Corneal hysteresis in mucopolysaccharidosis I and VI.

PURPOSE: High intraocular pressure (IOP) and glaucoma are often suspected in patients with mucopolysaccharidosis (MPS). To determine corneal hysteresis (CH) and IOP in children with mucopolysaccharidosis I-Hurler (MPS I-H) and MPS VI. METHODS: Clinical measurements with ocular response analyzer (ORA). RESULTS: In seven patients, five with MPS I-H treated with stem cell transplantation (SCT), and two with MPS VI, one treated with SCT and the other with enzyme therapy, the IOP was examined with ORA. Ocular response analyzer measurements were made at a median age of 8.7 years in the patients with MPS I-H and at a median age of 9.3 years in the patients with MPS VI. Earlier measurements had raised suspicion of high IOP in one patient. The ORA showed an increased CH and a falsely high IOP values in all 14 eyes. The recalculated IOPs were normal in all 14 eyes. Mild to severe corneal opacities were present in all 14 eyes. Optic disc areas, borders and cupping were clinically normal in the 12 of 14 eyes that were possible to examine. Severe corneal opacities hampered optic disc evaluation in the older patient with MPS VI. Three eyes in two patients had normal thickness of the retinal nerve fibre layer measured with scanning laser polarimetry with corneal compensation (GDx VCC). No patient was diagnosed or treated for glaucoma. CONCLUSION: The IOPs are often falsely high because of an increased resistance of the cornea and correlate to the extent of corneal clouding. In this small, cross-sectional study, it appears that corneal resistance is directly correlated with corneal clouding, although a longitudinal study that evaluates resistance as the cornea clears with treatment would provide more direct evidence that corneal deposits are directly related to resistance. A correct measured IOP can avoid unnecessary medical or surgical hypotensive treatment.

Trends in haematopoietic cell transplantation for inborn errors of metabolism.

For the last 25 years, haematopoietic cell transplantation (HCT) has been used as effective therapy for selected inborn errors of metabolism (IEMs), mainly lysosomal storage diseases and peroxisomal disorders. The main rational for HCT in IEMs is based on the provision of correcting enzymes by donor cells within and outside the blood compartment. The ultimate goal of HCT is to achieve a normal or near-normal life and normal neurodevelopment. HCT has been performed for more than 20 diseases. Only for Hurler syndrome, X-ALD and infantile Krabbe disease, are detailed studies available suggesting that HCT is indicated for carefully selected cases. Improvement of transplantation techniques and alternative therapies may change the recommended (contra-)indications for IEM. A recent example of emerging transplantation techniques is the fast availability of unrelated cord blood (UCB). UCB makes HCT feasible in patients with rapidly progressive neurological diseases. Because of the fast availability of UCB and therefore the ability to transplant shortly after diagnosis, there is no indication for patients in a moderate/good clinical condition to receive enzyme replacement therapy (ERT; in Hurler syndrome) prior to or during HCT and can ERT only be considered in patients with poor clinical condition. Mesenchymal stem cell infusions with HCT is an emerging technique, and might be interesting in halting the remaining defects after successful HCT. Improvement in HCT techniques and novel stem cell sources will significantly impact the safety and efficacy of this therapy as well as expand the list of candidate disorders. A good functioning worldwide registry would be necessary to measure the effects of the procedures performed in more detail.

Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice.

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.