Acute Coronary Syndrome Developed in a 17-year-old Boy with Sitosterolemia Comorbid with Takayasu Arteritis: A Rare Case Report and Review of the Literature

A 17-year-old boy with acute coronary syndrome was admitted to our hospital. He had xanthomas over his elbow and Achilles tendon and a high level of low-density lipoprotein cholesterol; therefore, his initial diagnosis was familial hypercholesterolemia. However, a genetic analysis revealed a compound heterozygous mutation in the ABCG5 gene with a high serum level of sitosterol, leading to the diagnosis of sitosterolemia. After lipid-lowering treatment, percutaneous coronary intervention was performed. Furthermore, a persistently high C-reactive protein level and images of large arteries led to a diagnosis of Takayasu arteritis. To our knowledge, this is the first case of sitosterolemia complicated by Takayasu arteritis.     

Variantes de un solo nucleótido asociadas con la hipercolesterolemia poligénica en familias diagnosticadas de hipercolesterolemia familiar

Introduction and objectives

Approximately 20% to 40% of clinically defined familial hypercholesterolemia cases do not show a causative mutation in candidate genes, and some of them may have a polygenic origin. A cholesterol gene risk score for the diagnosis of polygenic hypercholesterolemia has been demonstrated to be valuable to differentiate polygenic and monogenic hypercholesterolemia. The aim of this study was to determine the contribution to low-density lipoprotein cholesterol (LDL-C) of the single nucleotide variants associated with polygenic hypercholesterolemia in probands with genetic hypercholesterolemia without mutations in candidate genes (nonfamilial hypercholesterolemia genetic hypercholesterolemia) and the genetic score in cascade screening in their family members.

Biliary atresia combined Wilson disease identified by whole exome sequencing in Vietnamese patient with severe liver failure

Rationale:Hepatobiliary diseases such as biliary atresia (BA), Wilson disease, and progressive familial intrahepatic cholestasis are common causes of morbidity and mortality in young children. Affected patients progress rapidly to end-stage cirrhosis and require liver transplantation or die. Mutations in many genes have been identified to play an important role in the pathogenesis of hepatobiliary diseases.Patient concerns and diagnosis:In this study, we identified mutations in an 8-year-old girl who had severe liver failure. The patient was first diagnosed with BA at 2.5 months of age and has undergone Kasai surgery to connect the umbilical cord and jejunum. After that, the patient suddenly had unusual developments with symptoms of jaundice, acute liver failure with hemolysis. She was tested and diagnosed with Wilson disease.Interventions and outcomes:She was treated according to the regimen for a patient with Wilson disease but had abnormal progress leading to severe liver failure. Genetic analysis was performed by whole exome sequencing and Sanger sequencing methods. The genetic analysis revealed that the patient had a homozygous mutation (p.Gly17Glyfs77∗) in the KRT18 gene, a double heterozygous mutation (p.Ser105∗ and p.Pro992Leu) in the ATP7B gene, and a homozygous variant (p.Val444Ala) in the ABCB11 gene. In silico prediction of mutations indicated that these mutations are the cause of the severe liver failure in the patient.Lesson:This is a rare clinical case of a BA patient combined with Wilson disease. Our results suggested that whole exome sequencing is an effective diagnostic tool and emphasizes the importance of early diagnosis and appropriate management to save lives and prevent serious complications in the patient.     

De novo mutation in DMD gene in a patient with combined hemophilia A and Duchenne muscular dystrophy

We report an unusual case of a patient with two combined X-linked diseases, severe hemophilia A (HA) and Duchenne muscular dystrophy (DMD), of which only HA was hereditary. There was no family history of muscular dystrophy. Genetic analysis revealed that HA was caused by the hereditary coagulation factor VIII (F8) intron 22 inversion (distal/type I inversion), whereas DMD was caused by a de novo deletion in the dystrophin gene. This is the first report of a patient with two severe X-linked diseases, of which only HA was hereditary. Despite the fact that the probability of acquiring two X-linked abnormalities, one hereditary and one de novo, is extremely low, the emergence of such cases indicates that genetic testing for distinct X-linked diseases could be of importance in patients with hereditary hemophilia.     

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia

Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients.Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9.Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G>A, c.1747C>T, c.313+1G>A, c.400T>C, and APOB c.10579C>T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants.Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients.     

