Publications by authors named "Alejandro Iglesias"

31 Publications

Point-Mass Biomechanical Model of the Upper Extremity During Lofstrand Crutch-Assisted Gait.

IEEE Trans Neural Syst Rehabil Eng 2020 12 28;28(12):3022-3030. Epub 2021 Jan 28.

We propose a point-mass biomechanical model to estimate the forces and moments supported by the upper extremity during Lofstrand crutch-assisted gait. This model is based on the Newtonian classical mechanics and the angular momentum theorem. The system arm-crutch is divided into three segments: 1) crutch, 2) wrist-elbow, and 3) elbow-shoulder. The theoretical model was experimentally validated with a disabled person with spinal cord injury. Two crutch-assisted gait patterns have been chosen to carry out the experimental validation: two-point reciprocal gait and swing-through gait. Six position markers (three placed on the arm and three placed on the crutch) and two force sensors (placed on the crutch) were used in experiments for testing the model. The results were compared with a distributed-mass model based on studies previously published, concluding that the relative mean difference between models is less than 3% Body Weight and 1% Body Weight times Height when forces and moments are estimated, respectively. Some advantages of using a point-mass model are summarized: simple formulation, easy to understand; require less numerical calculation reducing the computational cost; requires less position markers placed on the subject, increasing therefore the comfort of the subject.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TNSRE.2020.3045268DOI Listing
December 2020

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.

Hum Genet 2020 Nov 8;139(11):1443-1454. Epub 2020 Jun 8.

Institute of Human Genetics, University Medical Center Göttingen, Heinrich-Düker-Weg 12, 37073, Göttingen, Germany.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02188-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519902PMC
November 2020

In vitro evaluation of apical microleakage in retrofillings with different resection angles.

Acta Odontol Latinoam 2019 Dec;32(3):126-132

Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Materiales Dentales, Buenos Aires, Argentina.

The aim of this study was to evaluate the effect of flowable composite or glass ionomer liners on the shrinkage stress of a restorative composite resin. Fifteen previously sandblasted metal boxes were attached to a universal mechanical testing machine (INSTRON 1011, Instron Corporation). Five of these boxes were filled with Filtek Z350 XT (FXT) Universal Restorative A2 (3M ESPE) (Group 1 or Control). Two further groups of 5 boxes were prepared by interposing a layer of Vitrebond Light Cure Glass Ionomer 3M ESPE (VGI) (Group 2 or G.I.) or Filtek Z350 XT Flowable Restorative A2 3M ESPE (FFR) (Group 3 or Flowable) between the box and the composite resin, completing with the same volume of composite as in Group 1. Upon activating lightcuring, the filled boxes mounted on the testing machine were videoed for 60 seconds (40 s photoactivation and 20 s postcuring), timed with a digital chronometer. Force values were recorded in newtons and converted into stress according to contact surface. Stress values were recorded every 10 s. Results were analyzed using repeated measures ANOVA. Mean and standard deviation in kPa (stress) recorded for each group were: Control group: 126.2 (30.8); G.I.: 48.4 (18); Flowable: 27.9 (19.5). Statistical analysis showed significant differences between the control group and the rest (p<0.01), with no significant difference between groups with glass ionomer liners and flowable resin liners (G.I. and Flowable). Under the experimental conditions of this study, it can be concluded that polymerization shrinkage stress can be reduced by the presence of a liner between the preparation and the restorative material.
View Article and Find Full Text PDF

Download full-text PDF

Source
December 2019

Impact of patient education videos on genetic counseling outcomes after exome sequencing.

Patient Educ Couns 2020 01 24;103(1):127-135. Epub 2019 Aug 24.

Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA. Electronic address:

Objective: Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated.

Methods: Parents of patients offered CES were randomized to watch educational videos before their visit or to receive routine care. Parents and GCs were surveyed about their experiences following the sessions. The responses of the video (n = 102) and no-video (n = 105) groups were compared.

