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Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families

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Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families International Journal of Neonatal Screening Article Glutaric Aciduria Type I Missed by Newborn Screening: Report of Four Cases from Three Families Johannes Spenger 1 , Esther M. Maier 2, Katharina Wechselberger 3 , Florian Bauder 3 , Melanie Kocher 4, Wolfgang Sperl 1, Martin Preisel 1, Katharina A. Schiergens 2, Vassiliki Konstantopoulou 5, Wulf Röschinger 6, Johannes Häberle 7, Thomas Schmitt-Mechelke 3 , Saskia B. Wortmann 1 and Ralph Fingerhut 7,8,*,† 1 Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria; [email protected] (J.S.); [email protected] (W.S.); [email protected] (M.P.); [email protected] (S.B.W.) 2 Division of Metabolism, Dr. von Hauner Children’s Hospital, D-80337 Munich, Germany; [email protected] (E.M.M.); [email protected] (K.A.S.) 3 Division of Neuropediatrics, Children’s Hospital Lucerne, CH-6004 Lucerne, Switzerland; [email protected] (K.W.); fl[email protected] (F.B.); [email protected] (T.S.-M.) 4 Kinderarztpraxis Arche, CH-3270 Aarberg, Switzerland; [email protected] 5 Austrian Newborn Screening Program, Departement of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria; [email protected] 6 Division of Newborn Screening, Laboratory Becker & Colleagues, D-81671 Munich, Germany; [email protected] 7 Division of Metabolism and Children’s Research Center, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland; [email protected] 8 Swiss Newborn Screening Laboratory, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland * Correspondence: [email protected]; Tel.: +49-961-309-327; Fax: +49-961-309-224 Citation: Spenger, J.; Maier, E.M.; † Present Address: Division of Newborn Screening, Synlab MVZ Weiden GmbH, D-92363 Weiden, Germany. Wechselberger, K.; Bauder, F.; Kocher, M.; Sperl, W.; Preisel, M.; Schiergens, Abstract: Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of K.A.; Konstantopoulou, V.; Röschinger, the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl- W.; et al. Glutaric Aciduria Type I CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of Missed by Newborn Screening: Report of Four Cases from Three glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in Families. Int. J. Neonatal Screen. 2021, whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were 7, 32. https://doi.org/10.3390/ either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also ijns7020032 not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute Academic Editor: Can Ficicioglu encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of Received: 18 April 2021 NBS for GA-1, by adjusting cut-offs and introducing various ratios, the biological diversity still leads Accepted: 13 June 2021 to false-negative NBS results for GA-1. Published: 18 June 2021 Keywords: glutaric aciduria type 1; newborn screening; glutaryl-carnitine; glutaric acid; Publisher’s Note: MDPI stays neutral 3-hydroxyglutaric acid; GCDH gene; missed cases with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degra- dation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. encoding glutaryl-CoA-dehydrogenase (for review see [1]). Affected patients typically This article is an open access article present in infancy or early childhood with progressive macrocephaly and an acute en- distributed under the terms and cephalopathic crisis, often caused by a catabolic state, e.g., a febrile viral illness. However, conditions of the Creative Commons there are also patients who present with insidious onset dystonia, where clinical symptoms Attribution (CC BY) license (https:// are less specific and show a slower progression. Accumulation of toxic metabolites may creativecommons.org/licenses/by/ lead to irreversible damage of the basal ganglia and severe progressive dystonic cerebral 4.0/). palsy [2]. Patients with GA-1 can also be biochemically subdivided into two groups. One Int. J. Neonatal Screen. 2021, 7, 32. https://doi.org/10.3390/ijns7020032 https://www.mdpi.com/journal/ijns Int. J. Neonatal Screen. 