Creatine kinase brain isoenzyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone disorders

Abstract

Creatine kinase (CK) isoenzyme BB-CK is predominantly found in brain and is not normally detected in the blood. A few recent reports, however, have described BB-CK in serum from several patients with osteopetrosis (OP). To evaluate the presence and specificity of BB-CK in serum in the osteopetroses among disorders that increase skeletal mass, we quantitated total CK activity and CK isoenzymes in 15 patients representing the five major clinical forms of OP (2 infantile, 3 intermediate, 7 adult [2 type I, 5 type II], and 3 carbonic anhydrase II [CA II] deficiency cases) and in 22 patients representing 14 other types of sclerosing bone disease. All OP patients (except the two adult type I subjects) had BB-CK readily detected in their serum. Conversely, only 1 of the 22 patients with other sclerosing bone disorders had detectable BB-CK in serum (1 of 3 patients with fibrodysplasia [myositis] ossificans progressiva who had barely measurable activity). In three OP patients (one of two with the infantile form and two of five with adult, type II disease), BB-CK values were sufficiently high that serum total CK activity was elevated. In a newborn with malignant OP, both cord blood plasma and peripheral blood serum had substantial amounts of BB-CK. In three subjects (with adult type II OP), who were restudied 2-6 years later, BB-CK was still elevated in their blood. BB-CK in serum appears to distinguish the osteopetroses among the sclerosing bone disorders. Absence of serum BB-CK in adult type I disease suggests that this condition may not be a genuine form of OP. Assay of BB-CK in fetal blood could be studied as a means for prenatal diagnosis of malignant OP. Why the osteoclast failure that characterizes all true forms of OP is associated with BB-CK in the circulation is a new question for skeletal biologists.

Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease (Chloride Channel 7 Deficiency Osteopetrosis) among the sclerosing bone disorders

“…(45) An increase in LDH was reportedly ''minor.'' (45) Like these authors and others, (11,(46)(47)(48) we found a marked elevation in serum TRACP-5b levels in A-SD and confirmed our initial report of markedly elevated BB-CK levels in A-SD patients, (9) subsequently verified by others. (47) In 2004, Letizia and colleagues (49) also recorded, but did not comment on, elevated serum LDH (including isoforms) and CK in a patient with A-SD due to a unique CLCN7 mutation.…”

“…(8) Elevated serum levels of the ''brain'' isoenzyme of creatine kinase (BB-CK; EC 2.7.3.2), the CK of osteoclasts, distinguish the OPTs among the sclerosing bone disorders. (9) Tartrate resistant acid phosphatase (EC 3.1.3.2), specifically TRACP-5b from osteoclasts, is markedly increased in the serum of patients with Albers-Schö nberg disease (A-SD), the autosomal dominant ''benign'' form of OPT due to CLCN7 deficiency. (10) Elevations of both enzymes could reflect excesses of, or defects within, these cells.…”

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

“…(68) The biochemical abnormalities of OPT can reflect impaired OC function and increased numbers of OCs, including elevations in serum of CK-BB and TRAP-5b, which emanate from the OCs. (26,29) Our patient's radiographic features of OPT included vertebral endplate sclerosis, lumbar spine DXA Z-score of þ5.7, and Erlenmeyer flask deformity of his distal femurs. His elevated serum CK-BB and TRAP-5b levels were also consistent with genetic or BP-induced OPT, and corrected with cessation of EHDP exposure.…”

“…His serum total creatine kinase (CK) activity was 105 IU/L (Nl: 31-152), but the brain isoenzyme of CK (BB-CK) was significantly elevated at 43 IU/L (Nl: 0-4), representing 41% of total CK, and was therefore consistent with an OPT. (29) Serum TRAP-5b was slightly increased at 28.2 IU/L (Nl: 6.8-26.7), but LDH and AST were normal at 208 IU/L (Nl: 141-237) and 30 IU/L (Nl: 0-36), respectively.…”

“…Similarly, serum levels of the brain isoenzyme of creatine kinase (CK-BB) (Kit #K20; Sebia, Norcross, GA, USA), (29) tartrate-resistant acid phosphatase, TRAP-5b (Kit #8033, Quidel; Los Angeles, CA, USA), lactate dehydrogenase (LDH), (26) and aspartate aminotransferase (AST) (26) were assayed for evidence of OPT. The methods, results, and interpretation of our molecular studies to determine the genetic basis and biochemical investigations to understand the pathogenesis of our patient's GACI are detailed in the Supplementary Appendix.…”