Maternal glutaric acidemia, type I identified by newborn screening

doi:10.1016/j.ymgme.2008.01.005

Molecular Genetics and Metabolism

Volume 94, Issue 1, May 2008, Pages 132-134

https://doi.org/10.1016/j.ymgme.2008.01.005 Get rights and content

Abstract

We report two women with glutaric acidemia type I in whom the diagnosis was unsuspected until a low carnitine level was found in their newborn children. Both mothers had low carnitine in plasma. In the first, organic acid analysis was only done after fibroblast studies revealed normal carnitine uptake. Having learned from the first family, organic acid analysis was done immediately in the mother of family 2. In both, the plasma acylcarnitine profile was normal but both excreted the metabolites typical of their disorder. One of the women was a compound heterozygote for distinct mutations in the glutaric acid dehydrogenase gene, whereas the second was either homozygous or hemizygous for a mutation in Exon 6 of the gene.

Section snippets

Family 1

A male child born in late 2005 was the product of the second pregnancy to a non- consanguineous couple. There was 1 normal older sibling and an older half sibling. Pregnancy and delivery were normal and the boy is healthy and developing normally. The biochemical results are shown in Table 1. The total carnitine concentration at 2 days in the newborn screening blood spot was 4 μM. At day 12 it was 12 μM. The level rose rapidly on addition of carnitine to the treatment (100 mg/kg/day in divided

Analytes

Expanded newborn screening was carried out by the California Newborn Screening program which operated with contracts to six independent laboratories. Perkin-Elmer tandem mass spectrometers and reagents supplied by the manufacturer are used.

Followup testing was performed by Quest Laboratories (San Juan Capistrano, CA using their usual methods).

Carnitine uptake studies

These were done in skin fibroblasts in the laboratory of Dr. Nicola Longo by his usual methods [6].

Mutation analysis

Mutation analyses were carried out in the University of

Results and discussion

Both mothers described in the paper had glutaric acidemia, type 1. Although plasma and urinary metabolite levels do not describe the potential severity of the genetic defect or the vulnerability of the person carrying them, the analyte levels are high enough, in urine, to suggest that the mutations are consequential and cause a severe disruption in the glutaryl-CoA catabolic pathway. On the other hand the normal results of the plasma glutarylcarnitine measurements underscores what is known from

Acknowledgments

Supported in part by the Mental Retardation Research Center at UCLA, by USPHS Grant HD-04612 and by a contract from the State of California. Supported in part by the Mental Retardation and Developmental Disabilities Center at UCDHSC (5 P30 HD004024-35, NIH/NICHD).

References (10)

S.I. Goodman et al.
Glutaric aciduria: a “new” disorder of amino acid metabolism
Biochem. Med.
(1975)
L.A. Schimmenti et al.
Expanded newborn screening identifies maternal primary carnitine deficiency
Mol. Genet. Metab.
(2007)
S.I. Goodman et al.
GlutarylCoA dehydrogenase mutations in glutaric acidemia (type 1): a review and report of 30 novel mutations
Human Mut.
(1998)
S.I. Goodman, F.E. Frerman, Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric...
D.H. Morton et al.
Glutaric acidemia type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania
Am. J. Med. Genet.
(1991)

There are more references available in the full text version of this article.

Cited by (36)

