Inborn errors of metabolism encompass a wide spectrum of disorders, frequently affecting bone. Conditions affecting skeletal growth and development are mainly the lysosomal storage disorders, in particular the mucopolysaccharidoses (MPS) and mucolipidosis (ML). In these disorders skeletal abnormalities are often the presenting symptom and early recognition and intervention improves outcome.
The typical symptoms of MPS include organomegaly, dysostosis multiplex, mental retardation and developmental delay. Definitive diagnosis is usually possible through enzymatic assays of the defective enzyme in cultured fibroblasts or leukocytes. MPS patients frequently exhibit failures of endochondral ossification during postnatal growth leading to skeletal deformity and short stature. With reference to the skeletal system, most important radiological findings include multiplex dysostosis, which is represented by several bone malformations found in the skull, hands, legs, arms and spine. The pathophysiology of skeletal disease involves direct substrate storage, inflammation and other complex alterations of cartilage and bone metabolism. Current treatments of MPS are enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation. ERT is available for MPS I, II, IVA, VI and VII. ERT is effective in reducing urinary glycosaminoglycans and liver and spleen volume, while heart and joints outcomes are variable in different studies. Effectiveness on cardiac valves, trachea, hearing and eyes is definitely poor, probably due to limited penetration in the specific tissues. ERT does not cross the blood–brain barrier, with the consequence that the central nervous system is not cured by intravenously injected ERT. Effects of these interventions on skeletal disease manifestations are less well established and outcomes are limited. Recombinant human growth hormone appears to have effectively reverted the growth deceleration in a few MPS patients diagnosed with growth hormone deficiency.
Newborns with ML II can present with radiographic and biochemical signs of hyperparathyroidism. Awareness of this phenomenon may help in establishing a proper diagnosis and therapy. As the ML disease progresses, the variety in bone pain increases, promoting the management of the pain by surgical procedures. ML patients suffer from severe osteopenia, the form hyper-resorption of the bone. Bisphosphonate counteracts this by inhibiting osteoclasts and ultimately preventing bone resorption. ML patients with a significant skeletal disease and a decrease in bone mineral density can be considered to be managed with this form of therapy.
It is now clear that adjunctive treatments that target skeletal disease are needed and should be part of future research.
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