Transcript 0001 fructose intolerance - Western Washington University

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Hereditary Fructose Intolerance
•
Fructose intolerance was first noted in severely ill infants with recurrent
hypoglycemia (low blood sugar) and vomiting, occurring at the time of
weaning when fructose or sucrose is added to the diet and resulting in marked
malnutrition.
– However, a 3-year-old brother of a severely affected infant was found to have
hepatomegaly (enlarged liver), and hypoglycemic shock was precipitated by an oral
test dose of fructose, although he was clinically healthy. He had a marked aversion
to sweets and fruit.
– Subsequently, 2 adults, aged 33 and 39 years were identified with the same
condition . In addition to the aversion to fructose-containing foods,
remarkable absence of dental caries was noted.
•
The defect resides in aldolase B, which catalyzes the cleavage of fructose1-phosphate to form dihydroxyacetone phosphate and D-glyceraldehyde.
Phenotype
• Hypoglycemia,
• Depletion of ATP resources,
• Degradation of purine (G and A in DNA),
• Hypermagnesemia,
CLINICAL MANAGEMENT
• Limit, fructose and related sugars…sucrose
and sorbitol,
– Difficult, if not impossible in modern, Western
society.
Glycolysis
•
Cells are run by the energy
produced through the oxidative
conversion of glyceraldehyde 3phosphate to pyruvate and the
coupled formation of ATP and
NADH,
•
You’ve learned the conversion of
glucose into G3P, but we can’t
live by glucose alone...
Liver, Kidney, Intestinal Mucosa
•
In aldolase 'B'-deficient tissues, cytoplasmic accumulation of fructose-1phosphate leads to sequestration of inorganic phosphate with resulting
activation of AMP deaminase that catalyzes the irreversible deamination of
AMP to IMP (inosine monophosphate), a precursor of uric acid.
•
Depletion of tissue ATP occurs through massive degradation to uric acid and
impairment of regeneration by oxidative phosphorylation in the mitochondria
because of inorganic phosphate depletion.
–
In the cell, ATP exists largely as a 1:1 complex with magnesium. Depletion of ATP in tissues
leads to depletion also of magnesium concentration.
Feeder Pathways for Glycolysis
AKA: aldolase B
Lactose intolerance
•
Lactose Intolerance is divided into the following categories:
–
1. Congenital Alactasia or hypolactasia This is an extremely rare condition except in
Scandinavian countries. Babies with this condition do not gain weight and are
dehydrated and extremely unwell.
–
2. Primary acquired or lactase non-persistence. This is an age related condition and
usually occurs after weaning and before the age of six years. This affects
approximately 70% of the world’s population and 10% of Australia’s population overall .
–
3. Secondary acquired or lactase non-persistence occurs as a result of damage to
the small intestinal mucosa due to for example gastroenteritis, cows milk protein
intolerance or coeliac disease.
OMIM#: 223000
Polymorphic
• A149P and A174D frequencies near 1%,
– no obvious advantage has been identified for
heterozygotes, although physiological manifestestions
of heterozygosity exist,
– Overall frequency in the population of homozygotes is
between 1 in 15,000 to 1 in 20,000.
Aldolase B Mutations
•
> 21 mutations that have been reported;
– 15 of these are single-base substitutions,
•
resulting in 9 amino acid replacements,
• 4 nonsense codons,
• and 2 putative splicing defects.
– The other 6 were deletions.
•
Recurrent mutations were observed in exons 5 and 9. Analysis suggests that
the A149P and A174D mutations originated from a single founder and
achieved a relatively high frequency through genetic drift.
Mutant Alleles
•
.0001 FRUCTOSE INTOLERANCE [ALDOB, ALA149PRO]
–
•
.0002 FRUCTOSE INTOLERANCE [ALDOB, ALA174ASP]
–
•
In addition, in 11 unrelated Italian patients, researchers found a G-to-C transversion in exon 9 which resulted in
substitution of lysine for asparagine at position 334.
.0008 FRUCTOSE INTOLERANCE [ALDOB, ARG3TER]
–
•
A 1-bp deletion in codon 288 causing a frameshift. The mutation seems restricted to Sicilian subjects.
0006 FRUCTOSE INTOLERANCE [ALDOB, ASN334LYS]
–
•
Point mutation found in Italy, Switzerland, and Yugoslavia but not in the UK, France, or the United States.
.0003 FRUCTOSE INTOLERANCE [ALDOB, LEU288DEL]
–
•
A G-to-C transversion in exon 5 resulted in a substitution of proline for alanine at position 149 of the protein
within a region critical for substrate binding.
A consanguineous family from eastern Turkey, has a C-to-T transition in codon 3 changing arg to stop codon.
.0011 FRUCTOSE INTOLERANCE [ALDOB, LEU182DEL, VAL183DEL ]
–
In a 6-year-old patient with a 6-bp deletion in exon 6 of the aldolase B gene that led to elimination of 2 amino
acid residues, leu182 and val183, but left the message in-frame. On the other allele, the patient carried the
asn334-to-lys mutation.
Structure/Mutation Sites
• Aldolase B associates in
quartenary structure as a
homotetramer,
– A149P and A147D mutations result in
a reduced affinity between sub-units.
• Other mutation my retain
quatenary structure, but lack
enzymatic activity.
OMIM
http://www.ncbi.nlm.nih.gov:80/entrez/dispomim.cgi?id=229600
Modern Disease
Slave Trade
Sickling and G6PD Defenciencies
• Heterozygotes carrying alleles for for red
blood cell sickling disorders, and for and
glucose-6-phosphate dehydrogenase
deficiency are resistant to malaria.
Sickle Cell Anemia
•
Walter Clement Noel, a first-year dental student at the Chicago College of
Dental Surgery, was admitted to the Presbyterian Hospital in late 1904 where
Ernest E. Irons, a 27-year-old intern, obtained a history and performed routine
physical, blood, and urine examinations.
•
He noticed that Noel's blood smear contained 'many pear-shaped and
elongated forms' and alerted his attending physician, James B. Herrick, to the
unusual blood findings.
Sickling Disease in Modern Culture
• Homozygotes for sickling disorders have from
mild ranging to debilitating disorders,
• Heterozygotes and homozygotes have health
complications in temperate climates due to cold
temperatures, and endemic infections.
G6PD Disease in Modern Culture
• First seen in WWII, African-American soldiers receiving
an anti-malaria drug experienced haemolysis.
• Presently,
– Sulphanomides,
– Anti-pyretic drugs,
– Broad Beans.
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