High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K.

INTRODUCTION: Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT. METHODS: Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced. RESULTS: The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 +/- 28 mg/cm(3) in patients vs. 290 +/- 6 mg/cm(3) in controls; p = 0.001), especially in the trabecular compartment (733 +/- 26 mg/cm(3) in patients vs. 195 +/- 8 mg/cm(3) in controls; p < 0.001), but also in the cortical bone (1108 +/- 22 in patients vs. 1020 +/- 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W). CONCLUSION: We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.

Invariant characteristics of gait initiation.

Studies were undertaken first to describe the invariant characteristics of gait initiation and second to better understand the function of each limb in the process of gait initiation. Analysis of variance indicated significant main effects for speed for time to onset of EMG activity and force plate recordings, time to swing toe-off and heel-strike and stance toe-off. However, when the dependent variables were expressed as a percentage of the initiation cycle, no significant main effects were noted. For the second study, two force plates were utilized, and reflective markers were placed on the sacrum and anterior superior iliac spines. The timing of heel-strike of the swing limb and toe-off of the stance limb showed a high degree of coordination in both experiments (r = 0.95 and 0.98). It was concluded that the relative invariance of selected parameters indicates that gait initiation is centrally programmed. It also appears that the swing limb, although forces were very small, is responsible for the initial weight shift to the stance limb and that the stance limb is then primarily responsible for the generation of momentum.