Tendon Xanthomata Research Articles

Familial Hypercholesterolaemia Patients with LDLR Mutation Among Asian Population in Southeast Asian Countries: Systematic Review

Familial hypercholesterolaemia (FH) is a genetic disorder associated with premature cardiovascular diseases; however, the majority of patients remain undertreated. This systematic review aimed to determine the prevalence of FH patients with low-density lipoprotein receptor (LDLR) gene pathogenic variants (PV) among the Asian population in Southeast Asian countries. Our search yielded 1,120 citations, with 28 deemed possibly suitable based on title and abstract screening. However, only six studies that utilised the Dutch Lipid Clinic Network (DLCN) or Simon Broome (SB) criteria were eligible to be included. These studies provided prevalence figures for clinically diagnosed FH patients, with a total of 17.1% (n=1,005/5,874); this rate was represented by three Malaysian studies, which estimated that 36–76% of clinically diagnosed FH patients had LDLR PV. Most patients reported having pre-existing cardiovascular disease, a family history of premature coronary artery disease and tendon xanthomata. This study found that the prevalence of LDLR PV among genetically confirmed FH patients in Southeast Asia is 20.5% (n=286/5,874). Genetically confirmed FH patients are at a higher risk of developing premature coronary artery disease, requiring more aggressive lipid-lowering treatment. Therefore, identifying LDLR PV among the population is essential for early FH diagnosis and treatment. KEYWORDS Arterial disease, autosomal dominant, LDL receptor, LDLR prevalence, pathogenic variants, premature CAD, Undertreated

Association of Clinical Characteristics With Familial Hypercholesterolaemia Variants in a Lipid Clinic Setting: A Case-Control Study.

Familial hypercholesterolaemia (FH) variant positive subjects have over double the cardiovascular risk of low-density-lipoprotein-cholesterol (LDL-C) matched controls. It is desirable to optimise FH variant detection. We identified 213 subjects with FH gene panel reports (LDLR, APOB, PCSK9, and APOE) based on total cholesterol >310 mg/dL; excluding triglycerides >400 mg/dL, cascade screening, and patients without pre-treatment LDL-C recorded. Demographic, clinical and lipid parameters were recorded. A 31/213 (14.6%) patients had pathogenic or likely pathogenic FH variants. 10/213 (4.7%) had variants of uncertain significance. Compared with patients without FH variants, patients with FH variants were younger (median age, 39 years vs. 48 years), had more tendon xanthomata (25.0% vs. 11.4%), greater proportion of first degree relatives with total cholesterol >95th percentile (40.6% vs. 16.5%), higher LDL-C (median, 271 mg/dL vs. 236 mg/dL), and lower triglycerides (median, 115 mg/dL vs. 159 mg/dL). The Besseling et al. model (c-statistic 0.798) improved FH variant discrimination over Friedewald LDL-C (c-statistic 0.724), however, Dutch Lipid Clinic Network Score (DLCNS) did not (c-statistic 0.665). Sampson LDL-C (c-statistic 0.734) had similar discrimination to Friedewald. Although tendon xanthomata and first degree relatives with high total cholesterol >95th percentile were associated with FH variants, DLCNS or Simon Broome criteria did not improve FH detection over LDL-C. Sampson LDL-C did not significantly improve discrimination over Friedewald. Although lower triglycerides and younger age of presentation are positively associated with presence of FH variants, this information is not commonly used in FH detection algorithms apart from Besseling et al.

Images in Endocrinology: Tendon xanthomata in a patient with mixed hypercholesterolaemia

Official Journal of the Endocrine Society of Sri Lanka. The Sri Lanka Journal of Diabetes Endocrinology and Metabolism (SJDEM) publishes original research articles, reviews, and other special features related to diabetes, endocrinology and metabolism in humans and human tissue.

Familial Hypercholesterolaemia in the Malaysian Community: Prevalence, Under-Detection and Under-Treatment.

