Review and metabolomic profiling of unsolved case reveals newly reported autosomal dominant congenital disorder of glycosylation, type Iw formerly thought to only be an autosomal recessive condition
(2024) Molecular Genetics and Metabolism Reports, 41, art. no. 101145, .
Ezell, K.M.a , Furuta, Y.a , Oglesbee, D.b , Pivnick, E.K.c , Rinker, D.d , Sheehan, J.H.e , Tinker, R.J.a , Hamid, R.a , Cogan, J.D.a , Rives, L.a , Neumann, S.a , Corner, B.a , Koziura, M.a , Phillips, J.A., IIIa , the Undiagnosed Diseases Networkf
a Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, United States
c Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
d Department of Biological Sciences, Center for Structural Biology, Vanderbilt University, Nashville, TN, United States
e Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Autosomal dominant congenital disorder of glycosylation (CDG) type Iw (OMIM# 619714) is caused by a heterozygous mutation in the STT3A gene. Most CDGs have an autosomal recessive (AR) mode of inheritance, but several cases with an autosomal dominant (AD) form of an AR CDG have been recently identified. This report describes a 17-year-old male who was referred to the Undiagnosed Diseases Network (UDN) with a history of macrocephaly, failure to thrive, short stature, epilepsy, autism, attention-deficit/hyperactivity disorder, mild developmental delay, intermittent hypotonia, dysmorphic features, and mildly enlarged aortic root. Trio exome sequencing was negative. His biochemical workup included normal plasma amino acids, ammonia, acylcarnitine profile and urine organic and amino acids. His UDN genome sequencing (GS) identified a previously unreported de novo STT3A variant (c.1631A > G: p.Asn544Ser). This variant removes a glycosylation site and was predicted to be destabilizing by structural biology modeling. The patient was formally diagnosed by the UDN Metabolomics Core as having an abnormal transferrin profile indicative of CDG type Iw through metabolomic profiling. We report here an affected male with phenotypic, molecular, and metabolic findings consistent with CDG type Iw due to a heterozygous STT3A variant. This case highlights the importance of further testing of individuals with the phenotypic and metabolic findings of an AR disorder who are heterozygous for a single disease-causing allele and can be shown to have a new AD form of the disorder that represents clinical heterogeneity. © 2024 The Authors
Author Keywords
Congenital disorders of glycosylation (CDGs); STT3A; Undiagnosed diseases network (UDN)
Document Type: Article
Publication Stage: Final
Source: Scopus
Determining the optimal challenge point for learning motor skills in children with attention deficit/hyperactivity disorder
(2024) Human Movement Science, 98, art. no. 103296, .
Tollabi, M.a , Boroujeni, S.T.a , Arabameri, E.a , Shahbazi, M.a , Lohse, K.R.b
a Department of Motor Behavior and Sport Analysis, Faculty of Sport Behavioral and Technology Sciences, School of Sport Sciences and Health, University of Tehran, Tehran, Iran
b Associate Professor of Physical Therapy, Neurology, Washington University School of Medicine in Saint Louis, United States
Abstract
The purpose of this study was to investigate the optimal challenge point for learning motor skills in children with and without attention deficit/hyperactivity disorder (ADHD). Ninety-six 9- to 10-year-old children, including 48 children with ADHD and 48 neurotypical children, were randomly assigned to one of four practice groups with varying levels of nominal and functional task difficulty. They performed 63 trials of a dart throwing task in the acquisition phase and 18 trials in the retention and transfer tests a day later. The results showed that neurotypical children outperformed children with ADHD in all phases of the study. Both groups improved in the acquisition phase and performed better in the retention and transfer tests. Interestingly, low nominal task difficulty was associated with better learning for both groups, despite lower average performance for children with ADHD. Thus, despite their performance differences, we did not find a difference in the effective challenge point between children with ADHD and their neurotypical peers. © 2024
Author Keywords
Dart throwing; Functional task difficulty; Motor learning; Nominal task difficulty
Document Type: Article
Publication Stage: Final
Source: Scopus
A peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice
(2024) Science Translational Medicine, 16 (767), p. eadk9524.
Li, F.a , Yang, K.b , Gao, X.a c , Zhang, M.a , Gu, D.d , Wu, X.a e , Lu, C.f , Wu, Q.e , Dixit, D.g , Gimple, R.C.h , You, Y.f , Mack, S.C.i , Shi, Y.j , Kang, T.k , Agnihotri, S.A.l , Taylor, M.D.m n , Rich, J.N.e o , Zhang, N.a , Wang, X.d p q
a Department of Neurosurgery, First Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangdong Translational Medicine Innovation Platform, Guangzhou, Guangdong 510080, China
b Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH 44195, United States
c Department of Breast and Thyroid Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou, Guangdong 510080, China
d National Health Commission Key Laboratory of Antibody Techniques, Department of Cell Biology, Jiangsu Provincial Key Laboratory of Human Functional Genomics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu 211166, China
e University of Pittsburgh Medical Center Hillman Cancer Center, PA 15213, Pittsburgh, United States
f Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 211100, China
g Department of Medicine, Division of Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA
h Physician Scientist Training Program, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
i Division of Brain Tumor Research, Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
j Institute of Pathology, Ministry of Education Key Laboratory of Tumor Immunopathology, Southwest HospitalChongqing 400038, China
k State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510080, China
l Brain Tumor Biology and Therapy Lab, Department of Neurosurgery, University of Pittsburgh Medical Center, PA 15213, Pittsburgh, United States
m Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Canada
n Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada
o Department of Neurology, University of Pittsburgh School of Medicine, PA 15213, Pittsburgh, United States
p Institute for Brain Tumors, Jiangsu Provincial Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
q Jiangsu Cancer Hospital, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China
Abstract
MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant MYC transcript encodes a 114-amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) MPEP. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor-bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a MYC-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Method for Quantitative Analysis of Vitreoretinal Adhesion in Ex Vivo Model” (2024) Translational Vision Science & Technology
Method for Quantitative Analysis of Vitreoretinal Adhesion in Ex Vivo Model
(2024) Translational Vision Science & Technology, 13 (10), p. 3.
Suresh, T.a , Ong, L.b , Marotta, C.B.c , Keller, W.d , Schwartz, D.d e , Brodie, F.d e
a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b California Northstate University College of Medicine, Elk GroveCA, United States
c Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, United States
d Department of Ophthalmology, University of California in San Francisco, San Francisco, CA, United States
e Department of Ophthalmology, San Francisco Veterans Administration, San Francisco, CA, United States
Abstract
Purpose: Posterior vitreous detachment (PVD) is implicated in numerous retinal pathologies. A necessary step in developing new therapies, an area of significant interest, is a quantifiable assessment of posterior vitreous adhesion (PVA) that is also clinically relevant. Methods: A 23-gauge vitrector was used at varying levels of vacuum to attempt PVD induction in a porcine eye model injected with either balanced salt solution (BSS) (control) or plasmin (2, 3, or 5 U), which can pharmacologically induce PVD. Results: The average minimum vacuum necessary to induce a PVD was 395 ± 28 mm Hg for BSS alone, 385 ± 58 mm Hg for 2 U of plasmin, 265 ± 53 mm Hg for 3 U of plasmin, and 145 ± 28 mm Hg for 5 U of plasmin. We demonstrated a dose-dependent response curve with increasing amounts of plasmin, leading to a statistically significantly lower minimum vacuum necessary to induce a PVD except between BSS and 2 U plasmin. Conclusions: A dose-dependent relationship between plasmin concentration and PVD was demonstrated. We believe that this model offers significant benefits over prior work as it minimizes confounding manipulations and offers a quantitative assessment that is translatable to in vivo surgical models. Translational Relevance: This is the first methodology to quantitatively assess the degree of vitreous adhesion in situ.
Document Type: Article
Publication Stage: Final
Source: Scopus
Recommendations for clinical implementation of blood-based biomarkers for Alzheimer’s disease
(2024) Alzheimer’s and Dementia, . Cited 1 time.
Mielke, M.M.a , Anderson, M.b , Ashford, J.W.c d , Jeromin, A.e , Lin, P.-J.f , Rosen, A.g h , Tyrone, J.i , Vandevrede, L.j , Willis, D.R.k , Hansson, O.l m , Khachaturian, A.S.n , Schindler, S.E.o , Weiss, J.p , Batrla, R.q , Bozeat, S.r , Dwyer, J.R.s , Holzapfel, D.t u , Jones, D.R.q , Murray, J.F.u , Partrick, K.A.t , Scholler, E.t u , Vradenburg, G.t u , Young, D.v , Braunstein, J.B.w , Burnham, S.C.x , de Oliveira, F.F.y , Hu, Y.H.q , Mattke, S.z , Merali, Z.aa , Monane, M.w , Sabbagh, M.N.ab , Shobin, E.ac , Weiner, M.ad , Udeh-Momoh, C.T.a aa
a Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, United States
b Atrium Health, Charlotte, NC, United States
c Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
d War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, CA, United States
e ALZpath, Carlsbad, CA, United States
f Center for the Evaluation of Value and Risk in Health Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, United States
g Palo Alto Veterans Affairs Medical Center, Palo Alto, CA, United States
h Stanford University School of Medicine, Stanford, CA, United States
i Patient Advocate, Sacramento, CA, United States
j Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
k Department of Family Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
l Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
m Memory Clinic, Skåne University Hospital, Malmö, Sweden
n The Campaign to Prevent Alzheimer’s Disease, Rockville, MD, United States
o Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
p US Department of Health and Human Services, Health Resources and Services Administration, Bureau of Health Workforce, Rockville, MD, United States
q Eisai Inc, Nutley, NJ, United States
r F. Hoffman–La Roche AG, Basel, Switzerland
s Global Alzheimer’s Platform Foundation, Washington, DC, United States
t The Global CEO Initiative on Alzheimer’s Disease, Philadelphia, PA, United States
u Davos Alzheimer’s Collaborative, Philadelphia, PA, United States
v Guidehouse, McLean, VA, United States
w C2N Diagnostics, St. Louis, MO, United States
x Eli Lilly & Co., Indianapolis, IN, United States
y Federal University of São Paulo, São Paulo, Brazil
z The USC Brain Health Observatory, University of Southern California, Los Angeles, CA, United States
aa Brain and Mind Institute, Aga Khan University, Nairobi, Kenya
ab Barrow Neurological Institute, Phoenix, AZ, United States
ac Biogen, Cambridge, MA, United States
ad Departments of Radiology and Biomedical Imaging, Medicine, Psychiatry, and Neurology, University of California, San Francisco, CA, United States
Abstract
Blood-based biomarkers (BBM) for Alzheimer’s disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer’s Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amyloid; biomarker; blood-based biomarkers; clinical implementation; clinical practice; cognitive impairment; disease-modifying treatment; patient journey; primary care; secondary care
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
IpsiHand Brain–Computer Interface Therapy Induces Broad Upper Extremity Motor Rehabilitation in Chronic Stroke
(2024) Neurorehabilitation and Neural Repair, .
Rustamov, N.a b , Souders, L.c , Sheehan, L.c , Carter, A.d e , Leuthardt, E.C.a b c f g
a Division of Neurotechnology, Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States
b Center for Innovation in Neuroscience and Technology, Division of Neurotechnology, Washington University in St. Louis, St. LouisMO, United States
c Neurolutions, Inc., St. Louis, MO, United States
d Department of Neurology, Washington University in St. Louis, St. LouisMO, United States
e Department of Orthopedic Surgery, Washington University in St. Louis, St. LouisMO, United States
f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
g Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Chronic hemiparetic stroke patients have very limited benefits from current therapies. Brain–computer interface (BCI) engaging the unaffected hemisphere has emerged as a promising novel therapeutic approach for chronic stroke rehabilitation. Objectives: This study investigated the effectiveness of contralesionally-controlled BCI therapy in chronic stroke patients with impaired upper extremity motor function. We further explored neurophysiological features of motor recovery driven by BCI. We hypothesized that BCI therapy would induce a broad motor recovery in the upper extremity, and there would be corresponding changes in baseline theta and gamma oscillations, which have been shown to be associated with motor recovery. Methods: Twenty-six prospectively enrolled chronic hemiparetic stroke patients performed a therapeutic BCI task for 12 weeks. Motor function assessment data and resting state electroencephalogram signals were acquired before initiating BCI therapy and across BCI therapy sessions. The Upper Extremity Fugl-Meyer assessment served as a primary motor outcome assessment tool. Theta–gamma cross-frequency coupling (CFC) was computed and correlated with motor recovery. Results: Chronic stroke patients achieved significant motor improvement in both proximal and distal upper extremity with BCI therapy. Motor function improvement was independent of Botox application. Theta–gamma CFC enhanced bilaterally over the C3/C4 motor electrodes and positively correlated with motor recovery across BCI therapy sessions. Conclusions: BCI therapy resulted in significant motor function improvement across the proximal and distal upper extremities of patients, which significantly correlated with theta–gamma CFC increases in the motor regions. This may represent rhythm-specific cortical oscillatory mechanism for BCI-driven rehabilitation in chronic stroke patients. Trial Registration: Advarra Study: https://classic.clinicaltrials.gov/ct2/show/NCT04338971 and Washington University Study: https://classic.clinicaltrials.gov/ct2/show/NCT03611855. © The Author(s) 2024.
Author Keywords
brain–computer interface; chronic stroke rehabilitation; theta–gamma cross-frequency coupling
Document Type: Article
Publication Stage: Article in Press
Source: Scopus