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Cover page of the Journal of Health Sciences


 
 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 11  |  Issue : 2  |  Page : 175-177

Rare case of diabetes mellitus, sensorineural hearing loss, and refractory megaloblastic anemia: SLC19A2 mutation


Department of Pediatrics, J. N. Medical College, Belagavi, Karnataka, India

Date of Web Publication18-May-2018

Correspondence Address:
Dr. Tanmaya Metgud
Department of Paediatrics, J. N. Medical College, Belagavi, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_44_18

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  Abstract 


Reporting a rare and treatable case of thiamine responsive Megaloblastic Anemia with Sensori-neural Hearing Loss with Diabetes Mellitus in a 6 year old child due to SLC19A2 mutation. Simple thiamine treatment is cost effective and can reverse this disorder except hearing loss.

Keywords: Diabetes mellitus, hearing loss, thiamine-responsive megaloblastic anemia


How to cite this article:
Metgud T, Jali S, Kamate M, Sampagar A, Mittal N. Rare case of diabetes mellitus, sensorineural hearing loss, and refractory megaloblastic anemia: SLC19A2 mutation. Indian J Health Sci Biomed Res 2018;11:175-7

How to cite this URL:
Metgud T, Jali S, Kamate M, Sampagar A, Mittal N. Rare case of diabetes mellitus, sensorineural hearing loss, and refractory megaloblastic anemia: SLC19A2 mutation. Indian J Health Sci Biomed Res [serial online] 2018 [cited 2020 Feb 25];11:175-7. Available from: http://www.ijournalhs.org/text.asp?2018/11/2/175/232694




  Introduction Top


Thiamine-responsive megaloblastic anemia (TRMA) is a rare autosomal recessive inherited disorder first described by Porter et al.[1] It comprises a triad of megaloblastic anemia, diabetes mellitus, and sensorineural hearing loss.[2] Megaloblastic anemia and diabetes mellitus occur between infancy and adolescence, whereas sensorineural hearing loss may be detected as early in toddler age group. Here, we report a 6-year-old girl with refractory megaloblastic anemia, diabetes mellitus, and sensorineural hearing loss with SLC19A2 mutation.


  Case Report Top


A 6-year-old child, born out of a second-degree consanguineous marriage, a known case of type 1 diabetes diagnosed at 1 year of age, presented to us with complaints of progressive pallor and progressive abdominal distension noted first at 4 years of age. On detailed history, the child had deafmutism noticed first at 1 year of life, with associated developmental delay.

For underlying diabetes, she was on insulin therapy. The child's requirement for insulin for adequate glycemic control was increasing over time. For pallor, the child was evaluated and a diagnosis of megaloblastic anemia was postulated. She was on oral Vitamin B12 and folic acid supplements for 2 years. She had also received multiple Vitamin B12 injections. There was no improvement in clinical as well as a hematological profile with these supplements. In fact, hepatomegaly worsened, and insulin requirement increased over time.

On examination, a deaf-mute child with stable vitals had severe pallor, abdominal distension, and bilateral horizontal nystagmus. On per abdominal examination, the liver span was 12 cm, soft, nonnodular surface with rounded margins. There was no splenomegaly or free fluid in the abdomen. Cardiac examination showed hemic murmur. CNS examination showed horizontal bilateral nystagmus with deaf-mutism leading to the consequent developmental delay. Other motor milestones were normal. There were no other focal neurological deficits.

On laboratory investigations, hemogram showed severe anemia (hemoglobin [Hb] 3.1 g%), red cell count was 1.38 mil, mean corpuscular volume was 74.9, mean corpuscular Hb was 22.2, mean corpuscular Hb concentration was 29.6, red cell distribution width was 24.6, and platelet count was 82,000. Peripheral smear showed dimorphic anemia with thrombocytopenia. Renal function test, electrolytes, and liver function test were normal. Anemia workup showed a negative Coombs test with serum B12 levels 1168 (pg/ml), ferritin 287(ng/ml), serum iron 316 (mcg/dL), and total iron binding capacity was 328 (mcmol/L) with raised lactate dehydrogenase of 435 (IU).

Bone marrow evaluation showed megaloblastic hypercellular marrow with reduced megakaryocytes. Her HbA1c was 12%, and c-peptide was 0.08 ng/mL. Brain-evoked response audiometry showed bilateral moderate to profound sensorineural hearing loss. Given refractory megaloblastic anemia not responding to conventional Vitamin B12 supplementation, a detailed literature search was done using diabetes, sensorineural hearing loss, and refractory megaloblastic anemia as keywords. A rare entity called TRMA was found that fitted in this clinical presentation. Genetic mutation analysis by next-generation sequencing was sent, and a homozygous loss of function mutation in the SLC19A2 gene was detected. The child was started on thiamine supplements (10 mg/kg/day) in three divided doses along with injectable insulins. On follow-up after 1 month, the child's HB was 8.8 g% and HbA1C was 10%. Detailed history showed similar complaints in the younger sibling, and genetic analysis for that child was also sent and report awaited.


