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CC HPO: Familial hypercholesterolemia is an autosomal dominant disorder characterized ipercolesteroelmia elevation of serum cholesterol bound to low density lipoprotein LDLwhich promotes deposition of cholesterol in the skin xanthelasmatendons xanthomasand coronary arteries atherosclerosis.

The disorder occurs in 2 clinical forms: Individuals with heterozygous familial hypercholesterolemia develop tendinous xanthomas, corneal arcus, and coronary artery disease; the last usually becomes evident in the fourth or fifth decade.

Homozygous individuals ipercolestwrolemia a more severe clinical picture with earlier presentation, usually in the first 2 decades of life Hobbs et al.

The ranges of serum cholesterol and LDL-cholesterol are, in mg per dl, and in heterozygotes, greater than and greater than in homozygous affecteds, and and in homozygous unaffecteds, with some positive correlation with age Khachadurian, ; Kwiterovich et al.

In ipecrolesterolemia familial hypercholesterolemia, the aortic root is prone to develop atherosclerotic plaque at an early age. Such plaques can accumulate in unusual sites, such as the ascending aorta and around the coronary ostia.

Individuals with coronary artery disease had a significantly higher mean lipoprotein a concentration than those without coronary heart disease, suggesting that lipoprotein a measurements may help predict the risk of coronary heart disease in individuals with familial hypercholesterolemia. They found that hypercholesterolemia was a risk factor in these patients and suggested that NAION might be the first manifestation of a previously unrecognized lipid disorder. The patients had experienced a focal, microvascular central nervous system ischemic event at a relatively young age.

By studies of cultured fibroblasts from homozygotes, Goldstein and Brown and Brown and Goldstein showed that the basic defect concerns the cell membrane receptor for LDL. Normally, LDL is bound at the cell ipercloesterolemia and taken into the cell ending up in lysosomes where the protein is degraded and the cholesterol is made available for repression of microsomal enzyme 3-hydroxymethylglutaryl coenzyme A HMG CoA reductase, the rate-limiting step in cholesterol synthesis.

In familial hypercholesterolemia, there is a binding defect due to a dysfunctional receptor. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. To determine the influences of intrauterine and genetic factors on atherogenic lipid profiles in later life, Ijzerman et al.

They found an association between low birth weight and high levels of total cholesterol, LDL cholesterol, and apolipoprotein B that persisted in the intrapair analysis in dizygotic twin pairs but was reversed within monozygotic twin pairs. Furthermore, they found that the association between low birth weight and low levels of HDL cholesterol tended to persist in the intrapair analysis in both dizygotic and monozygotic twins.

These data suggested that genetic factors may account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association of low ipercoolesterolemia weight with low ipercolestfrolemia of HDL cholesterol.

They suggested that serum noncholesterol sterols are a useful tool for the differential diagnosis of genetic hypercholesterolemias. By performing cholesterol tests on relatives, new patients with familial hypercholesterolemia were discovered.

The newly diagnosed patients were younger than the probands and were generally detected before they had clinically overt atherosclerosis. A case was made for organizing a genetic register approach, linking lipid clinics nationally.

Most of the identified patients sought treatment and were successfully started on cholesterol-lowering treatment to lower the risk of premature cardiovascular disease.

Newson and Humphries discussed cascade testing in familial hypercholesterolemia. They questioned whether and how family members should be contacted for testing. The implications of the test results for life planning, employment, or ability to obtain life insurance are concerns. The pros and cons of cascade testing were reviewed by de Wert After 1 year of a low-fat, low-cholesterol diet, children with a family history of premature cardiovascular disease had LDL cholesterol levels at or greater than 4.


The LDL cholesterol levels in the test group lowered by Growth ipercolesterolfmia was not adversely affected in the treatment group, although folate and hydroxyvitamin D deficiency were noted among a small number of treated children.

Additionally, a boy ipercolesteorlemia had an appendectomy 3 months before the study required surgery for intestinal obstruction after he had taken the first 2 cholestyramine doses. Given the number of gastrointestinal side effects, Tonstad et al. A reduction of LDL cholesterol levels was observed, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

The ‘statin’ drugs are potent competitive inhibitors of 3-hydroxymethylglutaryl coenzyme-A reductase and have proven useful in the treatment of hypercholesterolemia Betteridge et al.

They studied the response to treatment with fluvastatin in 28 patients familiaare heterozygous FH as a result of opercolesterolemia receptor-negative mutation trp23 to ter; They found no statistically significant ipercolesyerolemia.

A tabulation of the results of this and earlier studies suggested that differences in treatment response as an apparent function of LDLR gene mutation type occur mainly in populations with recent genetic admixture.

The authors suggested that in such populations persons with the same mutation in the LDLR gene are also more likely to share other but undetermined genetic variations affecting the pharmacology of statins.


They conducted a randomized clinical trial with simvastatin in 42 genetically diagnosed subjects with FH, with 22 classified as carriers of null mutations and 20 with defective mutations. FH with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and LDL cholesterol levels in these subjects was significantly lower than in subjects with defective mutations.

The side effects were mild, and no clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ipercolesterolemai seen. The authors concluded that the efficacy in children with slight or moderate hypercholesterolemia was satisfactory, but in children with severe hypercholesterolemia it was insufficient. The approach, which they proposed to use to treat homozygous FH patients with symptomatic coronary artery disease who have a relatively poor prognosis but can tolerate a noncardiac surgical procedure with acceptable risks, involves recovery of hepatocytes from the patient and reimplanting them after genetic correction by a retrovirus-mediated gene transfer.