Treatment with atorvastatin improves small artery compliance in patients with severe hypercholesterolemia

Background:We studied the effect of atorvastatin on arterial compliance in patients with severe hypercholesterolemia.Methods:Seventeen patients with low-density lipoprotein cholesterol levels above 170 mg/dL, were included in the study, none of whomever received hypolipidemic medication or had other risk factors. Patients were followed for five visits, every 4 weeks.Results:After 20 weeks of treatment, lipid profile improved significantly. Large artery elasticity index did not change significantly, but small artery elasticity index increased by 21% (4.6 ± 0.5 to 5.6 ± 0.9, P < .01). Although none of our patients suffered from hypertension, both systolic and diastolic blood pressure (BP) decreased significantly (6 mm Hg and 3 mm Hg, respectively).Conclusions:We conclude that atorvastatin improves the elasticity of small arteries and reduces systolic and diastolic BP in patients with severe hypercholesterolemia.     

Percepção Inadequada do Risco Cardiovascular e Baixo Conhecimento sobre Hipercolesterolemia Familiar em Indivíduos com Hipercolesterolemia Grave

BackgroundIndividuals with severe hypercholesterolemia are at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). Many of them have familial hypercholesterolemia (FH).ObjectivesTo assess from a patient perspective the degree of awareness about severe hypercholesterolemia, especially FH, ASCVD risk perception, cascade screening performance, and treatment of individuals participating in a routine health evaluation program.MethodsFrom a database of 70,000 Brazilian individuals evaluated between 2006 and 2016, 1,987 (2.8%) met the inclusion criteria (age ≥ 18 years and LDL-C ≥ 190 mg/dL or ≥ 160 mg/dL, respectively, if not in use of statins or on statin therapy). Two-hundred individuals were randomly invited to complete an extensive questionnaire. FH was diagnosed if suspected by the attending physician.ResultsAlthough 97% of the sample (age 48±9 years; 16% women; 95% college/university education; 88% primary prevention; LDL-C 209±47 mg/dL) had severe hypercholesterolemia, only 18% and 29.5% believed to be at high ASCVD risk and reported knowledge of their recommended LDL-C goal, respectively. Fifty-eight percent reported being informed that high cholesterol could be a family disease, 24.5% (n = 49) had ever heard about FH, and merely 14% (n = 29) had been previously identified as suspected of having FH (age at FH diagnosis 35±12 years; 79% and 31% diagnosed, respectively, > 30 and > 40 years old). Only 2.5% underwent genetic tests, 17% underwent cascade screening, and 17% were not in use of pharmacological treatment.ConclusionsAn important gap in risk perception, cholesterol management, and aspects related to FH was encountered in individuals with severe hypercholesterolemia. (Arq Bras Cardiol. 2021; [online].ahead print, PP.0-0)     

A male patient with ferroportin disease B and a female patient with iron overload similar to ferroportin disease B

Reticuloendothelial iron overload is associated with secondary hemochromatosis including repeated transfusions and iron over-supplementation. Ferroportin disease B is a severe subtype of hereditary iron overload syndrome with an activated reticuloendothelial system. The iron exporter ferroportin may be insensitive to hepcidin 25 in this subtype. However, the interactions between the hepcidin–ferroportin system and modifiers of reticuloendothelial iron overload have not yet been elucidated. We describe two patients with iron overload conditions that were compatible with ferroportin disease B, but their genetic backgrounds and habitual states differed. Both patients had diabetes, periportal fibrosis with severe iron deposits in their hepatocytes and Kupffer cells, and adequate levels of circulating hepcidin 25. However, the first patient was heterozygous for a mutation in the FP gene and free from the acquired factors of iron overload, while the second patient was a heavy drinker with a heterozygous mutation in the TFR2 gene and no mutations in the FP gene. The first patient was the second reported case of ferroportin disease B in Japan. Our study on these 2 patients suggests that liver fibrosis associated with compound iron overload of reticuloendothelial cells and hepatocytes may occur via multi-etiological backgrounds.     

Late-onset Hereditary ATTR Amyloidosis with a Novel p.P63S (P43S) Transthyretin Variant

The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C＞T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.     

Detecting familial hypercholesterolemia by serum lipid profile screening in a hospital setting: Clinical,genetic and atherosclerotic burden profile

Background and aims

Familial hypercholesterolemia (FH) is underdiagnosed and public cholesterol screening may be useful to find new subjects. In this study, we aim to investigate the prevalence of FH patients in a hospital screening program and evaluate their atherosclerotic burden using intima-media thickness (IMT).

