Thickened skull, scoliosis and other skeletal findings in Unverricht–Lundborg disease link cystatin B function to bone metabolism

PurposeUnverricht–Lundborg disease (EPM1) is a rare type of inherited progressive myoclonic epilepsy resulting from mutations in the cystatin B gene, CSTB, which encodes a cysteine cathepsin inhibitor. Cystatin B, cathepsin K, and altered osteoclast bone resorption activity are interconnected in vitro. This study evaluated the skeletal characteristics of patients with EPM1.MethodsSixty-six genetically verified EPM1 patients and 50 healthy controls underwent head MRI. Skull dimensions and regional calvarial thickness was measured perpendicular to each calvarial bone from T1-weighted 3-dimensional images using multiple planar reconstruction tools. All clinical X-ray files of EPM1 patients were collected and reviewed by an experienced radiologist. A total of 337 X-ray studies were analyzed, and non-traumatic structural anomalies, dysplasias and deformities were registered.ResultsEPM1 patients exhibited significant thickening in all measured cranial bones compared to healthy controls. The mean skull thickness was 10.0 ± 2.0 mm in EPM1 patients and 7.6 ± 1.2 mm in healthy controls (p < 0.001). The difference was evident in all age groups and was not explained by former phenytoin use. Observed abnormalities in other skeletal structures in EPM1 patients included thoracic scoliosis (35% of EPM1 patients) and lumbar spine scoliosis (35%), large paranasal sinuses (27%), accessory ossicles of the foot, and arachnodactyly (18%).ConclusionsSkull thickening and an increased prevalence of abnormal findings in skeletal radiographs of patients with EPM1 suggest that this condition is connected to defective cystatin B function. These findings further emphasize the role of cystatin B in bone metabolism in humans.

► We evaluated the skeletal characteristics of Unverricht–Lundborg disease (EPM1). ► We hypothesized that EPM1 may be associated with extensive skeletal changes. ► EPM1 patients exhibit significant skull thickening and various bone abnormalities. ► Bone findings in EPM1 emphasize the role of CSTB in bone metabolism in humans.