Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I (MPS I) is caused by a deficiency of the lysosomal hydrolase a-L-Iduronidase leading to accumulation of the GAGs, dermatan sulfate, and heparan sulphate, The disease spectrum includes a disorder with severe involvement and CNS disease Hurler disease (HPS I H) a chronic disease without CNS disease Scheie disease (HPS I S) and the intermediate Hurler/Scheie disease(HPS I H/S).The urine GAGs pattern, confirmed by Iduronidase enzyme assay is diagnostic. Over 200 mutations exist. Genotype/phenotype correlation is poor but two nonsense mutations results in Hurler disease. The skeletal disease dysostosis multiplex (DM) is seen in severe variants of MPS I. The hypoplastic odontoid putting these patients at high risk of cervical cord damage. MPS IH (Hurler Disease) affected infants develop a spinal 'gibbus' deformity, persistent nasal discharge, middle ear effusions and frequent upper respiratory infection. They have "coarse", facial features, and an enlarged tongue. Progressive upper airway disease leads to obstructive sleep apnoea. Corneal clouding and cognitive impairment appears, growth ceases. Joint stiffness and contractures limit mobility. Cardiac disease is universal. Death occurs before 10 years. SCHEIE patients are diagnosed as teenagers with hepatomegaly, joint contractures, cardiac valve abnormalities and corneal clouding. Prolonged survival with considerable disability without cognitive impairment is usual. MPS IH/S Hurler/Scheie. is diagnosed by 6.5 years, with variable skeletal and visceral manifestations without cognitive involvement. Joint stiffness, corneal clouding, umbilical hernia, abnormal facies, hepatomegaly, joint contractures, and cervical myelopathy occur. Patients die in their 20s. Haematopoietic stem cell transplantation (HSCT) the standard treatment of MPS IH for 30 years is unpredictable. When performed before 2 years it can stabilize cognitive impairment. Hepatosptenomegaly, urine GAGs excretion, upper airways obstruction and cardiomyopathy improve. The coarse hair and facial features soften and corneas partly clear,but dysostosis multiplex and cervical instability are not improved. Enzyme replacement therapy (ERT) in patients with MPS IH is associated with improved GAG excretion, left ventricular hypertrophy,sleep studies and liver size. The standard treatment of MPS IH/S and MPS IS is ERT, a-L-Iduronidase, laronidase, a life-long therapy. GAG excretion is reduced, respiratory function and physical endurance improve. Joint mobility improves but not dural thickening, cardiac valve lesions or eye changes. MPS I mice have been successfully treated with IDUA-expressing mesenchymal stem cells. Gene therapy may be developed for MPS I, via an ex vivo approach demonstrated to improve even skeletal outcomes in animal models.