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Familial hypercholesterolemia: genetic diagnosis

Table 3 Common hypercholesterolemia and hypertriglyceridemia Molecular mechanism

Clinical features

Familial defective APOB-100

APOB defect

Familial hypercholesterolemia type 3


Familial hypertriglyceridemia

Possible multiple unknown defects

Familial combined hyperlipidemia

Possible multiple unknown defects

Recessive inheritance Autosomal recessive hypercholesterolemia


LPL deficiency

endothelial LPL defect

Apo C-II deficiency

Apo C-ii defect

Hepatic lipase deficiency

Hepatic lipase

Dominant inheritance Familial hypercholesterolemia

LDLr defect

TX, arcus cornealis, premature CHD, TC: .400 mg/dL (.10.3 mmol/L) or TC: 190–400 mg/dL (4.9–10.3 mmol/L) in heFH Xanthomas, arcus cornealis, premature CHD, and TC: 250–350 mg/dL (7–13 mmol/L) Premature CHD TC: 250–500 mg/dL (6.5–9 mmol/L) No symptoms TG: 200–500 mg/dL (2.3–5.7 mmol/L) Premature CHD, Apo B elevated, TC: 250–500 mg/dL (6.5–13 mmol/L) TG: 250–750 mg/dL (2.8–8.5 mmol/L)

Cerebrotendinous xanthomatosis Sitosterolemia variable inheritance Familial dysbetalipoproteinemia

Hepatic mitochondrial 27-hydroxylase defect ABCG5/G8

Xanthomas, arcus cornealis, xanthelasmas, premature CHD. TC: .350 mg/dL (.9 mmol/L) Failure to thrive, xanthomas, hepatosplenomegaly, pancreatitis TG: .750 mg/dL (8.5 mmol/L) Pancreatitis and metabolic syndrome. TG: .750 mg/dL (8.5 mmol/L) Premature CHD TC: 250–1,500 mg/dL TG: 395–8,200 mg/dL Cataracts, premature CHD, neuropathy, ataxia Tendon xanthomas, premature CHD

APOE (usually e2/e2 homozygotes)

Palmar xanthomas, yellow palmar creases, premature CHD. TC: 250–500 mg/dL (6.5–13 mmol/L) TG: 250–500 mg/dL (2.8–5.6 mmol/L)

Polygenic hypercholesterolemia

Possibly multiple unknown defects

Premature CHD TC: 250–350 mg/dL (6.5–9 mmol/L)

Abbreviations: CHD, coronary heart disease; LDLr, low-density lipoprotein receptor protein; LPL, lipoprotein lipase;TC, total cholesterol;TG, triglycerides;TX, tendon xanthomas.

them included the presence of xanthomas), as well as the methods used for the identification of xanthomas.15

There are no absolutely predictive clinical criteria for the diagnosis of FH, and arbitrary criteria must be used. Several criteria have been proposed (Table 4) by SBRG,18 the USA Make Early Diagnosis to Prevent Early Death (MEDPED) Program,98 and the Dutch MEDPED Program.99 Our group demonstrated that MEDPED programs resulted in high sensitivities and specificities being more accurate as more complex is the scoring system.100 The best approach in most populations is to determine LDLc in all first degree of a FH proband and it is recommended that all second-degree family members are also screened.101

Although clinical diagnosis criteria have been extensively used for FH,18 the genetic testing is the preferred method for FH because it provides an unequivocal diagnosis.1,10,19 Since

2004, a genetic diagnostic platform for FH called Lipochip(Progenika-Biopharma, Derio, Spain) has been developed, which includes a microarray for the detection of common point mutations and small deletions in the LDLR and APOB genes, the diagnosis of large rearrangements, and a full LDLR coding sequence analysis when the former are negative.102 By provid- ing either a positive (presence of LDLR or APOB mutations) or negative (absence of defects in these genes) diagnosis, this platform has allowed the genetic characterization of .5,000 Spanish patients.100,103 Even though the diagnosis of FH based on the detection of a functional mutation on a causative gene is the recommended procedure in most suspicious cases but it cannot be recommended for all cases of hypercholesterolemia because the genetic testing is still complex, expensive, and require specific families for microarray analysis. For those reasons, clinical diagnosis is still very important and in the FH

The Application of Clinical Genetics 2010:3

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