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PGC is happy to provide assistance to students writing research papers, essays, etc. about galactosemia. The following information was prepared by Barb Bense, (the mother of a galactosemic child), Paul Taylor (ptaylortse@aol.com the father of a galactosemic child), and Paul Atkinson (also the father of a galactosemic child) to provide additional information to students who are researching galactosemia. Thank you Barb, Paul, and Paul !!

The first detailed description of galactosemia was given by F. Groppert (Galaktosurie nach Milchzuckergabe bei angeborenem, familiaerem chronischem Leberleiden. Klin. Wschr. 54: 473-477, 1917). This infant whose case served as the stimulus for a hereditary study; presented with large liver, jaundice, failure to thrive, and urinary excretion of albumen and sugar. After exclusion of galactose from the diet, these signs and symptoms normalized. He was mentally retarded (developmental quotient of 14 months at 36 months of age). He tolerated sucrose, maltose, glucose, and fructose at doses of 2 g/kg, but after lactose or galactose there was dose-dependent galactosuria. His oldest brother had suffered from jaundice and liver enlargement a few days after birth and had had a life-threatening bleed after ritual circumcision. He died after 6 weeks. At autopsy, a huge liver tumor was present (attributed to syphilis, although subsequent Wassermann reactions were negative), and the cause of his death was attributed to nephritis. His third sibling, born somewhat prematurely, became jaundiced, and died after 4 weeks. F. Groppert concluded that the patient was suffering from a familiar liver disorder and that in such cases lactose must be replaced by another sugar, e.g., sucrose or maltose.

Another early detailed description of galactosemia was given by Mason, H.H.; Turner, M. E.(Chronic galactosemia: report of case with studies on carbohydrates. Am. J. Dis. Child. 50: 359-374, 1935). Dr. S. Segal presented a picture of this 30-year-old man diagnosed in infancy by Mason, H. H.; Turner, M. E.

Beutler, E.; Baluda, M. C.; Sturgeon, P.; Day, R. : (A new genetic abnormality resulting in galactose-1-phosphate uridyltransferase (GALT) deficiency. Lancet I: 353-354, 1965) suggested that some persons with intermediate levels of the enzyme are not heterozygotes for the usual galactosemia but rather are homozygotes for what they termed the Duarte variant. Heterozygotes for this variant have about 75% normal activity. This new form was discovered in the course of a screening program. Patients with the Duarte variant of galactosemia are usually healthy, despite functional and structural abnormality in their galactose-1-phosphate uridyltransferase. An 8-month-old boy who had jaundice and liver enlargement during the first 2 months was reported by Kelly, S. Desjardins, L.; Khera, S. A : ( A Duarte variant with clinical signs. J. Med. Genet. 9: 129-131, 1972.) He was homozygote for the Duarte variant. Both parents and 2 sisters were carriers. Surgical biopsy of the liver showed marked fatty infiltration, periportal fibrosis and cirrhosis. His subsequent development was normal. Improvement, the authors suggested, may have been due to maturation of the enzyme. Two similar cases had been reported.

Galactosemia is a metabolic abnormality, inherited as an autosomal recessive trait. It can never be transmitted from person to person. The inherited trait involves a molecular structure in every cell of the body and only may be passed on at conception. Galactosemia is not a sex-linked disorder, so its occurrence is equal among males and females. However, one of the possible long-term effects of the disorder, infertility, appears to impact only women. Other long-term effects, such has learning disabilities and impairment of motor function, afflict both sexes equally.

Regarding prenatal prevention, there is nothing that current medicine can do to "prevent" galactosemia. Parents usually learn they are carriers for galactosemia only after the birth of an affected child. Some chose not to have any more children. Those that do want more children risk a 25% chance that each additional child will also be afflicted with galactosemia. Frequently, a doctor will recommend that the pregnant mother, as a precaution, limit her intake of galactose containing foods and, of course, give the child only a soy-based formula from the moment of birth until the child can be tested for the disease. No prenatal or postnatal actions will prevent galactosemia, but a carefully controlled diet will act to lessen the severity of the condition in the first few weeks of birth and they may act to improve the long-term outcome for the child too. Some day far in the future, gene transfer procedures might cure the disorder before or even after birth. Or maybe some day in the not-too-distant future, parents will be tested to see if they both are carriers for one of the hundreds of inherited disease before they marry. What would you do if you wanted to have a family but you learned in advance that you and your mate were carriers for the same inherited disease?

Galactosemia is the most common name given to a category of metabolic disorders in which an enzyme deficiency effects the normal metabolism of the sugar galactose.

Gene is a general term that describes "a unit of heredity" the concept of a gene is still being developed. A gene is made up of a combination of nucleotides within a chromosome. These combinations of chemical arrangements are what make each individual unique.

Galactosemia occurs in allelic genes, these are genes situated at corresponding locations in a pair of chromosomes. The chromosome pair location numbers for each enzyme deficiency is listed below:

There are over a hundred heritable mutations that can cause galactosemia. Some mutations (the most common mutation, Q188R, for example) cause complete loss of ability to process the sugar galactose. Others only diminish the body's ability to process galactose (an example of this sort of mutation is called Duarte, or N314D). Different ethnic groups tend to have different prevalence of the various mutations. For example, caucasians are much more likely than African-Americans to carry the Q188R mutation while AFs tend to have the S135L mutation at higher frequency. A small ethnic group in Ireland, known as The Travelers, can be as much as 60 times as prone to the Q188R mutation as is the general Irish population.

