A case of red cell membrane defect with distal renal tubular acidosis presenting as recurrent nephrolithiasis
Apollo Medicine 2011 DecemberCase Report
Volume 8, Number 4; pp. 317–318
© 2011, Indraprastha Medical Corporation Ltd
A case of red cell membrane defect with distal renal tubular acidosis presenting as recurrent nephrolithiasis
Sanjay Bafna*, Vibha Bafna**, Manoj Matnani†, Mayur Choudhari‡, Shweta Agarwal‡
*Senior Consultant, Paediatrician and Head of the Department, **Senior Consultant, Paediatrician and Paediatrics Hematologist-Oncologist, †IPNA Fellow, Paediatric Nephrology (London), Consultant Paediatric Nephrologist, ‡Senior Regisrar and DNB Resident, Jehangir Apollo Hospital, Pune – 411001, India.
ABSTRACT
A 10-year-old male child who presented with nephrolithiasis due to distal renal tubular acidosis (dRTA) was found to have red blood cell (RBC) membrane defect as well. On review of literature, we found that both the conditions are caused by mutations in anion exchanger gene 1 (AE1) on chromosome 17 which is expressed on the RBC mem-brane and on the membrane of renal tubule alfa intercalated cell. It has now been shown that some AE1 mutations are responsible for causing autosomal-recessive dRTA. These patients should be either homozygous or double het-erozygous with other AE1 mutations, one of which is the SAO (Southeast Asian ovalocytosis) mutation. In the latter situation, both the phenotypes, that is, dRTA and RBC membrane defect will coexist in the same patient.
Keywords: Anion exchanger 1 gene family, distal renal tubular acidosis (dRTA), hemolytic anemia, nephrolithiasis, Southeast Asian ovalocytosis (SAO)
Correspondence: Dr. Sanjay Bafna, E-mail: [email protected]; [email protected]: 10.1016/S0976-0016(11)60019-7
CASE HISTORY
A 10-year-old male child, born out of nonconsanguinous marriage, from Sindhi community was brought to the casu-alty with severe pain in abdomen and vomiting. His vitals and all other system were normal. He also had a mild icterus and a just palpable spleen. On past history, as a newborn, he had indirect hyperbilirubinemia for which he required two exchange transfusions and phototherapy. Mother and baby were both B-positive and his G6PD levels were normal. No cause for his hyperbilirubinemia could be ascertained. After that he was admitted twice at the age of 7 and 8 years with renal colic. He was found to have a left ureterovesical (UV) junction calculus first time and right UV junction calculus second time. He was treated conservatively and the calculus disappeared. Mild icterus and a just palpable spleen were noted during the second admission also.
During the present episode too, he had a renal colic and was found to have an obstructive right calculus and multiple bilateral nonobstructive calculi on ultrasonography (USG). He was investigated thoroughly for the cause of repeated epi-sodes of nephrolithiasis. His venous blood gas (VBG) had a normal anion gap acidosis. Hence, he was diagnosed to have a distal renal tubular acidosis. Meanwhile, his complete blood count (CBC) showed evidence of mild hemolytic anemia with anisopoikilocytosis and microcytic hypochromia. He had a
high reticulocyte-count and a mild indirect hyperbiliruben-emia. He had a just palpable spleen clinically and a splenom-egaly on USG. All this along with a history of severe neonatal jaundice, we worked him up for hemolytic anemia. His hemoglobin electrophoresis incidentally showed evidence of thalassemia trait. His G6PD levels were normal. Though his peripheral smear did not show any spherocytes or any other abnormal shaped red blood cell (RBC) and osmotic fragility was normal, we considered the possibility of a RBC membrane defect. Flow cytometric analysis for RBC membrane defect done at the National Institute of Immuno-hematology, ICMR, Mumbai, was positive for the patient and his father whereas the mother had thalassemia trait but had no membrane disorder. All his other investigations for nephrolithiasis, i.e., 24 h urine for oxalate, calcium, phos-phorus, uric acid, were normal. There was no evidence of rickets. Serum parathyroid hormone levels were normal.
