Assessment of ataxia phenotype in a new mouse model of galactose‐1 phosphate uridylyltransferase (GALT) deficiency

Abstract

Despite adequate dietary management, patients with Classic Galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

Impaired fertility and motor function in a zebrafish model for classic galactosemia

“…Moreover, the clinical findings in our zebrafish model are in line with observations in other animal models for classic galactosemia. GALT-deficient flies exhibited motor impairments (Kushner et al 2010 ), whereas GALT-deficient mice exhibited brain abnormalities, and females showed a smaller litter size and longer time to achieve pregnancy (Chen et al 2017 ; Tang et al 2014 ).…”

“…Animal models for classic galactosemia that tried to mimic the biochemical and clinical human phenotype(s) have been developed, a fruit fly (Kushner et al 2010 ) and two mouse models (Leslie et al 1996 ; Tang et al 2014 ), which have shown their value (Balakrishnan et al 2016 ; Chen et al 2017 ; Daenzer et al 2016 ; Jumbo-Lucioni et al 2013 , 2014 , b , 2016 ). We have created a zebrafish model for classic galactosemia that complements these models.…”

A galactose‐1‐phosphate uridylyltransferase‐null rat model of classic galactosemia mimics relevant patient outcomes and reveals tissue‐specific and longitudinal differences in galactose metabolism

“…Furthermore, the only wholeorganism mammalian model-a GALT-null mouse-was created twice by separate investigators 11,12 and in one instance showed no relevant phenotypes 11 and in the other was reported to show some phenotypes, but these were pronounced only following extraordinary dietary galactose intoxication. 12,13 To explore the relationship between metabolites and outcomes, we created and characterised an outbred GALT-null rat model of CG. As demonstrated here, our GALT-null rats exhibit a range of phenotypes reminiscent of CG in humans, including cataracts, mild growth delay, and both cognitive impairment and motor deficits in adults.…”

Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models

“…Furthermore, an increased abundance of BiP was found in this tissue. 61,62 Decreased thicknesses of the molecular and granular layer in the cerebellum of mutant mice suggested cerebellar hypoplasia. These mice manifested ataxia-related motor impairments with varying degrees of severity.…”

“…A progressive nature of the impairments in older mice was observed. 62 Additionally, studies by Balakrishnan et al showed down-regulated of the PI3/Akt pathway in isolated GALT-deficient ovaries. pAkt (Ser473), pGsk3β, and Hsp90 levels in the isolated GALT-deficient ovaries were significantly reduced and higher levels of BiP were found.…”