Carbonic anhydrase II deficiency (OMIM # 259730), initially called “osteopetrosis with renal tubular acidosis and cerebral calcification syndrome”, reveals an important role for the enzyme carbonic anhydrase II (CA II) in osteoclast and renal tubule function. Discovered in 1972 and subsequently given various names, CA II deficiency now describes >100 affected individuals encountered predominantly from the Middle East and Mediterranean region. In 1983, CA II deficiency emerged as the first osteopetrosis (OPT) understood metabolically, and in 1991 the first understood molecularly. CA II deficiency is the paradigm OPT featuring failure of osteoclasts to resorb bone due to inability to acidify their pericellular milieu. The disorder presents late in infancy or early in childhood with fracturing, developmental delay, weakness, short stature, and/or cranial nerve compression and palsy. Mental retardation is common. The skeletal findings may improve by adult life, and CA II deficiency can be associated with a normal life-span. Therefore, it has been considered an “intermediate” type of OPT. In CA II deficiency, OPT is uniquely accompanied by renal tubular acidosis (RTA) of proximal, distal, or combined type featuring hyperchloremic metabolic acidosis, rarely with hypokalemia and paralysis. Cerebral calcification uniquely appears in early childhood. The etiology is bi-allelic loss-of-function mutations of CA2 that encodes CA II. Prenatal diagnosis requires mutational analysis of CA2. Although this enzymopathy reveals how CA II is important for the skeleton and kidney tubule, the pathogenesis of the mental subnormality and cerebral calcification is less well understood. Several mouse models of CA II deficiency have shown growth hormone deficiency, yet currently there is no standard pharmacologic therapy for patients. Treatment of the systemic acidosis is often begun when growth is complete. Although CA II deficiency is an “osteoclast-rich” OPT, and therefore transplantation of healthy osteoclasts can improve the skeletal disease, the RTA and central nervous system difficulties persist.
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