Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening.
GCDH gene
Glutaric acidemia type 1
free carnitine
newborn screening
primary carnitine deficiency
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
03 08 2021
03 08 2021
Historique:
received:
27
04
2021
accepted:
19
07
2021
entrez:
4
8
2021
pubmed:
5
8
2021
medline:
7
10
2021
Statut:
epublish
Résumé
Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. GA1 diagnosis reports following newborn screening (NBS) are scarce in the Chinese population. This study aimed to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 identified through NBS. From January 2014 to September 2020, 517,484 newborns were screened by tandem mass spectrometry, 102 newborns with elevated glutarylcarnitine (C5DC) levels were called back. Thirteen patients were diagnosed with GA1, including 11 neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated at 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderate to markedly increased C5DC levels. Notably, one neonatal patient with low free carnitine (C0) level suggest primary carnitine deficiency (PCD) but was ultimately diagnosed as GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA and 3HGA levels, and one was reported to be within the normal range. Ten distinct GCDH variants were identified. Eight were previously reported, and two were newly identified. In silico prediction tools and protein modeling analyses suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2 A>C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G>A (p.Ala421Thr) at 9.09% (2/22). Neonatal GA1 patients with increased C5DC levels can be identified through NBS. Maternal GA1 patients can also be detected using NBS due to the low C0 levels in their infants. Few neonatal GA1 patients may have atypical acylcarnitine profiles that are easy to miss during NBS; therefore, multigene panel testing should be performed in newborns with low C0 levels. This study indicates that the GCDH variant spectra were heterogeneous in this southern Chinese cohort.
Sections du résumé
BACKGROUND
Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. GA1 diagnosis reports following newborn screening (NBS) are scarce in the Chinese population. This study aimed to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 identified through NBS.
RESULTS
From January 2014 to September 2020, 517,484 newborns were screened by tandem mass spectrometry, 102 newborns with elevated glutarylcarnitine (C5DC) levels were called back. Thirteen patients were diagnosed with GA1, including 11 neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated at 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderate to markedly increased C5DC levels. Notably, one neonatal patient with low free carnitine (C0) level suggest primary carnitine deficiency (PCD) but was ultimately diagnosed as GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA and 3HGA levels, and one was reported to be within the normal range. Ten distinct GCDH variants were identified. Eight were previously reported, and two were newly identified. In silico prediction tools and protein modeling analyses suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2 A>C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G>A (p.Ala421Thr) at 9.09% (2/22).
CONCLUSIONS
Neonatal GA1 patients with increased C5DC levels can be identified through NBS. Maternal GA1 patients can also be detected using NBS due to the low C0 levels in their infants. Few neonatal GA1 patients may have atypical acylcarnitine profiles that are easy to miss during NBS; therefore, multigene panel testing should be performed in newborns with low C0 levels. This study indicates that the GCDH variant spectra were heterogeneous in this southern Chinese cohort.
Identifiants
pubmed: 34344405
doi: 10.1186/s13023-021-01964-5
pii: 10.1186/s13023-021-01964-5
pmc: PMC8335863
doi:
Substances chimiques
Glutaryl-CoA Dehydrogenase
EC 1.3.8.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
339Informations de copyright
© 2021. The Author(s).
Références
J Inherit Metab Dis. 1999 Dec;22(8):867-81
pubmed: 10604139
Metab Brain Dis. 2013 Mar;28(1):61-7
pubmed: 23104440
J Inherit Metab Dis. 2017 Jan;40(1):75-101
pubmed: 27853989
Genet Med. 2021 Jan;23(1):13-21
pubmed: 32981931
Eur J Pediatr. 2008 May;167(5):569-73
pubmed: 17661081
J Inherit Metab Dis. 2014 Nov;37(6):881-7
pubmed: 24970580
Brain Dev. 2014 Oct;36(9):813-22
pubmed: 24332224
JIMD Rep. 2012;6:79-83
pubmed: 23430943
J Inherit Metab Dis. 2006 Feb;29(1):76-85
pubmed: 16601872
Clin Chim Acta. 2016 Jan 30;453:75-9
pubmed: 26656312
Orphanet J Rare Dis. 2017 Apr 24;12(1):77
pubmed: 28438223
Mol Genet Metab. 2011 Mar;102(3):343-8
pubmed: 21176883
Eur J Paediatr Neurol. 2013 Jul;17(4):383-9
pubmed: 23395213
Clin Chim Acta. 2019 Jul;494:106-111
pubmed: 30904546
Clin Chim Acta. 2018 Dec;487:133-138
pubmed: 30253142
Front Genet. 2019 Oct 29;10:1052
pubmed: 31737040
JIMD Rep. 2018;41:29-36
pubmed: 29292490
Front Genet. 2019 Feb 14;10:86
pubmed: 30838026
Mol Genet Metab. 2012 Aug;106(4):430-8
pubmed: 22728054
Front Genet. 2020 May 20;11:496
pubmed: 32508882
Mol Genet Metab. 2011 Dec;104(4):470-5
pubmed: 22000754
Orphanet J Rare Dis. 2013 Oct 17;8:167
pubmed: 24135440
Neurogenetics. 2020 Jul;21(3):179-186
pubmed: 32306145
Clin Chim Acta. 2020 Oct;509:25-29
pubmed: 32505769
Metab Brain Dis. 2020 Aug;35(6):1009-1016
pubmed: 32240488
N Engl J Med. 2003 Jun 5;348(23):2304-12
pubmed: 12788994
BBA Clin. 2014 Jun 01;1:30-2
pubmed: 26674492
Sci Rep. 2021 Jan 29;11(1):2699
pubmed: 33514801
J Formos Med Assoc. 2008 Feb;107(2):139-44
pubmed: 18285246
Med Sci Monit. 2011 Jul;17(7):PH55-9
pubmed: 21709643
Pediatr Res. 2006 Jun;59(6):840-7
pubmed: 16641220
Ann Neurol. 2018 May;83(5):970-979
pubmed: 29665094
J Inherit Metab Dis. 2004;27(6):861-8
pubmed: 15505393
J Inherit Metab Dis. 2012 Jul;35(4):603-11
pubmed: 22552820