Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal storage disease that seriously affects the brain. Severity of neurocognitive symptoms in attenuated MPS subtype (MPS IA) broadly varies partially, due to restricted permeability of blood-brain barrier (BBB) which limits treatment effects of intravenously applied α-L-iduronidase (rhIDU) enzyme. Intrathecal (IT) rhIDU application as a possible solution to circumvent BBB improved brain outcomes in canine models; therefore, our study quantifies effects of IT rhIDU on brain structure and function in an MPS IA patient with previous progressive cognitive decline. Neuropsychological testing and MRIs were performed twice prior (baseline, at 1 year) and twice after initiating IT rhIDU (at 2nd and 3rd years). The difference between pre- and post-treatment means was evaluated as a percentage of the change. Neurocognitive performance improved particularly in memory tests and resulted in improved school performance after IT rhIDU treatment. White matter (WM) integrity improved together with an increase of WM and corpus callosum volumes. Hippocampal and gray matter volume decreased which may either parallel reduction of glycosaminoglycan storage or reflect typical longitudinal brain changes in early adulthood. In conclusion, our outcomes suggest neurological benefits of IT rhIDU compared to the intravenous administration on brain structure and function in a single MPS IA patient.© 2017 Wiley Periodicals, Inc.

• MeSH
• White Matter drug effects   pathology   MeSH
• Enzyme Replacement Therapy * adverse effects   methods   MeSH
• Phenotype MeSH
• Iduronidase administration & dosage   adverse effects   MeSH
• Cognitive Dysfunction drug therapy   MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Young Adult MeSH
• Mucopolysaccharidosis I diagnosis   drug therapy   psychology   MeSH
• Neuropsychological Tests MeSH
• Injections, Spinal MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• Keywords
• syndrom Hurlerové, Scheieovův syndrom,
• MeSH
• Child MeSH
• Dysostoses diagnostic imaging   enzymology   MeSH
• Enzyme Replacement Therapy MeSH
• Iduronidase administration & dosage   MeSH
• Craniofacial Abnormalities MeSH
• Humans MeSH
• Mucopolysaccharidosis I enzymology   genetics   physiopathology   MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Mukopolysacharidóza I (MPS I) je závažné metabolické střádavé onemocnění způsobené poruchou funkce ?-L-iduronidázy. Cílem práce je popsat klinické projevy onemocnění a zhodnotit výsledky léčby u českých a slovenských dětí s MPS I. Metody: Soubor tvoří 24 dětí s MPS I z 23 rodin. U všech dětí byla diagnóza MPS I potvrzena na enzymatické úrovni a u všech dětí kromě dvou i na molekulární úrovni. Výsledky: První příznaky onemocnění – hepatosplenomegalie, kraniofacialní dysmorfie, zákal rohovky a opoždění psychomotorického vývoje – byly pozorovány u všech pacientů. Většina dětí měla makrocefalii (11/21) a kostní změny charakteru dysostosis multiplex (21/23). Mezi pozdější projevy onemocnění patřily kardiomyopatie s postižením chlopní (16/21), porucha sluchu (9/18), ztuhlost kloubů (19/22) a syndrom karpálního tunelu (7/23). Všechny děti měly zvýšené vylučování glykosaminoglykanů v moči a sníženou aktivitu ?-L-iduronidázy v izolovaných leukocytech. Dvě mutace v genu pro ?-L-iduronidázu byly prevalentní, mutace p.W402X byla nalezena u 9 a mutace p.Q70X u 7 dětí. U 7 dětí s těžší formou onemocnění byla provedena transplantace hematopoetických kmenových buněk (HSCT), u 5 z nich s dobrým klinickým výsledkem. Dlouhodobou enzymovou substituční terapii (ERT) s dobrým terapeutickým efektem dostalo 6 dětí s mírnější formou onemocnění, ale jedna pacientka zemřela na komplikace po neurochirurgické operaci stenózy krční míchy. Většina dětí, které byly bez léčby, zemřela (7/11). Závěr: Diagnostika dětí s MPS I v časných fázích onemocnění významně zlepšuje prognózu postižených dětí, protože umožňuje správnou volbu nejvhodnější terapie (HSCT nebo ERT). Prognóza dětí s pozdní diagnostikou je velmi nepříznivá. Včasná diagnostika je důležitá i pro eventuální prenatální diagnostiku v postižených rodinách.