2021, 7, 32 2 of 9 are the high excretors, where marker metabolites in urine are always elevated, with urinary glutaric acid > 100 mmol/mol creatinine. The second group are the low excretors, where marker metabolites are normal, or not detectable with the standard methods for the anal- ysis of organic acids in urine, with urinary glutaric acid < 100 mmol/mol creatinine [3]. Guidelines for screening, diagnosis, and treatment were recently published [4], and have proven success in improving the outcomes of patients [5,6]. An early diagnosis and pre- vention of metabolic deterioration is the key for this, and therefore newborn screening (NBS) for this condition has been done in Bavaria since 1999, in Austria since 2004, and in Switzerland since November 2014, based on elevated levels of glutaryl-carnitine (C5DC) in dried blood spots (DBS). Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1 by adjusting cut-offs and introducing various ratios, the biological diversity still leads to false-negative NBS results for GA-1 [5,7–10]. 2. Case Reports 2.1. Case 1 Patient 1 was born at term after an uneventful pregnancy. The boy was the second child of healthy, non-consanguineous Swiss parents. NBS was performed correctly with unremarkable results. His previous development and head circumference were normal. At the age of 9 months, he presented to the emergency department with fever, vomiting, diarrhea, and mild dehydration. His body weight was 9.45 kg (62nd percentile, 0.31 Z- score), length was 73 cm (39th percentile, −0.28 Z-Score), and head circumference was 46 cm (63rd percentile, 0.34 Z-Score). His older brother also was suffering from gastroenteritis. He was admitted due to several short clonic seizures with eye deviation. Serum electrolytes and glucose were normal, and rotavirus antigen was positive in feces. The initial diagnosis was convulsions associated with rotavirus gastroenteritis, and treatment with low-dose carbamazepine was started. His condition worsened the next day with the development of an acute encephalopathic crisis, including muscular hypotonia, sleepiness, and repeated dystonic posturing with paroxysmal eye movements. Cranial magnetic resonance imaging (MRI) showed bilateral signal alterations of the basal ganglia affecting caudate, putamen, and pallidum (Figure1), suggestive of GA-1. Carnitine supplementation and a protein- restricted diet were started according to current guidelines [4] and the family received an emergency plan. Metabolic testing showed elevation of urinary glutaric acid and 3- hydroxyglutaric acid (table). Diagnosis of GA-1 was genetically confirmed, showing a compound heterozygous GCDH genotype with pathogenic variants c.722G>T/p.Gly241Val (mutation not previously described) and c.1169G>C/p.Gly390Ala. Subsequently, the boy developed dystonic cerebral palsy and a global developmental delay. At the age of 23 months, he was still not able to sit, but was not dependent on tube feeding and had preserved good social contact. At his last visit at the age of 5 years, he showed dyskinetic cerebral palsy (GMFCS Level 5) but good social contact, and he is still not dependent on tube feeding. Int. J. Neonatal Screen. 2021, 7, 32 3 of 9 Int. J. Neonatal Screen. 2021, 7, x FOR PEER REVIEW 3 of 9 Figure 1. CranialFigure MRI 1. Cranialof patient MRI 1 during of patient encephalopathic 1 during encephalopathic crisis at the age crisis of 9 at months the age, showing of 9 months, distinct showing bilateral signal alteration of distinctcaudate, bilateral putamen, signal and alterationpallidum of(yellow caudate, arrows). putamen, (a): axial and pallidumT2, (b): coronar (yellow T2, arrows). (c): axial (a ):diffusion axial T2, weighted (DWI), (d): ADC-map imaging. (b): coronar T2, (c): axial diffusion weighted (DWI), (d): ADC-map imaging. 2.2. Case 2 2.2. Case 2 Patient 2 wasPatient the first 2 childwas the of healthyfirst child non-consanguineous of healthy non-consanguineous Moroccan parents. Moroccan Preg- parents. Preg- nancy and birthnancy were and unremarkable, birth were unremarkable, as was NBS. as Hewas had NBS. a surgicalHe had a correction surgical correction of an of an ob- obstructive mega-ureterstructive mega detected-ureter after detected pyelonephritis after pyelonephritis with consecutive with malfunctionconsecutive ofmalfunction the of the right kidney. right kidney. At the age ofAt 2 yearsthe age and of 42 months,years and he 4 was months first, referredhe was first to the referred neuropediatrician to the neuropediatrician because of non-progressivebecause of non- ataxiaprogressive and developmental ataxia and developmental
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