Explore Learn Connect

Galactosemia is a rare, potentially life threatening, autosomal recessive metabolic disorder in which patients are unable to metabolize galactose.^1,2

Galactose, a simple sugar produced endogenously and gained through the diet in lactose-containing dairy products and also at lower levels through fruits and vegetables,³ is normally metabolized in the Leloir pathway. The enzyme galactokinase, also known as GALK, metabolizes galactose to galactose-1-phosphate (Gal-1p).

The enzyme GALT subsequently metabolizes Gal-1p¹ to glucose-1-phosphate.

In Classic Galactosemia, patients either do not have GALT catalytic activity,¹ or the GALT enzyme is completely missing.⁴

Both outcomes lead to the accumulation of Gal-1p and galactose.⁵

However, levels of Gal-1p do not correlate with clinical severity or long-term outcomes of Galactosemia and therefore Gal-1p is not considered to be the toxic metabolite of the disease.⁶ Instead, Gal-1p levels are useful for monitoring dietary compliance.⁷

Build-up of galactose and Gal-1p triggers the alternate polyol pathway, through which galactose becomes an aberrant substrate of Aldose Reductase, an enzyme that metabolizes galactose to the toxic metabolite, galactitol.^8,9

Galactitol cannot be reduced further by sorbitol dehydrogenase, the next enzyme in the polyol pathway leading to accumulation of toxic galactitol and subsequent disease complications throughout the body and organs, including the CNS.^9,10

The majority of galactitol cannot cross the cell membrane, resulting in its accumulation in cells.⁴

The excess galactitol leads to an osmotic imbalance within cells that results in cell damage and cerebellar atrophy.^10-12

Further toxicity is attributed to the redox dysregulation caused by galactitol, affecting neuronal function and compromising signaling capabilities.¹³

Symptoms of Galactosemia manifest shortly after birth following the consumption of breast milk or dairy formula.⁴

While dietary restrictions in newborns may prevent fatalities,⁴ these restrictions do not address the long-term complications of Galactosemia due to the endogenous production of galactose within the cell.²

Therefore, health issues are likely to persist and develop through to adulthood, including cognitive and intellectual deficiencies,⁸ speech delays and apraxia, cataracts,¹⁴ tremor,¹² seizures,¹⁵ depression,¹⁶ fine and gross motor skill abnormalities,⁸ and primary ovarian insufficiency in females.⁸

As a result, adults with Galactosemia may find it difficult to live independent lives.

Research on the pathogenesis of Galactosemia has solidified understanding of galactitol as the primary toxic metabolite in the disease.

Galactosemia remains a disease with a high unmet medical need.¹⁷

REFERENCES:

1. Demirbas D, Huang X, Daesety V, et al. The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency. Mol Genet Metab. 2019;126(4):368-376.
2. Kotb MA, Mansour L, Shamma RA. Screening for galactosemia: is there a place for it?. Int J Gen Med. 2019;12:193-205.
3. Lai K, Elsas LJ, Wierenga KJ. Galactose toxicity in animals. IUBMB Life. 2009;61(11):1063-1074.
4. Mccorvie TJ, Timson DJ. Galactosemia: opportunities for novel therapies. In: Protein Homeostasis Diseases: Mechanisms and Novel Therapies. Pey AL (Ed.). Elsevier, USA (2020).
5. McCorvie TJ, Kopec J, Pey AL, et al. Molecular basis of classic galactosemia from the structure of human galactose-1-phosphate uridylyltransferase. Hum Mol Genet. 2016;25(11):2234-2244.
6. Welsink-Karssies MM, Ferdinandusse S, Geurtsen GJ, et al. Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers. Brain Communications. 2020;2(1):fcaa006.
7. Berry GT. Classic galactosemia and clinical variant galactosemia. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews^®. Seattle (WA): University of Washington; February 4, 2000.
8. Coelho AI, Rubio-Gozalbo ME, Vicente JB, Rivera I. Sweet and sour: an update on classic galactosemia. J Inherit Metab Dis. 2017;40(3):325-342. doi:10.1007/s10545-017-0029-3
9. Meyer WR, Doyle MB, Grifo JA, et al. Aldose reductase inhibition prevents galactose-induced ovarian dysfunction in the Sprague-Dawley rat. Am J Obstet Gynecol. 1992;167(6):1837-1843.
10. Berry GT, Hunter JV, Wang Z, et al. In vivo evidence of brain galactitol accumulation in an infant with galactosemia and encephalopathy. J Pediatr. 2001;138(2):260-262.
11. Martinelli D, Bernardi B, Napolitano A, Colafati GS, Dionisi-Vici C. Teaching NeuroImages: Galactitol peak and fatal cerebral edema in classic galactosemia: Too much sugar in the brain. Neurology. 2016;86(3):e32-e33.
12. Waisbren SE, Potter NL, Gordon CM, et al. The adult galactosemic phenotype. J Inherit Metab Dis. 2012;35(2):279-286. doi:10.1007/s10545-011-9372-y
13. Webb AL, Singh RH, Kennedy MJ, Elsas LJ. Verbal dyspraxia and galactosemia. Pediatr Res. 2003;53(3):396-402.
14. Stambolian D. Galactose and cataract. Surv Ophthalmol. 1988 Mar-Apr;32(5):333-49.
15. Aydin-Özemir Z, Tektürk P, Uyguner ZO, Baykan B. Galactosemia and phantom absence seizures. J Pediatr Neurosci. 2014;9(3):253-256.
16. Timmers I, van den Hurk J, Di Salle F, Rubio-Gozalbo ME, Jansma BM. Language production and working memory in classic galactosemia from a cognitive neuroscience perspective: future research directions. J Inherit Metab Dis. 2011;34(2):367-376.
17. Timson DJ. Repurposing drugs for the treatment of galactosemia. Expert Opin. Orphan Drugs. 2019. 7(10), 443-451.