Mucopolysaccharidosis I (MPS I) is severe metabolic storage disease caused by impaired function of ?-L-iduronidase. The aim of this study is to describe clinical symptoms, natural course and to evaluate results of treatment in Czech and Slovak children with MPS I. Methods: Study group consists of 24 children from 23 families. In all children diagnosis of MPS I was confirmed on enzymatic level and in 22 children on molecular level. Results: First symptoms of disease – hepatosplenomegaly, craniofacial dysmorphy, corneal clouding and psychomotor delay – were observed in all patients. The most of them have macrocephaly (11/21) and skeletal changes – dysostosis multiplex (21/23). Cardiomyopathy with valves impairment (16/21), hearing impairment (9/18), joint stiffness (19/22) and carpal tunnel syndrome (7/23) belongs to later symptoms. All children had increased glycosaminoglycans excretion in urine and decreased activity of ?-L-iduronidase in isolated leucocytes. Two mutations in gene ?-L-iduronidase were prevalent, the mutation p.W402X was found in 9 and the mutation p.Q70X in 7 children. Hematopoietic stem cell transplantation (HSCT) was performed in 7 children, in 5 of them with good clinical result. 6 children with milder form of disease were treated by a long-lasting enzyme replacement therapy (ERT) with good therapeutic effect, but one patient died due to complication after neurosurgery intervention for compression of cervical spinal cord. The most of children without therapy died (7/11). Conclusion: Diagnostic of MPS I in early phases of disease improves prognosis, because correct therapy (HSCT or ERT) can be chosen. Prognosis for children with later diagnosis is very unfavourable. The advance diagnosis is very important also for prenatal diagnostic in affected families.

• Keywords
• transplantace hematopoetickými kmenovými buňkami, lyzozomální onemocnění, ?-L-iduronidáza,
• MeSH
• Child MeSH
• Enzyme Replacement Therapy MeSH
• Financing, Organized MeSH
• Glycosaminoglycans MeSH
• Iduronidase metabolism   MeSH
• Humans MeSH
• Mucopolysaccharidosis I diagnosis   genetics   therapy   MeSH
• Signs and Symptoms MeSH
• Severity of Illness Index MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder that is caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). Of the 21 Czech and Slovak patients who have been diagnosed with MPS I in the last 30 years, 16 have a severe clinical presentation (Hurler syndrome), 2 less severe manifestations (Scheie syndrome), and 3 an intermediate severity (Hurler/Scheie phenotype). Mutation analysis was performed in 20 MPS I patients and 39 mutant alleles were identified. There was a high prevalence of the null mutations p.W402X (12 alleles) and p.Q70X (7 alleles) in this cohort. Four of the 13 different mutations were novel: p.V620F (3 alleles), p.W626X (1 allele), c.1727 + 2T > G (1 allele) and c.1918_1927del (2 alleles). The pathogenicity of the novel mutations was verified by transient expression studies in Chinese hamster ovary cells. Seven haplotypes were observed in the patient alleles using 13 intragenic polymorphisms. One of the two haplotypes associated with the mutation p.Q70X was not found in any of the controls. Haplotype analysis showed, that mutations p.Q70X, p.V620F, and p.D315Y probably have more than one ancestor. Missense mutations localized predominantly in the hydrophobic core of the enzyme are associated with the severe phenotype, whereas missense mutations localized to the surface of the enzyme are usually associated with the attenuated phenotypes. Mutations in the 130 C-terminal amino acids lead to clinical manifestations, which indicates a functional importance of the C-terminus of the IDUA protein.

• MeSH
• Child MeSH
• Financing, Organized MeSH
• Iduronidase genetics   MeSH
• Catalytic Domain genetics   MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Molecular Sequence Data MeSH
• Mucopolysaccharidosis I genetics   MeSH
• Mutation MeSH
• DNA Mutational Analysis MeSH
• Child, Preschool MeSH
• Amino Acid Sequence MeSH
• Protein Structure, Tertiary genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH

• Keywords
• Alturazym,
• MeSH
• Fabry Disease diagnosis   drug therapy   genetics   MeSH
• Gaucher Disease diagnosis   genetics   classification   MeSH
• Glycogen Storage Disease Type II diagnosis   drug therapy   genetics   MeSH
• Iduronidase administration & dosage   MeSH
• Humans MeSH
• Lysosomal Storage Diseases drug therapy   therapy   MeSH
• Mucopolysaccharidosis I drug therapy   therapy   MeSH
• Mucopolysaccharidosis IV drug therapy   therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

• MeSH
• Child MeSH
• Glycosaminoglycans urine   MeSH
• Iduronidase deficiency   MeSH
• Humans MeSH
• Mucopolysaccharidosis I therapy   MeSH
• Child, Preschool MeSH
• Bone Marrow Transplantation MeSH
• Metabolism, Inborn Errors MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Case Reports MeSH