A novel TNFRSF1A gene mutation in a patient with tumor necrosis factor receptor-associated periodic syndrome

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a periodic fever syndrome inherited in an autosomal dominant fashion. It stems from mutations in the TNFRSF1A (accession number: NM_001065) gene expressing the receptor for tumor necrosis factor α. A patient with TRAPS may present with prolonged episodes of fever attacks, abdominal pain, severe myalgia, and painful erythema on the trunk or extremities. Here, we report an 8-year-old boy with febrile attacks occurring every 1–2 months and continuing for 3–4 days. The patient experienced 40 °C-fever attacks without chills. Approximately 80% of fever attacks were accompanied by abdominal manifestations. Direct sequencing analysis was used to assess the genomic DNA of the patient, and a heterozygous R426L mutation in exon 10 of the TNFRSF1A gene in an autosomal dominant inheritance fashion was identified. Further genetic analyses were also carried out on his parents. Due to the fact that the mutation was not inherited from the parents, it was likely that R426L was a de novo and novel mutation in the TNFRSF1A gene, which can trigger TRAPS or TRAPS-like symptoms.     

Genetic Analysis in a Taiwanese Cohort of 750 Index Patients with Clinically Diagnosed Familial Hypercholesterolemia

Aim: Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan. Methods: Patients with LDL-C＞190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative. Results: The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows:LDLR (n=395),APOB (n=58),PCSK9 (n=0), andABCG5 (n=3). The most common mutations wereAPOB c.10579 C＞T (p.R3527W) (12.6%),LDLR c.986 G＞A (p.C329Y) (11.5%), andLDLR c.1747 C＞T (p.H583Y) (10.8%).LDLR c.1187-10 G＞A (IVS 8-10) andAPOB c.10580 G＞A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, includingLDLR c.1060＋2 T＞C (IVS 7＋2),LDLR c.1139 A＞C (p.E380A),LDLR c.1322 T＞C (p.A431T)＋c.1867 A＞G (p.I623V), and ABCG5 c.1337 G＞A (p.R447Q). Conclusion: LDLR andAPOB, but notPCSK9, mutations were the major genetic causes of FH. Four novel mutations inLDLR orABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.     

Higher Incidence of Mild Cognitive Impairment in Familial Hypercholesterolemia

Objective

Hypercholesterolemia is an early risk factor for Alzheimer's disease. Low-density lipoprotein (LDL) receptors might be involved in this disorder. Our objective was to determine the risk of mild cognitive impairment in a population of patients with heterozygous familial hypercholesterolemia, a condition involving LDL receptor dysfunction and lifelong hypercholesterolemia.

Methods

By using a cohort study design, patients with familial hypercholesterolemia (N = 47) meeting inclusion criteria and comparison patients without familial hypercholesterolemia (N = 70) were consecutively selected from academic specialty and primary care clinics, respectively. All patients were older than 50 years. Those with disorders that could affect cognition, including history of stroke or transient ischemic attacks, were excluded from both groups. Thirteen standardized neuropsychologic tests were performed in all subjects. Mutational analysis was performed in patients with familial hypercholesterolemia, and brain imaging was obtained in those with familial hypercholesterolemia and mild cognitive impairment.

Results

Patients with familial hypercholesterolemia showed a high incidence of mild cognitive impairment compared with those without familial hypercholesterolemia (21.3% vs 2.9%; P = .00). This diagnosis was unrelated to structural pathology or white matter disease. There were significant differences, independent of apolipoprotein E4 or E2 status, between those with familial hypercholesterolemia and those with no familial hypercholesterolemia in several cognitive measures, all in the direction of worse performance for those with familial hypercholesterolemia.

Conclusion

Because prior studies have shown that older patients with sporadic hypercholesterolemia do not show a higher incidence of mild cognitive impairment, the findings presented suggest that early exposure to elevated cholesterol or LDL receptor dysfunction may be risk factors for mild cognitive impairment.     

Diagnosis and Management of Sitosterolemia 2021

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in ATP-binding cassette (ABC) subfamily G member 5 or member 8 ( ABCG5 or ABCG8 , respectively), both of which play important roles in selective excretion of plant sterols from the liver and intestine, leading to failure to prevent absorption of food plant sterols. This disorder has been considered to be extremely rare. However, accumulated clinical data as well as genetics suggest the possibility of a much higher prevalence. Its clinical manifestations resemble those observed in patients with familial hypercholesterolemia (FH), including tendon xanthomas, hyper LDL-cholesterolemia, and premature coronary atherosclerosis. We provide an overview of this recessive genetic disease, diagnostic as well as therapeutic tips, and the latest diagnostic criteria in Japan.     

