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Table of Contents
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 91-93

Distal renal tubular acidosis with hemolytic anemia and myotonia: Unusual phenotype of a known mutation

1 Department of Pediatrics, Armed Forces Medical College (AFMC), Pune, Maharashtra, India
2 Department of Pediatrics and Pediatric Nephrology, Command Hospital and AFMC, Pune, Maharashtra, India

Date of Web Publication4-Dec-2019

Correspondence Address:
Suprita Kalra
Department of Pediatrics and Pediatric Nephrology, Command Hospital and Armed Forces Medical College, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_11_19

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Distal renal tubular acidosis (dRTA) is a tubulopathy with metabolic acidosis due to impaired renal acid excretion. Patients with dRTA present with hypokalemia, medullary nephrocalcinosis, nephrolithiasis, growth retardation, and rickets in childhood. Inherited dRTA due to solute carrier family 4 member 1 gene (SLC4A1) mutation on chromosome 17 is known to be associated with hemolytic anemia, whereas mutations in other genes might be associated with hearing loss (ATP6V1B1, ATPV0A4, or FOXI1) or dental enamel defects (WD repeat-containing protein 72). However, an association of dRTA with myotonia has not been reported. We report here an infant with dRTA with hemolytic anemia and persistent myotonia due to a homozygous missense mutation (p. Ala858Asp) in exon 19 of SLC4A1.

Keywords: Hypertonia, pseudohypertrophy, SLC4A1

How to cite this article:
Jain G, Kalra S, Joshi D. Distal renal tubular acidosis with hemolytic anemia and myotonia: Unusual phenotype of a known mutation. Asian J Pediatr Nephrol 2019;2:91-3

How to cite this URL:
Jain G, Kalra S, Joshi D. Distal renal tubular acidosis with hemolytic anemia and myotonia: Unusual phenotype of a known mutation. Asian J Pediatr Nephrol [serial online] 2019 [cited 2020 Jul 2];2:91-3. Available from: http://www.ajpn-online.org/text.asp?2019/2/2/91/272304

  Introduction Top

Distal renal tubular acidosis (dRTA) is caused by inherited defects in tubular transport or may be secondary to systemic diseases or certain drugs.[1] Inherited forms of dRTA are chiefly caused by mutations that result in defective action of either the hydrogen pump (H+-ATPase) located on the luminal surface of α-intercalated cells or Cl/HCO3 anion exchanger on the basolateral surface of distal convoluted tubules or collecting ducts. The three important causative genes are those encoding the Cl/HCO3 anion exchanger, solute carrier family 4 member 1 (SLC4A1) on chromosome 17q21-q22, and subunits of H+-ATPase, namely ATPase H+ transporting V1 subunit B1 (ATP6V1B1) on 2q13 and ATPase H+ transporting V0 subunit A4 (ATP6V0A4) on 7q33-q34.[1] Other defects include mutations in genes encoding cytosolic carbonic anhydrase II, resulting in a mixed picture of proximal renal tubular acidosis (RTA) and dRTA; WD repeat-containing protein 72, leading to associated dental enamel malformations; and forkhead box protein I1 (FOXI1), associated with early deafness.[1],[2],[3] Mutations in SLC4A1 mutations are known to have nonrenal manifestations such as hemolytic anemia.[4] We report here an infant with dRTA with hemolytic anemia and myotonia due to a homozygous missense mutation (p. Ala858Asp) in exon 19 of SLC4A1.

  Case Report Top

An 8-month-old boy, born to a couple with third-degree consanguinity, was brought with a history of failure to thrive, polyuria, and excessive irritability. His elder brother, who had similar symptoms since early infancy, had passed away at 10 years of age. On examination, his weight was 5.2 kg (<−3 standard deviation score [SDS]), length 71 cm (0 to −1 SDS), and weight for length <−3 SDS. The infant had triangular facies, prominent muscle contours, especially in the upper limbs, and generalized absence of subcutaneous pads of fat. Systemic examination revealed hepatosplenomegaly and percussion myotonia in limb muscles proximally. Deep tendon jerks were preserved in both upper and lower limbs. The developmental assessment revealed mild delay in gross motor milestones.