Not only were the technical details of vectors and viruses, transduction and delivery of hepatocytes, evaluation of engraftment and rejection, etc.

Associazione Nazionale Ipercolesterolemia Familiare

She tolerated the procedures well, liver biopsy after 4 months showed engraftment of the transgene, and there was no clinical or pathologic evidence for autoimmune hepatitis. The patient showed an improvement in serum lipids up to 18 months after the treatment. Three independent linkage studies, by Ott et al.

The LDLR gene was regionalized to 19p The maximum lod score was 7. In 3 adult Dutch, Swedish, and Australian twin ipercolesterolemla totaling dizygotic twin pairs, Beekman et al. No familiqre was observed in an adolescent Dutch twin sample of 83 dizygotic twin pairs.

Associazione Nazionale Ipercolesterolemia Familiare

Combined analysis of the adult samples increased the maximum lod to 5. In most, the restriction fragment pattern of the LDLR gene was indistinguishable from the normal; however, 3 patients were found to have a deletion of about 1 kb in the central portion of the gene.

In 2 patients, the deletion included all or part of exon 5 In a patient diagnosed with probable heterozygous FH, Bourbon et al. The RR variant was found in 2 probands of Chinese origin, whereas GG was found in 35 Dutch probands, 2 of whom were homozygous for the variant and had a more severe phenotype, with myocardial infarction occurring in both before the age of 20 years.

Twelve of 23 family members tested were heterozygous for the mutation, and carriers had significantly increased total cholesterol levels compared to noncarriers. In 1 proband’s family, the mutation was found in 6 of 7 tested family members, who all had LDL cholesterol levels above the 97th percentile.

They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: Carriers of rare nonsynonymous mutations in LDLR were at 4.


Carriers of rare nonsynonymous mutations in APOA5 were at 2. A patient was found to be a genetic compound, having inherited the internalization mutant from the father and the binding mutant from the mother. From the fact that an individual was shown by family studies to be a genetic compound and that complementation did not occur, Goldstein et al.

The LDL receptor is synthesized as a kD glycoprotein precursor that undergoes change to a kD mature glycoprotein through the covalent addition of a kD protein. In these persons 2 types of functional LDL receptors were found in cultured skin fibroblasts: Curiously and puzzlingly, the compound heterozygotes and the regular heterozygotes for the HMWR showed increased cholesterol synthesis, which the authors suggested may play a significant role in the pathology of the disease.

Ten had a receptor-negative form of the disease; 5 had a receptor-defective form; and 1 represented an internalization defect. The receptor-defective group, in which residual amounts of functional receptors were produced, showed a lower tendency to coronary artery disease than the receptor-negative group. He presented with multiple xanthomas of the elbows, interphalangeal joints and interdigital webs of the hands. Active lipid-lowering therapy caused regression of the xanthomas and significant decrease of cholesterol and triglycerides.

Flat xanthomas of the interdigital webs were described in 3 of 4 formerly reported patients with a combination of these disorders of lipoprotein metabolism. Expression of the LDL receptor, as assessed in vitro with measurements of activity and mRNA levels, was similar in normolipidemic and hyperlipidemic subjects carrying the deletion. Analysis of the apoE isoformson the other hand, revealed that most of the E2 allele carriers in this family, including the 2 normolipidemic 5-kb deletion carriers, had LDL cholesterol levels substantially lower than subjects with the other apoE isoforms.

Thus, this kindred provided evidence for the existence of a gene or genes, including the apoE2 allele, with profound effects on LDL-cholesterol levels. Heterozygous FH individuals in this family were also clearly distinguishable with respect to xanthoma size.

Segregation analysis suggested that a separate susceptibility gene may explain the formation of giant xanthomas. In a year-old girl with severe hypercholesterolemia, Ekstrom et al. Her 2 heterozygous sibs also carried the CF mutation, but only one of them was hypercholesterolemic. The authors concluded that there may be cholesterol-lowering mechanisms that are activated by mutations in other genes.

In this family, some heterozygous persons had normal LDL levels, while some homozygous individuals had LDL levels similar to those persons with heterozygous FH. The authors presented evidence for the existence of a cholesterol-lowering gene on 13q In the same large family reported by Takada et al. No such effect was observed among noncarriers of the LDLR mutation. In the pedigree reported by Takada et al. In most populations the frequency of the homozygote is 1 in a million probably a minimal estimate, being a prevalence figure rather than incidence at birth and the frequency of heterozygotes not less than 1 in Thus, heterozygous familial hypercholesterolemia is the most frequent mendelian disorder, being more frequent than either cystic fibrosis or sickle cell anemia which, in different populations, are often given that distinction.

Among survivors of myocardial infarction, the frequency of heterozygotes is about 1 in In a 7-year period, 34 homozygotes were seen in one clinic in Johannesburg. All were Afrikaners and most lived in Transvaal Province. The authors calculated the frequency of heterozygotes and homozygotes to be 1 in and 1 in 30, respectively.

The oldest of their patients was a year-old woman. Of the 34, six were age 30 or older. The authors concluded that the high frequency of the gene is attributable to founder effect, as in the case of porphyria variegatalipoid proteinosisand sclerosteosis Again, the data were consistent with a founder effect.

Defesche and Kastelein stated that more than different mutations had been found in patients with familial hypercholesterolemia. They tabulated the preferential geographic distribution that has been demonstrated for some of the LDL receptor mutations.