DISCUSSION
Therefore, we had a child with convincing evidence of distal RTA with nephrolithiasis and hemolytic anemia, most probably due to RBC membrane disorder. We reviewed litera-ture to see if these conditions could co-exist in a patient. SLC4A1
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(solute carrier family 4 anion exchanger membrane 1) gene on chromosome 17-q 21–22,1 codes for chloride–bicarbo-nate anion exchanger 1 family of glycoprotein in the band 3 of the RBC membrane (eAE1). It also codes for the chloride bicarbonate exchanger on the basolateral membrane of the renal collecting tubules alpha intercalated cells (kAE1). The eAE1 defect results in the morphologic changes of the RBC while the kAE1 defect leads to distal RTA.2,3 AE1 mutations expressed in these two different cells have distinct and seemingly unrelated phenotypes, hereditary spherocytosis (HS) or other forms of erythrocyte membrane defects and dRTA.2 The largest group of mutations in human AE1 is associated with autosomal-dominant red cell dysmorphol-ogy (hereditary spherocytosis [HS], Southeast Asian ovalo-cytosis [SAO]). Southeast Asian ovalocytosis is an RBC membrane defect, seen in Southeast Asian countries such as Philippines, Malay, Indonesia, and Thailand. RBCs in this condition are rigid and probably protect against malaria para-site invasion.2 It is a heterozygous condition and manifests as neonatal hyperbilirubinemia and subsequently as a mild hemolytic anemia. We may find the characteristic theta cells on the peripheral smear.4 The homozygous form of SAO is not seen, most probably because it is lethal in the fetal state itself.2
We could not find theta cells in our patient, most prob-ably the presence of thalassemia minor may be distorting the characteristic morphology. Southeast Asian ovalocyto-sis is caused by the deletion of 27 bp in codon 400–408 leading to a lack of nine amino acids in the protein which is hence inactive for anion transport.2,3
The AE1 gene also codes for the protein responsible for chloride bicarbonate exchange on the basolateral mem-brane of the renal alpha intercalated cell. Mutations in this gene are responsible for dRTA.2,3
Dominant HS-associated AE1 mutations are generally not associated with dRTA, conversely dRTA associated AE1 muta-tions are also not associated with HS. How can we explain this when both disorders are caused by mutations in the same gene?3
Recent genetic studies have shown that some of the AE1 mutations are responsible for autosomal-recessive dRTA in countries of Southeast Asia. These patients are either homozygous for the mutation or compound heterozygotes of two different AE1 mutations, one of which is the SAO mutations. AE1G701D mutation is one of the dRTA muta-tions which when present in the compound heterozygous form with the SAO mutation can present with both pheno-types in the same patient. Other mutations which cause hemolytic anemia with dRTA are V850/SAO, A858D/SAO and �V850/A858D. The mutation in the same gene that is the AE1 gene is responsible for both these conditions but they can co-exist in the same patient only if they are com-pound heterozygotes for both mutations causing these different disorders.3,7 There are case reports from Malaysia,
Papua New Guinea, Thailand, and Philippines describing patients with recessive dRTA and red cell dysmorphology.5,6,8 We could find only one case report from our country describ-ing two unrelated patients from Maratha Kunbi families.9
We would like to do a mutation analysis of our patient to conclusively prove that he has indeed a dRTA and hemolytic anemia due to RBC membrane defect phenotypes together.
ACKNOWLEDGMENTS
We express our thanks to Dr. Prasad Muglikar, Director of Medical Services, Jehangir Hospital, Pune, for permitting us to publish this case. We are grateful to the National Institute of Immunohematology for doing flow cytometry analysis for RBC membrane defect of our patient.
REFERENCES
1. SLC4A1-Genetics Home Reference. A service of the US National Library of Medicine.
2. Wrong O, Bruce LJ, Unwin RJ, Toye AM, Tanner MJ. Band 3 mutations, distal renal tubular acidosis and Southeast Asian ovalocytosis. Kidney Int 2002;62:10–9.
3. Pereira PC, Miranda DM, Oliveira EA, Silva AC. Molecular pathophysiology of renal tubular acidosis. Curr Genom 2009;10:51–9.
4. Nathan DG, Orkin SH. In: Hematology of Infancy and Childhood 7th ed. Saunders, Elsevier.
5. Bruce LJ, Wrong O, Toye AM, et al. Band 3 mutations, renal tubular acidosis and Southeast Asian ovalocytosis in Malaysia and Papua New Guinea—loss of up to 95% band 3 transport in red cell. Biochem J 2000;350:41–51.
6. Sritippayawan S, Sumboonnanonda A, Vasuvattakul S, et al. Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal RTA (renal tubular acidosis). Am J Kidney Dis 2004;44:64–70.
7. Khositseth S, Sirikanaerat A, Khoprasert S, et al. Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies. Am J Hematol 2008;83:465–71.
8. Anacleto FE, Bruce LJ, Clayton P, et al. Distal renal tubular acidosis in Filipino children, caused by mutations of anion-exchanger SLC4A1 (AE Band 3) gene. Nephron Physiol 2010;114:19–24.
9. Boris E Shmuckler, Prabhakar S Kedar, et al. Hemolytic ane-mia and distal renal tubular acidosis in two Indian patients homozygous for SLC4A1/AE1 mutation A858D. Wileyonline library. DOI: 10. 1002/ajh 21836. Am J Hematol 2010 [Letter published online on 23rd July].
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