1. Galactosemia screening why? when? how? Clinical Children`s Hospital “Louis Turcanu ” Timisoara, Romania

2. Galactosemia screening why?

3. Galactosemia  Is a genetic metabolic disease in which there is a defect in the body's ability to use the sugar galactose.  People with galactosemia are unable to metabolize the simple sugar galactose. Galactose makes up half of the sugar called lactose that is found in milk. Lactose is a disaccharide, and is made of two sugars, galactose and glucose, bound together.

4. History  Galactosemia was first discovered in 1908 by the physician Von Ruess.  Publication entitled, "Sugar Excretion in Infancy," reported on a breast-fed infant with failure to thrive, enlargement of the liver and spleen, and "galactosuria".

5.  In 1917, Goppert reported an infant with poor growth, lactose exposure, and hypergalactosuria  The first comprehensive description of the variant form of hereditary galactosemia was in 1935 by Mason and Turner of an African-American infant. It was also the first report of a patient with any form of galactosemia due to GALT deficiency in the American literature. This patient had not been placed on a lactose-restricted diet until 10 months of age.

6. Galactose metabolism  Normally, the body breaks down lactose into galactose and then into glucose (a sugar used for energy).  People with galactosemia are missing an enzyme called GALT, (galactose-1- phosphate uridyl transferase), GALK1 or GALE, which normally converts galactose into glucose.  Without this enzymes, harmful amounts of galactose build up in the blood.

7. Lactose metabolism

8. Galactosemia – a genetic disease  It occurs in approximately 1 out of every 60,000 births among Caucasians.  The rate is different for other groups. Galactosemia is an inherited disorder. Autosomal recessive pattern

9. Three forms of galactosemia  Galactose-1 phosphate uridyl transferase deficiency (classic galactosemia, the most common and most severe form)- (GALT) Type I  Deficiency of galactose kinase – (GALK1)Type II  Deficiency of galactose-6-phosphate – epimerase (GALE)-Type III

10.  Galactose-1-phosphate uridyltransferase defect causes accumulation of galactose (appears in blood, urine, reduced to galactitol in lens).  Galactose enters eye, aldose reductase changes it to galactitol. Galactitol accumulates in lens and causes infantile cataracts.  Jaundice, vomiting, poor feeding, infections  Failure to thrive, hepatomegaly  Speech disabilities, mental retardation Classic galactosemia – type I

11. Galactosemia clinical pictures

12.  The official name of this gene is “galactose-1- phosphate uridyltransferase.”  GALT is the gene's official symbol.  Cytogenetic Location: 9p13  Molecular Location on chromosome 9: base pairs 34,646,634 to 34,650,573  More precisely, the GALT gene is located from base pair 34,646,634 to base pair 34,650,573 on chromosome 9.

13. Genetic variations - GALT GeneSymbolActivity level NormalN100% Galactosemia - non- functioning g0% Duarte - partially functioning D50% Los Angeles - above normal functioning gene LA125%

14.  Most commonly seen are Duarte (a low enzyme producing gene) and Los Angeles (an enhanced enzyme producing gene).  These variants and combination of genes (gN, DN, DD, LAN, LAg, LAD) do not require treatment or dietary restriction of galactose.

15.  The Duarte variant is found in 1 in 20 persons.  GALT enzyme (10-25% to 50% activity ) and do not commonly have any symptoms.  The children with Duarte galactosemia who continue to receive breast milk in the first year of life might have higher than normal galactose-1-phosphate levels, but they do not have any symptoms or health problems related to the Duarte variant.

16. Galactokinase – deficiency or galactosemia Type II  In 1965, galactokinase deficiency was first identified in a patient who presented with cataracts and galactosuria that developed upon drinking milk.  This presentation differed from that of classic galactosemia in many important aspects; neither hepatosplenomegaly nor signs of mental retardation were present.  When the researchers realized that the patient did not accumulate galactose-1-phosphate despite the accumulated galactose, the patient's underlying defect was deduced as the lack of the enzyme mediating 1- phosphorylation of galactose.

17.  The official name of this gene is “galactokinase 1.”  GALK1 is the gene's official symbol.  Cytogenetic Location: 17q24  Molecular Location on chromosome 17: base pairs 73,754,017 to 73,761,279  More precisely, the GALK1 gene is located from base pair 73,754,017 to base pair 73,761,279 on chromosome 17.

19. Clinical pictures of Galactosemia Type II  Mild  Cataract in the infant

20. Galactose epimerase deficiency – galactosemia -Type III  The official name of this gene is “UDP-galactose-4- epimerase.”  More than 20 mutations in the GALE gene have been identified in people with a form of galactosemia known as type III or galactose epimerase deficiency.  Most of these genetic changes alter a single protein building block (amino acid) in UDP-galactose-4- epimerase, which makes the enzyme unstable or disrupts its usual function.

21.  Cytogenetic Location: 1p36-p35  Molecular Location on chromosome 1: base pairs 24,122,088 to 24,127,293

22. Galactosemia screening when? how?

23. Neo-natal screening  Dry blood spot collect in the 4 th day of life  From lateral parts of the heel and send it to the special center from Clinical Children's Hospital “Louis Turcanu”

24.  A positive newborn screen test must be followed by a quantitative erythrocyte galactose-1-phosphate uridyltransferase (GALT) analysis  A GALT isoelectric-focusing electrophoresis test helps distinguish variant forms such as the Duarte defect.  GALT genotyping may provide a specific molecular diagnosis

25. How is treated galactosemia?  The only way to treat galactosemia is through dietary restrictions from the first days of life  No brest feeding  Soya- based formula The newborn with questionable results on newborn screening should continue to be treated with soy- based formula pending definitive results of confirmatory testing.

26. Treatment  The mainstay of medical care in the postnatal period is to immediately discontinue ingestion of lactose-containing formula.  Totally eliminating galactose is difficult because it is present in a wide variety of foods (eg, infant foods, fruits, vegetables)  This ameliorates the acute toxicity associated with the neonatal period but does not prevent all long-term complications.

27. Galactosemia screening  Why? If unscreened and untreated, galactosemia is a life-threatening disorder.  When? Neonatal period: 4 th day  How? Screening of every neonates, followed by confirming tests. Thereby, affected infants are treated before they become ill.

28. Thank you !