Publications by authors named "Julie Fleischer"

13 Publications

  • Page 1 of 1

CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

Epilepsia 2021 07 26;62(7):e103-e109. Epub 2021 May 26.

Department of Neuropediatrics, APHP Sorbonne University, Trousseau Hospital, Paris, France.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.
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http://dx.doi.org/10.1111/epi.16931DOI Listing
July 2021

Genotype-phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders.

Genome Med 2021 May 21;13(1):90. Epub 2021 May 21.

Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.

Methods: Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.

Results: We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.

Conclusions: Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.
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http://dx.doi.org/10.1186/s13073-021-00900-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140440PMC
May 2021

TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.

Hum Mutat 2021 Apr 1;42(4):445-459. Epub 2021 Mar 1.

Department of Pediatrics, SIU School of Medicine, Springfield, Illinois, USA.

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.
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http://dx.doi.org/10.1002/humu.24176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248425PMC
April 2021

Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants.

Int J Neonatal Screen 2020 03 21;6(1). Epub 2020 Jan 21.

Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL 60603, USA; (R.S.); (K.B.).

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.
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http://dx.doi.org/10.3390/ijns6010004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422983PMC
March 2020

The Effect of Chemical Cleaning on Mechanical Properties of Three-Dimensional Printed Polylactic Acid.

J Med Device 2020 Mar 11;14(1):011109. Epub 2020 Feb 11.

BioMechanical Engineering, Delft University of Technology, Delft 2628CD, The Netherlands.

Three-dimensional (3D) printing may be a solution to shortages of equipment and spare parts in the healthcare sector of low- and middle-income countries (LMICs). Polylactic acid (PLA) for 3D printing is widely available and biocompatible, but there is a gap in knowledge concerning its compatibility with chemical disinfectants. In this study, 3D-printed PLA tensile samples were created with six different printer settings. Each of these six batches consisted of five sets with five or six samples. The first set remained untreated, the others were soaked in Cidex OPA or in a chlorine solution. These were applied for seven consecutive days or in 25 short cycles. All samples were weighed before and after treatment and subjected to a tensile test. Results showed that a third of the treatments led to an increase of the median weight with a maximum of 8.3%, however, the samples with the best surface quality did not change. The median strength increase was 12.5% and the largest decrease was 8.8%. The median stiffness decreased 3.6% in one set and increased in three others up to 13.6%. When 3D printing PLA medical tools, surface porosity must be minimized to prevent transfer of disinfectants to people. The wide variability of mechanical properties due to 3D printing itself and as a consequence of disinfection must be considered when designing medical tools by selecting appropriate printer settings. If these conditions are met, reusing 3D-printed PLA medical tools seems safe from a mechanical point of view.
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http://dx.doi.org/10.1115/1.4046120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164496PMC
March 2020

De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.

Am J Med Genet A 2020 05 7;182(5):962-973. Epub 2020 Feb 7.

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, Missouri.

CDC42BPB encodes MRCKβ (myotonic dystrophy-related Cdc42-binding kinase beta), a serine/threonine protein kinase, and a downstream effector of CDC42, which has recently been associated with Takenouchi-Kosaki syndrome, an autosomal dominant neurodevelopmental disorder. We identified 12 heterozygous predicted deleterious variants in CDC42BPB (9 missense, 2 frameshift, and 1 nonsense) in 14 unrelated individuals (confirmed de novo in 11/14) with neurodevelopmental disorders including developmental delay/intellectual disability, autism, hypotonia, and structural brain abnormalities including cerebellar vermis hypoplasia and agenesis/hypoplasia of the corpus callosum. The frameshift and nonsense variants in CDC42BPB are expected to be gene-disrupting and lead to haploinsufficiency via nonsense-mediated decay. All missense variants are located in highly conserved and functionally important protein domains/regions: 3 are found in the protein kinase domain, 2 are in the citron homology domain, and 4 in a 20-amino acid sequence between 2 coiled-coil regions, 2 of which are recurrent. Future studies will help to delineate the natural history and to elucidate the underlying biological mechanisms of the missense variants leading to the neurodevelopmental and behavioral phenotypes.
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http://dx.doi.org/10.1002/ajmg.a.61505DOI Listing
May 2020

Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience.

J Pediatr 2019 11 30;214:165-167.e1. Epub 2019 Aug 30.

Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL.

Objectives: To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois.

Study Design: Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago.

Results: One case of MPS II and 14 infants with pseudodeficiency for I2S were identified.

Conclusions: Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.053DOI Listing
November 2019

Intragenic CNTN4 copy number variants associated with a spectrum of neurobehavioral phenotypes.

Eur J Med Genet 2020 Mar 15;63(3):103736. Epub 2019 Aug 15.

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Deletions and duplications involving the CNTN4 gene, which encodes for the contactin 4 protein, have been reported in children with autism spectrum disorder (ASD) and other neurodevelopmental phenotypes. In this study, we performed clinical and genetic characterization of three individuals from unrelated families with copy number variants (CNV) (one deletion and two duplications) within CNTN4. The patients exhibited cognitive delay (3/3), growth restriction (3/3), motor delay (2/3), and febrile seizure/epilepsy (2/3). In contrast to previous reports, all probands presented with speech apraxia or delay with no diagnosis of ASD. Parental studies for the proband with the deletion and one of the 2 probands with the duplication revealed paternal origin of the CNTN4 CNV. Interestingly, previously documented CNV involving this gene were mostly inherited from unaffected fathers, raising questions regarding reduced penetrance and potential parent-of-origin effect. Our findings are compared with previously reported patients and patients in the DECIPHER database. The speech impairment in the three probands suggests a role for CNTN4 in language development. We discuss potential factors contributing to phenotypic heterogeneity and reduced penetrance and attempt to find possible genotype-phenotype correlation. Larger cohorts are needed for comprehensive and unbiased phenotyping and molecular characterization that may lead to better understanding of the underlying mechanisms of reduced penetrance, variable expressivity, and potential parent-of-origin effect of copy number variants encompassing CNTN4.
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http://dx.doi.org/10.1016/j.ejmg.2019.103736DOI Listing
March 2020

Real-time oncological guidance using diffuse reflectance spectroscopy in electrosurgery: the effect of coagulation on tissue discrimination.

