Introduction and background - GA I

Glutaric aciduria type I (GA1) is an inborn error of metabolism caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase in the catabolic pathway of the amino acids L-lysine, L-hydroxylysine and L-tryptophan. This results in an accumulation of the neurotoxic glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA).

GA1 is clinically characterized by encephalopathic crises resulting in high morbidity and mortality.¹

Neonates are mainly asymptomatic and if undiagnosed, most children present a the initial acute encephalopathic crisis occurs between 3-36 months, typically precipitated by an intercurrent febrile illness, such as a respiratory or GI illness, vaccination or a surgical intervention, and characterized by hypotonia, loss of motor skills and convulsions resulting in bilateral striatal injury with severe secondary dystonia and occasionally subdural and retinal hemorrhage ^3,4. GA1 can exceptionally present with hypoglycemia or acidosis.

With age (> 6 years), with appropriate treatment, the risk of encephalopathic crises subsides. In some patients, hypotonia and dystonia develop gradually with no encephalopathic crisis, which is known as late-onset or insidious-onset GA1.

Early diagnosis and immediate treatment has proven to be effective in preventing neurological disease and consists of 3 pillars ⁴.

The efficacy of all three interventions combined has been shown to be the most effective

Daily management comprises of⁵:

a low lysine diet, by the use of a lysine-free, tryptophan-reduced amino-acid supplement, in particular in patients up to age 6.
Lifelong carnitine supplementation
In association with prompt emergency treatment during intercurrent illness or surgery.

In severely disabled children, the life expectancy is significantly reduced, where the children diagnosed in the newborn period have a more favorable prognosis. Diagnosis through newborn screening and immediate treatment has significantly improved the neurological outcome.

Worldwide incidence of GA1 is estimated at 1 in 100-120.000 births. In some isolated communities, GA1 is more prevalent in the Amish community in Pennsylvania, Canadian Oji-Cree natives in Manitoba and north-western Ontario, Irish travelers in Ireland and Great Britain, Lumbee Native Americans in North Carolina and black South Africans.

References

Kölker S et al. Diagnosis and management of glutaric aciduria type I – revised recommendations. J Inher Metab Dis 2011;34:677-694)
http://www.e-imd.org/en/healthcare-professionals/individual-conditions/organic-acidurias/ga1/index.phtml
AStrauss, K.A. et al (2003) Type I glutaric aciduria, part 1: natural history of 77 patients. Am. J. Med. Genet. C Semin. Med. Genet. 2003;121C:38–52.
Koelker, S et al. Emergency treatment in glutaryl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 2004;27: 893–902.
Koelker S et al. Guildeles for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (Glutaric Acidurai type I). J Inherit Metab Dis 2007;30:5-22.

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