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OP2 – 2264: The effectiveness of hematopoietic cell transplantation (HCT) in metachromatic leukodystrophy (MLD): Promising results
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
19s (2015) S1 – S152
Abstracts of EPNS 2015 – 11th European Paediatric Neurology Society Congress, 27–30 May 2015, Vienna, Austria ORAL PRESENTATIONS Wednesday, 27 May 2015 Free paper session 1: Metabolic Disorders OP1 - 2527 Phenotypic variation between siblings with metachromatic leukodystrophy S. Groeschel, J. Waibel, D.F. van Rappard, C. Kehrer, J. Böhringer, L. Schöls, N. Wolf, I. Krägeloh-Mann. Department of Neuropaediatrics, Developmental Neurology, Social Paediatrics, University Children’s Hospital Tübingen, Germany Objective: Metachromatic Leukodystrophy (MLD) is a rare autosomal-recessive disorder caused by mutations in the Arylsulfatase A gene. Although over 160 mutations have been characterized, the genotype-phenotype correlation is only partly understood, and the variability in siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to a large MLD cohort. Methods: Patients with MLD of late-infantile and juvenile onset were recruited within the national research network LEUKONET. In order to increase the number of siblings, clinical data from the Netherlands were included. Data about disease onset and dynamic were obtained using a questionnaire; gross motor deterioration, cognitive decline and MRI changes were described. Results: Detailed clinical information was available from 11 sibling-pairs (2 late-infantile) and 61 single patients (44 late-infantile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (euclidean distances). This was even more marked in late-infantile than in juvenile patients. First symptoms and disease dynamic, also, were as variable in late-infantile patients as in the whole cohort. In juvenile patients, however, both the type of first symptoms and the dynamic of the disease course were more homogeneous within siblings compared to the variability in the whole cohort. Conclusions: For the first time, a systematic analysis of phenotypic variation in siblings with MLD is reported. Lateinfantile patients showed a similar variability between siblings as in the whole cohort, whereas siblings with juvenile MLD showed a more homogeneous course regarding type of first symptoms and dynamic of the disease (not regarding age at onset). These results seem of high relevance especially with respect to the evaluation of therapeutic effects, where non-treated siblings are often used as controls.
OP2 - 2264 The effectiveness of hematopoietic cell transplantation (HCT) in metachromatic leukodystrophy (MLD): Promising results D.F. van Rappard, J.J. Boelens, P.J.W. Pouwels, C.E.M. Hollak, M.S. van der Knaap, N.I. Wolf. Department of Pediatric Neurology, Center for Children with White Matter Disorders, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands Objective: MLD is an inherited neurodegenerative disorder caused by deficiency of arylsulfatase A. Aim of this study is to evaluate the effectiveness of HCT as possible treatment. Methods: Between 2005 and 2014, 13 transplanted (2 late-infantile, 5 juvenile and 6 adult) patients were evaluated (3 matched sibling, 10 unrelated cord blood donors) and compared with a cohort of 22 non-transplanted patients (6 late-infantile, 13 juvenile, 3 adult). Prior to transplantation, 6 (2 juvenile, 4 adult) were presymptomatic. Outcome was evaluated through overall survival analysis, neuropsychological evaluation, scoring of the MLD Gross Motor Function (GMF), and nerve conduction studies. MRI’s were scored with the modified Loes score. Results: 3 symptomatic transplanted patients (1 late-infantile, 1 juvenile, 1 adult) died due to disease progression, all within one year after transplantation. For transplanted patients, the probability of survival was 76.9%, with a mean survival of 90 months (SD 12.55, 95% CI 65.62–114.83, mean follow up 3.11 years) and, for non-transplanted patients 81.8%, mean survival of 72 months (SD 7.3, 95% CI 57.8–86.3, mean follow up 2.8 years). In the 10 surviving transplanted patients, the late infantile patient had a limited GMF of 5. All 4 juvenile patients were ambulant with or without help, all 5 adult patients without help. Nerve conduction improved in 1 transplanted patient. MRI improved in 5 out of 10 surviving transplanted patients, after initial worsening, and stabilized in the remainder. In all non-transplanted patients GMF and MRI deteriorated over time. Conclusion: HCT is a promising procedure for pre- and early symptomatic MLD patients with the juvenile or adult type, resulting in stabilization or even improvement. It is safe procedure – there was no treatment-related mortality. For more advanced and late-infantile patients, results are less positive, suggesting that HCT in these patients at best delays disease progression
1090-3798/$ – see front matter © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
