Publications by authors named "Tyler Reimschisel"

25 Publications

  • Page 1 of 1

Heart Transplantation in Children with Mitochondrial Disease.

J Pediatr 2020 02 8;217:46-51.e4. Epub 2019 Nov 8.

Department of Pediatric Cardiology, Monroe Carell Jr. Children's Hospital, Nashville, TN.

Objectives: To compare the outcomes and comorbidities of children with mitochondrial disease undergoing heart transplantation with children without mitochondrial disease.

Study Design: Using a unique linkage between the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases, pediatric heart transplantation recipients from 2002 to 2016 with a diagnosis of cardiomyopathy were included. Post heart transplantation survival and morbidities were compared between patients with and without mitochondrial disease.

Results: A total of 1330 patients were included, including 47 (3.5%) with mitochondrial disease. Survival after heart transplantation was similar between patients with and without mitochondrial disease over a median follow-up of 4 years. Patients with mitochondrial disease were more likely to have a stroke after heart transplantation (11% vs 3%; P = .009), require a longer duration of mechanical ventilation after heart transplantation (3 days vs 1 day; P < .001), and have a longer intensive care unit stay after heart transplantation (10 vs 6 days; P = .007). The absence of a hospital readmission within the first post-transplant year was similar among patients with and without mitochondrial disease (61.7% vs 51%; P = .14). However, patients with mitochondrial disease who were readmitted demonstrated a longer length of stay compared with those without (median, 14 days vs 8 days; P = .03).

Conclusions: Patients with mitochondrial disease can successfully undergo heart transplantation with survival comparable with patients without mitochondrial disease. Patients with mitochondrial disease have greater risk for post-heart transplantation morbidities including stroke, prolonged mechanical ventilation, and longer intensive care unit and readmission length of stay. These results suggest that the presence of mitochondrial disease should not be an absolute contraindication to heart transplantation in the appropriate clinical setting.
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http://dx.doi.org/10.1016/j.jpeds.2019.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012680PMC
February 2020

Clinical heterogeneity of mitochondrial NAD kinase deficiency caused by a NADK2 start loss variant.

Am J Med Genet A 2018 03 1;176(3):692-698. Epub 2018 Feb 1.

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.

Mitochondrial NAD kinase deficiency (NADK2D, OMIM #615787) is a rare autosomal recessive disorder of NADPH biosynthesis that can cause hyperlysinemia and dienoyl-CoA reductase deficiency (DECRD, OMIM #616034). NADK2 deficiency has been reported in only three unrelated patients. Two had severe, unremitting disease; one died at 4 months and the other at 5 years of age. The third was a 10 year old female with CNS anomalies, ataxia, and incoordination. In two cases mutations in NADK2 have been demonstrated. Here, we report the fourth known case, a 15 year old female with normal intelligence and a mild clinical and biochemical phenotype presumably without DECRD. Her clinical symptoms, which are now stable, became evident at the age of 9 with the onset of decreased visual acuity, bilateral optic atrophy, nystagmus, episodic lower extremity weakness, peripheral neuropathy, and gait abnormalities. Plasma amino acid levels were within normal limits except for mean lysine and proline levels that were 3.7 and 2.5 times the upper limits of normal. Whole exome sequencing (WES) revealed homozygosity for a g.36241900 A>G p. Met1Val start loss mutation in the primary NADK2 transcript (NM_001085411.1) encoding the 442 amino acid isoform. This presumed hypomorphic mutation has not been previously reported and is absent from the v1000GP, EVS, and ExAC databases. Our patient's normal intelligence and stable disease expands the clinical heterogeneity and the prognosis associated with NADK2 deficiency. Our findings also clarify the mechanism underlying NADK2 deficiency and suggest that this disease should be ruled out in cases of hyperlysinemia, especially those with visual loss, and neurological phenotypes.
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http://dx.doi.org/10.1002/ajmg.a.38602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6185736PMC
March 2018

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Am J Hum Genet 2017 Nov;101(5):856-865

Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.
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http://dx.doi.org/10.1016/j.ajhg.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673666PMC
November 2017

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.

