Nephrocalcinosis and urolithiasis in carbonic anhydrase II deficiency syndrome

Abstract

We report three new Kuwaiti patients with carbonic anhydrase II deficiency (CA II) from two unrelated families. Each patient had osteopetrosis, distal renal tubular acidosis, and cerebral calcification. Patients from family 1 (a brother and a sister) had some facial anomalies and delayed development. At the age of 14 months, ultrasound studies in the girl showed medullary nephrocalcinosis which has not been previously described in association with CA II, while cerebral CT scan revealed dilated ventricles. The patient from family 2, who had two previously reported affected siblings, developed bilateral recurrent renal stones and hypercalciuria but no nephrocalcinosis. None of his affected siblings had nephrocalcinosis or urolithiasis. DNA analysis of patients from both families showed that each of them was homozygous for the "Arabic" mutation in the CA II gene. We report new features in three Arab patients with CAII deficiency. Also review all previously reported CA II cases from Kuwait in order to highlight the inter-/intra-familial variability of the disease in this part of the world despite the overwhelming prevalence of the same "Arabic" mutation among the patient population.

Increased propensity for calcium phosphate kidney stones with topiramate use

“…The diagnosis of CA II deficiency is established by the absence of this isoenzyme in circulating red blood cells and in renal tubular cell membranes [91,92] . In some, but not all, kindred with CA II mutations, recurrent nephrolithiasis without the presence of nephrocalcinosis has been described [89] . These patients presented with hypokalemic hyperchloremic metabolic acidosis and urinary pH > 5.5, suggesting the possibility of the diagnosis of distal RTA.…”

“…These metabolic abnormalities not only increase the propensity for kidney stone formation but also raise the risk of skeletal bone loss. Although distal RTA is commonly encountered with immune-mediated disorders, a few genetic mutations in genes encoding CA II have been described in a kindred of Arabian origin [47,[86][87][88][89] .…”

Mechanisms of Stone Formation

“…[93] Other conditions where acidification of the urine is compromised, such as in medullary sponge kidney, hyperparathyroidism, use of carbonic anhydrase inhibitors or carbonic anhydrase deficiency and in hereditary and acquired forms of renal tubular acidosis. [94–96] Of course, some of these conditions induce nephrocalcinosis as well as nephrolithiasis, and the highest urinary pH values are associated with struvite, magnesium ammonium phosphate, rather than predominantly calcium stone formation, although carbonate apatite may be formed as well. [97]…”

New insights into the pathogenesis of renal tubular acidosis - from functional to molecular studies

“…However, the majority of patients come from North Africa and the Middle East, with nearly 75% being of Arabic descent. Most of the Mediterranean and Arab patients are homozygous for the so-called Arabic mutation, i.e., a unique splice junction mutation at the boundary of exon 2/intron 2 [109,110,111]. Despite the presence of the same mutation there is a great inter-/intra-familial phenotypic variability.…”