Bone marrow transplantation corrects osteopetrosis in the carbonic anhydrase II deficiency syndrome

Abstract

Carbonic anhydrase II (CAII), found in renal tubules, brain, and osteoclasts, is critical in acid-base homeostasis and bone remodeling. Deficiency of CAII gives rise to a syndrome of osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification with associated developmental delay. It is inherited in an autosomal recessive fashion and found most frequently in the Mediterranean region and the Middle East. We report 2 related Irish families with clinically severe CAII deficiency in whom the gene mutation has been fully elucidated. Two children, one from each family, have undergone allogeneic bone marrow transplantation because of severe progressive visual and hearing loss. The older 2 children had already developed cerebral calcification and marked visual loss at the time of diagnosis and were treated symptomatically. Post-transplantation evaluation at 2 and 3 years demonstrates histologic and radiologic resolution of their osteopetrosis with stabilization of hearing and vision. Both children remain developmentally delayed and continue to have RTA, and the older child has now developed cerebral calcification. Allogeneic bone marrow stem cell replacement cures the osteoclast component of CAII deficiency and retards the development of cerebral calcification, but it appears to have little or no effect on the renal lesions. IntroductionThe carbonic anhydrases (CA) have important physiologic functions in the body to accelerate the association of CO 2 and H 2 O to form H 2 CO 3 , which dissociates to H ϩ and HCO 3 Ϫ . Carbonic anhydrase II (CAII) is the most catalytically active of the group, with the widest tissue distribution being found in bone, kidney, brain, and erythrocytes, with osteoclasts being particularly rich in CAII. Deficiency of CAII impairs the production of H ϩ by the osteoclast and, thus, bone resorption is blocked, leading to the development of osteopetrosis. 1 The CA gene has been defined and located on chromosome 8. 2 CAII deficiency is an autosomal recessive inherited condition that gives rise to osteopetrosis, renal tubular acidosis (RTA), and cerebral calcification. 3 Short stature, fractures, cranial nerve compression, and developmental delay are variable findings. 1 Severe mental retardation occurs in the Arabic 4 and Japanese 5 populations, but normal or only mildly abnormal development has been reported in some American kindreds. 6 There are 12 described mutations of the CAII gene. However, 3 mutations (His107Tyr, 2971G3a, and 744delA) account for more than 90% of the reported patients with CAII deficiency. 7 Autosomal recessive "malignant" osteopetrosis is a more aggressive form of osteopetrosis. The failure of osteoclasts to reabsorb immature bone results in more severe impairment of bone remodeling, causing bony narrowing of the cranial nerve foramina with cranial nerve, especially optic nerve, compression; abnormal bone marrow cavity formation, resulting in bone marrow failure; and abnormal remodeling of primary, woven bone to lamellar bone, giving rise to "brittle" bone that is...

Inherited Distal Renal Tubular Acidosis

“…It is also thought that the bone thinning effect of the coexistent metabolic acidosis in CAII deficiency goes some way to protecting the osteopetrotic bones from the excessive thickening generated by osteoclast dysfunction (56). Other than alkali supplementation, specific treatment requires bone marrow transplantation (57). This can reverse the bone phenotype, but has no effect on the RTA.…”

Effects of Carbonic Anhydrase Inhibitor Acetazolamide (AZ) on Osteoclasts and Bone Structure

“…Protons are produced from water and carbon dioxide by the activity of carbonic anhydrase II (CA II) at the cell membrane 5) and are actively transported into resorption pits through V-ATPase (proton pump) at the surface of ruffled border 6) . Proton production by CA II is indispensable for bone resorption and congenital defects in CA II function are known to cause human osteopetrosis 7) . Though acetazolamide (AZ), a sulfonamide inhibit CA II specifically and suppress bone resorption 8) , the influences in the survival of osteoclasts and osteoblasts are not clear.…”

Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines

“…However, it has no impact on neurodegenerative disease in the latter form 116,118 and CNS amelioration in CAII deficiency seems unlikely. 115,119 . Therefore, these issues must be considered as transplantation is discussed in affected children.…”