Aim: Familial hypercholesterolaemia (FH) is the most common autosomal dominant lipid disorder, leading to severe hypercholesterolaemia. Early detection and treatment with lipid-lowering medications may reduce the risk of premature coronary artery disease in FH patients. However, there is scarcity of data on FH prevalence, detection rate, treatment and control with lipid-lowering therapy in the Malaysian community. Methods: Community participants ( n =5130) were recruited from all states in Malaysia. Blood samples were collected for lipid profiles and glucose analyses. Personal and family medical histories were collected by means of assisted questionnaire. Physical examination for tendon xanthomata and premature corneal arcus were conducted on-site. FH were clinically screened using Dutch Lipid Clinic Network Criteria. Results: Out of 5130 recruited community participants, 55 patients were clinically categorised as potential (Definite and Probable) FH, making the prevalence FH among the community as 1:100. Based on current total population of Malaysia (32 million), the estimated number of FH patients in Malaysia is 320,000, while the detection rates are estimated as 0.5%. Lipid-lowering medications were prescribed to 54.5% and 30.5% of potential and possible FH patients, respectively, but none of them achieved the therapeutic LDL-c target. Conclusion: Clinically diagnosed FH prevalence in Malaysian population is much higher than most of the populations in the world. At community level, FH patients are clinically under-detected, with majority of them not achieving target LDL-c level for high-risk patients. Therefore, public health measures are warranted for early detection and treatment, to enhance opportunities for premature CAD prevention.

Classifying Familial Hypercholesterolaemia: A Tree-based Machine Learning Approach

Familial hypercholesterolaemia is the most common and serious form of inherited hyperlipidaemia. It has an autosomal dominant mode of inheritance, and is characterised by severely elevated low-density lipoprotein cholesterol levels. Familial hypercholesterolaemia is an important cause of premature coronary heart disease, but is potentially treatable. However, the majority of familial hypercholesterolaemia individuals are under-diagnosed and under-treated, resulting in lost opportunities for premature coronary heart disease prevention. This study aims to assess performance of machine learning algorithms for enhancing familial hypercholesterolaemia detection within the Malaysian population. We applied three machine learning algorithms (random forest, gradient boosting and decision tree) to classify familial hypercholesterolaemia among Malaysian patients and to identify relevant features from four well-known diagnostic instruments: Simon Broome, Dutch Lipid Clinic Criteria, US Make Early Diagnosis to Prevent Early Deaths and Japanese FH Management Criteria. The performance of these classifiers was compared using various measurements for accuracy, precision, sensitivity and specificity. Our results indicated that the decision tree classifier had the best performance, with an accuracy of 99.72%, followed by the gradient boosting and random forest classifiers, with accuracies of 99.54% and 99.52%, respectively. The three classifiers with Recursive Feature Elimination method selected six common features of familial hypercholesterolaemia diagnostic criteria (family history of coronary heart disease, low-density lipoprotein cholesterol levels, presence of tendon xanthomata and/or corneal arcus, family hypercholesterolaemia, and family history of familial hypercholesterolaemia) that generate the highest accuracy in predicting familial hypercholesterolaemia. We anticipate machine learning algorithms will enhance rapid diagnosis of familial hypercholesterolaemia by providing the tools to develop a virtual screening test for familial hypercholesterolaemia.

A service evaluation: impact of nurse-led regional familial hypercholesterolaemia service on a hospital adult lipid clinic.

Patients with a lipid clinic diagnosis of definite and possible FH based on the SBR criteria were referred to a nurse-led regional service for FH genetic testing. 140 patients were referred for genetic testing. Six had SBR-definite FH due to the presence of tendon xanthomata and 134 had SBR-possible FH. A monogenic FH mutation was detected in all six patients (100%) with SBR-definite FH and in 34 (25%) of patients with possible FH. The appropriate use of molecular genetics in a lipid clinic will greatly facilitate the management of hyperlipidaemia and cardiovascular risk since the management of FH patients (National Institute for Health and Care Excellence (NICE) Clinical Guideline 71) is different from non-FH patients (NICE Clinical Guideline 181).

