GALACTOSEMIA

Disease

Brief Summary

Galactosemia is a rare hereditary metabolic disorder that affects the body’s ability to convert galactose to glucose (The main energy source of all organisms, particularly humans). Galactose is a sugar contained in milk, including human mother’s milk and other dairy products. The human body also produces galactose, which is called endogenous galactose. This disorder can cause several problems for newborns and is life-threatening if left untreated. Galactosemia is divided into classic galactosemia, galactokinase deficiency, and galactose epimerase deficiency. Classic galactosemia, also known as type I, is the most common and most severe form of the condition. On the other hand, galactokinase deficiency, also known as galactosemia type II, and galactose epimerase deficiency, also known as galactosemia type III, cause fewer medical problems than the classic type.

Source

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Child with galactosemia

Frequency

It affects 1 in 30,000 to 60,000 newborns. Less common types are galactosemia type II and type III; type II affects less than 1 in 100,000 newborns while type III is very rare. In the Philippines, individuals are affected with the classical form(1: 356,391), nonclassical form (1: 105,411), and the Duarte variant (1: 84,092)

Inheritance

Galactosemia disorder is inherited in an autosomal recessive manner.

History of Disease

Galactosemia was first "discovered" in 1908 by Von Ruess. It was in his 1908 publication entitled "Sugar Excretion in Infancy" which he reported that in a breast-fed infant with enlargement of the liver and spleen, failure to thrive, and "galactosuria," the infant ceased to excrete galactose through the urine when milk products were removed from the diet. Due to this, Von Ruess was generally accepted as the first to report on a patient with galactosemia.

Moreover, by 1917, "galactosuria" was a broadly recognized inherited disorder and was treated by removing milk products from the diet. In 1935, Mason and Turner recognized and described this disease in more detail. Furthermore, in 1970, Leloir won a Nobel prize in Chemistry for his work on the metabolic pathway and the process of sugar-nucleotides. Along with his coworkers, he explained the pathway for converting galactose to glucose in the early 50s.

The breakthrough for this disease happened in 1956 when the defective gene that caused this condition was discovered. Another breakthrough was in 1963, when this condition was found to be detectable through a newborn screening method. Guthrie and Paigen developed this screening method. Lastly, galactosemia was the second disorder found to be detectable through newborn screening methods by Robert Guthrie.

Brief Summary

History of Disease

Pathogenesis

Achondroplasia is caused by a mutation in the FGF3 gene in chromosome 4 at 4p 16.3. This mutation causes a decreased production of fibroblast growth factor receptor 3 which is crucial in the conversion of cartilage into bone which is vital in the proper development of a person. This mutation is inherited in an autosomal dominant manner. More than 80 percent of people with achondroplasia have parents with normal characteristics and are born with achondroplasia due to a recent (de novo) gene modification (mutation).

Pathogenesis

Galactosemia is a human recessive disorder caused by a point mutation of the structural chromosome 9p13.3 gene in the combination of a catalytically inactive transferase protein. Furthermore, it is also characterized by the functional deficiency of the galactose-1-phosphate uridyltransferase(GALT). This condition is classified into type I, II, and III. Moreover in type I Classic Galactosemia, the GALT enzyme's absence or its catalytic ability result in the accumulation of galactose-1-phosphate (Gal-1p) and galactose. Consecutively, initiating the alternate polyol pathway makes the galactose an anomalous substrate of Aldose Reductase. It is an enzyme that digests galactose to galactitol, a toxic metabolite. Excessive galactitol directs to an osmotic imbalance within cells, resulting in cell damage and cerebellar atrophy. Further, its toxicity is allocated to the redox dysregulation mainly caused via the galactitol, influencing the body's neuronal function and compromising signaling capabilities.

Source

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Galactosemia mechanism of disease

Source

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Galactosemia history timeline

Symptoms

convulsions

irrritability

lethargy

poor feeding

poor weight gain

yellow skin and whites of eyes

vomiting

Social Concerns

It is a must to have a dietary restriction to be implemented in newborns in order to control possible fatalities. However, there is still a chance of long-term complications such as cognitive impairment, and behavioral and social functioning including intellectual deficiencies, speech delays, apraxia, depression, and fine and gross motor skill abnormalities in a Galactosemia patient. Nevertheless, classic galactosemia can be prevented and a normal life expectancy is achievable with early life treatment.

Treatment

Lactose-restricted (dairy-free) diets for infants and children with galactosemia should include lactose-free milk replacements and other foods such as soybean products. A lactose tolerance test should not be given to galactosemia patients. Fortunately, without galactose in their diet, newborns with galactosemia can generate galactolipids and other necessary galactose-containing molecules. As a result, if a strict diet is followed, satisfactory physical growth is mostly attainable.

A low-galactose diet can help prevent or lessen the risk of some issues, but it may not be enough to prevent them all. Children can still suffer problems like speech delays, learning challenges, and reproductive disorder in some circumstances. Speech issues and delays as typical consequences, thus speech therapy may be beneficial as part of the treatment plan for some children. Since galactosemia increases the risk of infection, it’s critical to manage infections as soon as they arise. Treatment with antibiotics or other medicines may be necessary.

Source

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Lactose free milk

Updates on Clinical Trials

Title:

Safety and Pharmacokinetics of AT-007 in Healthy Subjects and in Adult Subjects With Classic Galactosemia

Intervention/treatment: Drug: AT007
Drug: Placebo

Goal:

To assess the safety and PK of AT-007 in healthy subjects and subjects with Classic Galactosemia and the effect of AT-007 on biomarkers of galactose metabolism (galactose, galactitol, and other galactose metabolites) in subjects with Classic Galactosemia.

Further details here.

Title:

Clinical Benefit, Safety, PK and PD Study of AT-007 in Pediatric Subjects With Classic Galactosemia

Intervention/treatment: Drug: AT007
Other: Placebo

Goal:

To assess the clinical benefit (changes in how pediatric patients with classic galactosemia feels and function, changes in ocular disorders, and changes in sexual maturation, growth, and development) as well as the safety, pharmacokinetics, and pharmacodynamics (reduction of galactitol levels) of AT-007 in pediatric subjects with classic galactosemia.

Further details here.

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