Results: GCs reported no significant differences between parents in the video and no-video groups on genetics knowledge or CES knowledge. In contrast, parents' scores on genetics knowledge questions were lower in the video than no-video group (p = 0.007). Most parents reported the videos were informative, and the groups did not differ in satisfaction with GCs or decisions to have CES.

Conclusion: GCs and parents perceived the videos to be beneficial. However, lower scores on genetics knowledge questions highlight the need for careful development of educational tools.

Practice Implications: Educational tools should be developed and assessed for effectiveness with the input of all stakeholders before widespread implementation. Better measures of the effectiveness of these educational tools are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pec.2019.08.018DOI Listing
January 2020

De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder.

Am J Hum Genet 2019 08 11;105(2):403-412. Epub 2019 Jul 11.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698880PMC
August 2019

Pearls & Oy-sters: Adolescent-onset adrenomyeloneuropathy and arrested cerebral adrenoleukodystrophy.

Neurology 2019 07;93(2):81-84

From the Department of Medicine (J.E.L.), University of Illinois at Chicago; Division of Child Neurology, Department of Neurology (J.E.L., E.A.A., A.H., J.M.B.), Division of Medical Genetics, Department of Pediatrics (C.U., A.D.I.), and Department of Anesthesia (J.C.), Columbia University College of Physicians and Surgeons; The Columbia University Irving Medical Center (J.E.L, E.A.A, A.H, J.M.B, C.U., A.D.I, J.J.C); and Division of Child Neurology (E.J.M.), Department of Pediatrics, Weill Cornell Medicine, New York-Presbyterian Hospital, New York.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656648PMC
July 2019

Noninvasive ventilation: education and training. A narrative analysis and an international consensus document.

Adv Respir Med 2019 4;87(1):36-45. Epub 2019 Mar 4.

Respiratory Unit, AO Ospedali dei Colli Naples PO, Monaldi, Italy.

Noninvasive ventilation (NIV) is an increasingly used method of respiratory support. The use of NIV is expanding over the time and if properly applied, it can save patients' lives and improve long-term prognosis. However, both knowledge and skills of its proper use as life support are paramount. This systematic review aimed to assess the importance of NIV education and training. Literature search was conducted (MEDLINE: 1990 to June, 2018) to identify randomized controlled studies and systematic reviews with the results analyzed by a team of experts across the world through e-mail based communications. Clinical trials examining the impact of education and training in NIV as the primary objective was not found. A few studies with indirect evidence, a simulation-based training study, and narrative reviews were identified. Currently organized training in NIV is implemented only in a few developed countries. Due to a lack of high-grade experimental evidence, an international consensus on NIV education and training based on opinions from 64 experts across the twenty-one different countries of the world was formulated. Education and training have the potential to increase knowledge and skills of the clinical staff who deliver medical care using NIV. There is a genuine need to develop structured, organized NIV education and training programs, especially for the developing countries.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5603/ARM.a2019.0006DOI Listing
February 2020

De novo mutations in the GTP/GDP-binding region of RALA, a RAS-like small GTPase, cause intellectual disability and developmental delay.

PLoS Genet 2018 11 30;14(11):e1007671. Epub 2018 Nov 30.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, United States of America.

Mutations that alter signaling of RAS/MAPK-family proteins give rise to a group of Mendelian diseases known as RASopathies. However, among RASopathies, the matrix of genotype-phenotype relationships is still incomplete, in part because there are many RAS-related proteins and in part because the phenotypic consequences may be variable and/or pleiotropic. Here, we describe a cohort of ten cases, drawn from six clinical sites and over 16,000 sequenced probands, with de novo protein-altering variation in RALA, a RAS-like small GTPase. All probands present with speech and motor delays, and most have intellectual disability, low weight, short stature, and facial dysmorphism. The observed rate of de novo RALA variants in affected probands is significantly higher (p = 4.93 x 10(-11)) than expected from the estimated random mutation rate. Further, all de novo variants described here affect residues within the GTP/GDP-binding region of RALA; in fact, six alleles arose at only two codons, Val25 and Lys128. The affected residues are highly conserved across both RAL- and RAS-family genes, are devoid of variation in large human population datasets, and several are homologous to positions at which disease-associated variants have been observed in other GTPase genes. We directly assayed GTP hydrolysis and RALA effector-protein binding of the observed variants, and found that all but one tested variant significantly reduced both activities compared to wild-type. The one exception, S157A, reduced GTP hydrolysis but significantly increased RALA-effector binding, an observation similar to that seen for oncogenic RAS variants. These results show the power of data sharing for the interpretation and analysis of rare variation, expand the spectrum of molecular causes of developmental disability to include RALA, and provide additional insight into the pathogenesis of human disease caused by mutations in small GTPases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1007671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291162PMC
November 2018

Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy.

Am J Hum Genet 2018 10 27;103(4):602-611. Epub 2018 Sep 27.

Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada. Electronic address:

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36 variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174287PMC
October 2018

Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature.

Am J Med Genet A 2018 11 8;176(11):2259-2275. Epub 2018 Sep 8.

Carle Physician Group, Urbana, Illinois.

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.40472DOI Listing
November 2018

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Am J Hum Genet 2018 08 26;103(2):221-231. Epub 2018 Jul 26.

Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080766PMC
August 2018

A Novel Mutation in Junctional Plakoglobin Causing Lethal Congenital Epidermolysis Bullosa.

J Pediatr 2017 12;191:266-269.e1

Department of Pediatrics, Columbia University, New York, NY; Department of Pathology and Cell Biology, Columbia University, New York, NY.

We report a case of neonatal generalized erythema and epidermolysis resulting from a novel mutation in the junctional plakoglobin gene causing truncation of the plakoglobin protein. Expedited genetic testing enabled diagnosis while the patient was in the neonatal intensive care unit, providing valuable information for the clinicians and family.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2017.08.029DOI Listing
December 2017

Loss-of-function variants in NFIA provide further support that NFIA is a critical gene in 1p32-p31 deletion syndrome: A four patient series.

Am J Med Genet A 2017 Dec 22;173(12):3158-3164. Epub 2017 Sep 22.

Department of Pediatrics, Division of Clinical Genetics, Columbia University Medical Center (CUMC), New York, New York.

The association between 1p32-p31 contiguous gene deletions and a distinct phenotype that includes anomalies of the corpus callosum, ventriculomegaly, developmental delay, seizures, and dysmorphic features has been long recognized and described. Recently, the observation of overlapping phenotypes in patients with chromosome translocations that disrupt NFIA (Nuclear factor I/A), a gene within this deleted region, and NFIA intragenic deletions has led to the hypothesis that NFIA is a critical gene within this region. The wide application and increasing accessibility of whole exome sequencing (WES) has helped identify new cases to support this hypothesis. Here, we describe four patients with loss-of-function variants in the NFIA gene identified through WES. The clinical presentation of these patients significantly overlaps with the phenotype described in previously reported cases of 1p32-p31 deletion syndrome, NFIA gene disruptions and intragenic NFIA deletions. Our cohort includes a mother and daughter as well as an unrelated individual who share the same nonsense variant (c.205C>T, p.Arg69Ter; NM_001145512.1). We also report a patient with a frameshift NFIA variant (c.159_160dupCC, p.Gln54ProfsTer49). We have compared published cases of 1p32-p31 microdeletion syndrome, translocations resulting in NFIA gene disruption, intragenic deletions, and loss-of-function mutations (including our four patients) to reveal that abnormalities of the corpus callosum, ventriculomegaly/hydrocephalus, macrocephaly, Chiari I malformation, dysmorphic features, developmental delay, hypotonia, and urinary tract defects are common findings. The consistent overlap in clinical presentation provides further evidence of the critical role of NFIA haploinsufficiency in the development of the 1p32-p31 microdeletion syndrome phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38460DOI Listing
December 2017

Neonatal detection of Aicardi Goutières Syndrome by increased C26:0 lysophosphatidylcholine and interferon signature on newborn screening blood spots.

