In this project, the investigators propose to genetically validate a novel therapeutic target for the treatment of glutaric aciduria type 1 (GA1; MIM 231670). GA1 is an autosomal recessive inborn error of lysine, hydroxylysine and tryptophan degradation. Patients can present with brain atrophy and macrocephaly and may develop dystonia after acute encephalopathic crises that lead to striatal degeneration. The disorder is caused by a defect of glutaryl-CoA dehydrogenase (GCDH) due to mutations in GCDH, leading to the accumulation of neurotoxic glutaric acid and 3-hydroxyglutaric acid. GA1 patients benefit from early intervention and the disorder is therefore included in many newborn screening programs. Current treatment consists of chronic dietary intervention and carnitine supplementation, and acute emergency treatment, which must be strictly maintained because the risk of an acute crisis is always present. Although effective, this treatment paradigm requires intense efforts from both caregiver and patient. These limitations illustrate the need for novel therapeutic options with improved reliability and convenience. The investigators hypothesize that GA1 can be treated with substrate reduction therapy through inhibiting an enzyme upstream of GCDH in the lysine degradation pathway. This approach will divert neurotoxic glutaric acid and 3-hydroxyglutaric acid to more tolerable metabolites. It has been shown that ?-aminoadipic and ?-ketoadipic aciduria is a biochemical phenotype without clinical significance. It is caused by mutations in DHTKD1 encoding the E1 subunit of ?- ketoadipic acid dehydrogenase, which is an enzyme upstream of GCDH. Therefore, the investigators believe that DHTKD1 is an excellent target for treatment of GA1. The overall objective of this proposal is to provide genetic evidence that substrate reduction through lowering DHTKD1 activity can prevent disease in an established GA1 mouse model.
In AIM 1, the investigators will establish a colony of Gcdh KO mice with functionally relevant variation in Dhtkd1. For this they will leverage the observation that Dhtkd1 is functionally polymorphic between different inbred mouse strains. DHTKD1 activity is deficient in C57BL/6J, while DBA/2J mice have normal activity. Through breeding they will generate Gcdh KO mice harboring C57BL/6J and/or DBA/2J Dhtkd1 alleles.
In AIM 2, the investigators will associate the severity of the neurometabolic phenotype of Gcdh KO mice to variation in Dhtkd1. For this they will measure clinical biomarkers for GA1 and perform histological analysis of brain to score neuropathology. Combined these two aims will provide genetic proof that in mice Dhtkd1 is a modifier gene for the neurometabolic phenotype of GA1 that acts via substrate reduction. Such genetic evidence will be an important impetus for our drug discovery project aiming to identify a small molecule inhibitor for DHTKD1.

Public Health Relevance

Glutaric aciduria type 1 is an inborn error of lysine degradation. This genetic disorder has been included in newborn screening programs, but the current therapeutic intervention needs improvement. The investigators have identified a potential drug target and will provide genetic evidence that inhibition of this target prevents disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Parisi, Melissa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
Zip Code