Berman, Peter

Davidson, Alan

Hartley, Patricia S

Shuttleworth, Margaret H G

South African Medical Journal (SAMJ)

September 2005, Vol. 95, No. 9  SAMJBRIEWEMegaloblastic anaemia, diabetesand deafness in a 2-year-oldchildTo the Editor: Megaloblastic anaemic in childhood is usuallycaused by dietary folate deficiency or, rarely, congenitaldisorders of vitamin B12 or folate metabolism. Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal-recessive disorder caused by inactivating mutations of athiamine transporter gene.1We report on a 2-year-old girl referred after 2 episodes ofdiabetic ketoacidosis. She was clinically pale and hadsensorineural deafness. Control of her diabetes required 18units of insulin daily.Her haemoglobin concentration was 5.4 g/dl, the mean cellvolume 101 fl, and the corrected reticulocyte count 1.4%. Therewere oval macrocytes on the blood smear. Red cell folate andserum vitamin B12 levels were normal. Her bone marrowaspirate was hypercellular with predominantly erythroidhyperplasia and trilineage megaloblastic dysplasia. An ironstain showed numerous ringed sideroblasts (20%).A provisional diagnosis of TRMA was made and weadministered an intramuscular dose of 100 mg of thiamine,followed by 50 mg daily by mouth. There was a rapidreticulocytosis (10.2%) and the haemoglobin concentrationincreased to 9.8 g/dl after 14 days. Her daily insulinrequirements fell to 4 units. Unfortunately attempts todemonstrate apoptosis of fibroblasts in a thiamine-free mediumproved unsuccessful. Three years after diagnosis the patient receives 100 mg oforal thiamine daily, maintains a haemoglobin concentration of12.2 g/dl and requires only 3 - 5 units of insulin daily. She hasa hearing aid and attends a school for deaf children.TRMA is the result of mutations of the SLC19A2 gene(chromosome 1), which codes for a high-affinity thiaminetransporter.2,3 Rapid transport of thiamine by this facilitatedtransport system appears to be essential only forhaematopoietic, pancreatic islet and auditory nerve cellfunction. Cumulative cell loss via apoptosis explains why theclinical manifestations are not apparent in early infancy.4Passive uptake by a separate low-affinity, high-capacity systemappears adequate to protect other tissues from intracellularthiamine depletion. Hence TRMA patients receiving adequatedietary thiamine seldom manifest the classic signs of beriberi(peripheral neuropathy and cardiomyopathy). Thiamine inpharmacological doses compensates by increasing passiveuptake via the low-affinity system in the affected tissues.Our patient ran a typical course with a rapid improvementin the anaemia and a partial response with regard to insulinrequirements on thiamine supplementation, butcharacteristically the sensorineural deafness has persisted.1We suggest that megaloblastic anaemia with normal vitaminB12 and folate levels should prompt a therapeutic trial ofthiamine, particularly in a deaf and/or diabetic child.Alan Davidson Patricia S Hartley Haematology Oncology ServiceSchool of Child and Adolescent Health Red Cross Children’s Hospital and University of Cape TownPeter Berman Department of Chemical PathologyGroote Schuur Hospital andUniversity of Cape TownMargaret H G ShuttleworthHaemotology Pathology ServiceRed Cross Children’s Hospital andUniversity of Cape Town1. Thiamine-Responsive Megaloblastic Syndrome; TRMA. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=249270 (last accessed 29 December 2004).2. Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ. Defective high-affinitythiamine transporter leads to cell death in thiamine-responsive megaloblastic anaemiasyndrome fibroblasts. J Clin Invest 1999; 103: 723-729.3. Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The genemutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes afunctional thiamine transporter. Nat Genet 1999; 22: 305-308.4. Diaz GA, Banikazemi M, Oishi K, Desnick RJ, Gelb BD. Mutations in a new gene encoding athiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome. Nat Genet1999; 22: 309-312.Sulpiride and breastfeedingTo the Editor: I have been informed by a number of womenthat in order to promote the production/flow of breastmilktheir obstetrician-gynaecologist has prescribed sulpiride. Thedosage used is on average 50 mg 3 times a day. The practice ofprescribing sulpiride appears to have become widespread and Iam concerned about the liberal use of a psychotropic agent thathas the potential to affect the newborn infant’s neurobiologicalsystem. According to the Maudsley Guidelines all psychotropics passinto the breastmilk so no decision is risk-free. The PsychotropicDrug Directory1 states the following: ‘Breast milk is more acidicthan plasma so basic compounds may be retained andconcentrations accumulate. Drug binding to milk protein is lessthan to plasma proteins and the higher lipid content of the‘hind’ milk makes it likely to have a higher drug concentrationthan the first half. Milk levels are usually around 1% ofmaternal plasma levels, but there have been few formalstudies. Furthermore drugs should be avoided if the infant ispremature (or has renal, hepatic, cardiac or neurologicalimpairment).’As sulpiride at low dose acts as a dopaminergic agent it islikely to have an influence on dopamine release and thereforereceptor synthesis in the newborn. This effect in turn may havean impact on early neurodevelopment as well as behaviour.Dopamine as a key neurotransmitter is implicated in a number624Pg 624-626  9/2/05  10:02 AM  Page 1

Megaloblastic anaemia, diabetes and deafness in a 2-year-old child

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Megaloblastic anaemia, diabetes and deafness in a 2-year-old child

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