Mol Genet Metab 2017 11 20;122(3):134-139. Epub 2017 Jul 20.

Department of Neurology, Children's National Health System, Washington, DC, USA; Center For Genetic Medicine, Children's National Health System, Washington, DC, USA; Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA; Department of Integrated Systems Biology and Pediatrics, George Washington University, Washington, DC, USA; Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Background: Aicardi Goutières Syndrome (AGS) is a heritable interferonopathy associated with systemic autoinflammation causing interferon (IFN) elevation, central nervous system calcifications, leukodystrophy and severe neurologic sequelae. An infant with TREX1 mutations was recently found to have abnormal C26:0 lysophosphatidylcholine (C26:0 Lyso-PC) in a newborn screening platform for X-linked adrenoleukodystrophy, prompting analysis of this analyte in retrospectively collected samples from individuals affected by AGS.

Methods: In this study, we explored C26:0 Lyso-PC levels and IFN signatures in newborn blood spots and post-natal blood samples in 19 children with a molecular and clinical diagnosis of AGS and in the blood spots of 22 healthy newborns. We used Nanostring nCounter™ for IFN-induced gene analysis and a high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS) newborn screening platform for C26:0 Lyso-PC analysis.

Results: Newborn screening cards from patients across six AGS associated genes were collected, with a median disease presentation of 2months. Thirteen out of 19 (68%) children with AGS had elevations of first tier C26:0 Lyso-PC (>0.4μM), that would have resulted in a second screen being performed in a two tier screening system for X-linked adrenoleukodystrophy (X-ALD). The median (95%CI) of first tier C26:0 Lyso-PC values in AGS individuals (0.43μM [0.37-0.48]) was higher than that seen in controls (0.21μM [0.21-0.21]), but lower than X-ALD individuals (0.72μM [0.59-0.84])(p<0.001). Fourteen of 19 children had elevated expression of IFN signaling on blood cards relative to controls (Sensitivity 73.7%, 95%CI 51-88%, Specificity 95%, 95% CI 78-99%) including an individual with delayed disease presentation (36months of age). All five AGS patients with negative IFN signature at birth had RNASEH2B mutations. Consistency of agreement between IFN signature in neonatal and post-natal samples was high (0.85).

Conclusion: This suggests that inflammatory markers in AGS can be identified in the newborn period, before symptom onset. Additionally, since C26:0 Lyso-PC screening is currently used in X-ALD newborn screening panels, clinicians should be alert to the fact that AGS infants may present as false positives during X-ALD screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgme.2017.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722655PMC
November 2017

Volumetric arc therapy for total scalp irradiation: case report for a recurrent basal cell carcinoma of the scalp.

Ecancermedicalscience 2017 11;11:737. Epub 2017 May 11.

Innovative Cancer Institute, 5995 SW 71st Street, South Miami, FL 33143, USA.

Total scalp irradiation may be used to treat numerous conditions including squamous and basal cell carcinomas. These conditions are relatively uncommon and patients are frequently treated with palliative intent. In this report, we describe a volumetric arc therapy technique using photon beams for curative intent in an 84 years old patient with recurrent basal cell carcinoma of the scalp. Dose was 50Gy (2Gy per session) to the planning target volume (PTV) followed by a 10 Gy boost to the macroscopic disease on the forehead. A custom made 1 cm superflab bolus helmet was used. Toxicities only consisted of Grade-1 transient radiation dermatitis and alopecia. A sustained clinical response was observed at 6 months follow-up. Volumetric arc therapy (VMAT) may offer an effective alternative modality to treat patients with very extensive scalp lesions as described in this case report.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3332/ecancer.2017.737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440184PMC
May 2017

Perioperative Risks of Untreated Obstructive Sleep Apnea in the Bariatric Surgery Patient: a Retrospective Study.