Genet Med 2017 12 27;19(12). Epub 2017 Jul 27.

Division of Neurology, McMaster University, Hamilton, Ontario, Canada.

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.
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http://dx.doi.org/10.1038/gim.2017.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804217PMC
December 2017

A systematic review of the published literature on team-based learning in health professions education.

Med Teach 2017 Dec 30;39(12):1227-1237. Epub 2017 Jun 30.

a Department of Pediatrics , Vanderbilt University Medical Center , Nashville , TN , USA.

Purpose: Summarize the published literature on team-based learning (TBL) in health professions education (HPE) using the TBL conceptual framework to identify gaps that can guide future research Methods: PubMed, Web of Science, ERIC, and Google Scholar were searched through May 2016 for English-language articles regarding the use of TBL in HPE. Reviewers independently extracted data and coded for the seven elements in Michaelsen's Model of TBL.

Results: A total of 118 articles met inclusion criteria. The number of articles published yearly on TBL has grown steadily, more than tripling between 2011 and 2016. Most studies (55; 47%) involved undergraduate medical students and took place in the US (72; 61%). The most commonly studied framework component was Teacher and Learner Attitudes (97; 82%). Other commonly studied elements included Learning Outcomes (85; 72%) and Team Characteristics (25; 21%). Contextual Factors affecting TBL was addressed in one study.

Conclusions: A substantial body of literature examines the effect that TBL has on traditional measures of achievement. However, many dimensions of TBL have not been well studied, including Teacher Decisions about TBL, Contextual Factors that affect TBL, Learners' Engagement, and Pattern of Engagement within Teams. Future research in these areas could determine the best use of TBL in HPE.
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http://dx.doi.org/10.1080/0142159X.2017.1340636DOI Listing
December 2017

Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance.

Am J Med Genet A 2015 Sep 11;167A(9):2052-64. Epub 2015 Jun 11.

Unique, Caterham, UK.

The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.
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http://dx.doi.org/10.1002/ajmg.a.37120DOI Listing
September 2015

Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges.

Mitochondrion 2014 Jan 26;14(1):26-33. Epub 2013 Jul 26.

Seattle Children's Hospital/University of Washington, Seattle, WA, United States.

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.
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http://dx.doi.org/10.1016/j.mito.2013.07.116DOI Listing
January 2014

A Systematic Review of BH4 (Sapropterin) for the Adjuvant Treatment of Phenylketonuria.

JIMD Rep 2013 29;8:109-19. Epub 2012 Jul 29.

Division of General Pediatrics and Vanderbilt Institute for Global Health, Vanderbilt Medical Center, 2200 Children's Way, 8232 Doctors' Office Tower, Nashville, TN, 37232-9225, USA,

Context: Dietary management is the mainstay of effective treatment in PKU, but dietary restriction is difficult and additional treatment options are needed.

Objective: To systematically review evidence regarding sapropterin (BH4) use as an adjunct to dietary restriction in individuals with PKU.

Data Sources: Five databases including MEDLINE up to August 2011.

Study Selection: Two reviewers independently assessed studies against predetermined inclusion/exclusion criteria.

Data Extraction: Two reviewers independently extracted data regarding participant and intervention characteristics and outcomes and assigned overall quality and strength of evidence ratings based on predetermined criteria.

Results: BH4 research includes two randomized controlled trials (RCTs) and three uncontrolled open-label trials. Phenylalanine (Phe) levels were reduced by at least 30 % in up to half of treated participants (32-50 %). In one RCT comparing placebo on likelihood of a 30 % reduction in Phe, 9 % of those on placebo achieved this effect, compared with 44 % of the treated group after 6 weeks. Phe tolerance and variability were improved in treated participants in studies assessing those outcomes. No comparative studies assessed long-term outcomes including cognitive effects, nutritional status, or quality of life.

