The Many Types of Galactosemia

Introduction

It is not uncommon to find diseases existing in several forms, and galactosemia is certainly one of them. Fundamentally, galactosemia is a genetic condition whereby galactose cannot be digested in the body or be utilized by the body to produce energy. Galactose is converted into glucose - a usable form of energy - through the action of 3 enzymes that are essential in starting up the reaction. 

Galactosemia occurs when a mutation in a particular gene wrecks up the activity of one of these enzymes and preventing the breakdown of galactose. The type of mutated gene and the type of enzymes affected by the mutation defines the type of galactosemia. 

There are 3 types of galactosemia known today.

Fig.1 Type 1 Galactosemia: The Classic

Classic galactosemia, also known as Type 1 galactosemia, is the most common and fatal type. 

It occurs when the GALT gene is mutated at the 9p13 locus. This mutation is associated with the deficiency of the enzyme, galactose-1-phosphate uridyl transferase, in the body.The absence of action by this enzyme halts the conversion of UDP-glucose to Glucose-1 phosphate, which is utilised during glycolysis to generate energy, and the conversion of Galactose-1-phosphate to UDP-Galactose. 

Rarer Types

Galactosemia Type 2 (galactokinase deficiency) and Galactosemia Type 3 (galactose epimerase deficiency) are the rarer forms of this disease. In Type 2 galactosemia, mutation occurs in the GALK1 gene at 17q24 locus. This causes the deficiency of the enzyme galactokinase, an enzyme which catalyzes the reaction that converts Galactose in its closed ring form to Galactose-1-phosphate.

Last but not least, in type 3 galactosemia, mutation occurs in the GALE gene at the 1p36-p35 locus, causing the deficiency of galactose epimerase enzyme in the body. This inhibits the regeneration of UDP-glucose , preventing the formation of glucose-1-phosphate and allowing galactose and galactose-1-phosphate to accumulate.

Novel Non-coding Variant in GALT

Introduction
Classic galactosemia is a genetically recessive disease caused by mutations in GALT gene, meaning a child has to inherit one defective gene from each parent before having galactosemia.

Galactosemia poses as a lethal threat to the lives of newborn babies, hence newborn screening (NBS) is usually carried out after the birth of a child to detect classic galactosemia.  However, this molecular diagnosis can become quite complicated due to the extensive and overlapping range of reactions involving GALT enzyme.
Allelic heterogeneity at the GALT locus - the gene location which encodes for GALT - also contributes to these complications. Allelic heterogeneity is a phenomenon whereby different mutations at the same locus causes the same phenotype. Meaning to say that, in some cases, the mutated GALT gene can still encode for GALT enzyme despite the belief that a mutated GALT gene cannot encode for  the GALT enzyme. Hence, due to these complications, NBS can sometimes generate false positive results for galactosemia during screenings.

Discovering the Non-coding Variant
A scientific finding was recently published in ScienceDirect revealing a novel non-coding variant, c.377+17C>T, in the GALT gene. This non-coding variant in the GALT gene is believed to be associated with false positive newborn screening results for galactosemia.

After conducting qRT-PCR studies on the lymphoblasts of the child flagged for galactosemia, the scientists found that his GALT-mRNA levels were normal. The values of Gal-1P, an intermediate in the intraconversion of glucose and galactose, in the child were also measured to be normal after exposure to galactose.
The novel non-coding GALT variant, c.377+17C>T, was later found to be homozygous in the child and heterozygous in the parents.

Conclusion
The existence of these rare but benign variants in the GALT gene highlights the need for further functional studies to distinguish benign variants from malign variants so as to prevent future false positive newborn screening results.

A Study of 2 Cases

Case 1
On July 31, 1961, the Department of Pediatrics, S.D, Medical College, Agra, published a case file depicting the medical history of 12 weeks old boy diagnosed with Galactosemia. He was admitted to Sarojini Naidu Hospital with complainants by his mother that he was experiencing frequent vomitting, failure to thrive (as also seen in the next case), lethargy. distention of the abdomen and jaundice which had appeared on the third day after a seemingly normal birth.

The doctors ran a physical examination on the emaciated infant and found his blood count and systemic function to be normal. It was only after they conducted an osazone test which resulted positive for galactose did the doctors then use paper chromatography to confirm that galactose was indeed present in the infant.

Although the doctors did manage to diagnose the infant with galactosemia and put him on Holzel's diet, a galactose-free diet, the infant's health still continued to deteriorate and he died at 3 months old of age.

Case 2 
On 22nd May 1961, an adopted boy of 9-months of age was admitted to the same hospital due cough, fever, diarrhea, occasional vomitting and failure to thrive. He was diagnosed with jaundice when he was 10 days old.

Similar to the previous case, osazone test and paper chromatography had revealed the presence of galactose in the child's body. He was put on Holzel's diet and stayed in the hospital for 22 days. Throughout his stay, the child improved in health. He was discharged in good health, prescribed a specific diet  and scheduled to return for regular check-ups.

Notes about these cases
In both cases, galactosemia was not detected in both children until they were brought to the hospital due to their symptoms. However, in one of the two cases, the boy did not survive. As both parents did not know that their child had the disease initially, they had fed their child breast-milk or cow's milk.
Apparently, there was no history of the disease in both families of the two cases.

At present time, babies are screened for galactosemia at birth as part of routine newborn screening. Hence, it is rare that the disease would go unnoticed.

A General Look into Galactosemia

What is Galactosemia?

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Galactosemia is an recessive inheritance of an enzymatic defect in the breaking down of galactose.

Due to the lack of the enzyme galactose-1-phosphate uridyl transferase (GALT), people with galactosemia cannot metabolise galactose. 

When galactose accumulates in the body, it becomes toxic. In fact, there is a 70% chance that an infant could die when this disorder is not treated.

Sources of Galactosemia
Galactose can be found in food commonly consumed in our everyday life. Surprisingly, many fruits are also listed among those containing galactose. How does one with galactosemia lead a healthy lifestyle when they cannot consume fruits, which has always been a major component of a healthy lifestyle? It makes me wonder what other food alternatives must they rely on get their daily nutrients.
(List of Food with High Galactose Content).

Galactose is also formed when lactose in milk is broken down. Milk is a major constituent of an infant's diet, it is essential to the growth and development of a child. Hence, as soon as a baby is diagnosed with galactosemia, breast milk and milk-based infant formulas must be stopped and an alternate diet must be constructed. There are two groups of formulas that are recommended for babies with galactosemia: soy formulas and elemental formulas. Both formulas supply all of the necessary nutrients and calories to help your baby grow and develop.

The body also synthesizes galactose during the formation of glycolipids and glycoproteins in several tissues.

Treatment

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Logically, the treatment for glycosemia would be to inhibit galactose and lactose in a person's diet. There is yet to be a drug substitute that can be taken for the missing enzyme. Having come to learn about bacteria being genetically modified to produce insulin to treat diabetic patients, I have personally come to wonder if it is possible to genetically engineer an organism to produce the GALT enzyme. However, I have not been able to find any articles pertaining to this route of interest.

As this is a genetic disorder, perhaps the concept of genetically designing a baby can be applied here. Technically, if the faulty gene is "corrected" to functionally produce GALT, wouldn't the disorder be cured?  Perhaps in the near future further research will be done to develop more treatments for people with glycosemia..