Galactosemia Szeged 27 June 2011 Galactose galactose glucose

Galactosemia Szeged, 27 June, 2011

Galactose γάλακτος galactose glucose lactose In the human body, glucose is changed into galactose via hexoneogenesis to enable the mammary glands to secrete lactose. However, most galactose in breast milk is synthesized from galactose taken up from the blood, and only 35± 6% is made by de novo synthesis.

Galactose Metabolism

Galactosemia is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Goppert first described the disease in 1917. Its incidence is about 1 per 60, 000 births. It is much rarer in Japan. Type Disease Enzyme Type 1 classic galactosemia galactose-1 -phosphate uridyl transferase Type 2 galactokinase deficiency galactokinase Type 3 galactose epimerase deficiency UDP-galactose-4 -epimerase deficiency UDP galactose epimerase

Galactosemia In individuals with galactosemia, the enzymes needed for further metabolism of galactose are severely diminished or missing entirely, leading to toxic levels of galactose 1 -phosphate in various tissues. In the case of classic galactosemia, it results in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.

Classic galactosemia If galactose 1 -phosphate uridylyltransferase is absent, galactose and G-1 -P would accumulate in blood and tissues as they could not be metabolized. The accumulation of G-1 -P is toxic and the biochemical mechanism is still an enigma. G-1 -P may modulate IMPase function in vivo. G-1 -P is suggested as a substrate for IMPase as well as galactose 1 -phosphate uridylyltransferase, as the brain depends on IMPase for the supply of free inositol in order to sustain the phosphatidylinositol bisphosphate signalling. The accumulation would inhibit the production of the second messenger in the signalling system and hence causing a mental retardation. Types Classic galactosemia, in which there is an extreme deficiency in galactose-1 phosphate uridyltransferase. The variant gene, responsible for Duarte galactosemia, leads to about half the normal levels of GALT. Individuals with Duarte galactosemia may experience few or none of the serious symptoms of classic galactosemia. Clinical: if untreated, poor growth in children, mental retardation, speech abnormality, vision impairment (due to formation of cataract) and liver enlargement (which may be fatal). Strict removal of galactose from diet is required.

Galactokinase-deficiency Accumulation of galactose and galactitol secondary to the decreased conversion of galactose to galactose-1 -phosphate by galactokinase. Unlike classic galactosemia, which is caused by deficiency of galactose-1 -phosphate uridyltransferase, galactokinase deficiency does not present with severe manifestations in early infancy. Its major clinical symptom is the development of cataracts during the first weeks or months of life, as a result of the accumulation, in the lens, of galactitol, a product of an alternative route of galactose utilization. The development of early cataracts in homozygous affected infants is fully preventable through early diagnosis and treatment with a galactose-restricted diet. Some studies have suggested that, depending on milk consumption later in life, heterozygous carriers of galactokinase deficiency may be prone to presenile cataracts at 20– 50 years of age.

Galactose epimerase deficiency 2 forms of epimerase deficiency: benign RBC deficiency, and severe liver deficiency. Severe form is similar to galactosemia. GALE deficiency inhibits UDP-glucose regeneration, preventing the formation of glucose-1 -phosphate and leading to the accumulation of galactose and galactose-1 phosphate. High galactose-1 -phosphate levels have been shown to interfere with Phosphoglucomutase, glycogen phosphorylase, UDP-glycopyrophosphorylase, and inositol monophosphatase

Type III galactosemia Symptoms of congenital Type III Galactosemia are apparent from birth, but vary in severity depending on whether the peripheral or generalized disease form is present. Symptoms may include: Infantile jaundice Infantile hypotonia Dysmorphic features Sensorineural hearing loss Impaired growth Cognitive deficiencies Depletion of cerebellar Purkinje cells Ovarian failure (POI) and hypertrophic hypergonadism Liver failure Renal failure Splenomegaly

Treatment The only treatment for classic galactosemia is eliminating lactose and galactose from the diet. Infants with classic galactosemia cannot be breast-fed due to lactose in human breast milk and are usually fed a soy-based formula. Even with an early diagnosis and a restricted diet, however, some individuals with galactosemia experience long-term complications such as speech difficulties, learning disabilities, neurological impairment (e. g. tremors, etc) … Due to the 1 g/day endogenous galactose synthesis These symptoms have not been associated with Duarte galactosemia, and many individuals with Duarte galactosemia do not need to restrict their diet at all.