Tolerability and effects of high doses acipimox as additional lipid-lowering therapy in familial hypercholesterolemia

Background: Acipimox, a derivative of nicotinic acid, lowers serum lipid levels by reducing the production of very-low-density and low-density lipoproteins (LDL).Methods: We studied the additional lipid-lowering effect of high doses of acipimox in 12 patients with severe familial hypercholesterolemia (FH) who were on treatment with an HMG CoA reductase inhibitor, in some cases in combination with a resin.Results: There was a significant reduction in total serum cholesterol (−9%), LDL-cholesterol (−9%) and serum triglycerides (−21%) when the standard doses of acipimox (750 mg/day) was added to treatment with simvastatin (and a resin). However, higher doses had no further hypolipidemic effect. In concordance with the reduction of serum cholesterol and LDL-cholesterol there was a significant decrease in apolipoprotein (apo)-B (−11%). There was no change in HDL-cholesterol, apo-A1 and lipoprotein(a). Acipimox in high doses up to 2250 mg/d was well tolerated except for initial gastric complaints and of flushing; because of these side effects one patient dropped out of the study.Conclusions: Acipimox in high doses, which were well tolerated, has no additional lowering effect on LDL-levels compared to the standard dose in patients with severe FH who are already treated with simvastatin.     

Genetics and kinetics of familial hypercholesterolemia,with the special focus on FH- Marburg p.W556R

ObjectiveFamilial hypercholesterolemia (FH) is an autosomal dominant inherited disorder, caused by mutations in the low density lipoprotein receptor (LDLR) gene. FH is characterized by elevated plasma LDL cholesterol, premature atherosclerosis and high risk of premature myocardial infarction. Extended work has been done to understand both, the primary genetic defect as well as the in vivo kinetic consequences of this disease. Both approaches, genetics and kinetics, are challenging but also fruitful approaches for a better understanding of this devastating disease. For this we reviewed the recent literature and used our in vitro and in vivo data on one of the most frequently occurring types of FH, the FH_Marburg p.W556R.MethodsTo identify the primary genetic defect of the FH_Marburg we used denaturing gradient gel electrophoresis (DGGE) mutation analysis. In vivo kinetic studies were performed in a heterozygote FH_Marburg subject and in 5 healthy control subjects utilizing a stable isotope tracer kinetic approach with 3D-leucine.ResultsDGGE screening of the LDLR gene identified a tryptophan (W) to arginine (R) substitution at residue 556 (p.W556R) in the fifth conserved YWTD repeat of the LDLR-β-propeller in FH_Marburg. In vivo kinetic studies in a heterozygote FH subject for FH_Marburg and in 5 healthy control subjects demonstrated a severe decrease in LDL FCR and a mild increase of LDL PR in FH compared to healthy controls.ConclusionsThe LDLR mutation p.W556R is a frequent and severe defect for FH. This defect has a major influence on the in vivo lipoprotein kinetics and lipid levels. In a heterozygote FH patient we found a dual defect for the increase in LDL cholesterol, namely a decrease in the fractional catabolic rate (FCR) of LDL but also an increase in LDL production rate (PR). By this a well defined, single genetic defect may have a series of different in vivo metabolic consequences which could be used for potential therapeutic approaches to this disease.     

Molecular characterization of familial hypercholesterolemia in Spain

Familial hypercholesterolemia (FH), characterized by isolated elevation of plasmatic low-density lipoprotein (LDL) cholesterol and premature coronary heart disease (CHD), is associated with mutations in three major genes: LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9). We have analyzed 5430 Spanish index cases and 2223 relatives since 2004 with LIPOchip^® genetic diagnostic platform, a microarray for the detection of Spanish common mutations in these three genes, including copy number variation (CNV) in LDLR, followed by sequencing analysis of the coding regions of LDLR and exon 26 of APOB, when the result is negative. Samples were received from hospitals of all around Spain. The preferred clinical criterion to diagnose FH was Dutch Lipid Clinic Network (DLCN) score. Our results show that there is a broad spectrum of mutations in the LDLR gene in Spain since about 400 different mutations were detected, distributed along almost the whole LDLR gene. Mutations in APOB (mainly p.Arg3527Gln) covered 6.5% of positive cases and only one PCSK9 mutation was detected. We found correlation between more severe mutations and the clinical diagnosis but also that 28% of FH patients harboring mutations do not have a definite clinical diagnosis. This study analyzes the mutation spectrum in Spain, remarks the importance of genetic diagnosis of FH patients, as well as the cascade screening, and shows how it is being carried out in Spain.     

