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G6PD Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hereditary disease featuring abnormally low levels of the G6PD enzyme, which plays an important role in red blood cell function. Individuals with the disease may exhibit nonimmune hemolytic anemia in response to a number of causes. It is closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava). Sometimes the name, favism, is alternatively used to refer to the enzyme deficiency as a whole.
Patients are almost exclusively male, due to the X-linked pattern of inheritance, but female carriers can be clinically affected due to lyonization where random inactivation of an X-chromosome in certain cells creates a population of G6PD deficient red cells coexisting with normal red cells. G6PD manifests itself in a number of ways:
• Prolonged neonatal jaundice
• Hemolytic crises in response to:
• Certain drugs (see below)
• Certain foods, most notably broad beans
• Illness (severe infections)
• Diabetic ketoacidosis
• Very severe crises can cause acute renal failure

G6PDD is said to be the most common enzyme deficiency disease in the world, affecting approximately 400,000,000 people globally. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria. A similar relationship exists between malaria and sickle-cell disease. An explanation is that cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This phenomenon might give G6PDD carriers an evolutionary advantage.

Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (most notably erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage. G6PD converts glucose-6-phosphate into 6-phosphoglucono-d-lactone and is the rate-limiting enzyme of the pentose phosphate pathway.

Patients with G6PD deficiency are at risk of hemolytic anemia in states of oxidative stress. This can be in severe infection, medication and certain foods. Broad beans contain high levels of vicine, divicine, convicine and isouramil — all are oxidants.
In states of oxidative stress, all remaining glutathione is consumed. Enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to electrolyte imbalance, membrane cross-bonding and phagocytosis and splenic sequestration of red blood cells. The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations) or excreted directly by the kidney (causing acute renal failure in severe cases).

Deficiency of G6PD in the alternative pathway causes the build up of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also causes a reduction of NADPH which is necessary for the formation of Nitric Oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to G6PD deficiency. Some other epidemiological reports have pointed out, however, that G6PD seems to decrease the susceptibility to cancer, cardiovascular disease and stroke.

Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).

Galactose- (Gal and Gal-1-P)

Classical galactosemia is a life threatening disorder. Symptoms of classical galactosemia appear soon after ingesting a lactose-based formula or breast milk and include: vomiting, rapid weight loss, hepatomegaly and jaundice. Excess amounts of a galactose metabolite, galactose-1-phosphate, inhibit the conversion of glycogen to glucose which can result in hypoglycemia and seizures. In untreated cases, cataracts result from the accumulation of galactitol, cirrhosis of the liver develops and irreversible brain damage occurs. Many infants die during the first week of life due to liver failure, severe hypoglycemia and/or sepsis (approximately 30% develop gram negative sepsis, often E.coli).

The incidence of classical galactosemia is estimated as 1 in 50,000 in the USA and ranges from 1 in 26,000 in Ireland to 1 in 600,000 in Japan. It is more frequent in Caucasians and less frequent in other ethnic groups.

Since classical galactosemia is a life threatening disorder, it is essential that the diagnosis be confirmed and treatment started as soon possible after the results of the first screening test are available. The serious complications of this disease can be prevented by adequate treatment. However, other symptoms such as speech and language delay and ovarian insufficiency may occur in treated cases for reasons that are not yet known.

Galactosemia is an inherited autosomal-recessive disorder of galactose metabolism. People with galactosemia cannot tolerate any form of milk (human or otherwise). The sugar lactose (a disaccharide present in milk) is made up of equal parts of glucose and galactose; thus a deficiency of the enzymes involved in galactose metabolism can lead to severe clinical consequences. Ingestion of milk produces toxic levels of galactose and its metabolite galactose-1-phosphate (gal-1-P) in the infant. The classical and most severe form is caused by a deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT).

Two other enzyme deficiencies also cause galactosemia, one is epimerase and the other is galactokinase. In cases with a deficiency of one of these enzymes the initial newborn screen will show elevated galactose level with normal GALT enzyme activity. This incongruent result would suggest the possibility of one of the other enzyme deficiencies. Children with galactosemia due to deficiency of these other enzymes may not become as severely ill as the infants with classical galactosemia. However, they may be mentally retarded or have cataracts if not treated. The incidence of these disorders is significantly lower than GALT related galactosemia.

Depending on the level of galactose/gal-1-P, the enzyme activity, and the clinical and feeding status of the infant, the Metabolic Center may recommend a simple repeat of the newborn screening analysis. However, if the specialists suspect the possibility of variant or classical galactosemia they will recommend diagnostic testing. Analysis of red cell gal-1-P, GALT enzyme activity, and electrophoresis to determine enzyme genotype are required to definitively identify classical or variant forms of galactosemia. These tests may take up to a week to complete.

Galactose- Uridyltransferase

Classic galactosemia is an autosomal recessive disorder that is caused by activity deficiency of the UDP-galactose uridyl transferase (GALT). The clinical spectrum of classic galactosemia differs according to the type and number of mutations in the GALT gene. Short-term clinical symptoms such as jaundice, hepatomegaly, splenomegaly and E. coli sepsis are typically associated with classic galactosemia. hese symptoms are often severe but quickly ameliorate with dietary restriction of galactose. However, long-term symptoms such as mental retardation and primary ovarian failure do not resolve irrespective of dietary intervention or the period of initial dietary intervention. There seem to be an association between deficient galactosylation of cerebrosides and classic galactosemia. Galactocerebrosides and glucocerebrosides are the primary products of the enzyme UDP-galactose:cerebroside galactosyl transferase (CGT). There has been an observation of deficient galactosylation coupled with over glucosylation in the brain tissue specimens sampled from deceased classic galactosemia patients. The plausible mechanism with which the association between GALT and CGT had not been explained before. Yet, UDP-galactose serves as the product of GALT as well as a substrate for CGT. In classic galactosemia, there is a consistent deficiency in cerebroside galactosylation. We postulate that the molecular link between defective GALT enzyme, which result in classic galactosemia; and the cerebroside galactosyl transferase, which is responsible for galactosylation of cerebrosides is dependent on the cellular concentrations of UDP-galactose. We further hypothesize that a threshold concentration of UDP-galactose exist below which the integrity of cerebroside galactosylation suffers.


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