Raphael Schiffmann M.D.

Schiffmann, R. and B. Banwell (2016). “Brain mri and motor function in leukodystrophies.” Neurology 87(8): 748-749.

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There is a need to develop clinical outcome measures for future treatment trials, particularly for pediatric studies and for studies of rare disorders for which such outcome metrics are neither currently well-defined nor validated.1 Patient-reported outcome measures should reflect outcomes that are meaningful to patient-perceived quality of life and sensitive to patient-identified change over time. Physician-reported outcome measures are typically quantifiable and consistently applied across multiple study sites by different investigators, which requires that the metrics be well-defined and that investigator training be rigorous. While clinically relevant outcomes are considered the “gold standard,” and are often the mandated primary outcome of federally funded research, many slowly progressive disorders do not demonstrate clinically apparent change over the time course of a clinical trial. Thus, there is a need for biomarkers, such as neuroimaging measures, that may be more sensitive to change over the typical 2- to 5-year period of a trial. Key to the applicability of such surrogate measures, however, is that they ultimately correlate with changes in neurologic function.

Kevelam, S. H., M. E. Steenweg, S. Srivastava, G. Helman, S. Naidu, R. Schiffmann, S. Blaser, A. Vanderver, N. I. Wolf and M. S. van der Knaap (2016). “Update on leukodystrophies: A historical perspective and adapted definition.” Neuropediatrics: 2016 Aug [Epub ahead of print].

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Leukodystrophies were defined in the 1980s as progressive genetic disorders primarily affecting myelin of the central nervous system. At that time, a limited number of such disorders and no associated gene defects were known. The majority of the leukodystrophy patients remained without a specific diagnosis. In the following two decades, magnetic resonance imaging pattern recognition revolutionized the field, allowing the definition of numerous novel leukodystrophies. Their genetic defects were usually identified through genetic linkage studies. This process required substantial numbers of cases and many rare disorders remained unclarified. As recently as 2010, 50% of the leukodystrophy patients remained unclassified. Since 2011, whole-exome sequencing has resulted in an exponential increase in numbers of known, distinct, genetically determined, ultrarare leukodystrophies. We performed a retrospective study concerning three historical cohorts of unclassified leukodystrophy patients and found that currently at least 80% of the patients can be molecularly classified. Based on the original definition of the leukodystrophies, numerous defects in proteins important in myelin structure, maintenance, and function were expected. By contrast, a high percentage of the newly identified gene defects affect the housekeeping process of mRNA translation, shedding new light on white matter pathobiology and requiring adaptation of the leukodystrophy definition.

Jenkinson, E. M., M. P. Rodero, P. R. Kasher, C. Uggenti, A. Oojageer, L. C. Goosey, Y. Rose, C. J. Kershaw, J. E. Urquhart, S. G. Williams, S. S. Bhaskar, J. O’Sullivan, G. M. Baerlocher, M. Haubitz, G. Aubert, K. W. Baranano, A. J. Barnicoat, R. Battini, A. Berger, E. M. Blair, J. E. Brunstrom-Hernandez, J. A. Buckard, D. M. Cassiman, R. Caumes, D. M. Cordelli, L. M. De Waele, A. J. Fay, P. Ferreira, N. A. Fletcher, A. E. Fryer, H. Goel, C. A. Hemingway, M. Henneke, I. Hughes, R. J. Jefferson, R. Kumar, L. Lagae, P. G. Landrieu, C. M. Lourenco, T. J. Malpas, S. G. Mehta, I. Metz, S. Naidu, K. Ounap, A. Panzer, P. Prabhakar, G. Quaghebeur, R. Schiffmann, E. H. Sherr, K. R. Sinnathuray, C. Soh, H. S. Stewart, J. Stone, H. Van Esch, C. E. Van Mol, A. Vanderver, E. L. Wakeling, A. Whitney, G. D. Pavitt, S. Griffiths-Jones, G. I. Rice, P. Revy, M. S. van der Knaap, J. H. Livingston, R. T. O’Keefe and Y. J. Crow (2016). “Mutations in snord118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts.” Nat Genet: 2016 Aug [Epub ahead of print].

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Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Schiffmann, R. and B. Banwell (2016). “Brain mri and motor function in leukodystrophies.” Neurology: 2016 Jul [Epub ahead of print].

Full text of this article.

There is a need to develop clinical outcome measures for future treatment trials, particularly for pediatric studies and for studies of rare disorders for which such outcome metrics are neither currently well-defined nor validated.1 Patient-reported outcome measures should reflect outcomes that are meaningful to patient-perceived quality of life and sensitive to patient-identified change over time. Physician-reported outcome measures are typically quantifiable and consistently applied across multiple study sites by different investigators, which requires that the metrics be well-defined and that investigator training be rigorous. While clinically relevant outcomes are considered the “gold standard,” and are often the mandated primary outcome of federally funded research, many slowly progressive disorders do not demonstrate clinically apparent change over the time course of a clinical trial. Thus, there is a need for biomarkers, such as neuroimaging measures, that may be more sensitive to change over the typical 2- to 5-year period of a trial. Key to the applicability of such surrogate measures, however, is that they ultimately correlate with changes in neurologic function.

Goker-Alpan, O., N. Longo, M. McDonald, S. P. Shankar, R. Schiffmann, P. Chang, Y. Shen and A. Pano (2016). “An open-label clinical trial of agalsidase alfa enzyme replacement therapy in children with fabry disease who are naive to enzyme replacement therapy.” Drug Des Devel Ther 10: 1771-1781.

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BACKGROUND: Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naive children with Fabry disease. METHODS: In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged >/=7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life. RESULTS: Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes. CONCLUSION: Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.