Raphael Schiffmann M.D.

Cougnoux, A., R. A. Drummond, M. Fellmeth, F. Navid, A. L. Collar, J. Iben, A. B. Kulkarni, J. Pickel, R. Schiffmann, C. A. Wassif, N. X. Cawley, M. S. Lionakis and F. D. Porter (2019). “Unique molecular signature in mucolipidosis type IV microglia.” J Neuroinflammation 16(1): 276.

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BACKGROUND: Lysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease. METHODS: We investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1(-/-)) and Fabry disease (Gla(y/-)) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses. RESULTS: We characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1(-/-) microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1(-/-) microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer’s disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in “disease-associated microglia” pattern among these diseases. CONCLUSIONS: The similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01067742, registered on February 12, 2010.

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 Nov 12. [Epub ahead of print].

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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.

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 90(12): 1375-1376.

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We present the positive long-term outcome of haematopoietic stem cell transplantation (HSCT) in a patient with CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (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 colony-stimulating factor 1 receptor (CSF1R)-related ALSP. Further observations are encouraged to confirm the ability of HSCT to halt disease progression in ALSP. These observations emphasise how critical it is to diagnose ALSP, particularly in patients with rapidly progressive pyramidal signs and/or cognitive alterations associated with white matter lesions. Important diagnostic clues for ALSP are hyperintense white matter dots on DWI and/or punctate calcifications in the absence of gadolinium enhancement, T2* microbleeds or spine lesions. The favourable clinical outcome of patient 1 post-transplant, the rapid disease progression in ALSP and the possibility of acute exacerbations (e.g., following head trauma) suggest that HSCT should be considered in the early phase of the disease. Patient 1 continued to deteriorate and MRI lesions progressively extended in the first months post-transplant as the colonisation of the donor cells into the brain takes several months to occur while the disease continues to progress. A major challenge for HSCT in ALSP is the identification of biomarkers reflecting disease progression. Neurofilament light chain is elevated in the plasma and CSF of patients with ALSP. Its potential as a biomarker of disease activity is yet to be shown. Novel imaging methods that can monitor demyelination may also help to properly time HSCT in patients with ALSP. (Excerpt from p. 1375; no abstract available.)

van der Knaap, M. S., R. Schiffmann, F. Mochel and N. I. Wolf (2019). “Diagnosis, prognosis, and treatment of leukodystrophies.” Lancet Neurology 18(10): 962-972.

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Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches to repair the damage already present.

Morand, O., J. Johnson, J. Walter, L. Atkinson, G. Kline, A. Frey, J. Politei and R. Schiffmann (2019). “Symptoms and Quality of Life in Patients with Fabry Disease: Results from an International Patient Survey.” Adv Ther 36(10): 2866-2880.

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INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients’ experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials. METHODS: An online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10. RESULTS: In total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants. CONCLUSIONS: Both male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life. FUNDING: This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.