Glutaric Acidemia Type I via the GCDH Gene

Glutaric acidemia type I (GA I; OMIM 231670) is an inborn error of metabolism resulting from glutaryl-CoA dehydrogenase (GCDH) deficiency. Patients with GA I suffer injury to the basal ganglia and develop severe, life threatening dystonia, and choreoathetosis (Strauss et al. Am J Med Genet 121C:38-52, 2003). Macrocephaly may be the only presenting feature at birth, and the extent of basal ganglia degeneration determines functional disability. GA I patients often present with an acute encephalopathic crisis, mostly associated with an upper respiratory or gastrointestinal infection or both early in life (Hoffmann et al. J Inher Metab Dis 18:173-176, 1995). Typical onset of symptoms is in infancy, although variability of age at onset occurs (Morton et al. Am J Med Genet 41:89-95, 1991). Some individuals remain asymptomatic. Patients with adult onset have been shown to respond effectively to therapy (Kulkens et al. Neurology 64:2142-2144, 2005). Biochemically, GA I patients have elevated glutaric acid and 3-OH-glutaric acid in urine and elevated glutarylcarnitine in blood. Unlike other organic acidemias, ketosis and acidosis are not features of GA I.

Glutaric acidemia type I is an autosomal recessive disorder. Over 100 pathogenic variants have been reported in the GCDH gene with the majority being missense changes. Relatively fewer nonsense, splice site, and small insertion/deletion variants are reported. Variants are found in every GCDH exon (Goodman et al. Hum Mut 12:141-4, 1998). A founder variant (p.Ala421Val) exists in the Old Order Amish of Lancaster County, Pennsylvania with a carrier frequency of approximately 0.10 (Morton et al. Am J Med Genet 41:89-95, 1991). Another founder variant appears to be the p.Arg402Trp missense change found among people of German descent. In German GA I patients, this variant accounts for about 40% of alleles (Zschocke et al. J Med Genet 37:177-181, 2000).

Schwartz et al. detected 95% of GCDH variants among 20 GA I patients from various European countries. The SSCP gel-based method to detect sequence variants in this report is likely less sensitive than direct DNA sequencing. Similarly, Zschocke et al. reported finding 100% of causative alleles among 48 patients diagnosed with GA I by biochemical studies.

This test provides full coverage of all coding exons of the GCDH gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).