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Table of Contents
Year : 2020  |  Volume : 23  |  Issue : 1  |  Page : 136-138

Stroke as an initial manifestation of thiamine-responsive megaloblastic anemia

1 Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
2 Pediatric Nephrology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication21-Jan-2020

Correspondence Address:
Prof. Sheffali Gulati
Child Neurology Division, Department of Pediatrics, Room No. 3056, Third Floor, Teaching Block, All India Institute of Medical Sciences, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_166_19

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How to cite this article:
Madaan P, Jauhari P, Michael SN, Sinha A, Chakrabarty B, Gulati S. Stroke as an initial manifestation of thiamine-responsive megaloblastic anemia. Ann Indian Acad Neurol 2020;23:136-8

How to cite this URL:
Madaan P, Jauhari P, Michael SN, Sinha A, Chakrabarty B, Gulati S. Stroke as an initial manifestation of thiamine-responsive megaloblastic anemia. Ann Indian Acad Neurol [serial online] 2020 [cited 2020 Feb 26];23:136-8. Available from:


Pediatric arterial ischemic stroke (AIS) is relatively uncommon and often under-recognized. It comprises 5%-10% of all strokes.[1] Pediatric stroke is an entity with diverse etiologies varying from cardiac diseases, hematological disorders, vasculopathies to malformations or genetic defects. Multiple risk factors might be contributory in a single patient. Despite extensive evaluation, no associated risk factor is identified in 25% cases of childhood stroke.[2]

Among hematological diseases, sickle cell disease is one of the most common and most studied disorder associated with pediatric ischemic stroke.[3] Literature regarding other hematological disorders such as megaloblastic anemia is scarce. Hereby we report an infant with acute-onset hemiplegia with left middle cerebral territory infarction associated with an underlying rare hematological and genetic disorder: Thiamine-responsive megaloblastic anemia (TRMA). TRMA is a clinical triad of megaloblastic anemia, diabetes mellitus and sensorineural hearing loss.[4] Among these manifestations, sensorineural hearing loss presents in toddlers while rest can manifest anytime till adolescence.[5] AIS in the index child is an atypical presentation of TRMA.

   Case Report Top

A 10-month-old developmentally normal boy, second born of third degree consanguineous parents, presented with right focal seizures. Postictally, the child had altered sensorium along with right hemiparesis. He was hospitalized for the same and was later referred to us on day 6 of illness.

At admission, the child was in altered sensorium with a Glasgow coma score (pediatric) of 12. He had significant pallor but was hemodynamically stable. All peripheral pulses were well- palpable. Clinical diagnosis of left middle cerebral artery territory AIS was kept and MRI brain confirmed the same [Figure 1]a. MR angiography revealed a sudden cut-off in left internal carotid artery just after the origin with complete occlusion of the same but dissection could not be ruled out. Intracranial left internal carotid artery and its branches were also not visualized and there were no significant collaterals [Figure 1]b. On sonography and Doppler of neck vessels, left internal carotid artery could not be visualized. Echocardiography was essentially normal.
Figure 1: (a and b) MRI brain and MR angiography of the index case. (a) MRI brain (T2-weighted axial section) of the index case revealing left middle cerebral artery territorial infarct.(b) MR angiography of the index case at the time of presentation reveals an absent flow in the left internal carotid artery and the distal vessels and absence of collat

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The child was extensively evaluated for all possible risk factors contributing to stroke, detailed in [Supplementary Table 1]. His blood investigations revealed a normocytic normochromic anemia (MCV = 94 μl) with a normal platelet and total leucocyte count. By the fourth day of hospitalization, he developed thrombocytopenia with elevated lactate dehydrogenase (LDH). Peripheral smear examination showed schistocytes (4%-5%) with a low reticulocyte count. His serum vitamin B12, folate, plasma homocysteine, and C3 levels were within normal limits. Subsequently, a gradual decline of hemoglobin levels and platelet count was noted. In addition to the evolution of bicytopenia, he also developed facial puffiness with hypertension. A working diagnosis of congenital thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) was considered and clinical exome sequencing was ordered. He was started on daily fresh frozen plasma transfusion followed by Plasma Exchange (PEX). Once platelet counts improved to >1 lac/mm3 with normalization of blood pressure records, the child was switched to oral steroids which were continued for about a month and gradually tapered monitoring the platelet count.{Table 1}

Exome sequencing revealed a novel homozygous nonsense variation in exon 2 of the SLC19A2 gene (chr1:169446604; G>C; Depth: 119x) that results in a stop codon and premature truncation of the protein at codon 199 (p. Ser199Ter; ENST00000236137). The region is conserved across species. The detected variant was predicted to be damaging by SIFT, LRT and Mutation Taster and was likely pathogenic.

At 3-month follow-up, the child developed sensorineural hearing loss. Bone marrow aspirate revealed cellular marrow with adequate megakaryocytosis and erythroid series showed megaloblastic maturation. HbA1c was 6.7 g/dl (normal < 6.5%). Child was initiated on thiamine in supratherapeutic doses (500 mg/day). Currently, at 2-year follow-up, hematological parameters are within normal limits. There has not been any recurrence of stroke. He failed a hearing-aid trial and has been planned for cochlear implant surgery. Informed consent was obtained from parents for publication.

