|Year : 2019 | Volume
| Issue : 2 | Page : 91-93
Distal renal tubular acidosis with hemolytic anemia and myotonia: Unusual phenotype of a known mutation
Gitanjali Jain1, Suprita Kalra2, Deepak Joshi1
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 Publication||4-Dec-2019|
Department of Pediatrics and Pediatric Nephrology, Command Hospital and Armed Forces Medical College, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
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 Apr 3];2:91-3. Available from: http://www.ajpn-online.org/text.asp?2019/2/2/91/272304
| Introduction|| |
Distal renal tubular acidosis (dRTA) is caused by inherited defects in tubular transport or may be secondary to systemic diseases or certain drugs. 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. 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.,, Mutations in SLC4A1 mutations are known to have nonrenal manifestations such as hemolytic anemia. 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|| |
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 and is predicted to be likely pathogenic as per the American College of Medical Genetics guidelines. The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv and HumVar), sorting intolerant from tolerant (SIFT) and MutationTaster2.
|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|| |
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. Several authors have attempted to correlate genotype with clinical phenotypes of patients with dRTA.,, 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). 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.,
Hypokalemic periodic paralysis in dRTA due to underlying SLC4A1 mutations is a well-known entity. 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. 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. 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|| |
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.
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[Figure 1], [Figure 2], [Figure 3]