Baylor Research Institute

Helman, G., Viaene, A.N., Takanohashi, A., Breur, M., Berger, R., Woidill, S., Cottrell, J.R., Schiffmann, R., Crow, Y.J., Simons, C., Bugiani, M. and Vanderver, A. (2020). “Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description.” J Child Neurol Sep 28;883073820958330. [Epub ahead of print.]. 883073820958330.

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Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in SNORD118. We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in SNORD118 result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances.

Bichet, D.G., Aerts, J.M., Auray-Blais, C., Maruyama, H., Mehta, A.B., Skuban, N., Krusinska, E. and Schiffmann, R. (2020). “Assessment of plasma lyso-Gb(3) for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease.” Genet Med Sep 30. [Epub ahead of print.].

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PURPOSE: To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. METHODS: A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3) and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3) and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3) and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. RESULTS: No significant correlations were identified between changes in lyso-Gb(3) and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3) levels nor the rate of change in lyso-Gb(3) levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for ≥24 months. Changes in lyso-Gb(3) correlated with changes in KIC Gb(3) inclusions in treatment-naive patients. CONCLUSIONS: Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3) may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.

Kirby, T., Walters, D.C., Shi, X., Turgeon, C., Rinaldo, P., Arning, E., Ashcraft, P., Bottiglieri, T., DiBacco, M., Pearl, P.L., Roullet, J.B. and Gibson, K.M. (2020). “Novel biomarkers and age-related metabolite correlations in plasma and dried blood spots from patients with succinic semialdehyde dehydrogenase deficiency.” Orphanet J Rare Dis 15(1): 261.

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BACKGROUND: Previous work has identified age-related negative correlations for γ-hydroxybutyric acid (GHB) and γ-aminobutyric acid (GABA) in plasma of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD). Using plasma and dried blood spots (DBS) collected in an ongoing natural history study, we tested the hypothesis that other biomarkers would follow a similar age-related negative correlation as seen for GHB/GABA. Samples (mixed sex) included: patients (n = 21 unique samples, 1-39.5 yrs) and parallel controls (n = 9 unique samples, 8.4-34.8 yrs). Archival control data (DBS only; n = 171, 0.5-39.9 yrs) was also included. RESULTS: Metabolites assessed included amino acids (plasma, DBS) and acylcarnitines, creatine, creatinine, and guanidinoacetate (DBS only). Age-related negative correlations for glycine (plasma, DBS) and sarcosine (N-methylglycine, plasma) were detected, accompanied by elevated proline and decreased levels of succinylacetone, argininosuccinate, formaminoglutamate, and creatinine. Significantly low acylcarnitines were detected in patients across all chain lengths (short-, medium- and long-chain). Significant age-dependent positive correlations for selected acylcarnitines (C6-, C12DC(dicarboxylic)-, C16-, C16:1-, C18:1-, C18:2OH-carnitines) were detected in patients and absent in controls. Receiver operating characteristic (ROC) curves for all binary comparisons revealed argininosuccinate and succinylacetone to be the most discriminating biomarkers (area > 0.92). CONCLUSIONS: Age-dependent acylcarnitine correlations may represent metabolic compensation responsive to age-related changes in GHB and GABA. Our study highlights novel biomarkers in SSADHD and expands the metabolic pathophysiology of this rare disorder of GABA metabolism

Jabbarzadeh-Tabrizi, S., Boutin, M., Day, T.S., Taroua, M., Schiffmann, R., Auray-Blais, C. and Shen, J.S. (2020). “Assessing the role of glycosphingolipids in the phenotype severity of Fabry disease mouse model.” J Lipid Res Aug 31;jlr.RA120000909. [Epub ahead of print.].

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Fabry disease is caused by deficient activity of α-galactosidase A-an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins–and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between these compounds and disease severity. In this study, we compared Gb3 isoforms (various fatty acids) and lyso-Gb3 analogs (various sphingosine modifications) in two strains of Fabry disease mouse models: a pure C57BL/6 (B6) background or a B6/129 mixed background, with the latter exhibiting more prominent cardiac and renal hypertrophy and thermosensation deficits. Total Gb3 and lyso-Gb3 levels in the heart, kidney and dorsal root ganglion (DRG) were similar in two strains. However, levels of the C20-fatty acid isoform of Gb3 and particular lyso-Gb3 analogs (+18, +34) were significantly higher in Fabry-B6/129 heart tissue when compared to Fabry-B6. By contrast, there was no difference in Gb3 and lyso-Gb3 isoforms/analogs in the kidneys and DRG between two strains. Furthermore, using immunohistochemistry, we found that Gb3 massively accumulated in DRG mechanoreceptors, a sensory neuron subpopulation with preserved function in Fabry disease. However, Gb3 accumulation was not observed in non-peptidergic nociceptors, the disease-relevant subpopulation that has remarkably increased isolectin-B4 (the marker of non-peptidergic nociceptors) binding and enlarged cell size. These findings suggest that specific species of Gb3 or lyso-Gb3 may play major roles in the pathogenesis of Fabry disease, and that Gb3 and lyso-Gb3 are not responsible for the pathology in all tissues or cell types.

Swank, C., Trammell, M., Bennett, M., Ochoa, C., Callender, L., Sikka, S. and Driver, S. (2020). “The utilization of an overground robotic exoskeleton for gait training during inpatient rehabilitation-single-center retrospective findings.” Int J Rehabil Res 43(3): 206-213.

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Overground robotic exoskeleton gait training is increasingly utilized during inpatient rehabilitation yet without clear guidelines. We describe clinical characteristics associated with robotic exoskeleton gait training and examine outcomes of people with spinal cord injury and stroke who completed usual rehabilitation care with or without robotic exoskeleton gait training. Retrospective review of medical records over a 36 months period. Inpatients with spinal cord injury or stroke and ≥1 robotic exoskeleton gait training session were included. After obtaining a complete list of robotic exoskeleton gait training participants, medical records were reviewed for comparable matches as determined by gait functional independence measure score <4, age 18-100 years, meeting exoskeleton manufacturer eligibility criteria, and participating in usual care only. Functional independence measure was collected on all patients. For spinal cord injury, we collected the walking index for spinal cord injury II. For stroke, we collected the Stroke Rehabilitation Assessment of Movement Measure. Fifty-nine people with spinal cord injury (n = 31 robotic exoskeleton gait training; n = 28 usual care) and 96 people post-stroke (n = 44 robotic exoskeleton gait training; n = 52 usual care) comprised the medical record review. Fifty-eight percent of patients with spinal cord injury and 56% of patients post-stroke completed 5+ robotic exoskeleton gait training sessions and were included in analyses. Robotic exoskeleton gait training dosage varied between our patients with spinal cord injury and patients post-stroke. Robotic exoskeleton gait training utilization during inpatient rehabilitation required consideration of unique patient characteristics impacting functional outcomes. Application of robotic exoskeleton gait training across diagnoses may require different approaches during inpatient rehabilitation.