J Biomed Opt 2018 11;23(11):1-10

Delft University of Technology, Biomechanical Engineering Department, Delft, The Netherlands.

In breast surgery, a lack of knowledge about what is below the tissue surface may lead to positive tumor margins and iatrogenic damage. Diffuse reflectance spectroscopy (DRS) is a spectroscopic technique that can distinguish between healthy and tumor tissue making it a suitable technology for intraoperative guidance. However, because tumor surgeries are often performed with an electrosurgical knife, the effect of a coagulated tissue layer on DRS measurements must be taken into account. It is evaluated whether real-time DRS measurements obtained with a photonic electrosurgical knife could provide useful information of tissue properties also when tissue is coagulated and cut. The size of the coagulated area is determined and the effect of its presence on DR spectra is studied using ex vivo porcine adipose and muscle tissue. A coagulated tissue layer with a depth of 0.1 to 0.4 mm is observed after coagulating muscle with an electrosurgical knife. The results show that the effect of coagulating adipose tissue is negligible. Using the fat/water ratio's calculated from the measured spectra of the photonic electrosurgical knife, it was possible to determine the distance from the instrument tip to a tissue transition during cutting. In conclusion, the photonic electrosurgical knife can determine tissue properties of coagulated and cut tissue and has, therefore, the potential to provide real-time feedback about the presence of breast tumor margins during cutting, helping surgeons to establish negative margins and improve patient outcome.
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http://dx.doi.org/10.1117/1.JBO.23.11.115004DOI Listing
November 2018

Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence.

Cell Metab 2017 Dec 26;26(6):872-883.e5. Epub 2017 Oct 26.

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

Mitochondrial fusion and fission are critical to heart health; genetically interrupting either is rapidly lethal. To understand whether it is loss of, or the imbalance between, fusion and fission that underlies observed cardiac phenotypes, we engineered mice in which Mfn-mediated fusion and Drp1-mediated fission could be concomitantly abolished. Compared to fusion-defective Mfn1/Mfn2 cardiac knockout or fission-defective Drp1 cardiac knockout mice, Mfn1/Mfn2/Drp1 cardiac triple-knockout mice survived longer and manifested a unique pathological form of cardiac hypertrophy. Over time, however, combined abrogation of fission and fusion provoked massive progressive mitochondrial accumulation that severely distorted cardiomyocyte sarcomeric architecture. Mitochondrial biogenesis was not responsible for mitochondrial superabundance, whereas mitophagy was suppressed despite impaired mitochondrial proteostasis. Similar but milder defects were observed in aged hearts. Thus, cardiomyopathies linked to dynamic imbalance between fission and fusion are temporarily mitigated by forced mitochondrial adynamism at the cost of compromising mitochondrial quantity control and accelerating mitochondrial senescence.
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http://dx.doi.org/10.1016/j.cmet.2017.09.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718956PMC
December 2017

Correcting mitochondrial fusion by manipulating mitofusin conformations.

Nature 2016 12 24;540(7631):74-79. Epub 2016 Oct 24.

Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Mitochondria are dynamic organelles that exchange contents and undergo remodelling during cyclic fusion and fission. Genetic mutations in MFN2 (the gene encoding mitofusin 2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A). It has not yet been possible to directly modulate mitochondrial fusion, in part because the structural basis of mitofusin function is not completely understood. Here we show that mitofusins adopt either a fusion-constrained or a fusion-permissive molecular conformation, directed by specific intramolecular binding interactions, and demonstrate that mitofusin-dependent mitochondrial fusion can be regulated in mouse cells by targeting these conformational transitions. On the basis of this model, we engineered a cell-permeant minipeptide to destabilize the fusion-constrained conformation of mitofusin and promote the fusion-permissive conformation, reversing mitochondrial abnormalities in cultured fibroblasts and neurons that harbour CMT2A-associated genetic defects. The relationship between the conformational plasticity of mitofusin 2 and mitochondrial dynamism reveals a central mechanism that regulates mitochondrial fusion, the manipulation of which can correct mitochondrial pathology triggered by defective or imbalanced mitochondrial dynamics.
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http://dx.doi.org/10.1038/nature20156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5315023PMC
December 2016

Digynic triploidy: utility and challenges of noninvasive prenatal testing.

Clin Case Rep 2015 Jun 9;3(6):406-10. Epub 2015 Apr 9.

Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine St. Louis, Missouri.

Low fraction fetal DNA in noninvasive prenatal testing in the context of fetal growth restriction and multiple congenital anomalies should alert medical professionals to the possibility of digynic triploidy. Single-nucleotide polymorphism microarray can detect the parental origin of triploidy and explain its mechanism.
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http://dx.doi.org/10.1002/ccr3.247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498852PMC
June 2015

Newborn screening by whole-genome sequencing: ready for prime time?

Clin Chem 2014 Sep 28;60(9):1243-4. Epub 2014 Aug 28.

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http://dx.doi.org/10.1373/clinchem.2014.226076DOI Listing
September 2014
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