Baylor Research Institute

Vanderver, A., C. Simons, G. Helman, J. Crawford, N. I. Wolf, G. Bernard, A. Pizzino, J. L. Schmidt, A. Takanohashi, D. Miller, A. Khouzam, V. Rajan, E. Ramos, S. Chowdhury, T. Hambuch, K. Ru, G. J. Baillie, S. M. Grimmond, L. Caldovic, J. Devaney, M. Bloom, S. H. Evans, J. L. Murphy, N. McNeill, B. L. Fogel, R. Schiffmann, M. S. van der Knaap and R. J. Taft (2016). “Whole exome sequencing in patients with white matter abnormalities.” Ann Neurol 79(6): 1031-1037.

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Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases.

Driver, S., L. Rachal, C. Swank and R. Dubiel (2016). “Objective assessment of activity in inpatients with traumatic brain injury: Initial findings.” Brain Impairment 17(1): 55-63.

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Purpose: Use accelerometers to examine the physical activity behaviours of individuals following TBI undergoing inpatient rehabilitation. Method: Twenty-one individuals with Traumatic brain injury (TBI) undergoing inpatient rehabilitation (9 females, 12 males; M age = 43.8 14.7 years; M GCS = 9.1 4.3; M time since injury = 40.8 +/- 22.1 days; M length of stay (LOS) = 30 +/- 14 days) wore accelerometers for an average of 8.4 +/- 2.0 consecutive days (1440 minutes/day). Activity counts (AC) were collected at 1 minute epochs and descriptive statistics were calculated to assess intensity of activity and time spent being active and sedentary. Results: During scheduled therapy, time individuals completed an average of 161.4 +/- 65.5 AC/minute, which decreased to 114.5 +/- 51.3 during non-therapy time and 22.2 +/- 10 when sleeping. Using population level cut points, individuals were on average considered inactive during therapy, inactive or sedentary during non-therapy time, and only one participant spent >1 minute in moderate intensity activity. The mean length of active and sedentary bouts was 9 minutes. Discussion: Findings indicate that the amount and intensity of activity completed is low amongst individuals completing inpatient rehabilitation after TBI, with the majority considered sedentary or inactive. While the sample is small, it is important to develop and implement safe and effective strategies to increase activity levels during rehabilitation.

Meng, X. L., T. S. Day, N. McNeill, P. Ashcraft, T. Frischmuth, S. H. Cheng, Z. P. Liu, J. S. Shen and R. Schiffmann (2016). “Molecular basis for globotriaosylceramide regulation and enzyme uptake in immortalized aortic endothelial cells from fabry mice.” J Inherit Metab Dis 39(3): 447-455.

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Fabry disease is caused by deficient activity of alpha-galactosidase A and subsequent intracellular accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3). Vascular endothelial cells may play important roles in disease pathogenesis, and are one of the main target cell types in therapeutic interventions. In this study, we generated immortalized aortic endothelial cell lines from a mouse model of Fabry disease. These cells retained endothelial cell-specific markers and functions. Gb3 expression level in one of these clones (referred to as FMEC2) was highly susceptible to culture media, and appeared to be regulated by glucosylceramide synthase. Results also showed that Gb3 could be upregulated by hydrocortisone. FMEC2 express the mannose 6-phosphate receptor and sortilin but not the mannose receptor. Uptake studies suggested that sortilin plays a role in the binding and internalization of mammalian cell-produced alpha-galactosidase A. Moss-aGal (a plant-made enzyme) was endocytosed by FMEC2 via a receptor other than the aforementioned receptors. In conclusion, this study suggests that glucosylceramide synthase and hydrocortisone may play important roles in modulating Gb3 levels in Fabry mouse aortic endothelial cells, and that endocytosis of recombinant alpha-galactosidase A involves a combination of multiple receptors depending on the properties of the enzyme.

Mochel, F., E. Hainque, D. Gras, I. M. Adanyeguh, S. Caillet, B. Heron, A. Roubertie, E. Kaphan, R. Valabregue, D. Rinaldi, S. Vuillaumier, R. Schiffmann, C. Ottolenghi, J. Y. Hogrel, L. Servais and E. Roze (2016). “Triheptanoin dramatically reduces paroxysmal motor disorder in patients with glut1 deficiency.” J Neurol Neurosurg Psychiatry 87(5): 550-553.

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OBJECTIVE: On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. METHODS: We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7-47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional (31)P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. RESULTS: Patients with GLUT1-DS experienced a mean of 30.8 (+/-27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (+/-2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (+/-21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. CONCLUSIONS: Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS.

Schiffmann, R., M. Fuller, L. A. Clarke and J. M. Aerts (2016). “Is it fabry disease?” Genet Med: May 2016 [Epub ahead of print].

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Fabry disease is caused by mutations in the GLA gene that lower alpha-galactosidase A activity to less than 25-30% of the mean normal level. Several GLA variants have been identified that are associated with relatively elevated residual alpha-galactosidase A. The challenge is to determine which GLA variants can cause clinical manifestations related to Fabry disease. Here, we review the various types of GLA variants and recommend that pathogenicity be considered only when associated with elevated globotriaosylceramide in disease-relevant organs and tissues as analyzed by mass spectrometry. This criterion is necessary to ensure that very costly and specific therapy is provided only when appropriate.