Role of branched-chain amino acid metabolism in maple syrup urine disease
Maple syrup urine disease(MSUD)is an autosomal recessive neurometabolic disorder caused by inacti-vation of branched-chain α-keto acid dehydrogenase complex(BCKDC),which catalyses the irreversible catabolism of the branched-chain amino acid(BCAA).BCAA metabolic blockage lead to BCAA including leucine,valine,isoleucine and branched-chain α-ketoacid(BCKA)accumulation in plasma,tissues and urea.The main pathophysiological symptoms of MSUD are seizures,coma and life-threatening cerebral edema in the first weeks of life,which is followed by progressive neurological deterioration with motor delay,ataxia,intellectual disability and psychiatric symptoms.Brain damage mainly attribute to BCAA metabolic disorder,which lead to protein synthesis and neurotransmitters deficiency in MSUD patients.Severe neurological symptoms may be due to the brain-specific roles of BCAA and BCKA.Many literatures verify that BCAA/BCKA particularly leucine and α-KIC play an important role in neurological damage in MSUD.In this review,we will focus on BCAA/BCKA metabolic disorders observed in the brain of MSUD patients and highlight the potential mechanisms driving neurologic dysfunction.Finally,we will specifically discuss the BCAA/BCKA's neurotoxicity,disturbing other neutral amino acid metabolism,protein and neurotransmitters synthesis and damaging brain bioenergetics homeostasis.An understanding of the pathomechanisms of MSUD,may facilitate the design of novel therapeutic strategies and drug targets in MSUD.
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