Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: Focus on cerebral amino acid influx

Abstract

Striatal degeneration from glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type 1, GA1) is associated with cerebral formation and entrapment of glutaryl-CoA and its derivatives that depend on cerebral lysine influx. In 2006 we designed a lysine-free study formula enriched with arginine to selectively block lysine transport across cerebral endothelia and thereby limit glutaryl-CoA production by brain. Between 2006 and present, we treated twelve consecutive children with study formula (LYSx group) while holding all other treatment practices constant. Clinical and biochemical outcomes were compared to 25 GA1 patients (PROx group) treated between 1995 and 2005 with natural protein restriction (dietary lysine/arginine ratio of 1.7±0.3 mg:mg). We used published kinetic parameters of the y+and LAT1 blood-brain barrier transporters to model the influx of amino acids into the brain. Arginine fortification to achieve a mean dietary lysine/arginine ratio of 0.7±0.2 mg:mg was neuroprotective. All 12 LYSx patients are physically and neurologically healthy after 28 aggregate patient-years of follow up (current ages 28±21 months) and there were no adverse events related to formula use. This represents a 36% reduction of neurological risk (95% confidence interval 14-52%, p=0.018) that we can directly attribute to altered amino acid intake. During the first year of life, 20% lower lysine intake and two-fold higher arginine intake by LYSx patients were associated with 50% lower plasma lysine, 3-fold lower plasma lysine/arginine concentration ratio, 42% lower mean calculated cerebral lysine influx, 54% higher calculated cerebral arginine influx, 15-26% higher calculated cerebral influx of several anaplerotic precursors (isoleucine, threonine, methionine, and leucine), 50% less 3-hydroxyglutarate excretion, and a 3-fold lower hospitalization rate (0.8 versus 2.3 hospitalizations per patient per year). The relationship between arginine fortification and plasma lysine indicates that transport competition exists at both cerebrovascular and gastrointestinal barriers, suggesting their co-administration is key to efficacy. Monitoring the ratio between lysine and arginine in diet and plasma may prove a useful strategy for treating children with GA1.

Lysine restricted diet for pyridoxine-dependent epilepsy: First evidence and future trials

“…For patient #7 the calculated cerebral lysine flux after institution of dietary therapy is similar to that reported in Glutaric Aciduria I patients [20]. These data provide proof of principle that reducing the flux through the lysine degradation pathway will lower the accumulation of potentially neurotoxic substrates arising from the enzymatic block.…”

Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child with glutaric aciduria type I

“…Metabolic treatment with a lysinefree formula, carnitine supplementation and aggressive emergency room management started before the onset of alarming neurological symptoms, especially in the first 6 years of life, has been associated with reduced risk of acute striatal injury [12,13]. Acute "metabolic stroke" in patients with GA1 primarily affects the putamen with secondary involvement of the caudate, and to a lesser degree, the globus pallidus [3,14].…”

Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations

“…Not only is this kind of initiative essential for collecting evidence for treatment of rare disorders where it is not practically possible to conduct randomizedcontrolled studies, it will also provide a framework to generate evidence regarding the evaluation of any new strategies, such as arginine fortification, which might be added in the future (Strauss et al 2011;K€ olker et al 2012).…”