In the United States and Britain the published incidence of galactosemia is 1 in 62,000 births. At the end of 1998, cases of galactosemia were recorded in 24 different populations and ethnic groups in 15 countries worldwide. The mutations most frequently cited are Q188R, K285N, S135L, and N314D. Q188R is the most common mutation in European populations or in those predominantly of European descent. Overall, it accounts for 60-70% of mutant chromosomes, but there are significant differences in its relative frequency in individual populations.

Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD. The Lewis Laboratories, Southmead Hospital, Bristol, England, United Kingdom. linda.tyfield@bris.ac.uk

A really short and easy to read review of galactosemia was written by the American Liver Foundation and can be found at http://sadieo.ucsf.edu/ALF/ALFfinal/infogalactosemia.html . In that review, you should be able to find out a lot of basic informationn about the condition, including the frequency of its occurrence in the live birth population. You can also find a lot more detailed discussion of the frequency at http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?230400#TEXT.

Normally, galactose is metabolized in the body to glucose, each step in the metabolic pathway being carried out by a specific organic catalyst, or enzyme.

In galactosemia, the enzyme that catalyzes the second step, converting galactose-1-phosphate to glucose-1-phosphate, is not active. As a result of this metabolic block, there is an accumulation of galactose-1-phosphate in body tissues, and this compound is believed to be the cause of the life threatening complications associated with galactosemia. Galactose is present in the blood and urine of persons suffering from galactosemia, and there is decreased formation of glucose in the body, which may result in a lowering of the blood glucose level.

Normally, galactose is metabolized in the body to glucose-1-phosphate by a unique uridyltransfer through the enzyme galactose-1-phosphate uridyltransferase (GALT).

Galactosemia is a deficiency of GALT. The normal GALT enzyme exhibits ping-pong bi-bi kinetics which denotes that one domain of the enzyme binds uridine diphosphate (UDP)-glucose to form a GALT enzyme UDP-glucose intermediate. Glucose 1-phosphate is released whereas uridine monophosphate remains bound to GALT. Galactose-1-phosphate then binds with the GALT-uridine monophosphate complex to form GALT-UDP-galactose, UDP-galactose is released, and GALT is freed for the next round of reactions. Galactosemia is a deficiency typically of the GALT enzyme involved in this process. In1998 there were more than 130 mutations associated with GALT deficiency. The most common allele in the white population is arginine substituted for a glutamine at position 188 (Q188R).

Little is known about the biochemical mechanisms by which glutamine-188 isessential or how GALT is impaired by the substitution of an arginine for glutamine at this position. By uperimposing the human GALT amino acid sequence on the highly homologous three-dimensional crystal structure of the E. coli GALT, glutamine-188 lies proximal to and in the beta sheet of His-Pro -His which initiates a nucleophilic attack in the release of glucose-1-phosphate from UDP-glucose.

When human GALT cDNA containing the Q188R mutation was expressed in the "knockout" yeast cells, no GALT activity was detected. When a Q188R-GALT monomeric subunit dimerized with a wild-type GALT subunit to form a "heterodimer", the resultant catalytic activity of the heterodimer was less than 50% of when only the wild type GALT cDNA was expressed. This may suggest that the Q188R-GALT subunit exerted a "dominant negative" effect on a wild type subunit when the two subunits dimerized. This observation was the first to address potential interactions between the GALT subunits, but did not explain the essentiality of glutamine-188 or how the Q188R mutation per se inactivated the catalytic function of the mutant enzyme subunits. Others found that patients homozygous for Q188R mutation had no GALT protein in the erythrocytes, leukocytes, or transformed lymphoblasts. Using site directed mutagenesis in an E. coli GALT "knockout" system, the Q188 residue was found to be crucial for GALT catalysis with normal amounts of protein. Therefore, the pathobiochemical effects of an arginine substituted for glutamine-188 involved both biostability of the GALT protein and its catalytic function.

Symptoms typically start about the third day of life. The skin is jaundiced which doesn't go away with the usual procedures. Cataracts, enlarged liver, vomiting and failure to thrive (can lead to death) are probably the most common and apparent symptoms.

Once the baby is diagnosed (and diagnosis is usually made within the first two weeks of life through the newborn screening heel prick test) and they are put on the correct formula, they usually survive. If they survive the "neonatal period" and they continue to follow the diet, their life expectancy is the same as everyone else.

Some galactosemics have fine and/or gross motor skill complications. Some estimate that as many as 70% have some sort of speech and/or language deficit. The majority have some sort of a developmental delay, but not all. Some are mentally retarded, some are just mildly delayed and some are just fine. A few are blind due to Vitreoretinal Hemorrhages (massive bleeding behind the eye). The degree of these complications varies and nobody knows why some do better than others. The majority of the girls will have ovarian failure at some point in their lives.

It is autosomal.

Galactosemia is a recessive gene passed by both parents. This is why it is so rare; 1 in 50,000. Both parents have to be carriers and then both parents have to pass a recessive gene in order for their child to have galactosemia. So even known carriers only have a 25% chance having a galactosemic child.

About the only known treatment for galactosemia is the strict diet they need to follow. Even the diet for a galactosemic is not unanimously agreed upon by all professionals. Many of course, receive therapy for their speech and motor skill problems as well as their learning disabilities. The dietary ingredient restrictions for galactosemia are described elsewhere on this site.