Author
Christina Lam
Other affiliations: Boston University, University of California, Los Angeles, Université de Montréal ...read more
Bio: Christina Lam is an academic researcher from University of Washington. The author has contributed to research in topics: Medicine & Congenital disorder of glycosylation. The author has an hindex of 18, co-authored 51 publications receiving 896 citations. Previous affiliations of Christina Lam include Boston University & University of California, Los Angeles.
Papers
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TL;DR: An extensive review takes a closer look at what is known about EMPD and the conclusions that have been drawn from this information and provides a practical approach to patients with EMPD.
165 citations
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TL;DR: Carohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis.
Abstract: Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways. The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial dysmorphisms, and variable coagulation and endocrine abnormalities. Carbohydrate deficient transferrin (CDT) and protein-linked glycan analysis with mass spectrometry can diagnose some subtypes of congenital disorders of glycosylation (CDG), while many currently rely on massively parallel genomic sequencing for diagnosis. Early detection is important, as a few of these disorders are treatable. Molecular and biochemical techniques continue
132 citations
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Erasmus University Medical Center1, Boston Children's Hospital2, GeneDx3, University of California, San Francisco4, University of Washington5, Baylor College of Medicine6, Stanford University7, French Institute of Health and Medical Research8, Arkansas Children's Hospital9, University of Dundee10, Radboud University Nijmegen11, Children's Hospital of Philadelphia12, University of Illinois at Chicago13, Belfast Health and Social Care Trust14, Nottingham University Hospitals NHS Trust15, Utrecht University16, Washington University in St. Louis17, Leiden University Medical Center18, Seattle Children's Research Institute19, Heidelberg University20, German Cancer Research Center21, University of Nantes22, University of Strasbourg23, University of Poitiers24, Baylor University25, Seattle Children's26, University of Limerick27, University of Rennes28, Wellcome Trust Sanger Institute29, University of Melbourne30
TL;DR: The importance of CAMK 2A and CAMK2B and their auto-phosphorylation in human brain function is established and the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway is expanded.
Abstract: Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
127 citations
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TL;DR: The prospective phenotyping expands the clinical spectrum of NGLY1-CDDG, offers prognostic information, and provides baseline data for evaluating therapeutic interventions.
93 citations
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Montreal Children's Hospital1, Katholieke Universiteit Leuven2, University of Catania3, Necker-Enfants Malades Hospital4, University of Paris-Sud5, Universidade Nova de Lisboa6, Charles University in Prague7, Boston Children's Hospital8, University of Queensland9, University of Murcia10, Paris Descartes University11, National Institutes of Health12, Discovery Institute13, University of Pécs14, Radboud University Nijmegen15, University College London16, Heidelberg University17, Seattle Children's Research Institute18, University of Washington19, Royal Children's Hospital20, Shiraz University of Medical Sciences21, University of Tartu22, Mayo Clinic23, Carlos III Health Institute24, Tulane University25
TL;DR: A systematic review of the literature on PMM2‐CDG was conducted by a group of international experts in different aspects of CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM 2‐ CDG patients are issued.
Abstract: Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.
78 citations
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01 Apr 2016
TL;DR: Tirosh et al. as discussed by the authors applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells.
Abstract: Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.
823 citations
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Boston Children's Hospital1, Innsbruck Medical University2, University of Zurich3, Necker-Enfants Malades Hospital4, University of Padua5, University Medical Center Freiburg6, Great Ormond Street Hospital7, First Faculty of Medicine, Charles University in Prague8, Autonomous University of Madrid9, Children's of Alabama10
TL;DR: These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness, and highlight gaps in knowledge that must be filled by future research.
Abstract: Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of~1: 50,000 and PA of~1:100’000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.
449 citations
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TL;DR: The importance of recent genetic findings on the different mechanisms of structural plasticity are discussed and it is proposed that these converge on shared pathways that can be targeted with novel therapeutics.
Abstract: The structure of neuronal circuits that subserve cognitive functions in the brain is shaped and refined throughout development and into adulthood. Evidence from human and animal studies suggests that the cellular and synaptic substrates of these circuits are atypical in neuropsychiatric disorders, indicating that altered structural plasticity may be an important part of the disease biology. Advances in genetics have redefined our understanding of neuropsychiatric disorders and have revealed a spectrum of risk factors that impact pathways known to influence structural plasticity. In this Review, we discuss the importance of recent genetic findings on the different mechanisms of structural plasticity and propose that these converge on shared pathways that can be targeted with novel therapeutics.
325 citations
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University of Düsseldorf1, University of Washington2, European Bioinformatics Institute3, German Cancer Research Center4, University of Michigan5, Harvard University6, Broad Institute7, Yale University8, Xi'an Jiaotong University9, University of Alabama at Birmingham10, University of Southern California11, University of Santiago de Compostela12, University of Maryland, Baltimore13, Temple University14, Pacific Biosciences15, Saarland University16, Max Planck Society17, Washington University in St. Louis18, University of Chicago19, Ewha Womans University20
TL;DR: In this article, the authors present 64 assembled haplotypes from 32 diverse human genomes, which integrate all forms of genetic variation, even across complex loci, and identify 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing.
Abstract: Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.
289 citations