Comprehensive metabolomics analysis reveals novel biomarkers and pathways in falsely suspected glutaric aciduria Type-1 newborns
2024, Clinica Chimica Acta
Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns.
DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites.
582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples.
A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.
Glutaric acidemia type 1: Treatment and outcome of 168 patients over three decades
2020, Molecular Genetics and Metabolism
Citation Excerpt :
Fourteen of them are >17 years, have been off protein restriction and dietary supplements since early childhood, and report no clinically significant neurological problems or health concerns. Similar stories emerge from false positive NBS results that reveal GCDH deficiency in otherwise healthy mothers [56,83,97,98]. The foregoing discussion should not be misinterpreted as a formal recommendation to stop dietary therapy for GA1 patients older than two years.
Glutaric acidemia type 1 (GA1) is a disorder of cerebral organic acid metabolism resulting from biallelic mutations of GCDH. Without treatment, GA1 causes striatal degeneration in >80% of affected children before two years of age. We analyzed clinical, biochemical, and developmental outcomes for 168 genotypically diverse GA1 patients managed at a single center over 31 years, here separated into three treatment cohorts: children in Cohort I (n = 60; DOB 2006–2019) were identified by newborn screening (NBS) and treated prospectively using a standardized protocol that included a lysine-free, arginine-enriched metabolic formula, enteral l-carnitine (100 mg/kg•day), and emergency intravenous (IV) infusions of dextrose, saline, and l-carnitine during illnesses; children in Cohort II (n = 57; DOB 1989–2018) were identified by NBS and treated with natural protein restriction (1.0–1.3 g/kg•day) and emergency IV infusions; children in Cohort III (n = 51; DOB 1973–2016) did not receive NBS or special diet. The incidence of striatal degeneration in Cohorts I, II, and III was 7%, 47%, and 90%, respectively (p < .0001). No neurologic injuries occurred after 19 months of age. Among uninjured children followed prospectively from birth (Cohort I), measures of growth, nutritional sufficiency, motor development, and cognitive function were normal. Adherence to metabolic formula and l-carnitine supplementation in Cohort I declined to 12% and 32%, respectively, by age 7 years. Cessation of strict dietary therapy altered plasma amino acid and carnitine concentrations but resulted in no serious adverse outcomes. In conclusion, neonatal diagnosis of GA1 coupled to management with lysine-free, arginine-enriched metabolic formula and emergency IV infusions during the first two years of life is safe and effective, preventing more than 90% of striatal injuries while supporting normal growth and psychomotor development. The need for dietary interventions and emergency IV therapies beyond early childhood is uncertain.
Biochemical characteristics of newborns with carnitine transporter defect identified by newborn screening in California
2017, Molecular Genetics and Metabolism
Carnitine transporter defect (CTD; also known as systemic primary carnitine deficiency; MIM 212140) is due to mutations in the SLC22A5 gene and leads to extremely low carnitine levels in blood and tissues. Affected individuals may develop early onset cardiomyopathy, weakness, or encephalopathy, which may be serious or even fatal. The disorder can be suggested by newborn screening. However, markedly low newborn carnitine levels can also be caused by conditions unrelated to CTD, such as the low carnitine levels often associated with normal pregnancies and some metabolic disorders occurring in the mother. In order to clarify the biochemical characteristics most useful for identification of CTD in newborns, we examined California Department of Public Health newborn screening data for CTD from 2005 to 12 and performed detailed chart reviews at six metabolic centers in California. The reviews covered 14 cases of newborn CTD, 14 cases of maternal disorders (CTD, 6 cases; glutaric aciduria, type 1, 5; medium-chain acyl CoA dehydrogenase deficiency, 2; and cobalamin C deficiency, 1), and 154 false-positive cases identified by newborn screening. Our results show that newborns with CTD identified by NBS exhibit different biochemical characteristics, compared to individuals ascertained clinically. Newborns with CTD may have NBS dried blood spot free carnitine near the lower cutoff and confirmatory plasma total and free carnitine levels near the normal lower limit, particularly if obtained within two weeks after birth. These findings raise the concern that true cases of CTD may exist that could have been missed by newborn screening. CTD should be considered as a possible diagnosis in cases with suggestive clinical features, even if CTD was thought to be excluded in the newborn period. Maternal plasma total carnitine and newborn urine total carnitine values are the most important predictors of true CTD in newborns. However, biochemical testing alone does not yield a discriminant rule to distinguish true CTD from low carnitine in newborns due to other causes. Because of this biochemical variability and overlap, molecular genetic testing is imperative to confirm CTD in newborns. Additionally, functional testing of fibroblast carnitine uptake remains necessary for cases in which other confirmatory testing is inconclusive. Even with utilization of all available diagnostic testing methods, confirmation of CTD ascertained by NBS remains lengthy and challenging. Incorporation of molecular analysis as a second tier step in NBS for CTD may be beneficial and should be investigated.
Arachnoid cysts in glutaric aciduria type I (GA-I)
2017, Arachnoid Cysts: Epidemiology, Biology, and Neuroimaging
Glutaric aciduria type I (GA-I) is a rare inherited metabolic disease caused by deficiency of glutaryl-CoA dehydrogenase located in the catabolic pathways of l-lysine, l-hydroxylysine and l-tryptophan. The enzymatic defect results in elevated concentrations of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine in body tissues. Neuropathophysiologic concepts involve disturbance of brain energy metabolism and neurotransmission. Untreated patients are at increased risk for striatal damage and consequent severe neurologic disease. Metabolic treatment is effective and improves neurologic outcome in early diagnosed individuals. Extrastriatal abnormalities frequently occur in all GA-I patients. Bilateral temporal fluid collections, most likely due to frontotemporal hypoplasia, are a characteristic neuroradiologic finding and have been classified (but rarely verified) as bilateral arachnoid cysts (AC). However, the true risk for development of bilateral AC in GA-I is still unknown.
Carnitine transport and fatty acid oxidation
2016, Biochimica et Biophysica Acta - Molecular Cell Research
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B^0,+. Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
Newborn Screening
2015, Clinics in Perinatology

View all citing articles on Scopus

^☆: Presented at the Annual Meeting of the American College of Medical Genetics, Nashville, TN, March 2007. Genet Med 9: Meeting Supplement, Abstract 006, 2007.

View full text

Brief CommunicationMaternal glutaric acidemia, type I identified by newborn screening☆

Abstract

Section snippets

Family 1

Analytes

Carnitine uptake studies

Mutation analysis

Results and discussion

Acknowledgments

Biochem. Med.

Mol. Genet. Metab.

GlutarylCoA dehydrogenase mutations in glutaric acidemia (type 1): a review and report of 30 novel mutations

Human Mut.

Glutaric acidemia type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania

Am. J. Med. Genet.

Brief Communication
Maternal glutaric acidemia, type I identified by newborn screening☆