Types of Renal Tubular Acidosis in Southeast Asian Ovalocytosis
Patients with Southeast Asian Ovalocytosis (SAO) can develop distal renal tubular acidosis (Type 1 RTA), which occurs through autosomal recessive inheritance when SAO is combined with additional mutations in the anion exchanger-1 (AE1) gene. 1
Primary RTA Type Associated with SAO
Type 1 (Distal) RTA
- SAO alone does not cause RTA - individuals with isolated SAO (27 bp deletion in exon 11 of the AE1 gene) maintain normal renal acidification capacity 1
- Compound heterozygosity is required - dRTA develops only when SAO is inherited together with a second pathogenic AE1 mutation (such as G701D missense mutation in exon 17), creating autosomal recessive dRTA 1
- The prevalence is striking: 81.8% of Malay patients with dRTA have SAO, compared to only 4% in healthy controls, indicating SAO significantly increases susceptibility to dRTA when combined with other genetic factors 2
Clinical Presentation in SAO-Associated dRTA
Metabolic Features
- Normal anion gap metabolic acidosis (anion gap 8-12 mEq/L) with hyperchloremia 3, 4
- Severe hypokalemia (potassium as low as 2.7 mmol/L) leading to proximal muscle weakness, paralysis risk, rhabdomyolysis, and cardiac arrhythmias 3, 4
- Inability to lower urine pH below 5.5-6.3 despite systemic acidemia 4, 5
Renal Manifestations
- Low ammonium (NH4+) excretion initially (26 micromol/min), though capacity for NH4+ production remains intact and can increase threefold with diuretic challenge 4
- Nephrocalcinosis and nephrolithiasis from hypercalciuria, alkaline urine, and low urinary citrate 3, 6
- Growth retardation in children and osteodystrophy 5, 6
Unique Finding in SAO-Associated dRTA
- Paradoxically elevated urine-blood PCO2 difference (U-B PCO2 of 27 mm Hg when urine pH reaches 7.7 after bicarbonate loading), possibly from misdirection of AE1 to the apical membrane of type A intercalated cells 4
Other RTA Types NOT Associated with SAO
Type 2 (Proximal) RTA
- Results from impaired bicarbonate reabsorption in the proximal tubule, not distal dysfunction 7
- Associated with Fanconi syndrome features: aminoaciduria, glucosuria, phosphaturia, and uricosuria 3, 7
- Not linked to SAO - the AE1 defect in SAO affects distal tubules, not proximal transport mechanisms 1
Type 4 (Hyperkalemic) RTA
- Characterized by hyperkalemia as the dominant feature, with mild metabolic acidosis 3
- Results from aldosterone deficiency or resistance, not AE1 dysfunction 8
- Not associated with SAO - the pathophysiology is unrelated to anion exchanger abnormalities 3
Critical Diagnostic Pitfall
Do not assume all individuals with SAO have RTA - parents and family members with isolated SAO demonstrate completely normal renal acidification on NH4Cl loading tests 1. The key distinction is that autosomal recessive inheritance of two abnormal AE1 alleles (SAO deletion plus an additional mutation) is required for dRTA to manifest 1.