Advertisement

Glutaric Aciduria Type 3: Three Unrelated Canadian Cases, with Different Routes of Ascertainment

  • Paula J. Waters
  • Thomas M. Kitzler
  • Annette Feigenbaum
  • Michael T. Geraghty
  • Osama Al-Dirbashi
  • Patrick Bherer
  • Christiane Auray-Blais
  • Serge Gravel
  • Nathan McIntosh
  • Komudi Siriwardena
  • Yannis Trakadis
  • Catherine Brunel-Guitton
  • Walla Al-Hertani
Research Report
Part of the JIMD Reports book series (JIMD, volume 39)

Abstract

Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally considered a likely “non-disease,” but this is based on limited supporting information, with only nine individuals with GA3 described in the literature. Clinicians encountering a patient with GA3 therefore still face a dilemma of whether or not this should be dismissed as irrelevant.

We have identified three unrelated Canadian patients with GA3. Two came to clinical attention because of symptoms, while the third was identified by a population urine-based newborn screening programme and has so far remained asymptomatic. We describe the clinical histories, biochemical characterisation and genotypes of these individuals. Examination of allele frequencies underlines the fact that GA3 is underdiagnosed. While one probable factor is that some GA3 patients remain asymptomatic, we highlight other plausible reasons whereby this diagnosis might be overlooked.

Gastrointestinal disturbances were previously reported in some GA3 patients. In one of our patients, severe episodes of cyclic vomiting were the major problem. A trial of antibiotic treatment, to minimise bacterial GA production, was followed by significant clinical improvement.

At present, there is insufficient evidence to define any specific clinical phenotype as attributable to GA3. However, we consider that it would be premature to assume that this condition is completely benign in all individuals at all times.

Keywords

ACY1 Aminoacylase 1 deficiency Benign condition C7orf10 Glutaric acid Glutaric aciduria type 3 Glutaric aciduria type III Non-disease Succinate-hydroxymethylglutarate CoA-transferase SUGCT gene 

Notes

Acknowledgements

We thank the dedicated personnel of the CHUS Biochemical Genetics Laboratory and of the Quebec Provincial Neonatal Urine Screening Programme for logistical, analytical and technical contributions to the laboratory studies.

Supplementary material

978-3-662-57577-2_49_MOESM1_ESM.zip (145 kb)
Supplementary Fig. 1 (a) MRI-head (axial T1): Image shows delayed myelination of the genu of the corpus callosum, since at 6 months of age the genu of the corpus callosum is expected to have the same intensity (i.e., brightness) as the splenium of the corpus callosum. This finding had resolved on repeat MRI at 12 months of age. (b) MRI-head (axial T2): Image shows marked widening of the extra-axial CSF spaces. Interestingly, this is a feature commonly found in glutaric acidemia type I. This finding had resolved on repeat MRI at 12 months of age (ZIP 134 kb)