Obes Surg 2016 11;26(11):2779-2780

Intensive Care Unit, Hospital Morales Meseguer, Av. Marqués de los Vélez, s/n, 30008, Murcia, Spain.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11695-016-2335-5DOI Listing
November 2016

Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.

Eur J Med Genet 2016 Oct 31;59(10):540-5. Epub 2016 Aug 31.

Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA. Electronic address:

Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045816PMC
http://dx.doi.org/10.1016/j.ejmg.2016.08.012DOI Listing
October 2016

Phenotypic Heterogeneity of Neutropenia and Gastrointestinal Illness Associated with G6PC3 Founder Mutation.

J Pediatr Hematol Oncol 2016 10;38(7):e243-7

*Department of Pediatric Hematology/Oncology, Winthrop University Medical Center, Mineola †Division of Pediatric Gastroenterology, Hepatology, and Nutrition Departments of §Pediatric Hematology, Oncology and Stem Cell Transplantation ‡Pathology, Cell Biology, and Personalized Genomic Medicine ∥Pediatrics, Division of Clinical Genetics, Columbia University Medical center, New York, NY.

Severe congenital neutropenia type IV (SCN IV) is a syndrome of severe neutropenia, cardiac and urogenital defects, prominent superficial veins, facial dysmorphism, failure to thrive (FTT), and intermittent thrombocytopenia, caused by a glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene mutation. SCN IV has been linked to glycogen storage disease type 1b as both disorders involve disruption of the glucose-6-phosphatase/glucose-6-phosphate transporter complex, leading to arrested neutrophil maturation. Emerging evidence suggests that neutrophil function plays an important role in intestinal integrity, evidenced by inflammatory bowel disease in certain neutropenic patients. Here, we report 3 unrelated Hispanic males from the Dominican Republic with classic features of SCN IV found to share an identical inherited canonical splice-site mutation of the G6PC3 gene (c.218+1G>A). All 3 patients presented with severe FTT and gastrointestinal manifestations. Two of the patients had significant improvement in growth and resolution of gastrointestional symptoms with initiation of granulocyte colony-stimulating factor. We hypothesize that the gene variant described represents a founder mutation in the Dominican Republic, the first to be described in this geographical region. We discuss the potential associations between neutropenia and gastrointestinal disease with FTT and the role of granulocyte colony-stimulating factor in improving neutrophil count and intestinal integrity and growth.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPH.0000000000000660DOI Listing
October 2016

Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO.

J Med Genet 2017 01 22;54(1):47-53. Epub 2016 Aug 22.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Background: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects.

Methods: We searched a clinical database of over 6000 individuals referred for exome sequencing and over 60 000 individuals referred for CNV analysis.

Results: We identified two males with atrial and ventricular septal defects, left ventricular non-compaction (LVNC), developmental delay and intellectual disability, who harboured de novo, loss-of-function variants in NONO. We also identified a male infant with developmental delay, congenital brain anomalies and severe LVNC requiring cardiac transplantation, who inherited a single-gene deletion of NONO from his asymptomatic mother.

Conclusions: We conclude that in addition to global developmental delay and intellectual disability, males with loss-of-function variants in NONO may also be predisposed to developing congenital heart defects and LVNC with the penetrance of these cardiac-related problems being influenced by genetic, epigenetic, environmental or stochastic factors. Brain imaging of males with NONO deficiency may reveal structural defects with abnormalities of the corpus callosum being the most common. Although dysmorphic features vary between affected individuals, relative macrocephaly is a common feature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2016-104039DOI Listing
January 2017

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

Genet Med 2016 12 12;18(12):1235-1243. Epub 2016 May 12.

Division of Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.

Background: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006.

Methods: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT.

Results: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease.

Conclusions: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2016.35DOI Listing
December 2016

Newborn screening for Krabbe disease in New York State: the first eight years' experience.

Genet Med 2016 Mar 21;18(3):239-48. Epub 2016 Jan 21.

Laboratory of Human Genetics, Wadsworth Center, New York State Department of Health, Albany, New York, USA.

