title: Elevated serum lactate dehydrogenase isoenzymes and aspartate transaminase distinguish Albers-Schönberg disease (Chloride Channel 7 Deficiency Osteopetrosis) among the sclerosing bone disorders.
abstract: Osteopetrosis (OPT) refers to the consequences of generalized failure of skeletal resorption during growth. Most cases are explained by loss-of-function mutation within the genes that encode either chloride channel 7 (CLCN7) or a vacuolar proton pump subunit (TCIRG1), each compromising acid secretion by osteoclasts. Patients suffer fractures and sometimes cranial nerve entrapment and insufficient medullary space for hematopoiesis. In 1996, we reported that a high serum level of the brain isoenzyme of creatine kinase (BB-CK), the CK of osteoclasts, characterizes OPT dueamong the sclerosing bone disorders (J Clin Endocrinol Metab. 1996;11:1438). Now, we show that elevation in serum of multiple lactate dehydrogenase (LDH) isoenzymes with aspartate transaminase (AST) distinguishes autosomal dominant OPT due to loss-of-function mutation in CLCN7 [Albers-Schönberg disease (A-SD)] among these conditions. Serum total LDH and AST levels as high as 3× and 2×, respectively, the upper limits of normal for age-appropriate controls, were persistent and essentially concordant in A-SD. Serum LDH was elevated in 7 of 9 children and in the 2 adults studied with A-SD. LDH isoenzyme quantitation showed excesses of LDH-2, -3, and -4. Neither total LDH nor AST increases were found in other forms of OPT, including bisphosphonate-induced OPT, or in 41 children and 6 adults representing 20 additional sclerosing bone disorders. Serum TRACP-5b and BB-CK also were markedly elevated in A-SD. Hence, high serum levels of several enzymes characterize A-SD. Elevated serum LDH isoenzymes and AST indicate a disturbance (of uncertain clinical significance) within multiple extraosseous tissues when there is CLCN7 deficiency.
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St Louis, MO 63131-3597, USA. mwhyte@shrinenet.org
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Lydia G
authors.initials: LG
authors.lastname: Kempa
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Steven
authors.initials: S
authors.lastname: Mumm
authors.forename: Deborah
authors.initials: D
authors.lastname: Wenkert
mesh_terms: D000293:Adolescent; D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000172:deficiency* / Q000378:metabolism; D016001:Confidence Intervals; D003402:Creatine Kinase / Q000097:blood; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D008297:Male; D009929:Organ Size; D010022:Osteopetrosis / Q000097:blood / Q000175:diagnosis / Q000201:enzymology / Q000473:pathology; D010026:Osteosclerosis / Q000097:blood* / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D012016:Reference Values
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase