Try a new search

Format these results:

Searched for:

person:chum01

in-biosketch:true

Total Results:

15


Biochemical characterization of two novel mutations in the human high-affinity choline transporter 1 identified in a patient with congenital myasthenic syndrome

Rizvi, Midhat; Truong, Tina K; Zhou, Janet; Batta, Manav; Moran, Ellen S; Pappas, John; Chu, Mary Lynn; Caluseriu, Oana; Evrony, Gilad D; Leslie, Elaine M; Cordat, Emmanuelle
Congenital myasthenic syndrome (CMS) is a heterogeneous condition associated with 34 different genes, including SLC5A7, which encodes the high affinity choline transporter 1 (CHT1). CHT1 is expressed in presynaptic neurons of the neuromuscular junction where it uses the inward sodium gradient to re-uptake choline. Bi-allelic CHT1 mutations often lead to neonatal lethality, and less commonly to non-lethal motor weakness and developmental delays. Here, we report detailed biochemical characterization of two novel mutations in CHT1, p.I294T and p.D349N, that we identified in an 11 year-old patient with a history of neonatal respiratory distress, and subsequent hypotonia and global developmental delay. Heterologous expression of each CHT1 mutant in human embryonic kidney cells showed two different mechanisms of reduced protein function. The p.I294T CHT1 mutant transporter function was detectable, but its abundance and half-life were significantly reduced. In contrast, the p.D349N CHT1 mutant was abundantly expressed at the cell membrane, but transporter function was absent. The residual function of the p.I294T CHT1 mutant may explain the non-lethal form of CMS in this patient, and the divergent mechanisms of reduced CHT1 function that we identified may guide future functional studies of the CHT1 myasthenic syndrome. Based on these in vitro studies that provided a diagnosis, treatment with cholinesterase inhibitor together with physical and occupational therapy significantly improved the patient's strength and quality of life.
PMID: 36611016
ISSN: 1460-2083
CID: 5433572

MRM2 variants in families with complex dystonic syndromes: evidence for phenotypic heterogeneity

Shafique, Anum; Arif, Beenish; Chu, Mary Lynn; Moran, Ellen; Hussain, Tooba; Zamora, Francisca Millan; Wohler, Elizabeth; Sobreira, Nara; Klein, Christine; Lohmann, Katja; Naz, Sadaf
BACKGROUND:Dystonia involves repetitive movements and muscle contractions leading to abnormal postures. We investigated patients in two families, DYAF11 and M, exhibiting dystonic or involuntary movement disorders. METHODS:specific transcripts were analysed from participants' blood samples in Family DYAF11 after cloning of gene-specific cDNA. RESULTS:c.8+1G>T allele, an aberrant alternative acceptor splice-site located within exon 2 was used in a subset of the transcripts, creating a frameshift in the open reading frame. Exome sequencing in Family M revealed a rare missense variant c.242C>T, p.(Ala81Val), which affected a conserved amino acid. CONCLUSIONS:transcripts, raising the possibility to develop treatment by understanding the disease mechanism.
PMID: 36002240
ISSN: 1468-6244
CID: 5338252

Measuring ambulation with wrist-based and hip-based activity trackers for children with cerebral palsy

Sala, Debra A; Grissom, Helyn E; Delsole, Edward M; Chu, Mary Lynn; Godfried, David H; Bhattacharyya, Surjya; Karamitopoulos, Mara S; Chu, Alice
AIM/OBJECTIVE:To assess the accuracy of consumer available wrist-based and hip-based activity trackers in quantitatively measuring ambulation in children with cerebral palsy (CP). METHOD/METHODS:Thirty-nine children (23 males, 16 females; mean age [SD] 9y 7mo [3y 5mo]; range 4-15y) with CP were fitted with trackers both on their wrist and hip. Each participant stood for 3 minutes, ambulated in a hallway, and sat for 3 minutes. The number of steps and distance were recorded on trackers and compared to manually counted steps and distance. Pearson correlation coefficients were determined for the number of steps during ambulation from each tracker and a manual count. Mean absolute error (MAE) and range of errors were calculated for steps during ambulation for each tracker and a manual count and for distance for each tracker and hallway distance. RESULTS:For the number of steps, a weak inverse relationship (r=-0.033) was found for the wrist-based tracker and a strong positive relationship (r=0.991) for the hip-based tracker. The MAE was 88 steps for the wrist-based and seven steps for the hip-based tracker. The MAE for distance was 0.06 miles for the wrist-based and 0.07 miles for the hip-based tracker. INTERPRETATION/CONCLUSIONS:Only the hip-based tracker provided an accurate step count; neither tracker was accurate for distance. Thus, ambulation of children with CP can be accurately quantified with readily available trackers.
PMID: 30883727
ISSN: 1469-8749
CID: 3734892

The Limb-Girdle Muscular Dystrophies: Is Treatment on the Horizon?

Chu, Mary Lynn; Moran, Ellen
There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage.
PMID: 30019308
ISSN: 1878-7479
CID: 3202172

Kufor-Rakeb Syndrome Due to a Novel ATP13A2 Mutation in 2 Chinese-American Brothers [Case Report]

Noch, Evan; Henchcliffe, Claire; Hellmers, Natalie; Chu, Mary Lynn; Pappas, John; Moran, Ellen; Alcaraz, Wendy; Sarva, Harini
PMCID:6336435
PMID: 30746398
ISSN: 2330-1619
CID: 3659352

Accuracy of activity monitors for measuring walking activity in ambulatory children with cerebral palsy [Meeting Abstract]

Sala, D; Grissom, H; Delsole, E; Chu, M; Godfried, D; Karamitopoulos, M; Bhattacharyya, S; Chu, A
Background and Objective(s): Commercially available activity tracking devices present the opportunity to quantify functional changes in ambulatory status of patients with cerebral palsy (CP). The purpose of this study was to assess the accuracy of a waist-based and a wrist-based wearable device for tracking steps and walking distance of children with CP in a controlled setting. Study Design: Prospective cohort study. Study Participants & Setting: Participants were 27 children, mean age of 9.6 years (range, 4-15), with CP and a Gross Motor Function Classification System (GMFCS) score between I and III. Thirteen children were diagnosed with hemiplegia (48%), 13 with diplegia (48%), and 1 with quadriplegia (4%). Seventeen were classified as GMFCS I (63%), 3 as II (11%), and 7 as III (26%). Fourteen children wore ankle-foot orthoses (52%), one wore HKAFO (4%) and 12 wore no orthotics (44%). Four patients used Lofstrand crutches (15%), two used posterior rollators (7%), and 21 patients used no assistive devices (78%). Materials/Methods: Each participant was outfitted with both a waist-based activity tracker, FitBitTM One, and a wrist-based tracker, FitBitTM Flex. They ambulated at a self-selected speed for 670 feet in a hallway. Orthotics and assistive devices were utilized as per the child's normal routine. Number of steps and distance were collected from both trackers. A researcher simultaneously used a tally counter to manually count total number of steps. Pearson correlation coefficients were determined for number of steps from each tracker and the manual count. Mean absolute percent error (MAPE) was calculated for steps for each tracker and the manual count, and for the distance from each tracker and the hallway distance. Results: For number of steps, a strong positive correlation was found between the waist tracker and the manual count (r=0.997), whereas a weak positive correlation was found between wrist tracker and manual count (r=0.223). MAPE for steps was 1% for the waist tracker and 12% for the wrist tracker. For distance, MAPE was 56% for the waist tracker and 41% for the wrist tracker. Conclusions/Significance: The waist-based activity tracker provided an accurate step count. Neither waist-based nor wristbased tracker was accurate for distance measurement. Thus, the walking ability of ambulatory children with CP can be accurately quantified with a readily available inexpensive activity tracker. This has the potential to enable clinicians to assess the effects of various treatments on the real-world activity level of patients with CP
EMBASE:618469751
ISSN: 1469-8749
CID: 2723772

A Founder Mutation in VPS11 Causes an Autosomal Recessive Leukoencephalopathy Linked to Autophagic Defects

Zhang, Jinglan; Lachance, Veronik; Schaffner, Adam; Li, Xianting; Fedick, Anastasia; Kaye, Lauren E; Liao, Jun; Rosenfeld, Jill; Yachelevich, Naomi; Chu, Mary-Lynn; Mitchell, Wendy G; Boles, Richard G; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Bagley, Kaytee; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa
Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway.
PMCID:4847778
PMID: 27120463
ISSN: 1553-7404
CID: 2092092

Fidelity of gamma-glutamyl transferase (GGT) in differentiating skeletal muscle from liver damage

Rosales, Xiomara Q; Chu, Mary-Lynn; Shilling, Christopher; Wall, Cheryl; Pastores, Gregory M; Mendell, Jerry R
This study tested the hypothesis that gamma-glutamyl transferase (GGT) can be used as a reliable biomarker to distinguish skeletal muscle from liver damage. Twenty-eight Duchenne muscular dystrophy subjects with proven dystrophin gene mutations were enrolled. Included were 14 ambulatory and 14 nonambulatory patients with approximately half of each cohort taking corticosteroids. Twenty normal males served as controls. Initial blood samples for serum GGT and creatine kinase were taken between 8AM and 9AM and redrawn 8 hours later to test for variability. Between blood draws, subjects resumed normal activities in a play environment or could leave the clinic. Not a single duchenne muscular dystrophy patient showed a GGT outside the control range at any time point, while creatine kinase levels were 14 to 200 times normal. Validation of this finding is essential for management of patients with muscle disorders exposed to potentially hepatotoxic drugs for clinical management or monitoring subjects participating in clinical trials
PMID: 18354148
ISSN: 1708-8283
CID: 96996

The use of tiagabine in pediatric spasticity management

Chu, Mary Lynn; Sala, Debra A
Tiagabine, developed as an anti-epileptic medication, has the potential to reduce spasticity. The purpose of the present study was to assess the effectiveness of tiagabine in decreasing spasticity and improving the functional abilities of children with spastic cerebral palsy (CP). Nine children (seven females, two males) with CP (six spastic quadriplegia, three moderate to severe spastic diplegia) were treated with tiagabine for a mean of 7.2 months. Median age was 4y 5mo (range 3y 2mo-10y). All children were non-ambulatory. According to the Gross Motor Function Classification System, six were Level IV and three were Level V. Only one child showed a median decrease >or=1.0 grade on the modified Ashworth scale in upper extremities, lower extremities, and overall. Another child had significant improvement in the Pediatric Evaluation of Disability Inventory Self-care score and improved feeding. None of the participants was found to have a significant improvement in motor function or a decrease in the number of motions (passive range of motion and muscle length test) that were limited. Reduction of nocturnal awakenings from painful spasms was reported in one child. Eight of the nine children experienced adverse side-effects during treatment. Although tiagabine was not found to be effective in decreasing children's spasticity or improving their function, its potential use in the relief of painful spasms associated with neurological conditions in the pediatric population warrants further investigation
PMID: 16700936
ISSN: 0012-1622
CID: 64669

Intrathecal baclofen in X-linked adrenoleukodystrophy [Case Report]

Chu ML; Sala DA; Weiner HL
X-linked adrenoleukodystrophy is a progressive neurodegenerative disorder involving the destruction of white matter in the brain and adrenocortical hormone deficiency. Clinical symptoms first appear between 4 and 8 years of age and include spasticity, visual loss, dysphagia, and seizures. In this report, continuous infusion of intrathecal baclofen was used to treat the severe spasticity of an 8-year-old patient with X-linked adrenoleukodystrophy. The improvement in this patient's quality of life, including the elimination of pain and the increased ease of care, suggests that intrathecal baclofen should be considered as part of the treatment strategy for spasticity associated with X-linked adrenoleukodystrophy and other neurodegenerative disorders in children and adults
PMID: 11275468
ISSN: 0887-8994
CID: 26761