Publications by authors named "Laura Konczal"

10 Publications

  • Page 1 of 1

Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis.

Mol Genet Metab 2021 02 13;132(2):119-127. Epub 2021 Jan 13.

Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. Electronic address:

Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was -0.5768 with a lower limit of the 95% confidence interval (CI) of -1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of -3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120-360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.
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http://dx.doi.org/10.1016/j.ymgme.2021.01.001DOI Listing
February 2021

Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?

J Med Genet 2020 Nov 16. Epub 2020 Nov 16.

Necker Hospital, APHP, Reference Center for Mitochondrial Diseases, Genetics Department, Institut Imagine, University of Paris, Paris, France

Background: Biallelic variants in cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs.

Objective And Methods: To document neuroimaging data in six patients with PNPT1 highlighting novel findings.

Results: Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection.

Conclusion: We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.
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http://dx.doi.org/10.1136/jmedgenet-2020-107367DOI Listing
November 2020

Life-threatening presentations of propionic acidemia due to the Amish founder variant.

Mol Genet Metab Rep 2019 Dec 6;21:100537. Epub 2019 Nov 6.

Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, United States of America.

Although individuals of Amish descent with propionic acidemia (PA) are generally thought to have a milder disease phenotype, we now have a better understanding of the natural history of PA in this population. Here we describe two Amish patients with emergent presentations of PA, one with metabolic decompensation and another with cardiogenic shock. PA can present with life-threatening metabolic decompensation or an adult-onset severe cardiomyopathy. We discuss critical clinical implications of this observation.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895572PMC
December 2019

Conducting an investigator-initiated randomized double-blinded intervention trial in acute decompensation of inborn errors of metabolism: Lessons from the N-Carbamylglutamate Consortium.

Transl Sci Rare Dis 2018 Dec 20;3(3-4):157-170. Epub 2018 Dec 20.

Children's National Health System, Washington, DC, USA.

Organic acidemias and urea cycle disorders are ultra-rare inborn errors of metabolism characterized by episodic acute decompensation, often associated with hyperammonemia, resulting in brain edema and encephalopathy. Retrospective reports and translational studies suggest that N-carbamylglutamate (NCG) may be effective in reducing ammonia levels during acute decompensation in two organic acidemias, propionic and methylmalonic acidemia (PA and MMA), and in two urea cycle disorders, carbamylphosphate synthetase 1 and ornithine transcarbamylase deficiency (CPSD and OTCD). We established the 9-site N-carbamylglutamate Consortium (NCGC) in order to conduct two randomized double-blind, placebo-controlled trials of NCG in acute hyperammonemia of PA, MMA, CPSD and OTCD. Conducting clinical trials is challenging in any disease, but poses unique barriers and risks in the ultra-rare disorders. As the number of clinical trials in orphan diseases increases, evaluating the successes and opportunities for improvement in such trials is essential. We summarize herein the design, methods, experiences, challenges and lessons from the NCGC-conducted trials.
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http://dx.doi.org/10.3233/TRD-180031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311376PMC
December 2018

Challenges in the diagnosis and management of disorders of sex development.

Birth Defects Res C Embryo Today 2016 Dec;108(4):293-308

Katherine Kutney, Beth Kaminski, and Naveen Uli are from the Division of Pediatric Endocrinology & Diabetes, University Hospitals/Rainbow Babies & Children's Hospital, Cleveland, Ohio.

Disorders of sex development (DSD) represent a spectrum of uncommon but very complex disorders with medical, psychosexual, and family implications for those affected by them. The diagnosis and management of these disorders requires a coordinated team of multiple specialists. Following an international conference in Chicago in 2005, a consensus statement was created and presented, which has resulted in a new paradigm in the nomenclature, classification, and management of DSDs. Since that time, many improvements have been forthcoming, most notably in the area of molecular genetic technologies. These developments have advanced our understanding of the specific etiologies underlying many of these conditions. In this article, we present an overview of the physiology of sex development, a few clinical vignettes highlighting specific pathologic conditions, discussions regarding the evaluation and management of these disorders, and some thoughts on future directions in this field. Birth Defects Research (Part C) 108:293-308, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdrc.21147DOI Listing
December 2016

The perils of SNP microarray testing: uncovering unexpected consanguinity.

Pediatr Neurol 2013 Jul;49(1):50-3

Child Health Evaluation and Research (CHEAR) Unit, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

Background: Although single nucleotide polymorphism chromosomal microarrays identify areas of small genetic deletions or duplications, they can also reveal regions of homozygosity indicative of consanguinity. As more nongeneticists order single nucleotide polymorphism microarrays, they must prepare for the potential ethical, legal, and social issues that result from revelation of unanticipated consanguinity.

