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Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan

View Article: PubMed Central - PubMed

ABSTRACT

Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly. For a patient with cutaneous or tendon xanthomas, the probability of FH is very high; however, an absence of xanthoma does not rule out FH.

Brown and Goldstein elucidated the pathogenesis of FH by their work on LDL-receptor (LDL-R), for which they were awarded the Nobel Prize in 1985. In the 1950s, FH patients were divided into heterozygous (hetero-) and homozygous (homo-) FH, and diagnosing homo- and hetero-FH based on the phenotypic features of ASCVD or xanthomas frequently became difficult without the DNA analysis of FH genes. It is estimated that heterozygous mutations in the LDL-R or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan.

Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it.

No MeSH data available.


Location of point mutations and small deletions/insertions in LDL-R gene in Japanese FH patients in Hokuriku district.
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Figure 8: Location of point mutations and small deletions/insertions in LDL-R gene in Japanese FH patients in Hokuriku district.

Mentions: In association with Brown and Goldstein, Yamamoto9) successfully cloned the LDL-R gene, which is located on the short arm of chromosome 19 and encodes for 839 amino acids. Abnormalities in this gene are associated with FH; more than 1200 mutations in the LDL-R gene have been reported till date10). Recently, the gain-of-function mutation of proprotein convertase subtilisin/kexin type 9 (PCSK9) that resolves LDL-R was shown to reduce LDL-R; reduce the number and activities of LDL-R, which mimics the clinical picture of FH caused by LDL-R abnormalities (Fig. 8)11, 12).


Half a Century Tales of Familial Hypercholesterolemia (FH) in Japan
Location of point mutations and small deletions/insertions in LDL-R gene in Japanese FH patients in Hokuriku district.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5383536&req=5

Figure 8: Location of point mutations and small deletions/insertions in LDL-R gene in Japanese FH patients in Hokuriku district.
Mentions: In association with Brown and Goldstein, Yamamoto9) successfully cloned the LDL-R gene, which is located on the short arm of chromosome 19 and encodes for 839 amino acids. Abnormalities in this gene are associated with FH; more than 1200 mutations in the LDL-R gene have been reported till date10). Recently, the gain-of-function mutation of proprotein convertase subtilisin/kexin type 9 (PCSK9) that resolves LDL-R was shown to reduce LDL-R; reduce the number and activities of LDL-R, which mimics the clinical picture of FH caused by LDL-R abnormalities (Fig. 8)11, 12).

View Article: PubMed Central - PubMed

ABSTRACT

Familial hypercholesterolemia (FH) is a disease characterized by a triad: elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary heart disease. Thus, it can be considered as a model disease for hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). For the diagnosis of hetero-FH, the detection of Achilles tendon xanthomas by palpation or on X-ray is an indispensable diagnostic skill in clinical lipidology. To prevent the under-diagnosis and under-treatment of FH, the diagnostic criteria should be more convenient and user-friendly. For a patient with cutaneous or tendon xanthomas, the probability of FH is very high; however, an absence of xanthoma does not rule out FH.

Brown and Goldstein elucidated the pathogenesis of FH by their work on LDL-receptor (LDL-R), for which they were awarded the Nobel Prize in 1985. In the 1950s, FH patients were divided into heterozygous (hetero-) and homozygous (homo-) FH, and diagnosing homo- and hetero-FH based on the phenotypic features of ASCVD or xanthomas frequently became difficult without the DNA analysis of FH genes. It is estimated that heterozygous mutations in the LDL-R or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene will be found at a combined frequency of 0.005, which corresponds to 1/199 people in the general population in Japan.

Statins and anti-PCSK9 monoclonal antibodies are highly specific and efficient drugs for treating hetero- or homo-FH patients. Most clinical studies have reported an amelioration of ASCVD using long-term statin therapy. Clinical results using anti-PCSK9 monoclonal antibodies will emerge in a few years. In homo-FH patients, mipomersen and lomitapide are expected to yield good results. It is important to sequentially unravel the unrecognized pathogenetic mechanisms of FH to reduce its under-recognition and develop new management strategies for it.

No MeSH data available.