Japanese Sisters Associated with Pseudohomozygous Familial Hypercholesterolemia and Sitosterolemia

Yoshida, Akihiro; Naito, Michitaka; Miyazaki, Kiyoshi

doi:10.5551/jat1994.7.33

Cited by 22 publications

(23 citation statements)

References 12 publications

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“…Several subjects with sitosterolaemia, especially infantile cases, have been described as exhibiting clinical manifestations resembling homozygous FH. Thus, they were sometimes diagnosed as having "pseudo-homozygous FH" in the past (Yoshida et al 2000). However, all four cases showed great reductions in serum cholesterol levels immediately after weaning, which would not have been observed in homozygous FH.…”

Section: Discussionmentioning

confidence: 99%

“…Serum LDL cholesterol (LDL-C) levels tend to vary more in sitosterolaemia than in other genetic or nongenetic hyperlipidaemias. Notably, LDL-C can be elevated significantly in some cases with sitosterolaemia, especially in infantile cases, due to unknown mechanisms (Yoshida et al 2000). Thus, those cases are sometimes misdiagnosed as homozygous FH.…”

Section: Introductionmentioning

confidence: 99%

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Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

et al. 2015

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Few data exists regarding the clinical impact of breastfeeding in infantile sitosterolaemic cases. We report four Japanese infantile cases of sitosterolaemia, an extremely rare inherited disease characterised by increased serum levels of plant sitosterol, presenting with severe hypercholesterolaemia and systemic xanthomas exacerbated by breastfeeding. In these four cases, genetic analyses were performed for low-density lipoprotein (LDL) receptor, proprotein convertase subtilisin/kexin type 9 (PCSK9), LDL receptor adaptor protein 1 and ATP-binding cassette (ABC) subfamily G member 5 and 8 (ABCG5 and ABCG8) genes. We assessed their clinical manifestations, including responsiveness to a variety of treatments, especially to weaning from breastfeeding and use of ezetimibe. Two pairs of mutations in the ABCG5 gene in each case, including two novel mutations (c.130C>T or p.Ser44Ala and c.1813_1817delCTTTT or p.Pro558GlufsX14) and two known mutations (c.1306G>A or p.Arg389His and c.1336C>T or p.Arg446X), were identified. Significant reductions in cholesterol levels were obtained by means of weaning from breastfeeding alone. Substantial reductions in sitosterol levels, without any apparent side effects, were observed with ezetimibe. In conclusion, we have identified infantile Japanese sitosterolaemic subjects with extreme hypercholesterolaemia exacerbated by breastfeeding. Their unique response to weaning from breastfeeding, as well as to use of ezetimibe, could provide insights into the metabolic basis of sterols in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

et al. 2015

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“…The major clinical manifestations of phytosterolemia are tendon and tuberous xanthomas and premature atherosclerotic diseases [7][8][9][10] , and several lipid-lowering agents have been proven to be effective in amelioration of the lipid profile of phytosterolemia [11][12][13] . In spite of the clear association of phytosterolemia and atherosclerotic diseases, the underlying mechanisms leading to atherogenesis have not been elucidated.…”

Section: J Atherosclermentioning

confidence: 99%

Plant Sterols Increased IL-6 and TNF-α Secretion from Macrophages, but to a Lesser Extent than Cholesterol

