Successful unrelated umbilical cord blood transplantation in Lesch-Nyhan syndrome.
ABSTRACT Lesch-Nyhan syndrome (LNS) is a chronic, progressive neurodevelopmental disorder causing motor and behavioral dysfunction due to decreased synthesis of the enzyme hypoxantine-guanine phosphoribosyltransferase (HPRT). Affected boys have mental retardation, delayed development, extrapyramidal motor disturbances and self-injuring behavior. As hematopoietic stem cell transplantation (HSCT) has been shown to be effective in several neurodevelopmental inborn errors, we hypothesized that it could be favorable in LNS as well. Following a myeloablative conditioning regimen (busulphan 3.2 mg/kg/day for 4 days, cyclophosphamide 60 mg/kg/day for 2 days with ATG Thymoglobin 2.5 mg/kg/day for 4 days) an unrelated umbilical cord blood unit was transfused at the age of 2 years. The graft was a 6/6 HLA-matched at HLA-A, B loci by antigen level, and at DRB1 by allelic level typing. Infused total nucleated cell dose was 3.6 × 10e7 per kilogram body weight. Serum HPRT levels reached normal values by the end of the sixth month post transplant. Slow neurodevelopmental improvement seen during the three-year follow-up and the missing self-injuring behavior can be considered as a proof for the presence of enzyme-competent cells behind the blood-brain barrier.
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ABSTRACT: Intellectual developmental disorders (IDD), characterized by significant impairment of cognitive functions, with limitations of learning, adaptive behavior and skills, are frequent (2.5% of the population affected) and present with significant co-morbidity. The burden of IDD, in terms of emotional suffering and associated health care costs are significant; prevention and treatment therefore are important. A systematic literature review, updated in 2013, identified 89 inborn errors of metabolism (IEMs), which present with IDD as prominent feature and are amenable to causal therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/ cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=53), Level 4–5 (n=27). Five experts translated this data into a 2-tiered diagnostic algorithm: The first tier comprises metabolic “screening” tests in urine and blood, which are relatively accessible, affordable, less invasive, and have the potential to identify 60% of all treatable IEMs. The second tier investigations for the remaining disorders are ordered based on individual clinical signs and symptoms. This algorithm is supported by an App www.treatable-id.org, which comprises up-to-date information on all 89 IEMs, relevant diagnostic tests, therapies and a search function based on signs and symptoms. These recommendations support the clinician in early identification of treatable IEMs in the child with IDD, allowing for timely initiation of therapy with the potential to improve neurodevelopmental outcomes. The need for future studies to determine yield and usefulness of these recommendations, with subsequent updates and improvements to developments in the field, is outlined.Molecular Genetics and Metabolism 04/2014; · 2.83 Impact Factor
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ABSTRACT: Background The identification of inborn errors of metabolism (IEM) in adults presenting with a wide range of neurological symptoms is a relatively new field in medicine. We sought to identify which treatable IEM have been diagnosed for the first time in adults and generate a protocol for metabolic screening targeting those treatable disorders. Methods Medline/Pubmed searches of English language literature limited to the adult age group were performed. Diseases identified through this search were then compared to previously published lists of treatable IEM in both adults and children. Results 85% of the treatable conditions known to cause global developmental delay or intellectual disability in children had reports where the diagnosis of that IEM was made in one or more adult patients with neurological symptoms. Screening tests in blood, urine, CSF and MRI can detect most of these treatable conditions but the diagnostic accuracy of these screening tests in adults is not clear. Conclusion Treatable IEM need to be considered in the differential diagnosis of neurological symptoms in patients of any age.Molecular Genetics and Metabolism 12/2013; 110(4):431–438. · 2.83 Impact Factor
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ABSTRACT: Neurodevelopmental disorders (NDs) are impairments that affect the development and growth of the brain and the central nervous system during embryonic and early postnatal life. Genetically manipulated animals have contributed greatly to the advancement of ND research, but many of them differ considerably from the human phenotype. Cellular in vitro models are also valuable, but the availability of human neuronal cells is limited and their lifespan in culture is short. Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, comprise a powerful tool for studying developmentally regulated diseases, including NDs. We reviewed all recent studies in which hPSCs were used as in vitro models for diseases and syndromes characterized by impairment of neurogenesis or synaptogenesis leading to intellectual disability and delayed neurodevelopment. We analyzed their methodology and results, focusing on the data obtained following in vitro neural differentiation and gene expression and profiling of the derived neurons. Electrophysiological recording of action potentials, synaptic currents and response to neurotransmitters is pivotal for validation of the neuronal fate as well as for assessing phenotypic dysfunctions linked to the disease in question. We therefore focused on the studies which included electrophysiological recordings on the in vitro-derived neurons. Finally, we addressed specific issues that are critical for the advancement of this area of research, specifically in providing a reliable human pre-clinical research model and drug screening platform.Stem cell reviews 04/2014; · 5.08 Impact Factor