References

  1. Al-Dirbashi OY, Kölker S, Ng D et al (2011) Diagnosis of glutaric aciduria type 1 by measuring 3-hydroxyglutaric acid in dried urine spots by liquid chromatography tandem mass spectrometry. J Inherit Metab Dis 34:173–180CrossRefPubMedGoogle Scholar
  2. Auray-Blais C, Cyr D, Drouin R (2007) Quebec neonatal mass urinary screening programme: from micromolecules to macromolecules. J Inherit Metab Dis 30:515–521CrossRefPubMedGoogle Scholar
  3. Bennett MJ, Pollitt RJ, Goodman SI, Hale DE, Vamecq J (1991) Atypical riboflavin-responsive glutaric aciduria, and deficient peroxisomal glutaryl-CoA oxidase activity: a new peroxisomal disorder. J Inherit Metab Dis 14:165–173CrossRefPubMedGoogle Scholar
  4. Bherer P, Cyr D, Buhas D, Al-Hertani W, Maranda B, Waters PJ (2015) Acylglycine profiling: a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, applied to disorders of organic acid, fatty acid and ketone metabolism. J Inherit Metab Dis 38(Suppl 1):S69–S70. Abstract P-028Google Scholar
  5. Boukouris AE, Zervopoulos SD, Michelakis ED (2016) Metabolic enzymes moonlighting in the nucleus: metabolic regulation of gene transcription. Trends Biochem Sci 41:712–730CrossRefPubMedGoogle Scholar
  6. Boy N, Mülhausen C, Maier EM et al (2017) Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J Inherit Metab Dis 40:75–101CrossRefPubMedGoogle Scholar
  7. Frerman FE, Goodman SI (2001) Defects of electron transfer flavoprotein and electron transfer flavoprotein-ubiquinone oxidoreductase: glutaric acidemia type II. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 2357–2365Google Scholar
  8. Gerlo E, Van Coster R, Lissens W, Winckelmans G, Meirleir D, Wevers R (2006) Gas chromatographic-mass spectrometric analysis of N-acetylated amino acids: the first case of aminoacylase I deficiency. Anal Chim Acta 571:191–199CrossRefPubMedGoogle Scholar
  9. Gertsman I, Gangoiti JA, Nyhan WL, Barshop BA (2015) Perturbations of tyrosine metabolism promote the indolepyruvate pathway via tryptophan in host and microbiome. Mol Genet Metab 114:431–437CrossRefPubMedGoogle Scholar
  10. Goodman SI, Frerman FE (2001) Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 2195–2204Google Scholar
  11. Knerr I, Zschocke J, Trautmann U et al (2002) Glutaric aciduria type III: a distinctive non-disease? J Inherit Metab Dis 25:483–490CrossRefPubMedGoogle Scholar
  12. Kumps A, Duez P, Mardens Y (2002) Metabolic, nutritional, iatrogenic, and artifactual sources of urinary organic acids: a comprehensive table. Clin Chem 48:708–717PubMedGoogle Scholar
  13. Marlaire S, Van Schaftingen E, Veiga-da-Cunha M (2014) C7orf10 encodes succinate-hydroxymethylglutarate CoA-transferase, the enzyme that converts glutarate to glutaryl-CoA. J Inherit Metab Dis 37:13–19CrossRefPubMedGoogle Scholar
  14. Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I (2008) Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 94:4–15CrossRefPubMedGoogle Scholar
  15. Sass JO, Mohr V, Olbrich H et al (2006) Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism. Am J Hum Genet 78:401–409CrossRefPubMedPubMedCentralGoogle Scholar
  16. Sass JO, Olbrich H, Mohr V et al (2007) Neurological findings in aminoacylase 1 deficiency. Neurology 68:2151–2153CrossRefPubMedGoogle Scholar
  17. Sherman EA, Strauss KA, Tortorelli S et al (2008) Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in C7orf10. Am J Hum Genet 83:604–609CrossRefPubMedPubMedCentralGoogle Scholar
  18. Skaricic A, Zekusic M, Fumic K et al (2016) New symptomatic patients with glutaric aciduria type 3: further evidence of high prevalence of the c.1006C>T (p.Arg336Trp) mutation. J Inherit Metab Dis 39(Suppl 1):S138. Abstract P-275Google Scholar
  19. Tortorelli S, Hahn SH, Cowan TM et al (2005) The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I. Mol Genet Metab 84:137–143CrossRefPubMedGoogle Scholar
  20. Tylki-Szymanska A, Gradowska W, Sommer A et al (2010) Aminoacylase 1 deficiency associated with autistic behaviour. J Inherit Metab Dis 33(Suppl 3):S211–S214CrossRefPubMedGoogle Scholar
  21. Vilardo E, Rossmanith W (2015) Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. Nucleic Acids Res 43:5112–5119CrossRefPubMedPubMedCentralGoogle Scholar
  22. Wendel U, Bakkeren J, de Jong J, Bongaerts G (1995) Glutaric aciduria mediated by gut bacteria. J Inherit Metab Dis 18:358–359CrossRefPubMedGoogle Scholar
  23. Zschocke J (2012) HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherited Metab Dis 35:81–89CrossRefPubMedGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2017

Authors and Affiliations

  • Paula J. Waters
    • 1
  • Thomas M. Kitzler
    • 2
  • Annette Feigenbaum
    • 3
    • 4
  • Michael T. Geraghty
    • 5
  • Osama Al-Dirbashi
    • 5
    • 6
  • Patrick Bherer
    • 1
  • Christiane Auray-Blais
    • 1
  • Serge Gravel
    • 1
  • Nathan McIntosh
    • 5
  • Komudi Siriwardena
    • 3
    • 7
  • Yannis Trakadis
    • 2
  • Catherine Brunel-Guitton
    • 8
  • Walla Al-Hertani
    • 2
    • 9
  1. 1.Division of Medical Genetics, Departments of Pediatrics and Medical BiologyUniversity of Sherbrooke Hospital Centre (CHUS)SherbrookeCanada
  2. 2.Department of Medical GeneticsMcGill University Health Centre (MUHC)MontrealCanada
  3. 3.Division of Clinical and Metabolic GeneticsThe Hospital for Sick Children and University of TorontoTorontoCanada
  4. 4.Division of Genetics, Department of PediatricsUniversity of CaliforniaSan DiegoUSA
  5. 5.Newborn Screening OntarioChildren’s Hospital of Eastern Ontario (CHEO)OttawaCanada
  6. 6.College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUAE
  7. 7.Department of Medical GeneticsUniversity of Alberta HospitalEdmontonCanada
  8. 8.Division of Medical Genetics, Department of PaediatricsSainte-Justine Hospital and University of MontrealMontrealCanada
  9. 9.Departments of Medical Genetics and Paediatrics, Cumming School of MedicineAlberta Children’s Hospital and University of CalgaryCalgaryCanada

Personalised recommendations