Investigations revealed a normal anion gap dRTA with hypokalemia [Table 1]. Peripheral blood smear showed schistocytes suggestive of hemolysis [Figure 1]. Ultrasonography of the kidneys did not reveal any nephrocalcinosis. Needle electromyography revealed diffuse myotonic discharges. Echocardiography, electrocardiography, and Holter test were normal. Clinical exome sequencing revealed a homozygous missense variation in exon 19 of the SLC4A1 (chr17: 42328609 G > T; depth: × 83), resulting in the substitution of aspartic acid for alanine at codon 858 (c.2573C > A; p. Ala858Asp). The variation was confirmed on Sanger sequencing [Figure 2]. The mutation is previously reported in patients with dRTA and hemolytic anemia[5] and is predicted to be likely pathogenic as per the American College of Medical Genetics guidelines.[6] The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv and HumVar), sorting intolerant from tolerant (SIFT) and MutationTaster2.[7]
Table 1: Investigations at hospital admission

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Figure 1: Peripheral blood smear showing schistocytes, acanthocytes, and spherocytes

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Figure 2: Sequence chromatogram and alignment to reference sequence on Sanger sequencing showing variation in exon 19 of SLC4A1 (chr17:42328609G>T; c. 2573C>A; p. Ala858Asp) in homozygous condition

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The infant was managed with oral alkali and potassium supplements along with low doses of phenytoin (1 mg/kg in two divided doses) for myotonia. He required one transfusion of packed red blood cells at admission. Six months after the diagnosis and initiation of treatment, parents reported an overall improvement in the general condition of the child and consistent weight gain to 7.5 kg. However, wasting, pseudohypertrophy and myotonia have persisted into late childhood [Figure 3].
Figure 3: Image demonstrating (a) prominent muscle contours with pseudohypertrophy, and (b) severe wasting, in the index patient

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  Discussion Top

dRTA presents with growth failure, polyuria, polydipsia, rickets, and nephrocalcinosis in children and is characterized by hyperchloremic normal anion gap metabolic acidosis, hypokalemia, and hypercalciuria.[1] Several authors have attempted to correlate genotype with clinical phenotypes of patients with dRTA.[1],[8],[9] In a case series from Korea, patients with SLC4A1 mutations (58.8% of all cases), compared to those with ATP6V1B1 or ATP6V0A4 mutations, had milder metabolic acidosis (mean pH 7.30 ± 0.06 vs. 7.20 ± 0.06) and older age at onset (3.7 ± 2.6 vs. 0.2 ± 0.1 years).[1] However, our patient had early onset of symptoms and novel phenotype with myotonia, pseudohypertrophy of proximal muscles, and hemolytic anemia along with dRTA.

Anion exchanger proteins encoded by SLC4A1 are also expressed on the erythrocyte plasma membrane and help in maintaining the cytoskeletal structure and ion transport. Mutations in SLC4A1 in erythrocytes result in hemolytic anemia due to spherocytosis or stomatocytosis and ovalocytosis. Our patient had a recessively inherited homozygous missense mutation (p. Ala858Asp) in exon 19 of SLC4A1, which is commonly reported in patients with dRTA and ovalocytosis both within and outside Southeast Asian countries.[1],[10]

Hypokalemic periodic paralysis in dRTA due to underlying SLC4A1 mutations is a well-known entity.[11] However, myotonia or pseudohypertrophy has never been reported in association with SLC4A1 mutation. Careful evaluation of the clinical exome excluded variations in SNC4A (gene encoding skeletal muscle voltage-gated sodium channel α-subunit) and CLCN1 (gene encoding muscle voltage-gated chloride channels), which are implicated in the causation of inherited myotonia.[12] Myotonia is rarely described in patients with hypokalemic periodic paralysis due to missense mutations in the voltage-gated sodium channel (NaV1.4) that impair sodium channel gating and inactivation of muscle fibers.[13] We hypothesize that SLC4A1 mutation causing defective Cl/HCO3 anion exchanger resulting in dRTA might affect ion transport in skeletal muscles, producing myotonia in our patient. This hypothesis requires confirmation on detailed molecular and electrophysiological studies in patients with a similar phenotype.