Purpose: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006.

Methods: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination.

Results: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease.

Conclusions: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2015.211DOI Listing
March 2016

TMEM107 Is a Critical Regulator of Ciliary Protein Composition and Is Mutated in Orofaciodigital Syndrome.

Hum Mutat 2016 Feb 23;37(2):155-9. Epub 2015 Nov 23.

Department of Genetics, Yale University, School of Medicine, P.O. Box 208005, SHM I-142D, 333 Cedar Street, New Haven, CT, 06520.

The proximate causes of multiple human genetic syndromes (ciliopathies) are disruptions in the formation or function of the cilium, an organelle required for a multitude of developmental processes. We previously identified Tmem107 as a critical regulator of cilia formation and embryonic organ development in the mouse. Here, we describe a patient with a mutation in TMEM107 that developed atypical Orofaciodigital syndrome (OFD), and show that the OFD patient shares several morphological features with the Tmem107 mutant mouse including polydactyly and reduced numbers of ciliated cells. We show that TMEM107 appears to function within cilia to regulate protein content, as key ciliary proteins do not localize normally in cilia derived from the Tmem107 mouse mutant and the human patient. These data indicate that TMEM107 plays a key, conserved role in regulating ciliary protein composition, and is a novel candidate for ciliopathies of unknown etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22925DOI Listing
February 2016

Mutations in ARID2 are associated with intellectual disabilities.

Neurogenetics 2015 Oct 4;16(4):307-14. Epub 2015 Aug 4.

Department of Pediatrics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY, 10032, USA.

The etiology of intellectual disabilities (ID) remains unknown for the majority of patients. Due to reduced reproductive fitness in many individuals with ID, de novo mutations account for a significant portion of severe ID. The ATP-dependent SWI/SNF chromatin modifier has been linked with neurodevelopmental disorders including ID and autism. ARID2 is an intrinsic component of polybromo-associated BAF (PBAF), the SWI/SNF subcomplex. In this study, we used clinical whole exome sequencing (WES) in proband-parent-trios to identify the etiology of ID. We identified four independent, novel, loss of function variants in ARID2 gene in four patients, three of which were confirmed to be de novo. The patients all have ID and share other clinical characteristics including attention deficit hyperactivity disorder, short stature, dysmorphic facial features, and Wormian bones. All four novel variants are predicted to lead to a premature termination with the loss of the two conservative zinc finger motifs. This is the first report of mutations in ARID2 associated with developmental delay and ID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-015-0454-0DOI Listing
October 2015

Staging and outcome in acute exacerbation of idiopathic pulmonary fibrosis: are all limits and determinants under control?

Lung 2015 Feb 14;193(1):155-6. Epub 2014 Oct 14.

Intensive Care Unit and Non Invasive Ventilatory Unit, Hospital Morales Meseguer, Avenida Marques Vélez s/n, 30008, Murcia, Spain,

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00408-014-9656-8DOI Listing
February 2015

The usefulness of whole-exome sequencing in routine clinical practice.

Genet Med 2014 Dec 5;16(12):922-31. Epub 2014 Jun 5.

1] Division of Molecular Genetics, Department of Pediatrics, Columbia University Medical Center, New York, New York, USA [2] Department of Medicine, Columbia University Medical Center, New York, New York, USA.

Purpose: Reports of the use of whole-exome sequencing in clinical practice are limited. We report our experience with whole-exome sequencing in 115 patients in a single center and evaluate its feasibility and clinical usefulness in clinical care.

Methods: Whole-exome sequencing was utilized based on the judgment of three clinical geneticists. We describe age, gender, ethnicity, consanguinity, indication for testing, family history, insurance, laboratory results, clinician interpretation of results, and impact on patient care.

Results: Most patients were children (78.9%). The most common indications for testing were birth defects (24.3%) and developmental delay (25.2%). We identified four new candidate human disease genes and possibly expanded the disease phenotypes associated with five different genes. Establishing a diagnosis led to discontinuation of additional planned testing in all patients, screening for additional manifestations in eight, altered management in fourteen, novel therapy in two, identification of other familial mutation carriers in five, and reproductive planning in six.

