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Introduction

Galactosemia: A rare metabolic disease

Galactosemia is a rare, slowly progressive disease caused by a genetic inability to metabolize the sugar galactose. There are 2 subtypes of Galactosemia: Classic Galactosemia (or GALT deficiency) and Type II Galactosemia (or Galactokinase/GALK deficiency). Each type is caused by a different enzyme that does not work properly or is missing in the body. In healthy individuals, these enzymes are involved in metabolizing galactose. Classic Galactosemia and GALK deficiency can greatly affect development and quality of life, resulting in CNS complications, including deficiencies in speech, cognition, behavior, and motor skills. The CNS phenotype present in Galactosemia patients has been shown to progressively worsen over time with age. CNS deficiencies may emerge in early childhood as mild to moderate, but they often progress to severe deficiencies in later childhood and adulthood. Galactosemia also causes ovarian insufficiency in females, and it often results in ophthalmic complications, such as cataracts.1-3

Classic Galactosemia, the most common form, is caused by the absence or deficiency of the GALT enzyme.1,4

GALK deficiency is caused by the absence or deficiency of the GALK enzyme.1,4

Presently there are over 3000 individuals with Classic Galactosemia in the U.S. Most patients with Galactosemia are younger than 40 years of age, as newborn screening was not widely adopted until the 1980s. Galactosemia is now included as part of routine newborn screening in all 50 states in the U.S. and in many European countries.5,6

Galactosemia PATHOGENESIS

The role of toxic galactitol

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Toxic galactitol has been linked to long-term complications, including2:

Speech
Speech
Cognition
Cognition
Behavior
Behavior
Motor skills
Motor skills
Cataracts
Cataracts
Primary Ovarian Insufficiencies
Primary ovarian insufficiency

These long-term complications are due in large part to endogenous production of galactose, which contributes significantly to the total free-galactose pool.7

Endogenous galactose production is thought to be a major factor in the pathogenesis of complications and accounts for the elevation of galactose metabolites in patients with Galactosemia; therefore, dietary galactose restrictions alone are not enough to manage Galactosemia.11

Galactose Sources

The 2 sources of galactose and their risks in Galactosemia

The total pool of galactose is composed of exogenous (dietary) and endogenously produced galactose. Endogenous production of galactose is 10x higher than that found in a restricted diet.7

Timely introduction of a galactose-restricted diet can prevent or resolve acute symptoms in infants with Classic Galactosemia. Yet despite early dietary intervention, patients still experience 1 or more of the long-term complications associated with this disease.2,7

Patients living with Galactosemia have historically been advised to undertake a more severe dietary restriction of galactose. However, as the body produces 10x more galactose than that found in a galactose-restricted diet, recent studies have found no significant association between dietary restrictions and long-term outcomes.7,12

Adapted from Bernstein LE, van Calcar S. The diet for galactosemia. In: Bernstein L, Rohr F, Helm J, eds. Nutrition Management of Inherited Metabolic Diseases. Springer; 2015:285-293. https://doi.org/10.1007/978-3-319-14621-8_25

Management

Dietary restriction alone is not sufficient

Currently, the only method of managing Galactosemia is timely implementation of a galactose-restricted diet. Galactose is found in dairy products, dairy-based infant formula, breast milk, and many fruits and vegetables. However, galactose is also endogenously produced by the body through de novo synthesis, so long-term complications continue to worsen despite strict adherence to a restricted diet. Dietary restriction alone is not sufficient to prevent progression of long-term disease complications.7

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References

  1. Galactosemia. MedlinePlus US National Library of Medicine. Updated August 18, 2020. Accessed September 18, 2020. https://medlineplus.gov/genetics/condition/galactosemia/
  2. Forges T, Monnier-Barbarino P, Leheup B, Jouvet P. Pathophysiology of impaired ovarian function in galactosemia. Hum Reprod Update. 2006;12(5):573-584.
  3. Demirbas D, Coelho AI, Rubio-Gozalbo ME, Berry GT. Hereditary galactosemia. J Metabolism. 2018;83:188-196.
  4. 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.
  5. SHA Patient Transactional Dataset, February 2017 – January 2021 (Data on File).
  6. Coelho AI, Rubio-Gozalbo ME, Vicente JB, Rivera I. Sweet and sour: an update on classic galactosemia. J Inherit Metab Dis. 2017;40:325-342. doi:10.1007/s10545-017-0029-3
  7. Bernstein LE, van Calcar S. The diet for galactosemia. In: Bernstein L, Rohr F, Helm J, eds. Nutrition Management of Inherited Metabolic Diseases. Springer; 2015:285-293.
  8. Coelho AI, Trabuco M, Ramos R, et al. Functional and structural impact of the most prevalent missense mutations in classic galactomsemia. Mol Genet Genomic Med. 2014;2(6):484-496. doi:10.1002/mgg3.94
  9. 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.
  10. Welling L, Bernstein LE, Berry GT, et al. International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow-up. J Inherit Metab Dis. 2017;40(2):171-176. doi:10.1007/s10545-016-9990-5
  11. Berry GT, Nissim I, Lin Z, et al. Endogenous synthesis of galactose in normal men and patients with hereditary galactosemia. Lancet. 1995;345:1073-1074.
  12. Frederick AB, Cutler DJ, Fridovich-Keil JL. Rigor of non-dairy galactose restriction in early childhood, measured by retrospective survey, does not associate with severity of five long-term outcomes quantified in 231 children and adults with classic galactosemia. J Inherit Metab Dis. 2017;1-9. doi:10.1007/s10545-017-0067-x

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.