Raphael Schiffmann M.D.

Mistry, P., M. Balwani, D. Barbouth, T. A. Burrow, E. I. Ginns, O. Goker-Alpan, G. A. Grabowski, R. V. Kartha, P. S. Kishnani, H. Lau, C. U. Lee, G. Lopez, G. Maegawa, S. Packman, C. Prada, B. Rosenbloom, T. R. Lal, R. Schiffmann, N. Weinreb and E. Sidransky (2020). “Gaucher disease and SARS-CoV-2 infection: Emerging management challenges.” Mol Genet Metab 130(3): 164-169.

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The 2020 SARS-CoV-2 pandemic has introduced many unanticipated challenges related to the treatment and support of patients with rare disease. Like with GD, other inborn errors of metabolism likely have unique aspects that must be considered during these uncertain times. Prospective plans for patient management and for collecting and communicating disease parameters real-time are essential for providing optimal care during the current pandemic and potentially in the future. [No abstract; excerpt from article].

Schiffmann, R., J. Sevigny, A. Rolfs, E. H. Davies, O. Goker-Alpan, M. Abdelwahab, A. Vellodi, E. Mengel, E. Lukina, H. W. Yoo, T. Collin-Histed, A. Narita, T. Dinur, S. Revel-Vilk, D. Arkadir, J. Szer, M. Wajnrajch, U. Ramaswami, E. Sidransky, A. Donald and A. Zimran (2020). “The definition of neuronopathic Gaucher disease.” J Inherit Metab Dis Apr 3. [Epub ahead of print].

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Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials

Nowak, A., U. Huynh-Do, P. A. Krayenbuehl, F. Beuschlein, R. Schiffmann and F. Barbey (2020). “Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.” J Inherit Metab Dis 43(2): 326-333.

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by alpha-galactosidase A (alpha-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual alpha-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

Helman, G., B. R. Lajoie, J. Crawford, A. Takanohashi, M. Walkiewicz, E. Dolzhenko, A. M. Gross, V. G. Gainullin, S. J. Bent, E. M. Jenkinson, S. Ferdinandusse, H. R. Waterham, I. Dorboz, E. Bertini, N. Miyake, N. I. Wolf, T. E. M. Abbink, S. M. Kirwin, C. M. Tan, G. M. Hobson, L. Guo, S. Ikegawa, A. Pizzino, J. L. Schmidt, G. Bernard, R. Schiffmann, M. S. van der Knaap, C. Simons, R. J. Taft and A. Vanderver (2020). “Genome sequencing in persistently unsolved white matter disorders.” Ann Clin Transl Neurol 7(1): 144-152.

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Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.

Steward, A. M., E. Wiggs, T. Lindstrom, S. Ukwuani, E. Ryan, N. Tayebi, T. Roshan Lal, G. Lopez, R. Schiffmann and E. Sidransky (2019). “Variation in cognitive function over time in Gaucher disease type 3.” Neurology 93(24): e2272-e2283.

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OBJECTIVE: To identify relevant efficacy parameters essential in designing clinical trials for brain-penetrant therapies for Gaucher disease, we evaluated cognitive function longitudinally in 34 patients with Gaucher disease type 3 seen at the NIH Clinical Center. METHODS: Individuals were tested with age-appropriate Wechsler Intelligence Scales administered between 1 and 18 times over 29 years. Variation in all IQ domains was not linear with time and was best characterized with the coefficient of variation (SD/mean) for each individual. Mixed-effects regressions were used to determine whether IQ was associated with clinical features. Models were controlled for variation in test version, participant identification, and test administrator. RESULTS: Mean verbal, performance, and full-scale IQs were 81.77, 75.98, and 82.02, respectively, with a consistent discrepancy between verbal and performance IQs. Mean (SD) verbal, performance, and full-scale coefficient of variations were 0.07 (0.04), 0.09 (0.05), and 0.06 (0.02), respectively. IQ varied about a mean, with no clear trajectory, indicating no clear patterns of improvement or decline over time. EEG lateralization and behavioral issues were consistently associated with IQ. CONCLUSIONS: The observed variation in IQ in Gaucher disease type 3 across the cohort and within single individuals over time may be characteristic of other neuronopathic diseases. Therefore, to reliably use IQ as an efficacy measure in any clinical trial of neurotherapeutics, a normal variation range must be established to assess the clinical relevance of any IQ change.