All Phenotypes Bckdhb<em1(IMPC)J> MGI Mouse

mortality/aging

postnatal lethality, complete penetrance ( J:344897 )

• all mice die before the end of the first week of life

• following gene therapy via a single temporal vein injection of a AAV8-EF1alpha-hBCKDHB vector (10¹⁴ vg/kg) at P0, one of 8 injected mice dies at P26 while the remaining 7 mice survive to >6 months of age with no apparent defects (2 of these 7 survive to 12 months with good control of plasma leucine levels and a normal hindlimb test)

growth/size/body

postnatal growth retardation ( J:344897 )

• mice that survive to P5 display severe growth delay

• neonatal AAV8-EF1alpha-hBCKDHB gene therapy restores the growth (weight) of both sexes to control values up to P196

homeostasis/metabolism

abnormal circulating amino acid level ( J:344897 )

• mice show a striking increase in plasma levels of the branched-chain amino acids (BCAA) valine, leucine and alloisoleucine at P1, along with a decrease in alanine levels resulting in a high leucine/alanine ratio

• neonatal AAV8-EF1alpha-hBCKDHB gene therapy reduces plasma BCAA levels to less than 2-fold above normal until 6 months of age and alloisoleucine is not detectable

decreased circulating alanine level ( J:344897 )

• mice show a significant decrease in plasma alanine levels at P1

increased circulating leucine level ( J:344897 )

• mice show a significant increase in plasma leucine levels at P1

increased circulating valine level ( J:344897 )

• mice show a significant increase in plasma valine levels at P1

abnormal enzyme/coenzyme activity ( J:344897 )

• mice show absence of branched-chain 2-ketoacid dehydrogenase (BCKD) activity in the liver at P1

• neonatal gene therapy increases liver BCKD activity to 16 +/- 8 % and 17 +/- 1 % the values of age-matched untreated wild-type controls at 6 and 12 months, respectively

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
maple syrup urine disease		DOID:9269	OMIM:246900 OMIM:248600 OMIM:615135	J:344897

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

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