Severe hypercholesterolemia mediated by lipoprotein X in a patient with cholestasis

Lipoprotein X (LpX) is an abnormal lipoprotein associated with cholestasis. It is a significant cause of severe hypercholesterolemia and should always be considered in patients with cholestatic liver disease. This case highlights the significance of LpX as a cause of severe hypercholesterolemia in a patient with cholestasis secondary to a granulomatous hepatitis attributed to tuberculosis. Lipoprotein agarose gel electrophoresis and gradient gel electrophoresis were performed for the detection of LpX. The liver function tests, electrolytes, lipid profile and bile acids were also determined. Anti-tuberculous therapy was initiated and the liver functions improved with normalisation of the lipid profile.     

Treatment Difficulties in Hypomagnesemia Secondary to the Transient Receptor Potential Melastatin 6 Gene: A Case Report with Novel Mutation

Hypomagnesemia is a rare cause of seizures in childhood but should be kept in mind in recurrent and intractable seizures and hypocalcemia in communities where consanguineous marriages are common. Familial hypomagnesemia with secondary hypocalcemia is a rare genetic cause of hypomagnesemia, due to variants in the transient receptor potential melastatin 6 (TRPM6) genes. Here, a three year-old boy with a novel variant in this gene and had difficulties with enteral hypomagnesemia treatment is presented. He had recurrent seizures since two years of age and was diagnosed with epilepsy and treated with multiple antiepileptic drugs. Subsequently, he was diagnosed with rickets due to severe hypocalcemia at another center. The patient was hypotonic and neurodevelopmentally poor. The most prominent laboratory finding was of hypomagnesemia with secondary hypocalcemia. The genetic analysis revealed a novel variant in the TRPM6 gene. After parental treatment of intravenous magnesium (Mg²⁺) sulfate and calcium, the treatment was switched to enteral Mg²⁺ medications, due to persistent hypomagnesemia and the gastrointestinal side-effects, different oral preparations were used. The patient was stable on an oral maintenance dose of Mg²⁺ oxide with borderline blood Mg²⁺ levels and resolution of hypocalcemia. Hypomagnesemia is one of the causes of hypocalcemia. Enteral replacement is the key treatment but the treatment should be individualized for each patient. Normalization of hypomagnesemia is not always easy and should not be the aim of the treatment.     

The decrease of mean platelet volume after extracorporeal LDL-cholesterol elimination

ObjectiveMean platelet volume is arousing increasing interest as a new independent cardiovascular risk factor. Large platelets are likely to be more reactive. If mean platelet volume would drop after LDL-lowering therapy, decreased MPV could be one of the markers of successful therapy. Therefore, we investigated mean platelet volume after extracorporeal LDL-cholesterol elimination.MethodsMean platelet volume was investigated in patients with severe familial hypercholesterolemia long-term treated (3–12 years) by LDL-apheresis (immunoapheresis) or cascade filtration. Plasma was obtained by centrifugation. Adsorbers Lipopak 400 were used for immunoapheresis and filters Evaflux 4A were used for cascade filtration. 95 pair samples were measured (before and after the procedures) in a group of 12 patients – each patient 8 times in 4 years.ResultsMean platelet volume before the procedures was 10.891 fl, CI 10.25–11.53. Mean platelet volume after the procedures decreased – 10.478 fl, CI 09.84–11.11. The difference is statistically significant (p = 0.036). Mean platelet volume did not correlate with age, sex, platelet count, duration of therapy. At the same time, we used rheohemapheresis in the therapy of 40 patients with age-related macular degeneration. But mean platelet volume was not changed.ConclusionMean platelet volume is easily available and is often disregarded, and sometimes may suggest the need for a careful assessment in patients with familial hypercholesterolemia. Mean platelet volume could be one of the markers of therapeutic efficacy in patients with familial hypercholesterolemia treated by extracorporeal LDL-cholesterol elimination that is simple and inexpensive.