  Conclusion Top

Inherited tubulopathies can be associated with myriad extrarenal symptoms. The identification of molecular defects in inherited tubulopathies is important to confirm the diagnosis to enable prenatal counseling and antenatal screening and might provide bases for future targeted therapeutic interventions.


Col Vishal Sondhi, Dept of Pediatrics and Pediatric Neurology, performed the EMG to confirm myotonia.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Park E, Cho MH, Hyun HS, Shin JI, Lee JH, Park YS, et al. Genotype-phenotype analysis in pediatric patients with distal renal tubular acidosis. Kidney Blood Press Res 2018;43:513-21.  Back to cited text no. 1
Zhang H, Koruyucu M, Seymen F, Kasimoglu Y, Kim JW, Tinawi S, et al. WDR72 mutations associated with amelogenesis imperfecta and acidosis. J Dent Res 2019;98:541-8.  Back to cited text no. 2
Enerbäck S, Nilsson D, Edwards N, Heglind M, Alkanderi S, Ashton E, et al. Acidosis and deafness in patients with recessive mutations in FOXI1. J Am Soc Nephrol 2018;29:1041-8.  Back to cited text no. 3
Kager L, Bruce LJ, Zeitlhofer P, Flatt JF, Maia TM, Ribeiro ML, et al. Band 3 null VIENNA, a novel homozygous SLC4A1 p. Ser477X variant causing severe hemolytic anemia, dyserythropoiesis and complete distal renal tubular acidosis. Pediatr Blood Cancer 2017;64:e26227.  Back to cited text no. 4
Fawaz NA, Beshlawi IO, Al Zadjali S, Al Ghaithi HK, Elnaggari MA, Elnour I, et al. dRTA and hemolytic anemia:First detailed description of SLC4A1 A858D mutation in homozygous state. Eur J Haematol 2012;88:350-5.  Back to cited text no. 5
Tavtigian SV, Greenblatt MS, Harrison SM, Nussbaum RL, Prabhu SA, Boucher KM, et al. Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med 2018;20:1054-60.  Back to cited text no. 6
Mutation Taster2. Available from: http://www.mutationtaster.org. Mutation taster. [Last accessed on 2019 Apr 20].  Back to cited text no. 7
Besouw MTP, Bienias M, Walsh P, Kleta R, Van't Hoff WG, Ashton E, et al. Clinical and molecular aspects of distal renal tubular acidosis in children. Pediatr Nephrol 2017;32:987-96.  Back to cited text no. 8
Gómez J, Gil-Peña H, Santos F, Coto E, Arango A, Hernandez O, et al. Primary distal renal tubular acidosis: Novel findings in patients studied by next-generation sequencing. Pediatr Res 2016;79:496-501.  Back to cited text no. 9
Khositseth S, Sirikanaerat A, Khoprasert S, Opastirakul S, Kingwatanakul P, Thongnoppakhun W, et al. Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies. Am J Hematol 2008;83:465-71.  Back to cited text no. 10
Bresolin NL, Grillo E, Fernandes VR, Carvalho FL, Goes JE, da Silva RJ, et al. A case report and review of hypokalemic paralysis secondary to renal tubular acidosis. Pediatr Nephrol 2005;20:818-20.  Back to cited text no. 11
Cherian A, Baheti NN, Kuruvilla A. Muscle channelopathies and electrophysiological approach. Ann Indian Acad Neurol 2008;11:20-7.  Back to cited text no. 12
[PUBMED]  [Full text]  
Khositseth S, Sirikanaerat A, Khoprasert S, Opastirakul S, Kingwatanakul P, Thongnoppakhun W, Pa-thai Yenchitsomanus. Hematological abnormalities in patients with distal renal tubular acidosis and hemoglobinopathies. Am J Hematol 2008;83:465-71.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1]


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