Classification of Familial Hypercholesterolaemia Using Ordinal Logistic Regression

Familial hypercholesterolaemia (FH) is a genetic disease that causes the elevation of low-density lipoprotein cholesterol (LDL-C), which subsequently leads to premature coronary heart disease (CHD). Features which have been reported to be associated with FH include lipids level, tendon xanthomata, and history of CHD. The Ordinal Logistic Regression model using the classification of FH patients with the Dutch Lipid Clinic Network Criteria (DLCN) as the dependent variable (where 1=Possible, 2=Probable, 3=Definite) was developed and evaluated for different types of link functions. The FH patients (n = 449) were recruited from health screening programmes conducted in hospitals and clinics in Malaysia from 2010 to 2018. Results indicate there is a significant association between FH categories with demographic factors (ethnicity and smoking) and physical symptoms (corneal arcus and xanthomata). The Ordinal Logistic Regression using Cauchit link function has lower Akaike Information Criterion (AIC) value, higher Nagelkerke's R-Square and classification accuracy compared to Probit and Logit link function, diastolic blood pressure, corneal arcus and xanthomata were found to be significant covariates of FH.

Familial hypercholesterolaemia workshop for leveraging point-of-care testing and personalised medicine in association with the Lipid and Atherosclerosis Society of Southern Africa.

Familial hypercholesterolaemia (FH) is a common autosomal dominantly inherited disorder in which impaired clearance of plasma low-density lipoprotein cholesterol causes premature atherosclerotic vascular disease and tendon xanthomata. This workshop aimed to consolidate information on the diagnosis and management of FH in South Africa. The genetic causes include mutations in the LDL receptor, apolipoprotein B100 and proprotein convertase subtilisin/kexin type 9 (PCSK9). Additionally, the concatenation of multiple gene variants can result in polygenic FH. Therapeutic measures include a healthy lifestyle, statins and cholesterol-absorption inhibitors that will achieve control of the dyslipidaemia in the majority of cases. The recently introduced monoclonal antibodies to PCSK9 can improve achievement of target concentration in severe cases. FH is present in all sectors of the South African population but there is sparse documentation in the indigenous African populations. FH should be actively sought, diagnosed and treated with judicious pharmacotherapy and screening of relatives.

Diagnosis and Treatment of Familial Hypercholesterolemia

Diagnosis and Treatment of Familial Hypercholesterolemia Abstract. Familial hypercholesterolemia secondary to heterozygous mutations in the LDL receptor, Apolipoprotein B or PCSK9 gene is characterized by 2- to 3-fold elevated LDL cholesterol levels, premature atherosclerosis and extravascular cholesterol deposits (tendon xanthomata, corneal arcus). The same phenotype may occur if a person carries several LDL cholesterol rising polymorphisms (polygenic FH). Primary prevention with statins has been shown to dramatically reduce the cardiovascular burden in patients with the disease. However, it is estimated that less than 10 % of affected subjects in Switzerland have received the diagnosis, and undertreatment is frequent. Thus, clinical cardiovascular events are still the first manifestation of the disease in many cases. A correct diagnosis in index patients and cascade screening of families are mandatory to identify and treat patients before they suffer the sequelae of untreated severe hypercholesterolemia. In patients with clinical cardiovascular disease combination lipid lowering treatment with potent statins, ezetimibe and the newly available PCSK9 inhibitors will successfully lower LDL cholesterol to normal or even target levels.

A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia

Context The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available. Objective To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation. Design, Setting, and Patients An adult cohort of unrelated patients referred to a lipid clinic for genetic testing. Main Outcome Measures Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity. Results A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation. Conclusions The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.

A Comparative Analysis of Phenotypic Predictors of Mutations in Familial Hypercholesterolemia.

The gold standard for diagnosing familial hypercholesterolemia (FH) is identification of a causative pathogenic mutation. However, genetic testing is expensive and not widely available. To compare the validity of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), Make Early Diagnosis to Prevent Early Deaths (MEDPED), and American Heart Association (AHA) criteria in predicting an FH-causing mutation. An adult cohort of unrelated patients referred to a lipid clinic for genetic testing. Odds ratio (OR), area under the curve (AUC), sensitivity, and specificity. A pathogenic FH-causing mutation was detected in 30% of 885 patients tested. Elevated low-density lipoprotein (LDL) cholesterol and personal or family history of tendon xanthomata were independent predictors of a mutation (OR range 5.3 to 16.1, P < 0.001). Prediction of a mutation for the DLCN and SB definite and MEDPED criteria (ORs 9.4, 11.7, and 10.5, respectively) was higher than with the AHA criteria (OR 4.67). The balance of sensitivity and specificity was in decreasing order DLCN definite (Youden Index 0.487), MEDPED (0.457), SB definite (0.274), and AHA criteria (0.253), AUC being significantly higher with DLCN definite and MEDPED than other criteria (P < 0.05). Pretreatment LDL cholesterol and tendon xanthomata had the highest AUC in predicting a mutation. The DLCN, SB, and MEDPED criteria are valid predictors of an FH-causing mutation in patients referred to a lipid clinic, but concordance between these phenotypic criteria is only moderate. Use of pretreatment LDL cholesterol and tendon xanthomata alone may be particularly useful for deciding who should be genetically tested for FH.