Conclusion: Our results show that whole-exome sequencing is feasible, has clinical usefulness, and allows timely medical interventions, informed reproductive choices, and avoidance of additional testing. Our results also suggest phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2014.58DOI Listing
December 2014

Volumetric-modulated arc therapy with RapidArc(®): An evaluation of treatment delivery efficiency.

Rep Pract Oncol Radiother 2013 Aug 17;18(6):383-6. Epub 2013 Aug 17.

Innovative Cancer Institute, 6141 Sunset Drive, Suite 102, South Miami, FL 33143, USA.

Aim/background: To evaluate how the use of volumetric-modulated arc therapy (VMAT) with RapidArc(®) can improve treatment delivery efficiency based on the analysis of the beam-on times and monitor units (MU) needed to deliver therapy for multiple clinical applications in a large patient population.

Materials And Methods: A total of 898 treatment courses were delivered in 745 patients treated from October 2008 to March 2013 using RapidArc® treatment plans generated in Eclipse™ TPS. All patients were treated with curative or palliative intent using different techniques including conventional fractionation (83%) and radiosurgery or SBRT (17%), depending on the clinical indications. Treatment delivery was evaluated based on measured beam-on time and recorded MU values delivered on a Varian Trilogy™ linear accelerator.

Results: For conventional fractionation treatments using RapidArc®, the delivery times ranged from 38 s to 4 min and 40 s (average 2 min and 6 s). For radiosurgical treatments the delivery times ranged from 1 min and 42 s to 9 min and 22 s (average 4 min and 4 s). The average number of MU per Gy was 301 for the entire group, with 285 for the conventional group and 317 for the radiosurgical group.

Conclusions: In this study with a large heterogeneous population, treatments using RapidArc® were delivered with substantially less beam-on time and fewer MUs than conventional fractionation. This was highly advantageous, increasing flexibility of the scheduling allowing treatment of radiosurgery patients during the regular daily work schedule. Additionally, reduction of leakage radiation dose was achieved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.rpor.2013.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863300PMC
August 2013

Validation of a method to quantify titanium, vanadium and zirconium in oral mucosa cells by inductively coupled plasma-mass spectrometry (ICP-MS).

Talanta 2014 Jan 23;118:238-44. Epub 2013 Oct 23.

Stomatology Department, School of Dentistry, University of Seville, C/Avicena sn, C.P. 41009, Seville, Spain. Electronic address:

The release of metal ions from fixed orthodontic appliances is a source of major concern. Various studies have evaluated the discharge of metals from these appliances in biological fluids, such as saliva or blood, overlooking the cells with prolonged contact with fixed appliances. The aim of this work is to develop and optimize an analytical procedure to determine Ti, V and Zr in oral mucosa cells in patients with and without orthodontic appliances by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The analytical procedure is based on an extraction and digestion of the samples and quantification of the elements. A suitable and practical procedure for assessing the trueness and precision of the proposed method has been applied by using validation standards. The method has been suitably validated: the regression equation was calculated from standards prepared in the same matrix without oral mucosa cells and the linear range was 0.5-50.0 ng/mL for Zr and 5.0-50.0 ng/mL for Ti and V. Limits of detection were 0.9, 2.8 and 0.4 ng/mL and limits of quantification 1.8, 3.4 and 0.7 ng/mL for Ti, V and Zr, respectively. The recovery percentages (%) obtained oscillated between 101 and 108 for Ti, 98 and 111 for V, and 92 and 104 for Zr. Intermediate precision (RSD%) data obtained were also adequate. The present method showed to be robust for the three factors considered: heating time, volume of the deionized water, and volume of PlasmaPure 65% HNO₃ used to dilute the samples, which permits its validation and application to oral mucosa cells from orthodontic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.talanta.2013.10.035DOI Listing
January 2014

New York State cystic fibrosis consortium: the first 2.5 years of experience with cystic fibrosis newborn screening in an ethnically diverse population.