  Discussion Top


TRMA or Rogers syndrome is a rare autosomal recessively inherited condition with a characteristic triad of megaloblastic anemia, sensorineural hearing loss, and diabetes.[1],[2] Historically, this has been described in < 40 pedigrees worldwide, thus indicating a strong family history.[3] The case reported here is the first case report from this part of the subcontinent. Insulin insufficiency is said to be the cause of diabetes in these children.

In literature, thiamine supplementation has been reported to decrease insulin requirement.[4] Sensorineural hearing loss results from the loss of inner hair cells, and it has been noted to be irreversible in the previous case reports; although, some animal studies have shown a reversal in auditory acuity with thiamine supplementation.[5] The patient, a 6-year-old girl, was born out of a second-degree consanguineous marriage. There was a history of deafness and diabetes in a maternal uncle, thus affirming the strength of association of family history. Consequent case reports reported an increased incidence of congenital heart diseases, arrhythmias, abnormalities of the retina, and optic nerve in addition to the classical triad of symptoms.[6] The gene associated with TRMA is located on chromosome 1q23.2-23.3 (chr1:169454910A>Tc. 95T>A p. Leu32Ter) and is designated as SLC19A2 that encodes the high-affinity thiamine transporter.[7],[8] Thiamine transport protein facilitates the transport of thiamine in hemopoietic tissues, cochlear cells, and pancreatic islets. Intracellular thiamine deficiency in TRMA leads to decreased activity of enzymes dependent on thiamine pyrophosphate (TPP), the active form of thiamine: the pentose phosphate shunt enzyme transketolase and three mitochondrial enzyme complexes, the pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase, and branched-chain α-ketoacid dehydrogenase.[9],[10] A study by Abboud et al. postulated a defect in the binding of TPP to the enzyme [11] and Poggi et al. noted that TRMA erythrocytes were deficient in TPP.[12] Stagg et al. documented the absence of the high-affinity thiamine transporter on fibroblasts of TRMA patients.[9]

Oral thiamine treatment is a simple, cost-effective, and reversible treatment for this chronic debilitating disorder.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Porter FS, Rogers LE, Sidbury JB Jr. Thiamine-responsive megaloblastic anemia. J Pediatr 1969;74:494-504.  Back to cited text no. 1
[PUBMED]    
2.
Viana MB, Carvalho RI. Thiamine-responsive megaloblastic anemia, sensorineural deafness, and diabetes mellitus: A new syndrome? J Pediatr 1978;93:235-8.  Back to cited text no. 2
[PUBMED]    
3.
Oishi K, Diaz GA. Thiamine-responsive megaloblastic anemia syndrome. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. Gene Reviews. Seattle (WA): University of Washington, Seattle; 1993.  Back to cited text no. 3
    
4.
Valerio G, Franzese A, Poggi V, Tenore A. Long-term follow-up of diabetes in two patients with thiamine-responsive megaloblastic anemia syndrome. Diabetes Care 1998;21:38-41.  Back to cited text no. 4
[PUBMED]    
5.
Borgna-Pignatti C, Azzalli M, Pedretti S. Thiamine-responsive megaloblastic anemia syndrome: Long term follow-up. J Pediatr 2009;155:295-7.  Back to cited text no. 5
[PUBMED]    
6.
Bazarbachi A, Muakkit S, Ayas M, Taher A, Salem Z, Solh H, et al. Thiamine-responsive myelodysplasia. Br J Haematol 1998;102:1098-100.  Back to cited text no. 6
[PUBMED]    
7.
Neufeld EJ, Mandel H, Raz T, Szargel R, Yandava CN, Stagg A, et al. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am J Hum Genet 1997;61:1335-41.  Back to cited text no. 7
[PUBMED]    
8.
Raz T, Barrett T, Szargel R, Mandel H, Neufeld EJ, Nosaka K, et al. Refined mapping of the gene for thiamine-responsive megaloblastic anemia syndrome and evidence for genetic homogeneity. Hum Genet 1998;103:455-61.  Back to cited text no. 8
[PUBMED]    
9.
Stagg AR, Fleming JC, Baker MA, Sakamoto M, Cohen N, Neufeld EJ, et al. Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts. J Clin Invest 1999;103:723-9.  Back to cited text no. 9
    
10.
Dutta B, Huang W, Molero M, Kekuda R, Leibach FH, Devoe LD, et al. Cloning of the human thiamine transporter, a member of the folate transporter family. J Biol Chem 1999;274:31925-9.  Back to cited text no. 10
[PUBMED]    
11.
Barrett TG, Poulton K, Baines M, McCowen C. Muscle biochemistry in thiamin-responsive anaemia. J Inherit Metab Dis 1997;20:404-6.  Back to cited text no. 11
[PUBMED]    
12.
Poggi V, Rindi G, Patrini C, De Vizia B, Longo G, Andria G, et al. Studies on thiamine metabolism in thiamine-responsive megaloblastic anaemia. Eur J Pediatr 1989;148:307-11.  Back to cited text no. 12
    




 

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