Conclusions: Adjuvant pharmacologic therapy has the potential to support individuals in achieving optimal Phe levels. BH4 has been shown to reduce Phe levels in some individuals, with significantly greater reductions seen in treated versus placebo groups. The strength of the evidence is moderate for short-term effects on reducing Phe in a subset of initially BH4-responsive individuals, moderate for a lack of significant harms, low for longer-term effects on cognition, and insufficient for all other outcomes.
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http://dx.doi.org/10.1007/8904_2012_168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565680PMC
February 2013

Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis.

J Inherit Metab Dis 2013 Sep 30;36(5):757-66. Epub 2012 Nov 30.

Department of Biostatistics, Vanderbilt University Medical Center, 1161 21st Ave South, S-2323 Medical Center North, Nashville, TN 37232-2158, USA.

Though the control of blood phenylalanine (Phe) levels is essential for minimizing impairment in individuals with phenylketonuria (PKU), the empirical basis for the selection of specific blood Phe levels as targets has not been evaluated. We evaluated the current evidence that particular Phe levels are optimal for minimizing or avoiding cognitive impairment in individuals with PKU. This work uses meta-estimates of blood Phe-IQ correlation to predict the probability of low IQ for a range of Phe levels. We believe this metric is easily interpretable by clinicians, and hence useful in making recommendations for Phe intake. The median baseline association of Phe with IQ was estimated to be negative, both in the context of historical (median = -0.026, 95 % BCI = [-0.040, -0.013]) and concurrent (-0.007, [-0.014, 0.000]) measurement of Phe relative to IQ. The estimated additive fixed effect of critical period Phe measurement was also nominally negative for historical measurement (-0.010, [-0.022, 0.003]) and positive for concurrent measurement (0.007, [-0.018, 0.035]). Probabilities corresponding to historical measures of blood Phe demonstrated an increasing chance of low IQ with increasing Phe, with a stronger association seen between blood Phe measured during the critical period than later. In contrast, concurrently-measured Phe was more weakly correlated with the probability of low IQ, though the correlation is still positive, irrespective of whether Phe was measured during the critical or non-critical period. This meta-analysis illustrates the utility of a Bayesian hierarchical approach for not only combining information from a set of candidate studies, but also for combining different types of data to estimate parameters of interest.
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http://dx.doi.org/10.1007/s10545-012-9564-0DOI Listing
September 2013

You too can teach clinical reasoning!

Pediatrics 2012 Nov 22;130(5):795-7. Epub 2012 Oct 22.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-9225, USA.

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http://dx.doi.org/10.1542/peds.2012-2410DOI Listing
November 2012

Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.

Genet Med 2012 Oct 21;14(10):868-76. Epub 2012 Jun 21.

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

Purpose: A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype-phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking.

Methods: We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content.

Results: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated.

Conclusion: STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.
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http://dx.doi.org/10.1038/gim.2012.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713627PMC
October 2012

Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148.

Hum Mol Genet 2012 Aug 27;21(15):3345-55. Epub 2012 Apr 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R809, Houston, TX 77030, USA.

We have identified a rare small (~450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ~109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses.
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http://dx.doi.org/10.1093/hmg/dds166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392111PMC
August 2012

Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females.

Genet Med 2011 May;13(5):447-52

Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland.

Purpose: Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT)-like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5.

Methods: We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5.

Results: We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5.

Conclusion: We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders.
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http://dx.doi.org/10.1097/GIM.0b013e31820605f5DOI Listing
May 2011

Phenotypic manifestations of copy number variation in chromosome 16p13.11.

Eur J Hum Genet 2011 Mar 8;19(3):280-6. Epub 2010 Dec 8.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.
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http://dx.doi.org/10.1038/ejhg.2010.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3061988PMC
March 2011

Detection of clinically relevant exonic copy-number changes by array CGH.

Hum Mutat 2010 Dec 2;31(12):1326-42. Epub 2010 Nov 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes.
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http://dx.doi.org/10.1002/humu.21360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158569PMC
December 2010

Four-year prospective clinical trial of agalsidase alfa in children with Fabry disease.

J Pediatr 2010 May 25;156(5):832-7, 837.e1. Epub 2010 Jan 25.

Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226, USA.

Objectives: To investigate a 4-year prospective clinical trial of agalsidase alfa in children with Fabry disease, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A.

Study Design: Seventeen (16 boys, 1 girl; age range, 7.3 to 18.4 years) of the 24 children who completed a 6-month, open-label agalsidase alfa study enrolled in a 3.5-year extension study that investigated the safety and potential efficacy of long-term treatment. All 17 patients completed the initial 6-month study, and 10 patients (9 boys) completed the extension study.

Results: Agalsidase alfa was well tolerated. In treated boys, there were sustained, statistically-significant improvements in the clinical features of Fabry disease, including reduced plasma globotriaosylceramide levels, reduced pain severity assessed by the Brief Pain Index, and improved heart rate variability. Mean urine globotriaosylceramide levels were reduced to normal range (P < .05 compared with baseline during 1.5 to 4 years). Kidney function and left ventricular mass indexed to height remained stable throughout.

Conclusions: This clinical trial demonstrates that treatment with agalsidase alfa was well tolerated and associated with improvement of Fabry disease-related features.
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http://dx.doi.org/10.1016/j.jpeds.2009.11.007DOI Listing
May 2010

High-frequency detection of deletions and variable rearrangements at the ornithine transcarbamylase (OTC) locus by oligonucleotide array CGH.

Mol Genet Metab 2009 Mar 12;96(3):97-105. Epub 2009 Jan 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Ornithine transcarbamylase (OTC) deficiency is an X-linked inborn error of metabolism characterized by impaired synthesis of citrulline from carbamylphosphate and ornithine. Previously reported data suggest that only approximately 80% of OTC deficiency (OTCD) patients have a mutation identified by OTC gene sequencing. To elucidate the molecular etiology in patients with clinical signs of OTCD and negative OTC sequencing, we subjected their DNA to array comparative genomic hybridization (aCGH) using a custom-designed targeted 44k oligonucleotide array. Whenever possible, parental DNA was analyzed to determine the inheritance or to rule out copy number variants in the OTC locus. DNA samples from a total of 70 OTCD patients were analyzed. Forty-three patients (43/70 or 61.5%) were found to have disease-causing point mutations in the OTC gene. The remaining 27 patients (27/70 or 38.5%) showed normal sequencing results or failure to amplify all or part of the OTC gene. Among those patients, eleven (11/70 or 15.7%) were found to have deletions ranging from 4.5kb to 10.6Mb, all involving the OTC gene. Sixteen OTCD patients (16/70 or 22.8%) had normal sequencing and oligoarray results. Analysis of the deletions did not reveal shared breakpoints, suggesting that non-homologous end joining or a replication-based mechanism might be responsible for the formation of the observed rearrangements. In summary, we demonstrate that approximately half of the patients with negative OTC sequencing may have OTC gene deletions readily identifiable by the targeted oligonucleotide-based aCGH. Thus, the test should be considered in OTC sequencing-negative patients with classic symptoms of the disease.
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http://dx.doi.org/10.1016/j.ymgme.2008.11.167DOI Listing
March 2009

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

Nat Genet 2008 Dec;40(12):1466-71

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

Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.
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http://dx.doi.org/10.1038/ng.279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680128PMC
December 2008

Rapid comprehensive amino acid analysis by liquid chromatography/tandem mass spectrometry: comparison to cation exchange with post-column ninhydrin detection.

Rapid Commun Mass Spectrom 2008 Nov;22(22):3481-8

Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.

