SISANews

Ipercolesterolemia familiare. Genotipo e fenotipo

Sotto la denominazione di ipercolesterolemia familiare sono accomunati almeno quattro disordini ereditari, tre a trasmissione dominante e uno a trasmissione recessiva. La forma più frequente è quella da difetto recettoriale, che rende conto di circa il 90-95% di tutte le ipercolesterolemie monogeniche, dovuta ad una mutazione del gene che codifica per il recettore LDL. Su 832 pazienti con diagnosi clinica di ipercolesterolemia eterozigote in cui si è potuto definire il difetto genetico, il 97.4% era portatore di una mutazione a carico del recettore LDL, il 2.2% a carico dell'apo B e lo 0.36% a carico di PCSK9. Sono state identificate 237 diverse mutazioni del gene per il recettore; il 39% dei pazienti con difetto recettoriale riusciva ad esprimere parzialmente i recettori LDL (recettori difettivi) ed il 47% non esprimeva alcun recettore (recettori negativi). I due gruppi si differenziavano per il livello del colesterolo LDL (270 versus 321 mg/dl) e, come atteso, per la prevalenza di cardiopatia ischemica (25.8% versus 40.7%). Differenti mutazioni a carico del recettore LDL hanno perciò una differente espressione fenotipica ed un diverso rischio di cardiopatia ischemica.

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S

Atherosclerosis 2013;227:342-8

OBJECTIVE: To determine the spectrum of gene mutations and the genotype-phenotype correlations in patients with Autosomal Dominant Hypercholesterolemia (ADH) identified in Italy.
METHODS: The resequencing of LDLR, PCSK9 genes and a selected region of APOB gene were conducted in 1018 index subjects clinically heterozygous ADH and in 52 patients clinically homozygous ADH. The analysis was also extended to 1008 family members of mutation positive subjects.
RESULTS: Mutations were detected in 832 individuals: 97.4% with LDLR mutations, 2.2% with APOB mutations and 0.36% with PCSK9 mutations. Among the patients with homozygous ADH, 51 were carriers of LDLR mutations and one was an LDLR/PCSK9 double heterozygote. We identified 237 LDLR mutations (45 not previously reported), 4 APOB and 3 PCSK9 mutations. The phenotypic characterization of 1769 LDLR mutation carriers (ADH-1) revealed that in both sexes independent predictors of the presence of tendon xanthomas were age, the quintiles of LDL cholesterol, the presence of coronary heart disease (CHD) and of receptor negative mutations. Independent predictors of CHD were male gender, age, the presence of arterial hypertension, smoking, tendon xanthomas, the scalar increase of LDL cholesterol and the scalar decrease of HDL cholesterol. We identified 13 LDLR mutation clusters, which allowed us to compare the phenotypic impact of different mutations. The LDL cholesterol raising potential of these mutations was found to vary over a wide range.
CONCLUSIONS: This study confirms the genetic and allelic heterogeneity of ADH and underscores that the variability in phenotypic expression of ADH-1 is greatly affected by the type of LDLR mutation.

Atherosclerosis 2013;227:342-8