Kurano

Iso-O

Hara

et al. 2011

JAT

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Aim:Phytosterolemia is an inherited disorder characterized by hypercholesterolemia and premature atherosclerosis, together with increased inflammatory states in some cases. The underlying mechanisms of atherogenesis in phytosterolemia, however, have not been completely elucidated. In this study, we investigated whether phytosterols would affect inflammatory reactions in macrophages and macrophage cell lines. Methods:We incubated RAW264.7 cells (RAW) and mouse peritoneal macrophages (MPMs) with sitosterol (Sito), campesterol (Camp) or cholesterol (Chol) at low (8 M, 16 M) or high (160 M) concentrations, and investigated their effects on LPS-induced secretion of IL-6 and TNF-. We also analyzed their effects on endoplasmic reticulum (ER) stress in both cells, and on the cell proliferation of RAW.Results: At low sterol concentrations, only Chol resulted in a tendency toward the increased secretion of TNF-from MPMs. At high concentrations, Chol induced a significant increase in TNF-secretions from both cells; however, Sito resulted in a non-significant increase in TNF-secretion. The effects on IL-6 secretions of Sito were also significantly less than those of Chol. Camp increased the secretions of both cytokines from MPMs; however, the extent of these increases was less pronounced than that of Chol. Augmentation of ER stress was greatest with Chol among the sterols, and the proliferation of RAW cells was inhibited only with Chol. Conclusion: The lesser degree of inflammatory reactions and toxicity in macrophages with phytosterols than with cholesterol suggests that plant sterols themselves might not be primarily responsible for atherogenesis in phytosterolemia. , raising controversy regarding the role of plant sterols in atherosclerosis. J AtherosclerPhytosterolemia or sitosterolemia, characterized by elevated plasma levels of plant sterols, is a rare autosomal recessive disease which is caused by mutations in either of the 2 sterolins, sterolin-1 and sterolin-2 4-7). The major clinical manifestations of phytosterolemia are tendon and tuberous xanthomas and premature atherosclerotic diseases [7][8][9][10] , and several lipid-lowering agents have been proven to be effective in amelioration of the lipid profile of phytosterolemia [11][12][13] . In spite of the clear association of phytosterolemia and atherosclerotic diseases, the underlying mechanisms leading to atherogenesis have not been elucidated. One possible mechanism proposed is the increased plasma levels of plant sterols in phytosterolemia, leading to the accumulation of plant sterols in atherosclerotic lesions. The autopsy of patients with phytosterolemia revealed that the proportion of plant sterols and cholesterol in atherosclerotic lesions was almost the same as that found in plasma LDL particles 14,15) , leading to the speculation that plant sterols might be more proatherogenic than cholesterol. Another proposal is elevated cholesterol levels in phytosterolemia 9) ; however, phytosterolemia patients whose plasma cholesterol levels are not elevated have be...

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“…However, an additional rare documented presentation of sitosterolemia includes profound hypercholesterolemia and xanthomas in childhood. [19][20][21][22] These patients with sitosterolemia may also exhibit stomatocytosis and macrothrombocytopenia, as described in the present case. Further, these patients do not have family histories of hypercholesterolemia (unless coincidental), and like our index patient, exhibit normal LDL receptor function in in vitro assays.…”

mentioning

confidence: 54%

“…26,27 Diagnosis is validated via plasma sterol profiling by gas chromatography to determine levels of sitosterol, campesterol and stigmasterol. [2][3][4] Only few case reports in patients where sitosterolemia was recognized as a cause of PHT2HC have been previously reported including three Japanese reports of two unrelated subjects and one pair of sisters, [19][20][21] and one report on two unrelated Chinese patients, 22 with a history of xanthoma development during childhood. In 2001, Lee et al 28 were the first to demonstrate that subjects identified as pseudohomozygous familial hypercholesterolemia had sitosterolemia.…”

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confidence: 99%

Sitosterolemia Presenting as Pseudohomozygous Familial Hypercholesterolemia

Renner¹,

Connor

Steiner

2016

Clin Med Res

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A young girl, age 8.5 years, presented with profound hypercholesterolemia and early xanthomatosis, suggesting homozygous familial (or type II) hypercholesterolemia. The patient's low density lipoprotein (LDL) receptor function and parental lipoprotein profiles were determined to be normal, prompting revision of the initial diagnosis to pseudohomozygous familial hypercholesterolemia. When she subsequently presented with giant platelets, the case was presented to colleagues on an electronic mailing list. It was recommended that plasma and sterol analysis be performed, which led to a diagnosis of sitosterolemia. The presentation of profound hypercholesterolomia in childhood that ultimately is not attributed as due to homozygous or compound heterozygous defects in the LDL receptor gene has been termed pseudohomozygous familial (or type II) hypercholesterolemia (PHT2HC). Patients diagnosed with PHT2HC subsequently confirmed to have sitosterolemia have been previously reported only rarely. The challenge of achieving accurate specific diagnosis and appropriate workup for these conditions in children is discussed in the context of this rare case and review of the historical literature concerning these conditions.

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Japanese Sisters Associated with Pseudohomozygous Familial Hypercholesterolemia and Sitosterolemia

Cited by 22 publications

References 12 publications

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

Infantile Cases of Sitosterolaemia with Novel Mutations in the ABCG5 Gene: Extreme Hypercholesterolaemia is Exacerbated by Breastfeeding

Plant Sterols Increased IL-6 and TNF-α Secretion from Macrophages, but to a Lesser Extent than Cholesterol

Sitosterolemia Presenting as Pseudohomozygous Familial Hypercholesterolemia

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