Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I.
J Clin Invest
; 117(11): 3258-70, 2007 Nov.
Article
in En
| MEDLINE
| ID: mdl-17932566
Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Aging
/
Brain Diseases, Metabolic, Inborn
/
Glutaryl-CoA Dehydrogenase
/
Amino Acid Metabolism, Inborn Errors
/
Glutarates
Type of study:
Prognostic_studies
Limits:
Animals
/
Child
/
Humans
Language:
En
Journal:
J Clin Invest
Year:
2007
Document type:
Article
Affiliation country:
United States
Country of publication:
United States