Recommendations for the assessment and monitoring of skeletal manifestations in children with Gaucher disease

Abstract

Gaucher disease (GD), the most common of the lysosomal storage disorders, results from mutations in the gene for acid β-glucosidase (glucocerebrosidase, GBA) leading to insufficient enzyme activity [1]. Glucocerebroside accumulation in the lysosomes of various cell types is responsible for the clinical manifestations of GD, which may include hepatomegaly, splenomegaly, anemia, thrombocytopenia, and bone marrow infiltration by lipid-engorged “Gaucher cells.” Occurring panethnically, type 1 (non-neuronopathic) is the most prevalent form of GD, while the less frequent type 2 (acute neuronopathic) and type 3 (chronic neuronopathic) are characterized by neurological involvement. More than half of type 1 patients are diagnosed in childhood and an earlier age of onset is indicative of more severe disease due to its progressive nature. Affecting both the marrow and mineral compartments, GD-related bone disease is the most significant cause of morbidity and long-term disability for patients. GD-related bone disease in children is a major cause for concern as it puts them at risk of developing irreversible and debilitating bone complications and interferes with normal growth and achievement of optimal bone mass during a critical period of growth. Timely initiation of appropriate disease management is necessary to avoid serious long-term complications such as growth retardation, osteoporosis, and fractures, and includes an initial radiological assessment and ongoing monitoring of both the bone marrow and mineral components. General guidelines for the monitoring of skeletal disease in children with type 1 GD recommend magnetic resonance imaging (MRI) of the spine and femora; radiography of the spine (when clinically indicated), chest, pelvis, and long bones; and dual-energy X-ray absorptiometry (DXA) of the spine and hips at baseline and every 12–24 months [2, 3]. However, these recommendations require further clarification in view of the challenges associated with their use in children with GD, especially since the use of conventional radiography is limited by a high burden of radiation and lack of sensitivity and specificity. The current standard of care for type 1 GD is enzyme replacement therapy (ERT) with imiglucerase (Cerezyme®; Genzyme Corporation, Cambridge, MA, USA). Oral substrate reduction therapy with miglustat (Zavesca®; Actelion, San Francisco, CA, USA) is also available for the treatment of patients with mild to moderate GD for whom ERT is not an option. The availability of therapy that may prevent or reverse GD-related bone disease heightens the need for early diagnosis and initiation of disease management in children. A Working Group of international experts met in October 2006 to recommend evidence- and consensus-based guidelines to facilitate the assessment and monitoring of bone disease in children with type 1 or type 3 GD.