 |
|
Case Reports Indian Pediatrics 2001; 38: 1295-1298 |
||
|
Five Years Followup of Diabetes Mellitus in Two Siblings with Thiamine Responsive Megaloblastic Anemia |
||
|
Thiamine responsive megaloblastic anemia also known as Roger syndrome(1) is an autosomal recessive disorder resulting from the deficiency of thiamine (Vitamin B1) transporter protein(2). The disease is characterized by megaloblastic anemia, myelodysplasia(3), sensorineural deafness and diabetes mellitus(4). Congenital heart defect(5) and optic atrophy(4) have been reported to occur in the affected individuals. Pharmacological dose of thiamine completely normalizes hematological abnormalities, but it may or may not have any effect on the course of diabetes. Sensorineural deafness on the other hand remains irreversible in all(2). We report on five years follow up of diabetes mellitus in two siblings with thiamine responsive megaloblastic anemia. Case Report Case 1: A female child presented in 1991 at the age of 18 months with severe anemia, thrombocytopenia, neutropenia and diabetic ketoacidosis. Her parents were 3rd degree relatives and her eldest sister a deaf-mute had died at the age of 2 years and 3 months with severe transfusion dependent anemia and diabetic ketoacidosis (DKA). Her blood sugar was 28.5 mmol/L, serum bicarbonate was 12 mmol/L and urine showed 2+ ketones. Islet cell antibody was negative, plasma C-peptide level was <265 pmol/L (265-1324 pmol/L). Hematological investigations revealed: Hemoglobin - 2.7 g/dl, hematocrit - 0.158, reticulocytes - 0.2%, MCV - 94, total WBC - 2.9×109/L with 10% neutrophilis, platelets - 42 × 109/L. Peripheral smear showed hypo-chromia, anisopoikilo-cytosis and moderate macrocytosis. Serum cyanocobalamin was 9.5 pmol/L (normal >5.7), RBC folate was 162 pmol/L (130-520). Hemolglobin electro-phoresis was normal. Bone marrow examina-tion showed ring sideroblasts with megalo-blastic changes. Her brain stem auditory evoked potential (BSAP) revealed bilateral sensory neural deafness. Her optic fundi were normal. With the above constellation of clinical and laboratory findings, a diagnosis of thiamine responsive megaloblastic anemia (TRMA) with diabetes mellitus was made. She was transfused, diabetic ketoacidosis was treated with intravenous fluids and insulin and 100 mg thiamine per day was added to the treatment regimen. Hematological parameters rapidly improved and remained stable thereafter, but she continued to require insulin. When thiamine therapy was inter-rupted temporarily because of the non-availability, diabetes worsened, hemoglobin and platelet count dropped rapidly. With reintroduction of thia-mine, hematological parameters normalized and hyperglycemia promptly improved. Even though she was maintained on 100 mg of thiamine regularly, her insulin requirement gradually increased to 1.5 units/kg/day over a period of three years. She also had a few episodes of DKA during this period. At the age of 3.5 years the dose of thiamine was stepped up to 200 mg per day. There was a rapid fall in insulin requirement followed by cessation of insulin requirement within 3 weeks. She has remained in good health without any deterioration of her diabetic control during the last 5 year period of follow up. The OGTT performed at the age of 3.5, 5 and 10 years of age has been normal. The concentration of glycosylated hemo-globin has remained in the normal range throughout the period of follow up. Case 2: She is a sibling of the Case 1, who presented in 1995 at the age of 5 months with atrial septal defect and heart failure. Her hemoglobin was 6.9 g/dl, MCV 91 and reticulocytes 0.3%. Her platelet count was 124 × 109/L and total WBC count was 12.3 × 109/L with 30% neutrophils. Bone marrow aspirate showed megaloblasts and ring sideroblasts. Her fasting blood glucose (>10 mmol/L) and post prandial blood glucose (>15 mmol/L) were persistently high. Islet Cell antibody was negative and C-peptide level was <265 pmol/L. BAEP revealed bilateral sensory neural deafness and the ocular fundi were normal. She was not transfused. She was treated with decongestive therapy, thiamine (200 mg/day) and crystal-line insulin (0.2 units/kg/day). Insulin was discontinued on the 4th day of hospitaliza-tion as the blood glucose remained well controlled. Hematological parameters normalized within 7 days. She was maintained on anti-failure treatment and ASD was repaired at the age of 4 years. She has remained in good health without any deterioration of her diabetic control during the last 5 year period of follow up. The OGTT performed at the age of 1.5 years and 5 years has been normal. The concentration of glyco-sylated hemoglobin has remained in the normal range throughout the period of follow up. Discussion TRMA with diabetes mellitus and sensorineural deafness is an autosomal recessive disorder. The gene for TRMA has been identified and is located to chromosome 1q 23.3 (2,6,7). The deficiency of gene product thiamine transport protein (TTP) results in defect in intracellular thiamine transport. It is presumed that TTP may play a crucial role in facilitating the transport of thiamine not only into hemopoietic tissues but also into pancreatic islet cells, cochlear cells and many other cells and tissues in the body(8). Thiamine administration is reported to correct megaloblastic anemia but is ineffective in preventing the progression of sensorineural deafness. Diabetes on the other hand responds variably to thiamine. Interestingly diabetes in both siblings rapidly and completely responded to 2000 mg of thiamine per day and both ceased to require insulin within a short period of time. Diabetes mellitus continues to remain under good control for the last 5 years in both siblings. The response to thiamine therapy in 17 patients with TRMA reported in the literature over the period of last 30 years has been reviewed(8). The response to thiamine therapy in majority of them was either absent or partial in terms of insulin requirement. Only two out of the 17 patient’s responded completely to thiamine therapy over a variable period of time. Deterioration of the metabolic control was inevitable even in thiamine responders especially at the onset of puberty. Generally they require oral hypo-glycemic agents or reinstitution of insulin therapy at puberty(8). Intracellular thiamine deficiency resulting in slow deterioration of islet cell function due to islet cell apoptosis may be an explanation for cessation of response in the initial thiamine responders(9). The elder sibling is 11 years old and she is pre-pubertal. OGTT test done at the age of 10 years was normal. Normal response to OGTT test during 200 mg of thiamine therapy in our patients indirectly supports the possibility that the deficiency of TTP in TRMA in few patients could be overcome by higher dose of thiamine. The variable response to thiamine in TRMA may depend on the degree of TTP deficiency or to some yet unknown factors. Literature review revealed that the dose of thiamine used by different authors varied from 25 mg to 100 mg/day. We recommend a trial of 200 mg or even higher dose in all cases of TRMA before declaring ineffectiveness of thiamine in controlling diabetes in this rare condition. Contributors: BB, RN HAS helped during data collection and initial drafting. SMAK edited the manuscript. VDS helped in planning investigations and discussion part of the article. BB will act as the guarantor for the manuscript. Funding: None. Competing interests: None stated.
| ||
| References | ||
|
