Effect of dietary lysine restriction and arginine supplementation in two patients with pyridoxine-dependent epilepsy.
Pyridoxine-Dependent Epilepsy (PDE) is a recessive disorder caused by deficiency of α-aminoadipic semialdehyde dehydrogenase in the catabolic pathway of lysine. It is characterized by intractable seizures controlled by the administration of pharmacological doses of vitamin B6. Despite seizure control with pyridoxine, intellectual disability and developmental delays are still observed in some patients with PDE, likely due to the accumulation of toxic intermediates in the lysine catabolic pathway: alpha-aminoadipic semialdehyde (AASA), delta-1-piperideine-6-carboxylate (P6C), and pipecolic acid. Here we evaluate biochemical and clinical parameters in two PDE patients treated with a lysine-restricted diet and arginine supplementation (100-150mg/kg), aimed at reducing the levels of PDE biomarkers. Lysine restriction resulted in decreased accumulation of PDE biomarkers and improved development. Plasma lysine but not plasma arginine, directly correlated with plasma levels of AASA-P6C (p<0.001, r(2)=0.640) and pipecolic acid (p<0.01, r(2)=0.484). In addition, plasma threonine strongly correlated with the levels of AASA-P6C (p<0.0001, r(2)=0.732) and pipecolic acid (p<0.005, r(2)=0.527), suggesting extreme sensitivity of threonine catabolism to pyridoxine availability. Our results further support the use of dietary therapies in combination with pyridoxine for the treatment of PDE.
Department of Pathology, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA. Electronic address: tatiana.n.yuzyuk@aruplab.com.
Tatiana
T
Yuzyuk
Department of Pathology, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA.
Amanda
A
Thomas
Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Krista
K
Viau
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Aiping
A
Liu
Department of Pathology, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA.
Irene
I
De Biase
Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Lorenzo D
LD
Botto
Department of Pathology, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Marzia
M
Pasquali
Department of Pathology, University of Utah, Salt Lake City, UT, USA; ARUP Laboratories, Salt Lake City, UT, USA; ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT, USA; Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.
Nicola
N
Longo
D001120:Arginine / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood*; D002675:Child, Preschool; D019587:Dietary Supplements; D004827:Epilepsy / Q000178:diet therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008239:Lysine / Q000097:blood* / Q000172:deficiency; D008297:Male; D010875:Pipecolic Acids / Q000097:blood; D012189:Retrospective Studies; D012443:Saccharopine Dehydrogenases / Q000097:blood; D016896:Treatment Outcome
D015415:Biomarkers; D010875:Pipecolic Acids; D001120:Arginine; C043044:AASS protein, human; D012443:Saccharopine Dehydrogenases; C031345:pipecolic acid; D008239:Lysine
ALDH7A1 gene; Alpha-aminoadipic semialdehyde; Dietary therapy; Pipecolic acid; Piperideine-6-carboxylate; Pyridoxine-dependent epilepsy