnormalities. Historically, the association of diabetes mellitus (DM) with optic atrophy (OA) was first described by Von Graeffe in 1858 as quoted by Fishman and Ehrlich [1]. Thereafter, in 1938, Wolfram [2] described a family of eight siblings, four of whom had DM and OA; three of the four affected siblings subsequently developed neurosensory hearing losses; and later, two developed neurogenic bladders. Since then, over 100 cases of this syndrome have been described in the literature and analysis of multiple pedigrees revealed an autosomal recessive mode of inheritance [1,2].The akined but less common triad of thiamine responsive anemia, diabetes mellitus, and sensorineural deafness has been described so far in only 14 patients [3][4][5][6][7][8][9][10][11][12]. We describe two additional patients (sister and brother) both of whom presented with thiamine responsive anemia, diabetes mellitus, and sensorineural deafness. Case Report Case 1A 5½-year-old Yemeni girl was initially seen in a primary care clinic at the age of two years because of unsatisfactory growth and pallor. Hematological tests at the time revealed that she was anemic and an iron therapeutic trial was exhibited but without benefit. During a follow-up visit at three years of age, her random blood glucose level was noted to be high at 14.8 mmol/L and she was then admitted for further work-up. During admission, insulin therapy was started after studies showed an elevated fasting blood glucose concentration (8.8 mmol/L) and an abnormal oral glucose tolerance test result. She was maintained on two daily doses of insulin, five units of NPH insulin plus two units of regular insulin in the morning and two units of NPH insulin in the evening. At five years of age, she developed bilateral sensorineural deafness confirmed by auditory evoked responses and audiometry. Her physical examination revealed a pale and deaf girl who was not in distress. Her weight was 15 kg (5th percentile) and her height 101 cm (< 5th percentile). There were several hyperpigmented cafe-au-lait-like spots on her trunk and extremities measuring 0.5 to 1 cm in diameter. Ophthalmic tests including electroretinography (ERG) and flash visual evoked potential (FVEP) revealed optic subatrophy mainly involving the right eye. The remainder of her physical examination was unremarkable.Investigation of her anemia revealed a hemoglobin of 7.5 g/dl, hematocrit 21.8%, MCV 90.4 fl, MCH 31.2 pg, MCHC 34.5 g/dl, platelets 194 × 10 9 /L and leukocyte count 6.6 × 10 9 /L. The leukocyte differential was: neutrophils 23%, eosinophils 4%, monocytes 3%, and lymphocytes 70%. The peripheral blood smear showed seve...

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Section: Discussionsupporting

confidence: 48%

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confidence: 99%

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confidence: 99%

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Thiamine Dependent Anemia in Didmoad (Wolfram) Syndrome: Further Studies and Report of Two Additional Cases

Al-Fawaz

Al‐Herbish²,

Al-Jurayyan³

et al. 1992

Ann Saudi Med

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“…Haworth et al performed deoxyuridine suppression tests on marrow from a Pakistani child with TRMA and found no defect. 23 Deoxyuridine fails to inhibit incorporation of [ 3 H]thymidine into DNA if it cannot be converted (via folatedependent uridine methyltransferase) into thymidine monophosphate (TMP). This step is unaffected in TRMA fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA)

Boros

Steinkamp

Fleming

et al. 2003

Blood

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Fibroblasts from patients with thiamineresponsive megaloblastic anemia (TRMA) syndrome with diabetes and deafness undergo apoptotic cell death in the absence of supplemental thiamine in their cultures. The basis of megaloblastosis in these patients has not been determined. Here we use the stable [1,2-13 C 2 ]glucose isotope-based dynamic metabolic profiling technique to demonstrate that defective high-affinity thiamine transport primarily affects the synthesis of nucleic acid ribose via the nonoxidative branch of the pentose cycle. RNA ribose isolated from TRMA fibroblasts in thiamine-depleted cultures shows a time-dependent decrease in the fraction of ribose derived via transketolase, a thiamine-dependent enzyme in the pentose cycle. The fractional rate of de novo ribose synthesis from glucose is decreased several fold 2 to 4 days after removal of thiamine from the culture medium. No such metabolic changes are observed in wild-type fibroblasts or in TRMA mutant cells in thiaminecontaining medium. Fluxes through glycolysis are similar in TRMA versus control fibroblasts in the pentose and TCA cycles. We conclude that reduced nucleic acid production through impaired transketolase catalysis is the underlying biochemical disturbance that likely induces cell cycle arrest or apoptosis in bone marrow cells and leads to the TRMA syndrome in patients with defective high-affinity thiamine transport. IntroductionThe pentose cycle, or "pentose-monophosphate shunt," allows de novo synthesis of ribose from glucose by either or both of 2 possible routes: a nonoxidative pathway via transaldolase and transketolase, and an oxidative pathway, via glucose-6-phosphate (G6P) and 6-phosphogluconate dehydrogenase (G6PDH). The oxidative pathway also generates nicotinamide adenine dinucleotide phosphate-positive (NADPH ϩ ) reducing equivalents. Whereas the oxidative branch of the pathway predominates in circulating red blood cells, in many tissues the nonoxidative branch is quantitatively more important for ribose synthesis destined for nucleic acids. 1-3 Thiamine pyrophosphate is a cofactor for transketolase, a key rate-limiting enzyme in the nonoxidative pathway of the pentose cycle. Defective thiamine uptake in fibroblasts isolated from patients with thiamine-responsive megaloblastic anemia (TRMA) is associated with the mutation and loss of function of the high-affinity, low-capacity thiamine transporter. 4 Fibroblasts isolated from patients with TRMA show cycle arrest and increased apoptosis in low-thiamine-containing media. 5 Although thiamine deficiency has been known to cause apoptosis of cells in sensitive brain regions including the thalamus, mammillary, and medial geniculate nuclei, 6 the biochemical disturbance resulting from defective high-affinity thiamine transport in human cells is yet to be elucidated.Metabolic pathway flux changes appear to be critical factors in cell differentiation, in apoptosis, and in mediating the antiproliferative effect of imatinib mesylate in Bcr-Abl-positive myeloid leukemia cells in culture. 7...

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“…She is off insulin now and maintaining sugars on oral hypoglycemic agent, glimepiride 0.5 mg orally daily. Progressive sensori-neural deafness, which is irreversible is due to selective inner hair cell loss, occurs in early life [5]. Role of high-dose thiamine in improving hearing loss is not clear; however animal studies have shown reversibility of hearing loss with thiamine supplementation [6].…”

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confidence: 99%