Thiamine responsive megaloblastic anemia (Roger syndrome) is characterized by a clinical triad of megaloblastic anemia, deafness, and diabetes. Megaloblastic anemia and diabetes may manifest from infancy to adolescence while deafness usually manifests in the toddler age group. This entity was first described in 1969 by Roger et al.[4] It is caused by a mutation in SLC19A2 gene, which encodes the high-affinity thiamine transporter. Besides classical triad, other features include abnormalities of retina and optic nerve, stroke-like episodes, congenital heart disease, arrhythmias, aminoaciduria, tri-lineage myelodysplasia, short stature, and situs inversus.

Thiamine deficiency is known to affect respiratory chain complex I activity. The neurological features of TRMA, resembling those of mitochondrial complex I deficiency, may be caused due to a secondary defect in mitochondrial energy production.[6] But, the association with stroke and pathophysiology of stroke in TRMA is unclear.

Till date, there are two patients with TRMA reported with AIS and one with cerebral sinus thrombosis.[7],[8],[9] Possible pathogenic mechanisms include: Mapping of human coagulation factor V and antithrombin III precursor to nearby region as SLC19A2 gene (a complex mutational event in this region may also involve coagulation cascade genes, causing susceptibility to thrombosis)[6] and prothrombotic tendency due to hyperglycemic state (increased levels of plasminogen activator inhibitor-1 and the decreased endogenous fibrinolysis activity).[7] Besides these, the clinical spectrum of TRMA is still evolving due to the rarity of this disorder; microvascular and coagulation pathway affection are still ambiguous. Also, the role of a particular genotype causing disease and stroke as a presenting feature is also unclear.

Our initial clinical possibility in the index patient was congenital HUS/TTP in view of thrombocytopenia, hypertension, consanguinity and early infantile onset, and exome sequencing was done suspecting the same. But it revealed a likely pathogenic variation in the gene for TRMA. Anecdotal reports suggest that TRMA may be associated with stroke however its association with TTP/HUS is speculative. There have been rare reports of atypical HUS associated with cobalamin C defect which presents with megaloblastic anemia, methylmalonic acidemia, and homocystinuria.[10],[11] However, no direct link between TRMA and HUS/TTP have been mentioned. Both acquired HUS and TRMA seem to have coexisted in the index case and this probable unusual association merits documentation.

The basis for responsiveness of thrombocytopenia to plasma exchange in the index case is uncertain. Possibilities include superadded consumption coagulopathy, acquired hemolytic uremic syndrome/TTP, thiamine repletion, and prothrombotic state due to disease per se which also might have responded to plasma exchange.

This patient had two uncommon manifestations of this rare disorder: AIS and thrombocytopenia. Also, the child had a novel nonsense mutation in SLC19A2 gene. History of consanguinity, in this case, was another pointer towards a genetic disorder. Later, clinical features such as sensorineural hearing loss and slightly elevated HbA1c confirmed the clinical phenotype.

This case brings forth association between TRMA, prothrombotic state, and AIS; although the exact physiological basis still remains indeterminate. TRMA as a possible risk factor for stroke still remains a mystery. Evolving phenotypic spectrum of this disease might make the intricate pathways more lucid.

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.


Authors are grateful to the patient and his family.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Biller J. Stroke: Improving characterization of childhood cerebral arteriopathies. Nat Rev Cardiol 2009;6:395-7.  Back to cited text no. 1
Fullerton HJ, Wu YW, Sidney S, Johnston SC. Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: The importance of cerebrovascular imaging. Pediatrics 2007;119:495-501.  Back to cited text no. 2
Earley CJ, Kittnner SJ, Freeser BR, Gardner J, Epstein A, Woznaik MA, et al. Stroke in children and sickle-cell disease. Baltimore – Washington cooperative young stroke study. Neurology 1998;51:169-76.  Back to cited text no. 3
Porter FS, Rogers LE, Sidbury JB Jr. Thiamine-responsive megaloblastic anemia. J Pediatr 1969;74:494-504.  Back to cited text no. 4
Bergmann AK, Sahai I, Falcone JF, Fleming J, Bagg A, Borgna- Pignati C, et al. Thiamine- responsive megaloblastic anemia: Identification of novel compound heterozygotes and mutation update. J Pediatr 2009;155:888-92.  Back to cited text no. 5
Scharfe C, Hauschild M, Klopstock T, Janssen AJM, Heidemann PH, Meitinger T, et al. A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I. J Med Genet 2000;37:669-73.  Back to cited text no. 6
Setoodeh A, Haghighi A, Saleh-Gohari N, Ellard S, Haghighi A. Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia. Gene 2013;519:295-7.  Back to cited text no. 7
Villa V, Rivellese A, Di Salle F, Iovine C, Poggi V, Capaldo B. Acute ischemic stroke in a young woman with the thiamine-responsive megaloblastic anemia syndrome. J Clin Endocrinol Metab 2000;85:947-9.  Back to cited text no. 8
Ho J, Mah JK, Hill MD, Pacaud D. Pediatric stroke associated with new onset type 1 diabetes mellitus: Case reports and review of the literature. Pediatr Diabetes 2006;7:116-21.  Back to cited text no. 9
Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, et al. Late onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 2005;45:588-95.  Back to cited text no. 10
Bouts AH, Roofthooft MT, Salomons GS. CD-46 associated atypical hemolytic syndrome with uncommon course caused by cblC deficiency. Pediatr Nephrol 2010;25:2547-8.  Back to cited text no. 11


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