Raphael Schiffmann M.D.

Helman, G., M. I. Mendes, F. Nicita, L. Darbelli, O. Sherbini, T. Moore, A. Derksen, P. Amy, R. Carrozzo, A. Torraco, M. Catteruccia, C. Aiello, P. Goffrini, S. Figuccia, D. E. C. Smith, K. Hadzsiev, A. Hahn, S. Biskup, I. Brösse, U. Kotzaeridou, D. Gauck, T. A. Grebe, F. Elmslie, K. Stals, R. Gupta, E. Bertini, I. Thiffault, R. J. Taft, R. Schiffmann, U. Brandl, T. B. Haack, G. S. Salomons, C. Simons, G. Bernard, M. S. van der Knaap, A. Vanderver and R. A. Husain (2021). “Expanded phenotype of AARS1-related white matter disease.” Genet Med Aug 27. [Epub ahead of print].

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PURPOSE: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease. METHODS: A cross-sectional survey was performed on individuals with biallelic variants in AARS1. Clinical data, neuroimaging, and genetic testing results were reviewed. Alanyl tRNA synthetase (AlaRS) activity was measured in available fibroblasts. RESULTS: We identified 11 affected individuals. Two phenotypic presentations emerged, one with early infantile-onset disease resembling the index cases of AARS1-related epileptic encephalopathy with deficient myelination (n = 7). The second (n = 4) was a later-onset disorder, where disease onset occurred after the first year of life and was characterized on neuroimaging by a progressive posterior predominant leukoencephalopathy evolving to include the frontal white matter. AlaRS activity was significantly reduced in five affected individuals with both early infantile-onset and late-onset phenotypes. CONCLUSION: We suggest that variants in AARS1 result in a broader clinical spectrum than previously appreciated. The predominant form results in early infantile-onset disease with epileptic encephalopathy and deficient myelination. However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.

Bichet, D. G., R. Torra, E. Wallace, D. Hughes, R. Giugliani, N. Skuban, E. Krusinska, U. Feldt-Rasmussen, R. Schiffmann and K. Nicholls (2021). “Long-term follow-up of renal function in patients treated with migalastat for Fabry disease.” Mol Genet Metab Rep 28: 100786.

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The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)-naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m(2)) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m(2)) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR(CKD-EPI)) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFR(CKD-EPI) were – 1.6 mL/min/1.73 m(2) overall and – 1.8 mL/min/1.73 m(2) and – 1.4 mL/min/1.73 m(2) in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFR(CKD-EPI) were – 1.6 mL/min/1.73 m(2) overall and – 2.6 mL/min/1.73 m(2) and – 0.8 mL/min/1.73 m(2) in male and female patients, respectively. Mean annualized rate of change in eGFR(CKD-EPI) in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was -1.7 mL/min/1.73 m(2). When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFR(CKD-EPI) change was minimal (mean: -0.1 and 0.1 mL/min/1.73 m(2) in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype.

Zerem, A., Ben-Sira, L., Vigdorovich, N., Leibovitz, Z., Fisher, Y., Schiffmann, R., Grishchuk, Y., Misko, A.L., Orenstein, N., Lev, D., Lerman-Sagie, T. and Kidron, D. (2021). “White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology.” Metab Brain Dis May 8. [Epub ahead of print].

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Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.

Wu, Y.S., Khanna, R., Schmith, V., Lun, Y., Shen, J.S., Garcia, A., Dungan, L., Perry, A., Martin, L., Tsai, P.C., Hamler, R., Das, A.M., Schiffmann, R. and Johnson, F.K. (2021). “Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.” Clin Pharmacol Drug Dev.

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Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.

Moreno-Martinez, D., Aguiar, P., Auray-Blais, C., Beck, M., Bichet, D.G., Burlina, A., Cole, D., Elliott, P., Feldt-Rasmussen, U., Feriozzi, S., Fletcher, J., Giugliani, R., Jovanovic, A., Kampmann, C., Langeveld, M., Lidove, O., Linhart, A., Mauer, M., Moon, J.C., Muir, A., Nowak, A., Oliveira, J.P., Ortiz, A., Pintos-Morell, G., Politei, J., Rozenfeld, P., Schiffmann, R., Svarstad, E., Talbot, A.S., Thomas, M., Tøndel, C., Warnock, D., West, M.L. and Hughes, D.A. (2021). “Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.” Mol Genet Metab 132(4): 234-243.

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BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.