A diet-induced mouse model for glutaric aciduria type I

Abstract

In the autosomal recessive human disease, glutaric aciduria type I (GA-1), glutaryl-CoA dehydrogenase (GCDH) deficiency disrupts the mitochondrial catabolism of lysine and tryptophan. Affected individuals accumulate glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in the serum and often suffer acute striatal injury in childhood. Prior attempts to produce selective striatal vulnerability in an animal model have been unsuccessful. We hypothesized that acute striatal injury may be induced in GCDH-deficient (Gcdh-/-) mice by elevated dietary protein and lysine. Here, we show that high protein diets are lethal to 4-week-old and 8-week-old Gcdh-/- mice within 2-3 days and 7-8 days, respectively. High lysine alone resulted in vasogenic oedema and blood-brain barrier breakdown within the striatum, associated with serum and tissue GA accumulation, neuronal loss, haemorrhage, paralysis, seizures and death in 75% of 4-week-old Gcdh-/- mice after 3-12 days. In contrast, most 8-week-old Gcdh-/- mice survived on high lysine, but developed white matter lesions, reactive astrocytes and neuronal loss after 6 weeks. Thus, the Gcdh-/- mouse exposed to high protein or lysine may be a useful model of human GA-1 including developmentally dependent striatal vulnerability.

Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

“…Changes in brain 3-OHGA paralleled those of glutaric acid although 3-OHGA concentrations were 20-fold lower than glutaric acid levels (not shown). Although symptoms of encephalopathy were less evident at the earlier time points examined in the current work, brain glutaric acid levels correlate with acute injury of symptomatic mice as previously shown (12). To determine whether lysine diet exposure had any effect on other basic or neutral amino acids, we compared serum and brain alanine and arginine levels.…”

“…Similar changes, though less severe, were found in adult Gcdh -/-mice after 60 hours ( Figures 2H and 3B). Although adult Gcdh -/-mice do not show obvious behavioral differences (12), further testing may reveal deficits associated with these pathologic changes after long-term diet exposure.…”

“…To determine the mechanism of age-dependent susceptibility to encephalopathy in Gcdh deficiency, we considered that brain glutaric acid levels were previously shown to correlate with severity of disease presentation (12). Therefore, we considered the possibilities that (a) brain lysine catabolism, which produces glutaric acid, may be reduced with age; (b) brain lysine uptake may be reduced with age; or (c) clearance of glutaric acid from the brain may be enhanced with age.…”

“…Since glutamine is exclusively produced in glia (22), depletion of more glutamate than glutamine in this model suggests a neuronal origin of metabolic impairment. GABA depletion may be responsible for the seizures observed in children and mice with Gcdh deficiency (7,12).…”

“…Children with GA-I who escape encephalopathy in their first 5 years typically remain asymptomatic (2). We recently developed an animal model of GA-I encephalopathy in GCDH-deficient (Gcdh -/-) mice by introducing added dietary protein or lysine (12). This model shows age-dependent susceptibility to acute brain injury similar to human GA-I.…”