Pediatrics 2007 Feb;119(2):e460-7

Departments of Pediatrics, Long Island College Hospital, Brooklyn, New York 11201, USA.

Objective: The purpose of this work was to report on the first 2.5 years of newborn screening for cystic fibrosis in New York.

Methods: Directors of the 11 New York cystic fibrosis centers were asked to provide mutation data, demographic data, and selected laboratory results for each patient diagnosed by newborn screening and followed at their center. Summary data were also submitted from the New York newborn screening laboratory on the total number of patients screened, the number of positive screens, and the number of patients that were lost to follow-up. A second survey was submitted by each center regarding the availability of genetic counseling services at the center.

Results: A total of 106 patients with cystic fibrosis were diagnosed through newborn screening in the first 2.5 years and followed at the 11 Cystic Fibrosis Foundation-sponsored cystic fibrosis care centers in New York. Two screen-negative infants were subsequently diagnosed with cystic fibrosis when symptoms developed. The allele frequency of deltaF508 was 57.4%, which is somewhat lower than the allele frequency of deltaF508 in the US cystic fibrosis population of 70%. There were 90 non-Hispanic white (84%), 12 Hispanic, 2 Asian, and 1 black infants diagnosed with cystic fibrosis during this period. Five patients were diagnosed secondary to a positive screen based on a high immunoreactive trypsinogen and no mutations.

Conclusions: Newborn screening for cystic fibrosis has been effectively conducted in New York using a unique screening algorithm that was designed to be inclusive of the diverse racial makeup of the state. However, this algorithm results in a high false-positive rate, and a large number of healthy newborns are referred for confirmatory sweat tests and genetic counseling. This experience indicates that it would be helpful to convene a working group of cystic fibrosis newborn screening specialists to evaluate which mutations should be included in a newborn screening panel.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2006-1415DOI Listing
February 2007

Duplication of distal 20q: clinical, cytogenetic and array CGH. Characterization of a new case.

Clin Dysmorphol 2006 Jan;15(1):19-23

Division of Genetics, Department of Pediatrics, Beth Israel Medical Center, New York, USA Division of Medical Genetics, Department of Pediatrics, Division of Medical Genetics, University of California, San Francisco, USA Comprehensive Cancer Center, University of California, San Francisco, USA Department of Laboratory Medicine, University of California, San Francisco, USA Department of Pathology, Children's Hospital and Research Center, Oakland, USA.

Trisomy of the long arm of chromosome 20 is rare. We describe an 18-month-old male who was born at 36 weeks via Caesarian section after an uneventful pregnancy. During the newborn period he was found to have a right-sided cleft lip and cleft palate, hypertelorism, strabismus and mildly over-folded ears with cupping. Cardiovascular examination was consistent with the diagnosis of severe aortic coarctation, which was confirmed by echocardiogram. Additionally, hypothyroidism was diagnosed. Neurological evaluation at 18 months revealed a hypotonic infant with delayed acquisition of motor milestones. Cytogenetic analysis showed additional material on the long arm of chromosome 20, confirmed by fluorescence in situ hybridization (FISH) analysis as being of chromosome 20 origin. Because of the indistinct GTG-banding pattern it was not possible to distinguish between a proximal [dup(20)(q11.2q13.1)] or distal duplication [dup(20)(q13.1q13.3)]. To further define the duplication we used array comparative genomic hybridization (CGH) which demonstrated a 7.8 Mb interstitial duplication in distal 20q. Thus, the proband's karyotype was interpreted as 46,XY,dup(20)(q13.2q13.2). The proband is the first reported case of a pure duplication of this region. This case further highlights the utility of array CGH in characterizing aneusomies and, in particular, for accurate breakpoint designation and quantitation of ambiguous rearrangements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/01.mcd.0000184969.84280.e1DOI Listing
January 2006
-->