8,5
6,5-8,4
5,0-6,4
4,0-4,9
molekulární biologie - testování mutací
mutace v genu pro LDL-R, ApoB, PCSK9
Body
1
1
2
2
2
1
6
4
8
5
3
1
8
SUMMARY Ceska, R., Votavova, L., Schwarzova, L., Vaclova, M., Freiberger, T. Hyperliporoteinaemias as rare diseases Hypolipoproteinaemia and dyslipidaemia (HLP and DLP) are considered to be common diseases, with mass occurrence and they are often associated with the cardiovascular disease pandemic (CVD) as the most significant risk factors (RF). It is of course true that HLP and DLP affects tens of percent of the adult population, but on the other hand it is necessary to keep in mind that there exist (primarily congenital, genetically determined) fat metabolism disorders which might not formally have the status of “rare diseasesŽ, but they certainly fulfil the criteria to be classified as such. The presented article presents merely an overview of rare HLPs, sorted according to the dominant fat metabolism disorder, mentioning rare primary hypercholesterolemias, primary hypertriglyceridemias and rare primary mixed HLPs. There has been tremendous progress in recent years when it comes to these diseases, especially in terms of identifying the genetic defect at play and the mechanism of how the disorder develops. Each of these diseases would merit its own article, but that is unfortunately out of our current scope. We are going to deal with homozygote familial hypercholesterolemia (FH) in greater detail and to some extent we will also touch upon “seriousŽ heterozygote FH and then, in further chapters, we will be dealing with lipoprotein lipase deficit, all of which are diseases which can be fatal already in young age and for the treatment of which it is possible to use newly developed methods. An internal medicine practitioner should know when to consider these diseases in terms of differential diagnosis, where to send such a patient and how to treat him or her. Homozygote FH occurs in a frequency of 1 : 1,000,000 (or possibly more commonly - 1 : 160,000), it is characteristic by severe isolated hypercholesterolemia (overall cholesterol levels over 15 mmol/l), xanthomata and by frequent manifestation of CVDs. Myocardial infarctions in childhood are not uncommon in such cases. High doses of statins, combined with ezetimibe and newly also with PCSK9-inhibitors form the basis of treatment. Lomitapid and mipomersen are showing a great promise. LDL-aferese represents an aggressive form of treatment. Lipoprotein lipase deficit (HLP type I) is characterised by severe hypertriglyceridemia, milky colour of the serum and xanthomata. Acute, repeating pancreatitis can be a fatal complication. Proper diet is essential for treatment of this condition, but in itself it is not enough to manage this genetic disorder. Gene therapy is the only approved form of curative treatment. Lomitapid is sometimes used as experimental “off labelŽ therapy. KEY WORDS rare diseases * hypolipoproteinaemia * familial hypercholesterolemia * homozygote FH * lipoprotein lipase deficit * PCSK9-inhibitors * lomitapid * mipomerses * gene therapy * LDL aferese
O autorovi| 1Prof. MUDr. Richard Češka, CSc., 2, 3Ing. Lucie Votavová, 1PhDr. Lucie Schwarzová, Ph. D., 1MUDr. Martina Vaclová, Ph. D., 2,4MUDr. Tomáš Freiberger, Ph. D. 1Univerzita Karlova v Praze, 1. lékařská fakulta a Všeobecná fakultní nemocnice, 3. interní klinika - klinika endokrinologie a metabolismu 2ScreenProFH, z. s., Praha 3korespondující autor 4Centrum kardiovaskulární a transplantační chirurgie, Brno e-mail: richard.ceska@lf1.cuni.cz, votavova@interna-cz.eu
Obr. 2 Homozygotní projevy xantomatózy u nemocného heterozygota FH. Xantomy na Achillově šlaše.
Obr. 1 Sérum nemocného s HLP typ I
Obr. 3 FH - receptorová nemoc
Obr. 4 PCSK9 reguluje expresi jaterních LDL-receptorů