Ion-exchange chromatography with ninhydrin detection remains the gold standard for detecting inborn errors of amino acid catabolism and transport. Disadvantages of such analysis include long chromatography times and interference from other ninhydrin-positive compounds. The aim of this project was to develop a more rapid and specific technique using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Optimal fragmentation patterns for 32 amino acids were determined on a triple quadrupole mass spectrometer following butylation. Chromatographic characteristics of each of the amino acids were determined using C8 reversed-phase chromatography with 20% acetonitrile/0.1% formic acid as isocratic mobile phase. Quantitation using eleven deuterated internal standards was compared to cation exchange and ninhydrin detection on a Beckman 7300 system. Following methanol extraction and butylation, determination of 32 amino acids required 20 min. The dynamic range of each amino acid was generally 1-1000 micromol/L. Imprecision ranged from 7 to 23% (CV) over 6 months and recovery ranged from 88-125%. Deming regression with the Beckman 7300 yielded slopes from 0.4-1.2, intercepts from -21 to 65 micromol/L, correlation coefficients from 0.84-0.99 and Syx from 2-125 micromol/L. Isobaric amino acids were separated by chromatography (e.g. leucine, isoleucine) or by unique fragmentation (e.g., alanine, beta-alanine). LC/MS/MS is comparable to traditional LC-ninhydrin detection. Mass spectral detection shortens analysis times and reduces potential for interference in detecting inborn metabolic errors.
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http://dx.doi.org/10.1002/rcm.3754DOI Listing
November 2008

Impact of congenital talipes equinovarus etiology on treatment outcomes.

Dev Med Child Neurol 2008 Jul;50(7):498-502

Department of Orthopedic Surgery, Washington University School of Medicine, One Children's Place, St Louis, MO 63110, U.S.A.

Although congenital talipes equinovarus (CTEV) is often idiopathic, additional birth defects occur in some patients that may have an impact on the treatment of this disorder. The purpose of this study was to determine the prevalence of associated malformations, chromosomal abnormalities, or known genetic syndromes, and to compare treatment outcomes of children with idiopathic CTEV with children with non-idiopathic CTEV. Of 357 children evaluated, 273 (76%) had idiopathic CTEV (179 males, 94 females; mean age 2 y 1 mo [SD 1 y 2 mo], range 0-18 y) and 84 (24%) had non-idiopathic CETV (51 males, 33 females; mean age 2 y 5 mo [SD 2 y], range 0-16 y). Disorders affecting the nervous system were found in 46 (54%) children with non-idiopathic CTEV. In a subgroup of patients treated entirely at our institution (n=196), children with non-idiopathic CTEV (n=47) required more casts for correction than those with idiopathic CTEV (n=149; 5.3 vs 4.6; p=0.016). There was also a greater risk of recurrence in non-idiopathic CTEV (14.9% vs 4%; p=0.009), but no significant difference in the need for extensive surgery (2.7% vs 8.5%; p=0.096). Treatment was initiated at a mean age of 13 weeks (range 1 wk to 2 y 6 mo) for both idiopathic and non-idiopathic patients, and treatment was assessed during a minimum 2-year follow-up. Non-idiopathic CTEV can be successfully treated with the Ponseti method of serial casting, with low recurrence rates or need for surgery.
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http://dx.doi.org/10.1111/j.1469-8749.2008.03016.xDOI Listing
July 2008

A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression.

Eur J Hum Genet 2005 Mar;13(3):330-5

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore MD 21205, USA.

Nail patella syndrome (NPS) is an autosomal dominant disorder affecting development of the limb, kidney and eye. NPS is the result of heterozygous loss-of-function mutations in the LIM-homeodomain transcription factor, LMX1B. Recent studies suggest that the NPS phenotype may be more extensive than recognized previously including neurologic and neurobehavioral aspects. To determine whether these findings correlated with the expression of Lmx1b during development, an internal ribosomal entry site-LacZ reporter was inserted into the 3'UTR of the endogenous murine gene. The pattern of Lmx1b expression during the development of the limb, eye and kidney correlates with the NPS phenotype. Additional sites of expression were observed in the central nervous system (CNS). The effects of the absence of Lmx1b in the CNS were determined in lmx1b-/- mice by histology and immunocytochemistry. Lmx1b is required for the differentiation and migration of neurons within the dorsal spinal cord. The inability of afferent sensory neurons to migrate into the dorsal horn is entirely consistent with diminished pain responses in NPS patients.
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http://dx.doi.org/10.1038/sj.ejhg.5201332DOI Listing
March 2005