Hereditary
Hemochromatosis (Iron-storage disease, HFE-HHC, HH) is an inborn
error of the iron metabolism with an estimated prevalence of 1:
200 to 400 in Caucasians of Northern European descent. It is one
of the most common genetic diseases among this population.
The cause of the disease lies in the increased uptake of iron in
the small intestine, leading to iron deposits in tissues and
organs (Liver, skin, joints, heart and endocrine organs
(pituitary gland).
Hemochromatosis in general manifests in males between the age of
20 and 40, in females after menopause. Non-specific symptoms are
unexplaned fatigue, joint pain, depression, abdominal pain,
repeated infections and impotence. Iron deposits in the skin can
lead to a brown-grey (bronze) pigmentation of the skin.
In fully developed hemochromatosis, liver
disease predominates: Elevated aminotransferase levels, with or
without hepatomegaly, cirrhotic changes of the liver and
pancreas and hepatocellular carcinoma. Endocrine disorders like
diabetes, hypogonadotropic hypogonadism, impotence and
hypothyreoidism as well as cardiac diseases (arrhythmia,
cardiomyopathy) and arthropathy can belong to the symptoms of
hemochromatosis1). Biochemically, elevated
transferrin saturation (>60%) and serum-ferritin levels as
well as elevated iron concentrations in liver byopsies can be
detected.
Therapy aims at reducing the iron stores in
serum and organs by therapeutic phlebotomy. An early treatment
of hemochromatosis, before organ damage occurs, leads to a
normal life expectance. Untreated, hemochromotosis is lethal.
Hemochromatosis is inherited in an autosomal
rezessiv order. Mutations in the HFE gene are the cause of
hereditary hemochromatosis type 12). This gene codes
for a 348 amino acid protein and is located on 7 exons and
approximately 12 kB on chromosome 6p21.3. Expression of the 4 kB
HFE-mRNA was detected in all organs but the brain. The
postulated function of the HFE protein is the regulation of
transferrin-coupled iron uptake.
The most common HFE-mutation is the Cys282Tyr
mutation in exon 4. 0.5% of the population of Northern European
descent was found to be homozygous for this mutation3).
80-90% of hemochromatosis patients are homozygous for Cys282Tyr4).
A second HFE Mutation (His63Asp) is
found in a compound heterozygous constellation with the Cys282Tyr
mutation in 5% of the patients. Several (rare) mutations have
been found in all 5 protein coding exons of the gene5).
Heterozygous carriers of HFE Mutationen
(estimated at 10% of the European population) show elevated iron
levels. In some diseases, like in chronic hepatitis C the
heterozygous carrier status can have an influence on the
severity of the disease6).
The screening of the HFE gene for mutations
supports the clinical diagnosis of hemochromatosis and enables
detection of presymptomatic carriers of mutant alleles.
When suspecting hemochromatosis, we routinely
amplify and sequence the exons 2 and 4 from the genomic DNA of
the patient. Mutations in these two parts of the gene cover up
to 95% of the alleles affected in HH-patients 4).
When these exons are free of mutations, it is possible to screen
the remaining 4 protein-coding exons of the gene for mutations.
We usually provide results of the initial
screening for mutations in exon 2 and 4 within 3 days after
receipt of the sample.
When mutations are found, we recommend
analyzing the corresponding HFE-alleles of the patient's
relatives to detect carrier of the gene defect.
1) Pietrangelo A.
(2004) N. Engl. J. Med. 350:2383-2397.
2) Feder et. al. (1996) Nature Genet. 13:399-408.
3) Rochette et al. (1999) Am. J. Hum. Genet. 64:1056-1062
4) Merrywheather-Clarke et al. (1997) J.Med.Genet.
34:275-278.
5) Human Gene Mutation Database, Cardiff University,
UK.
6) Geier et al. (2004) Liver Int. 24:285-294.
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Please
contact us for an estimate
for this analysis.
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| We
usually provide results of the initial screening for
mutations in exon 2 and 4 within 3 days after receipt of
the sample. |
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