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

Department of Paediatric Haematology, Tallaght Hospital, Dublin, Ireland, United Kingdom.
Blood (Impact Factor: 10.43). 05/2001; 97(7):1947-50. DOI: 10.1182/blood.V97.7.1947
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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. (Blood. 2001;97:1947-1950)

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    • "The eleven patients with novel mutations reported here come from ten families. Patient #022098A from England is of Irish Traveller origin (McMahon et al., 2001). Two siblings, #101298A and #101298B, are from a Turkish family of non-Arabic descent. "
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    ABSTRACT: The carbonic anhydrase II (CA II) deficiency syndrome is an autosomal recessive disorder that produces osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. With one exception, all patients with osteopetrosis and renal tubular acidosis examined have proven to have CA II deficiency. All CA II-deficient patients analyzed have been found to have mutations in the CA2 gene. Previously, we used single strand conformational (SSCP) analysis to identify exons to be sequenced from CA II-deficient patients. In this report, we amplified all seven exons by PCR from genomic DNA and directly sequenced the amplified products. Application of this method allowed identification of eleven new mutations in 21 patients referred for confirmation of the diagnosis of CA II deficiency. These mutations were scattered over the genome from exon 2 to 7. In two opportunities for prenatal diagnosis, one from cultured amniocytes and one from chorionic villus biopsy, we demonstrated the general utility of the direct sequencing method for prenatal DNA diagnosis. These studies expand our knowledge of the heterogeneity in mutations underlying the CA II deficiency syndrome.
    Human Mutation 09/2004; 24(3):272. DOI:10.1002/humu.9266 · 5.05 Impact Factor
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    ABSTRACT: Bone is a dynamic tissue in which osteoblasts synthesize bone matrix while osteoclasts resorb bone. Therefore, bone density is dependent on the relative function of these two types of cells. Osteoclasts are multinucleated cells of hematopoietic lineage that are critical for bone remodeling; osteoblasts, in contrast, are of mesenchymal origin. [1] Osteoblasts synthesize bone matrix and in so doing lay down a microenvironment that supports osteoclast growth, maturation, and function. They also secrete macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1, and interleukin-6, [2] all of which influence the activities of osteoclasts. Direct interactions between osteoblasts or marrow stromal cells and osteoclast precursors are essential for the differentiation of osteoclasts. [3,4] Osteopetrosis is a heterogeneous group of heritable conditions in which there is a defect in bone resorption by osteoclasts. A century ago, Albers-Schonberg described the radiographic findings in a patient with increased bone density. [5] Since then, various types of osteopetrosis have been described. The disease is associated with an increased skeletal mass due to abnormally dense bone. Generalized osteosclerosis is apparent radiographically, often with a "bone within a bone" appearance [6,7]; transverse radiolucent bands may be observed, and it may be difficult to discern the marrow cavity. The decrease in osteoclast activity also affects the shape and structure of bone by altering its capacity to remodel during growth. In severely affected patients, the medullary cavity is filled with endochondral new bone, with little space remaining for hematopoietic cells. This abnormality contributes to the brittleness of bone in osteopetrosis. The abnormal skeletal radiographs and microscopical appearance of bone can be reversed by hematopoietic stem-cell transplantation (Figure 1).
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