Screening of a healthy newborn identifies three adult family members with symptomatic glutaric aciduria type I

Janssen, Manoe J.; Kluijtmans, Laj; Wortmann, S. B.

doi:10.1016/j.bbacli.2014.05.003

Cited by 4 publications

(5 citation statements)

References 24 publications

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“…Adult-onset GA1 is extremely rare. Only a few adult cases have been reported to date, and most of them were asymptomatic female patients who were incidentally diagnosed due to the abnormal NBS results of their infants [ 22 – 25 ]. This study described two asymptomatic maternal GA1 patients with detailed acylcarnitine profiles, which improves our understanding of this disorder.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Lin¹,

Wang²,

Cai³

et al. 2021

Orphanet J Rare Dis

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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.

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Section: Discussionmentioning

confidence: 99%

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Lin¹,

Wang²,

Cai³

et al. 2021

Orphanet J Rare Dis

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show abstract

“…This special finding is well known and there are a few cases reported in the literature. Some mothers were symptomatic and others asymptomatic at the time of diagnosis [ 14 , 15 , 16 , 17 ]. Curiously, levels of C5DC in the newborn are normal and what is usually observed is a secondary depletion of free carnitine levels [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Serendipities of Expanded Newborn Screening

Yahyaoui

Blasco‐Alonso

Gonzalo-Marín

et al. 2020

Genes

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Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B12 status. All cases provide new or interesting data that will help guide differential diagnosis in the future.

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“…The phenotypic spectrum of GA1 is broad and ranges from severely affected patients to asymptomatic adults (Straus et al 2003;Janssen et al 2014). Our patient was diagnosed with GA1 at the age of 11 after high-risk family screening.…”

Section: Intra-familial Variabilitymentioning

confidence: 91%

“…Some patients with GA1 remain asymptomatic, even in their adulthood (Kolker et al 2006). Moreover, several maternal GA1 cases have been diagnosed based on the findings in their offspring (Crombez et al 2008;Garcia et al 2008;Janssen et al 2014;Boy et al 2017b). Often the only complaint these patients present is chronic fatigue (Janssen et al 2014;Haworth et al 1991;Prevett et al 1996), and provided that they avoid severe illness, these individuals are unlikely to decompensate metabolically.…”

Section: Introductionmentioning

confidence: 99%

Two Uneventful Pregnancies in a Woman with Glutaric Aciduria Type 1

et al. 2018

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Glutaric aciduria type 1 (GA1) is an autosomal recessive rare disorder caused by mutations in the GCDH gene resulting in deficiency of glutaryl-CoA dehydrogenase, leading to accumulation of the amino acids lysine, hydroxylysine and tryptophan and other metabolites. The phenotypic spectrum of disease is broad. Stress caused by infection and fever and possibly pregnancy may lead to worsening of the signs and symptoms, often with uncertain recovery.We describe a case of a female patient with GA1 who had two clinically uneventful pregnancies.At the age of 11 she was diagnosed with GA1 by family screening. The cultured skin fibroblast showed reduced glutaryl-CoA dehydrogenase activity (0.16 mg protein per min).The initial diagnostic urine glutaric acid level for this patient was 1,784 μmol/mmol creatinine. Mutation analysis showed compound heterozygosity for the p.(Gly185Arg), c.553G>A in exon 7 and p.(Arg402Trp), c.1204C.T in exon 11 mutations of the GCDH.Her pregnancy at the age of 23 was complicated by pre-eclampsia and required treatment with beta-blockers. Four years later the second pregnancy was uncomplicated. The management plan during the caesarean section included intravenous dextrose and lipid infusions. The patient rapidly recovered from both surgeries.Both babies have had normal development to date. On newborn screening, plasma acylcarnitine showed a transient increase in glutarylcarnitine, and the urine organic acid analysis showed a trace of 3-hydroxyglutarylcarnitine, likely to be of maternal transfer.The multidisciplinary team, consisting of metabolic, dietetic and obstetric care providers, have responsibility to ensure the risk of acute decompensation in pregnant GA1 women is minimal.

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Screening of a healthy newborn identifies three adult family members with symptomatic glutaric aciduria type I

Cited by 4 publications

References 24 publications

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Biochemical and molecular features of Chinese patients with glutaric acidemia type 1 detected through newborn screening

Metabolic Serendipities of Expanded Newborn Screening

Two Uneventful Pregnancies in a Woman with Glutaric Aciduria Type 1

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