Raphael Schiffmann M.D.

Mochel, F., C. Delorme, V. Czernecki, J. Froger, F. Cormier, E. Ellie, N. Fegueux, S. Lehericy, S. Lumbroso, R. Schiffmann, P. Aubourg, E. Roze, P. Labauge and S. Nguyen (2019). “Haematopoietic stem cell transplantation in CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.” J Neurol Neurosurg Psychiatry Jun 18. [Epub ahead of print].

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Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a severe neurodegenerative disease leading to death usually within a few years after symptoms onset. Patients present with cognitive decline, behavioural changes and pyramidal signs in the context of patchy white matter lesions. ALSP is a primary microgliopathy caused by haploinsufficiency of the colony-stimulating factor 1 receptor (CSF1R). CSF1R is critical for the development, maintenance and activation of microglia. We hypothesised that haematopoietic stem cell transplantation (HSCT) can be relevant in ALSP by correcting CSF1R loss-of-function in microglia. We provide the first prospective report of a patient with ALSP with a 30-month follow-up after a successful HSCT. We present in parallel the clinical outcome of a consecutive patient with similar age, sex and disease course who did not undergo HSCT . . . We present the positive long-term outcome of HSCT in a patient with CSF1R-related ALSP. This patient presented with a rapidly progressive disease evolution before HSCT, as usually observed in ALSP. Her dreadful neurological decline stopped from 6 months post-transplant and DWI lesions kept regressing 30 months post-transplant. A consecutive patient with similar age, sex and disease course who did not undergo HSCT suffered a dramatic worsening of her disease. A patient with ALSP, misdiagnosed as metachromatic leukodystrophy and transplanted for that reason, seems to have remained stable but no further detail is available. Instead, we provide the first detailed prospective report of HSCT in CSF1R-related ALSP. Further observations are encouraged to confirm the ability of HSCT to halt disease progression in ALSP. (Excerpts from text, p. 1, 2; no abstract available.)

Hughes, D. A., K. Nicholls, G. Sunder-Plassmann, A. Jovanovic, U. Feldt-Rasmussen, R. Schiffmann, R. Giugliani, V. Jain, C. Viereck, J. P. Castelli, N. Skuban, J. A. Barth and D. G. Bichet (2019). “Safety of switching to Migalastat from enzyme replacement therapy in Fabry disease: Experience from the Phase 3 ATTRACT study.” Am J Med Genet A 179(6): 1069-1073.

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Migalastat is the only oral treatment for Fabry disease, which provides a suitable alternative to once‐every‐2‐weeks intravenous ERT in patients with amenable mutations who are ERT‐experienced and can also be utilized as a first‐line therapy in ERT‐naive patients. Although there has not yet been a consensus among physicians who treat patients with Fabry disease on when to choose migalastat over ERT, we have developed some criteria in our clinical practices, which include: age 16 years and older (18 years and older in the United States and Canada), a confirmed amenable mutation, an eGFR > 30 mL/min/1.73 m2, compliance with every‐other‐day oral administration, and no intention by female patients to become pregnant. Patients’ preference and hypersensitivity to ERT are also factors in considering the best treatment option for patients. We suggest having a comprehensive counseling session with the patient to discuss the mechanism of action, clinical data, and approved indication for migalastat, as well as schedule of administration. For patients switching from ERT, migalastat is commonly initiated ~2 weeks after the last dose of ERT based on the infusion interval; however, other practical considerations may influence the exact duration between the last ERT infusion and first dose of migalastat. Migalastat may be safely initiated within days of the last ERT infusion. In conclusion, patients with amenable mutations who have been receiving ERT infusions can be safely switched to migalastat 150 mg QOD, and no special procedure is needed for the switch. (Excerpt from text, p. 1071-1072; no abstract available.)

Tian, W., Z. Ye, S. Wang, M. A. Schulz, J. Van Coillie, L. Sun, Y. H. Chen, Y. Narimatsu, L. Hansen, C. Kristensen, U. Mandel, E. P. Bennett, S. Jabbarzadeh-Tabrizi, R. Schiffmann, J. S. Shen, S. Y. Vakhrushev, H. Clausen and Z. Yang (2019). “The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells.” Nat Commun 10(1): 1785.

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Lysosomal replacement enzymes are essential therapeutic options for rare congenital lysosomal enzyme deficiencies, but enzymes in clinical use are only partially effective due to short circulatory half-life and inefficient biodistribution. Replacement enzymes are primarily taken up by cell surface glycan receptors, and glycan structures influence uptake, biodistribution, and circulation time. It has not been possible to design and systematically study effects of different glycan features. Here we present a comprehensive gene engineering screen in Chinese hamster ovary cells that enables production of lysosomal enzymes with N-glycans custom designed to affect key glycan features guiding cellular uptake and circulation. We demonstrate distinct circulation time and organ distribution of selected glycoforms of alpha-galactosidase A in a Fabry disease mouse model, and find that an alpha2-3 sialylated glycoform designed to eliminate uptake by the mannose 6-phosphate and mannose receptors exhibits improved circulation time and targeting to hard-to-reach organs such as heart. The developed design matrix and engineered CHO cell lines enables systematic studies towards improving enzyme replacement therapeutics.

Saint-Val, L., T. Courtin, P. Charles, C. Verny, M. Catala, R. Schiffmann, O. Boespflug-Tanguy and F. Mochel (2019). “GJA1 Variants Cause Spastic Paraplegia Associated with Cerebral Hypomyelination.” AJNR Am J Neuroradiol Apr 25. [Epub ahead of print].

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Oculodentodigital dysplasia is an autosomal dominant disorder due to GJA1 variants characterized by dysmorphic features. Neurologic symptoms have been described in some patients but without a clear neuroimaging pattern. To understand the pathophysiology underlying neurologic deficits in oculodentodigital dysplasia, we studied 8 consecutive patients presenting with hereditary spastic paraplegia due to GJA1 variants. Clinical disease severity was highly variable. Cerebral MR imaging revealed variable white matter abnormalities, consistent with a hypomyelination pattern, and bilateral hypointense signal of the basal ganglia on T2-weighted images and/or magnetic susceptibility sequences, as seen in neurodegeneration with brain iron accumulation diseases. Patients with the more prominent basal ganglia abnormalities were the most disabled ones. This study suggests that GJA1-related hereditary spastic paraplegia is a complex neurodegenerative disease affecting both the myelin and the basal ganglia. GJA1 variants should be considered in patients with hereditary spastic paraplegia presenting with brain hypomyelination, especially if associated with neurodegeneration and a brain iron accumulation pattern.

Guo, L., D. R. Bertola, A. Takanohashi, A. Saito, Y. Segawa, T. Yokota, S. Ishibashi, Y. Nishida, G. L. Yamamoto, J. Franco, R. S. Honjo, C. A. Kim, C. M. Musso, M. Timmons, A. Pizzino, R. J. Taft, B. Lajoie, M. A. Knight, K. H. Fischbeck, A. B. Singleton, C. R. Ferreira, Z. Wang, L. Yan, J. Y. Garbern, P. O. Simsek-Kiper, H. Ohashi, P. G. Robey, A. Boyde, N. Matsumoto, N. Miyake, J. Spranger, R. Schiffmann, A. Vanderver, G. Nishimura, M. Passos-Bueno, C. Simons, K. Ishikawa and S. Ikegawa (2019). “Bi-allelic CSF1R Mutations Cause Skeletal Dysplasia of Dysosteosclerosis-Pyle Disease Spectrum and Degenerative Encephalopathy with Brain Malformation.” Am J Hum Genet 104(5): 925-935.

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Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.