Tendons Involvement in Congenital Metabolic Disorders.

Congenital metabolic disorders are consequence of defects involving single genes that code for enzymes. Blocking metabolic pathways, the defect leads to the shortage of essential compounds, and/or to the accumulation of huge quantities of precursors, which interfere with normal functions. Only few of these diseases are characterized by a clinically significant tendon involvement.Heterozygous Familial Hypercholesterolaemia results from the inheritance of a mutant low-density lipoprotein receptor gene; patients show high cholesterol levels, precocious coronary artery disease, and may develop tendon xanthomata (mainly in Achilles tendon). The detection of xanthomata is important, because it allows an early diagnosis and treatment of the disorder. Cerebrotendinous Xanthomatosis is a rare genetic metabolic disorder of cholesterol and bile acid metabolism, characterized by accumulation of cholestanol in brain and tendons. Tendon abnormalities are similar to those reported in Heterozygous Familial Hypercholesterolaemia. Alkaptonuria is caused by a deficiency of the enzyme homogentisic acid oxidase. Due to the accumulation of the homogentisic acid, tendons and ligaments are characterized by a typical ochre/yellow pigmentation (ochronosis), with ensuing inflammation, calcification and rupture. In Congenital Hypergalactosemia an increased tendon collagen cross-linking by non-enzymatic galactosylation can be observed. Finally, Congenital Hypophosphatasia may be associated to deposition of hydroxyapatite crystals in rotator cuff, elbow, and Achilles tendons.

Clinical Management of Familial Hypercholesterolemia: New Insights from International Guidelines and Recent Studies

This review article assesses the clinical features, diagnosis and management of familial hypercholesterolemia (FH). FH is mostly an autosomally dominantly inherited with an incidence of 1 in 250. Tendon xanthomata are pathognomonic. Untreated FH is associated with 100-200 fold increase in risk of cardiovascular disease (CVD). FH is diagnosed by screening for elevated low density lipoprotein cholesterol (LDL-C) and confirmed by DNA techniques. Once index cases have been identified cascade family screening should occur. FH is primarily treated with high dose statin therapy. This reduces progression of surrogate markers of coronary arterial disease and registry studies show a 70% long-term decrease in CVD mortality. The justification for other lipidlowering therapies e.g., ezetimibe relies on the high population attributable risk of LDL-C in FH. Novel therapies with greater LDL-C reducing actions such as proprotein convertase subtilisin kexin-9 inhibitors show promise in FH Children with FH should be identified through cascade screening but drug treatment is dependent on LDL-C and family history. They should be managed in specialist paediatric units or in family clinics. Cases of homozygous FH are rare. This orphan condition should be managed in specialist centers with a combination of drug therapy, apheresis and liver transplantation. Novel therapies for the treatment of homozygous FH such as mipomersen and lomitapide are gradually coming into use FH is a common underdiagnosed condition. Current, let alone future, therapies are extremely effective in reducing both LDL-C and CVD events in patients with FH. Identification and treatment of FH should be a feature of preventative CVD medicine programmes.

A CLEAN PAIR OF HEELS; LEUKODYSTROPHY IN A 40 YEAR OLD MALE

A 40 year old man presented with a slowly progressive history of worsening gait unsteadiness and cognitive decline for further review, following several recent falls. A spastic paraparesis was present on examination, without cerebellar or extrapyramidal signs. Previous and current imaging was reexamined and found to be consistent with leukodystrophy despite previously being reported as ‘normal’. Retrospective history of first cousin marriage and the patient9s bilateral juvenile cataract removal was elicited from his family. Cerebrotendinous xanthomatosis was subsequently diagnosed on biochemical testing and despite lack of tendon xanthomata.

