Branched-chain ketoacid dehydrogenase kinase deficiency (BCK...

created [InstanceEdit:9912456] Rothfels, Karen, 2024-06-08
dbId 9912457
displayName Branched-chain ketoacid dehydrogenase kinase deficiency (BCK...
modified [InstanceEdit:9918895] Rothfels, Karen, 2024-08-18
schemaClass Summation
text Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) is a neurological disorder that arises due to mutations in branched-chain ketoacid dehydrogenase kinase (BCKDK) (Joshi et al 2006; Novarino et al, 2012; Garcia-Cazorla et al, 2014; Tangeraas et al, 2023). BCKDK is a negative regulator of the branched-chain ketoacid dehydrogenase complex (BCKDH), the enzyme responsible for oxidative decarboxylation of branched-chain amino acid derivatives. BCKDK-dependent phosphorylation of serine residues in the E1 alpha subunit of the enzyme BCKDHA inactivates the BCKDH (Popov et al, 1992; Li et al, 2004; Wynn et al, 2004).
Inactivating mutations of BCKDK are associated with impaired intellectual development, microencephaly and autism (Joshi et al 2006; Novarino et al, 2012; Garcia-Cazorla et al, 2014; Tangeraas et al, 2023). Consistent with the role of BCKDK in inhibiting BCKDH activity, inactivating mutations in BCKDK result in higher levels of BCKDH activity and reduced BCAAs in plasma, tissues and urine in mouse models, patients and cell lines (Joshi et al, 2006; Novarino et al, 2012). Symptoms of BCKDK deficiency are alleviated in mouse models by dietary supplementation with a BCAA-enriched diet (Joshi et al, 2006; Novarino et al, 2012).
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