19s (2015) S1 – S152
Abstracts of EPNS 2015 – 11th European Paediatric Neurology Society Congress, 27–30 May 2015, Vienna, Austria ORAL PRESENTATIONS Wednesday, 27 May 2015 Free paper session 1: Metabolic Disorders OP1 - 2527 Phenotypic variation between siblings with metachromatic leukodystrophy S. Groeschel, J. Waibel, D.F. van Rappard, C. Kehrer, J. Böhringer, L. Schöls, N. Wolf, I. Krägeloh-Mann. Department of Neuropaediatrics, Developmental Neurology, Social Paediatrics, University Children’s Hospital Tübingen, Germany Objective: Metachromatic Leukodystrophy (MLD) is a rare autosomal-recessive disorder caused by mutations in the Arylsulfatase A gene. Although over 160 mutations have been characterized, the genotype-phenotype correlation is only partly understood, and the variability in siblings is unclear with some evidence for a discrepant clinical course in juvenile patients. The aim of this study was to systematically investigate the phenotypic variation in MLD siblings in comparison to a large MLD cohort. Methods: Patients with MLD of late-infantile and juvenile onset were recruited within the national research network LEUKONET. In order to increase the number of siblings, clinical data from the Netherlands were included. Data about disease onset and dynamic were obtained using a questionnaire; gross motor deterioration, cognitive decline and MRI changes were described. Results: Detailed clinical information was available from 11 sibling-pairs (2 late-infantile) and 61 single patients (44 late-infantile). Variability of age at onset was similar between the siblings and randomly chosen pairs of the remaining cohort (euclidean distances). This was even more marked in late-infantile than in juvenile patients. First symptoms and disease dynamic, also, were as variable in late-infantile patients as in the whole cohort. In juvenile patients, however, both the type of first symptoms and the dynamic of the disease course were more homogeneous within siblings compared to the variability in the whole cohort. Conclusions: For the first time, a systematic analysis of phenotypic variation in siblings with MLD is reported. Lateinfantile patients showed a similar variability between siblings as in the whole cohort, whereas siblings with juvenile MLD showed a more homogeneous course regarding type of first symptoms and dynamic of the disease (not regarding age at onset). These results seem of high relevance especially with respect to the evaluation of therapeutic effects, where non-treated siblings are often used as controls.
OP2 - 2264 The effectiveness of hematopoietic cell transplantation (HCT) in metachromatic leukodystrophy (MLD): Promising results D.F. van Rappard, J.J. Boelens, P.J.W. Pouwels, C.E.M. Hollak, M.S. van der Knaap, N.I. Wolf. Department of Pediatric Neurology, Center for Children with White Matter Disorders, VU University Medical Center and Neuroscience Campus, Amsterdam, The Netherlands Objective: MLD is an inherited neurodegenerative disorder caused by deficiency of arylsulfatase A. Aim of this study is to evaluate the effectiveness of HCT as possible treatment. Methods: Between 2005 and 2014, 13 transplanted (2 late-infantile, 5 juvenile and 6 adult) patients were evaluated (3 matched sibling, 10 unrelated cord blood donors) and compared with a cohort of 22 non-transplanted patients (6 late-infantile, 13 juvenile, 3 adult). Prior to transplantation, 6 (2 juvenile, 4 adult) were presymptomatic. Outcome was evaluated through overall survival analysis, neuropsychological evaluation, scoring of the MLD Gross Motor Function (GMF), and nerve conduction studies. MRI’s were scored with the modified Loes score. Results: 3 symptomatic transplanted patients (1 late-infantile, 1 juvenile, 1 adult) died due to disease progression, all within one year after transplantation. For transplanted patients, the probability of survival was 76.9%, with a mean survival of 90 months (SD 12.55, 95% CI 65.62–114.83, mean follow up 3.11 years) and, for non-transplanted patients 81.8%, mean survival of 72 months (SD 7.3, 95% CI 57.8–86.3, mean follow up 2.8 years). In the 10 surviving transplanted patients, the late infantile patient had a limited GMF of 5. All 4 juvenile patients were ambulant with or without help, all 5 adult patients without help. Nerve conduction improved in 1 transplanted patient. MRI improved in 5 out of 10 surviving transplanted patients, after initial worsening, and stabilized in the remainder. In all non-transplanted patients GMF and MRI deteriorated over time. Conclusion: HCT is a promising procedure for pre- and early symptomatic MLD patients with the juvenile or adult type, resulting in stabilization or even improvement. It is safe procedure – there was no treatment-related mortality. For more advanced and late-infantile patients, results are less positive, suggesting that HCT in these patients at best delays disease progression
1090-3798/$ – see front matter © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.