Familial hypercholesterolemia in China: Prevalence and evidence of underdetection and undertreatment in a community population

Familial hypercholesterolemia (FH) is the most common and serious monogenic disorder of lipid metabolism that causes premature coronary and heart disease [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. FH is often undetected and undertreated [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. The prevalence of FH is at least one in 500 in the general population, depending on diagnostic criteria [ [2] Benn M. Watts G.F. Tybjaerg-Hansen A. Nordestgaard B.G. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012; 97: 3956-3964 Crossref PubMed Scopus (468) Google Scholar ]. Currently there is no consensus on the diagnosis of FH although the Dutch Lipid Clinic Network (DLCN) criteria have been widely used [ [1] Watts G.F. Gidding S. Wierzbicki A.S. et al. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol. 2014; 171: 309-325 Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar ]. In Asia, diagnostic criteria has been proposed by Harada-Shiba et al. [ [3] Harada-Shiba M. Arai H. Oikawa S. et al. Guidelines for the management of familial hypercholesterolemia. J Atheroscler Thromb. 2012; 19: 1043-1060 Crossref PubMed Scopus (144) Google Scholar ], but as with the Simon-Broome criteria from the UK [ [4] Scientific Steering Committee Simon Broome Register Group Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991; 303: 893-896 Crossref PubMed Google Scholar ], may have low sensitivity for detecting FH, since it does not use a numerical score and relies on the detection of tendon xanthomata, an infrequent sign in young subjects.

JCL Roundtable: Diagnosis of severe familial hypercholesterolemia

The diagnosis of familial hypercholesterolemia is usually straightforward. The severely elevated low-density lipoprotein cholesterol and the occurrence of high concentrations of low-density lipoprotein cholesterol in the parents provide the diagnosis. The presence of tendon xanthomata is confirmation but not necessary. However, this relatively simple picture becomes much more complicated when one attempts to define the genetic variants that actually produced this clinical syndrome. In this Roundtable discussion, I am joined by two experts in the identification of genetic abnormalities discovered in those with phenotypic familial hypercholesterolemia. Dr. John Kane from the University of California, San Francisco, and Dr. Daniel Rader from the University of Pennsylvania share their knowledge in and experience with this topic.

