• Test code: 06195
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit

Invitae Glutaric Acidemia Type I Test

Test description

The Invitae Glutaric Acidemia Type I Test analyzes the GCDH gene, which is associated with glutaric acidemia type 1 (GA1). Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants would also guide testing and diagnosis of at-risk relatives.

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Primary panel (1 gene)

Alternative tests to consider

The Invitae Organic Acidemias Panel has been designed to provide a broad genetic analysis of this class of disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.

  • glutaric acidemia type I – also known as glutaryl-CoA dehydrogenase deficiency

Elevated glutarylcarnitine (C5-DC) acylcarnitine may be detected during newborn screening or acylcarnitine analysis due to glutaric acidemia type I (GA1). GA1 typically presents within the first few months of life with an acute encephalopathic crisis during a time of increased catabolic demand, such as intercurrent illness or immunization. This crisis causes irreversible neurological sequelae, particularly acute bilateral striatal injury, which can lead to dystonia, axial hypotonia, rigidity, and spasms, and can cause increased morbidity and mortality. Some patients may have an “insidious onset”: onset of clinical symptoms without a precipitating encephalopathic crisis. Macrocephaly is a common finding in GA1, and some patients can have subdural and retinal hemorrhages. Although the majority of patients present with severe disease in the infantile period, later-onset childhood forms and rare, milder adult-onset forms have been reported.

GA1 is caused by a defect of the glutaryl-CoA dehydrogenase enzyme, which is involved in the lysine, hydroxylysine, tryptophan degradation pathway. In GA1 patients, intermediates of this pathway (C5-DC, 3-hydroxyglutaric acid, glutaric acid, and, less frequently, glutaconic acid) accumulate in the body. Such accumulation can be detected by plasma or urine acylcarnitine analysis and urine organic-acid analysis. Of note, some patients with GA1 have normal or near-normal biochemical studies, despite having clinical disease; therefore, molecular testing may be warranted in patients with clinical suspicion of GA1 but normal biochemical studies.

A low-lysine diet with carnitine supplementation and emergency diet during intercurrent illness has been shown to effectively treat patients, provided treatment is started before the onset of symptoms. Outcome remains poor in patients who are diagnosed after the onset of neurological damage, even with treatment, so early diagnosis and detection are critical to improving the long-term outcome for GA1 patients.

For patients with biochemical features consistent with glutaric aciduria type I (elevated C5-DC on acylcarnitines and elevated urine 3-hydroxyglutaric acid), >99% will have two pathogenic variants in GCDH.

GA1 is inherited in an autosomal recessive manner.

The overall incidence of confirmed GA1 cases has been estimated at 1 in 72,000–100,000 live births. Incidence may be much higher in certain populations, including in the Old Order Amish, Canadian Indian natives, Irish travellers, and Lumbee Native Americans in North Carolina. The incidence rate among Vietnamese Americans is an estimated 1 in 29,000.

This test may be appropriate for patients:

  • with elevated C5DC on newborn screening or plasma acylcarnitine analysis
  • with elevated 3-hydroxyglutaric acid, with or without elevated glutaric acid in urine.
  • with macrocephaly and encephalopathic crisis resulting in basal ganglia damage and movement disorder

For considerations for testing please refer to:

  1. American College of Medical Genetics. NBS ACT Sheet. Glutaryl-CoA Dehydrogenase Deficiency. https://www.acmg.net/StaticContent/ACT/C5-DC.pdf Accessed February 2016.
  2. Baby's first test. Newborn screening. http://www.babysfirsttest.org/ Accessed February 2016.
  3. Baric, I, et al. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J. Inherit. Metab. Dis. 1999; 22(8):867-81. PMID: 10604139
  4. Basinger, AA, et al. Glutaric acidemia type 1 in patients of Lumbee heritage from North Carolina. Mol. Genet. Metab. 2006; 88(1):90-2. PMID: 16466958
  5. Christensen, E, et al. Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 2004; 27(6):861-8. PMID: 15505393
  6. Feuchtbaum, L, et al. Birth prevalence of disorders detectable through newborn screening by race/ethnicity. Genet. Med. 2012; 14(11):937-45. PMID: 22766612
  7. Heringer, J, et al. Use of guidelines improves the neurological outcome in glutaric aciduria type I. Ann. Neurol. 2010; 68(5):743-52. PMID: 21031586
  8. Hoffmann GF, Kölker S. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 23, Cerebral organic acid disorders and other disorders of lysine catabolism; p. 333–348.
  9. Kölker, S, et al. Diagnosis and management of glutaric aciduria type I--revised recommendations. J. Inherit. Metab. Dis. 2011; 34(3):677-94. PMID: 21431622
  10. Kölker, S, et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr. Res. 2006; 59(6):840-7. PMID: 16641220
  11. Lindner, M, et al. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 2004; 27(6):851-9. PMID: 15505392
  12. Morton, DH, et al. Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania. Am. J. Med. Genet. 1991; 41(1):89-95. PMID: 1951469
  13. Naughten, ER, et al. Glutaric aciduria type I: outcome in the Republic of Ireland. J. Inherit. Metab. Dis. 2004; 27(6):917-20. PMID: 15505400
  14. Wilcken B, Rinaldo P, Matern D. Inborn metabolic diseases: diagnosis and treatment. 5th ed. Heidelberg: Springer; 2012. Chapter 3, Newborn screening for inborn errors of metabolism; p. 75–86.

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GCDH NM_000159.3