Phenotypes Associated with This Genotype

Genotype
MGI:2654880

• Allelic Composition: Aldh5a1^tm1Kmg/Aldh5a1^tm1Kmg
• Genetic Background: involves: 129/Sv * C57BL/6

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

mortality/aging

postnatal lethality, complete penetrance ( J:71949 )

• if untreated, homozygotes die of fatal seizures at day P16-P22

• therapeutic intervention with anticonvulsants phenobarbital or phenytoin fails to ameliorate survival

• in contrast, intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 prevents tonic-clonic convulsions and prolongs survival

• administration of taurine, which is derived from the metabolism of cysteine and is highly present in mother's milk, via drinking water (up to 5,000 mg/kg/d) provides rescue through the critical period

behavior/neurological

ataxia ( J:71949 )

• homozygotes display truncal ataxia at ~P15-P18

myoclonus ( J:71949 )

• at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

tonic seizures ( J:71949 )

• at about P15-P18, homozygotes display spasms and tonic seizures

absence seizures ( J:91856 )

• at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

growth/size/body

decreased body weight ( J:71949 )

• homozygotes appear normal during the first days of life but display a 20-30% reduction in body weight relative to wild-type

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:71949 , J:75773 )

N • in mutant brain, the concentrations of glutamic acid and succinic acid are comparable to those of wild-type (J:71949)

N • homozygotes exhibit normal levels of Kreb's cycle intermediates in brain extracts, suggesting that global brain oxidative metabolism is unaffected (J:75773)

abnormal amino acid level ( J:91856 )

• in brain extracts, P0-P18 homozygotes show high GABA/low glutamine both before and after the period of lethal tonic-clonic seizures

• brain homogenates show additional amino acid neurotransmitter abnormalities which may temporally correlate with the onset of lethal convulsions

increased beta-alanine level ( J:75773 )

• homozygotes exhibit normal levels of total beta-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in kidney and liver homogenates

increased gamma-aminobutyric acid level ( J:71949 , J:75773 , J:91856 )

• in mutant liver and brain homogenates, the amounts of GHB and total GABA are increased 30-45 and 2.5-3 fold, respectively, relative to wild-type (J:71949)

• homozygotes show elevated amounts of GHB and total GABA in homogenates of mutant kidney, pancreas and heart (J:75773)

• in brain extracts, P0-P18 homozygotes show high GABA/low glutamine both before and after the period of lethal tonic-clonic seizures (J:91856)

increased urine gamma-aminobutyric acid level ( J:71949 )

• homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine

decreased glutamine level ( J:75773 , J:91856 )

• homozygotes show a significant reduction of glutamine in mutant brain homogenates, despite normal glutamine synthetase protein and mRNA levels (J:75773)

• in brain, glutamine depletion is detected in the frontal cortex, parietal cortex, hippocampus and cerebellum (J:75773)

• however, glutamine levels are normal in mutant liver and kidney extracts (J:75773)

• in brain extracts, P0-P18 homozygotes show low glutamine both before and after the period of lethal tonic-clonic seizures (J:91856)

muscle

myoclonus ( J:71949 )

• at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

renal/urinary system

increased urine gamma-aminobutyric acid level ( J:71949 )

• homozygotes contain elevated amounts of gamma-hydroxybutyric (GHB) and total 4-aminobutyric acid (GABA) in urine

nervous system

myoclonus ( J:71949 )

• at ~P15-P18, homozygotes display spasms and myoclonic seizures, leading to status epilepticus and death

tonic seizures ( J:71949 )

• at about P15-P18, homozygotes display spasms and tonic seizures

absence seizures ( J:91856 )

• at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

gliosis ( J:71949 )

• in homozygotes, preliminary data indicated astrogliosis of the hippocampus

abnormal brain wave pattern ( J:91856 )

• at P1-P16, unrestrained mutant neonates exhibit absence seizures identified by EEG analysis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
epilepsy		DOID:1826		J:91856