Raphael Schiffmann M.D.

Raymond, G. V. and R. Schiffmann (2018). “Cerebrotendinous xanthomatosis: The rare “treatable” disease you never consider.” Neurology Dec 7. [Epub ahead of print].

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Cerebrotendinous xanthomatosis (CTX; Online Mendelian Inheritance in Man No. 213700) is an autosomal recessive disorder due to pathogenic variant in the CYP27A1 gene resulting in a defect in the mitochondrial enzyme sterol 27-hydroxylase. The enzyme catalyzes multiple hydroxylation reactions involved in cholesterol metabolism and bile acid synthesis. When affected, it results in decreased synthesis of bile acids, with the resultant production of cholestanol and cholesterol affecting all tissues.

Mirchi, A., F. Pelletier, L. T. Tran, S. Keller, N. Braverman, D. Tonduti, A. Vanderver, A. Pizzino, M. E. Dilenge, C. Poulin, M. Shevell, A. Majnemer, G. Sebire, M. Srour, B. Osterman, R. M. Boucher, M. Vanasse, E. Rossignol, J. Mitchell, S. Venkateswaran, D. Pohl, M. Kauffman, R. Schiffmann, C. Goizet, S. Moutton, F. Roncarolo and G. Bernard (2018). “Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy.” Pediatr Neurol 84: 21-26.

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BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

Schiffmann, R., D. G. Bichet, A. Jovanovic, D. A. Hughes, R. Giugliani, U. Feldt-Rasmussen, S. P. Shankar, L. Barisoni, R. B. Colvin, J. C. Jennette, F. Holdbrook, A. Mulberg, J. P. Castelli, N. Skuban, J. A. Barth and K. Nicholls (2018). “Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial.” Orphanet J Rare Dis 13(1): 68.

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BACKGROUND: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. METHODS: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). RESULTS: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). CONCLUSIONS: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease. TRIAL REGISTRATION: NCT00925301

Meng, X. L., E. Arning, M. Wight-Carter, T. S. Day, S. Jabbarzadeh-Tabrizi, S. Chen, R. J. Ziegler, T. Bottiglieri, J. W. Schneider, S. H. Cheng, R. Schiffmann and J. S. Shen (2018). “Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression.” J Inherit Metab Dis 41(2): 231-238.

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Fabry disease is a glycosphingolipidosis caused by deficient activity of alpha-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to alpha-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.

Bremova-Ertl, T., R. Schiffmann, M. C. Patterson, N. Belmatoug, T. Billette de Villemeur, S. Bardins, C. Frenzel, V. Malinova, S. Naumann, J. Arndt, E. Mengel, J. Reinke, R. Strobl and M. Strupp (2017). “Oculomotor and Vestibular Findings in Gaucher Disease Type 3 and Their Correlation with Neurological Findings.” Front Neurol Jan 15; 8:711.

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Objectives: To evaluate the function of the oculomotor and vestibular systems and to correlate these findings with the clinical status of patients with Gaucher disease type 3 (GD3). The goal of this cross-sectional and longitudinal study was to find oculomotor biomarkers for future clinical trials. Methods: Twenty-six patients with GD3 were assessed for eligibility and 21 were able to perform at least one task. Horizontal and vertical reflexive saccades, smooth pursuit, gaze-holding, optokinetic nystagmus, and horizontal vestibulo-ocular reflex (VOR) were examined by video-oculography/video-head impulse test and compared concurrently with 33 healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA), the modified Severity Scoring Tool (mSST), and Grooved Pegboard Test (GPT) were administered to assess overall neurological function. Eleven patients were also re-assessed after 1 year. Results: Nine out of 17 patients exhibited gaze-holding deficits. One patient had upbeat nystagmus. Three patients presented with bilateral abducens palsy in combination with central oculomotor disorders, suggesting a bilateral involvement of the abducens nucleus. Horizontal angular VOR gain was reduced in all patients (0.66 +/- 0.37) compared with controls (1.1 +/- 0.11, p < 0.001). Most strongly correlated with clinical rating scales were peak velocity of downward saccades (SARA: rho = -0.752, p < 0.0005; mSST: rho = -0.611, p = 0.003; GPT: rho = -0.649, p = 0.005) and duration of vertical saccades (SARA: rho = 0.806, p < 0.001; mSST: rho = 0.700, p < 0.0005; GPT: rho = 0.558, p = 0.02) together with the VOR gain (SARA: rho = -0.63, p = 0.016; mSST: rho = -0.725, p = 0.003; GPT: rho = -0.666, p = 0.004). Vertical smooth pursuit gain decreased significantly at follow-up. Interpretation: This study shows neuronal degeneration of the brainstem and cerebellum with combined involvement of both supranuclear and nuclear oculomotor structures and the vestibular system in GD3. We also identified oculomotor parameters that correlate with the neurological status and can be used as biomarkers in future clinical trials.