Patient: We describe an infant with multiple congenital anomalies who underwent single nucleotide polymorphism microarray testing.

Results: The results of the single nucleotide polymorphism microarray revealed several large regions of homozygosity that indicated identity by descent most consistent with a second-degree or third-degree relative mating (e.g., uncle/niece, half-brother/sister, first cousins). The mother was not aware of the test's potential to reveal consanguinity. When informed of the test results, she reluctantly admitted to being raped by her half-brother around the time of conception.

Conclusions: During the pretesting consent process, providers should inform parents that single nucleotide polymorphism microarray testing could reveal consanguinity. Providers must also understand the psychological implications, as well as the legal and moral obligations, that accompany single nucleotide polymorphism microarray results that indicate consanguinity.
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http://dx.doi.org/10.1016/j.pediatrneurol.2013.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703098PMC
July 2013

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Am J Hum Genet 2013 Feb 17;92(2):210-20. Epub 2013 Jan 17.

Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.
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http://dx.doi.org/10.1016/j.ajhg.2012.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567268PMC
February 2013

Germline mosaicism in Cornelia de Lange syndrome.

Am J Med Genet A 2012 Jun 11;158A(6):1481-5. Epub 2012 May 11.

Department of Genetics and Center for Human Genetics, University Hospitals of Cleveland, Case Medical Center, Cleveland, Ohio, USA.

Cornelia de Lange syndrome (CdLS) is a genetic disorder associated with delayed growth, intellectual disability, limb reduction defects, and characteristic facial features. Germline mosaicism has been a described mechanism for CdLS when there are several affected offspring of apparently unaffected parents. Presently, the recurrence risk for CdLS has been estimated to be as high as 1.5%; however, this figure may be an underrepresentation. We report on the molecularly defined germline mosaicism cases from a large CdLS database, representing the first large case series on germline mosaicism in CdLS. Of the 12 families, eight have been previously described; however, four have not. No one specific gene mutation, either in the NIPBL or the SMC1A gene, was associated with an increased risk for germline mosaicism. Suspected or confirmed cases of germline mosaicism in our database range from a conservative 3.4% up to 5.4% of our total cohort. In conclusion, the potential reproductive recurrence risk due to germline mosiacism should be addressed in prenatal counseling for all families who have had a previously affected pregnancy or child with CdLS.
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http://dx.doi.org/10.1002/ajmg.a.35381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356507PMC
June 2012

Underlying genetic diagnosis of Pierre Robin sequence: retrospective chart review at two children's hospitals and a systematic literature review.

J Pediatr 2012 Apr 1;160(4):645-650.e2. Epub 2011 Nov 1.

Center for Human Genetics, University Hospitals Case Medical Center and the Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH, USA.

Objectives: To determine the underlying genetic diagnosis of Pierre Robin sequence (PRS) in 2 cohorts of individuals, assess the accuracy of genetic evaluation in young infants with PRS, and contrast the interventions provided to children with isolated and syndromic PRS.

Study Design: The study involved retrospective chart reviews at 2 children's hospitals and a systematic literature review.

Results: Approximately 40% of the patients had isolated PRS, and 60% of the patients had additional syndromic features. The patients with PRS with syndromic features required more aggressive medical management. Stickler syndrome was the most common syndromic diagnosis in PRS. The difficulty of making an accurate genetic diagnosis during the neonatal period was demonstrated.

Conclusion: All infants with PRS should be evaluated to check for the presence of syndromic features, and a longitudinal follow-up is warranted to monitor for the development of any syndromic features.
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http://dx.doi.org/10.1016/j.jpeds.2011.09.021DOI Listing
April 2012

Acute dilated cardiomyopathy in a patient with deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase.

Pediatr Cardiol 2009 May 16;30(4):523-6. Epub 2008 Dec 16.

Department of Pediatrics, Nationwide Children's Hospital Heart Center, Columbus, OH 43205-2696, USA.

Deficiency of long-chain 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase (LCHADD) is a rare inborn error of metabolism. It is associated with hypertrophic cardiomyopathy and less frequently with dilated cardiomyopathy. The incidence and pathophysiology of cardiac involvement in LCHADD is poorly understood. This report describes the acute decompensation of a 3-year-old girl who had LCHADD with rapidly developing dilated cardiomyopathy. A review of the literature and possible causes of cardiomyopathy in LCHADD are explored.
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http://dx.doi.org/10.1007/s00246-008-9351-8DOI Listing
May 2009