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
Prevalence
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).
Prevalence
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.
Pathophysiology
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.
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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