Lipoprotein X: clinical implications

In this issue of the journal, Stepien et al. describe a case of serum lipoprotein X (Lp-X) in a patient with cholestasis and severe hyperlipidaemia. This abnormal lipoprotein is rich in phospholipid and unesterified cholesterol. The main protein component is albumin within the core and apolipoprotein C upon the surface. Unlike low-density lipoprotein (LDL), Lp-X does not contain apolipoprotein B nor is it removed by the LDL receptor, but Lp-X is cleared by the reticuloendothelial system and the kidneys. Lp-X is about 50 nm in diameter and its major component bile acid is lithocholic. Early studies reported the presence of Lp-X in the serum of patients with cholestasis. The failure of Lp-X to exert feedback inhibition on cholesterol synthesis may contribute to the mechanism of hypercholesterolaemia in obstructive jaundice. However, the presence of serum Lp-X does not facilitate the distinction between intrahepatic and extrahepatic cholestasis. Bile lipoprotein is a precursor of Lp-X and in cholestasis this refluxes into the plasma pool and binds to albumin to form Lp-X. Serum Lp-X usually disappears soon after the cholestasis is relieved. The ratio of plasma bile salts to albumin is important for the integrity of Lp-X and it is catabolized by the action of phospholipase which helps convert lecithin into lysolecithin. In graft versus host disease involving the liver and with cholestasis plasma Lp-X can result in severe hypercholesterolaemia, xanthelasma and cholesteroloma. Lp-X can also be found in cholestasis of pregnancy and primary biliary cirrhosis (PBC). The case presented by Stepien et al. confirms these earlier observations of raised serum Lp-X in cholestasis. Increased serum cholesterol concentrations occur in PBC and this is largely due to the presence of Lp-X, although it is debatable whether this confers increased cardiovascular risk. Indeed, Lp-X may not be atherogenic and data suggest it may have antioxidant LDL activity. Additionally, Lp-X is not significantly taken up by macrophages but is taken up by hepatocytes. Sometimes severe and prolonged cholestasis can result in very high serum Lp-X concentrations resulting in severe hypercholesterolaemia and tendon xanthomata. Complete regression of these xanthomata has been described by treatment with apheresis, which the authors stated should be considered possible first-choice treatment for patients with massive Lp-X accumulation due to cholestasis. Statin therapy may be ineffective in lowering Lp-X. Lecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for cholesterol esterification in plasma. Lp-X is found in LCAT deficiency which is characterized by low concentrations of high-density lipoprotein (HDL) as well as anaemia, corneal opacities, proteinuria and chronic kidney disease. The Lp-X found in LCAT deficiency may contribute to the renal disease observed in this condition by stimulating monocyte renal infiltration. Proteoglycans have an important role in regulating the uptake of Lp-X into kidney mesangial cells and this mechanism is independent of the scavenger receptor. Guerin et al. reported that in LCAT deficiency the presence of Lp-X is correlated with a progressive change in renal function. In addition to cholestasis and LCAT deficiency, Lp-X may also be found in the plasma after intravenous infusion of Intralipid emulsion such as occurs with total parenteral nutrition. Intralipid administration can elicit an increase in serum total cholesterol (mainly unesterified), phospholipid and LDL. The Lp-X associated with Intralipid infusion seems to occur when phospholipid clearance is exceeded, resulting in phospholipid accumulation with unesterified cholesterol. Pseudohyponatraemia has also been described in some patients with severe hypercholesterolaemia secondary to raised Lp-X. Thus the presence of Lp-X should be considered in pseudohyponatraemia associated with cholestasis. Sivakumar et al. described not only pseudohyponatraemia, but also pseudohypokalaemia and pseudohypochloridaemia in the presence of high concentrations of Lp-X. Various researchers have also found assay bias for serum LDL-cholesterol in the presence of Lp-X. This is an important practical point when it comes to interpreting LDL cholesterol results in severely cholestatic serum samples. Lp-X possesses strong aggregatory properties and can bind to alkaline phosphatase (ALP) producing a Lp-X-ALP complex. This complex may be found in cholestasis; typically that evoked by hepatic malignancy. The Lp-X-ALP complex is also associated with the presence of high-molecular mass ALP and the liver isoenzyme of ALP. Brocklehurst et al. described a stationary band of ALP using starch gel electrophoresis of serum samples from patients with biliary obstruction which was thought to be due to ALP binding to Lp-X. The strong aggregating ability of Lp-X may be important as it can bind and remove free cholesterol from the circulation. There are various assays available for measuring serum Lp-X. Agarose gel electrophoresis utilizes the cathodal

Cerebrotendinous Xanthomatosis Presenting with Bilateral Achilles Tendon Xanthomata

Xanthomas are described as deposits in the skin and subcutaneous tissues. Mostly known as pseudotumors, xanthomas consist of connective tissue containing mainly cholesterol, triglycerides, and numerous foamy macrophages. Bilateral Achilles tendon xanthomata is pathognomonic for cerebrotendinous xanthomatosis in the case of normal cholesterol levels but increased cholestanol levels in serum. In this article, we present findings regarding bilateral xanthomas of Achilles tendons in a patient with cerebrotendinous xanthomatosis.

Atypical parkinsonism and cerebrotendinous xanthomatosis: Report of a family with corticobasal syndrome and a literature review

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of cholesterol metabolism. It presents with systemic and neurological symptoms, rarely including parkinsonism. Presented here are a clinical description of a new family with cerebrotendinous xanthomatosis and parkinsonism and a review of 13 additional cases reported in the literature. The index case developed corticobasal syndrome, previously not reported in cerebrotendinous xanthomatosis. His brother had parkinsonism with cerebellar features and cognitive impairment. In a literature review, median age of onset of parkinsonism was found to be 40 years. Nearly all patients had other neurological symptoms: cognitive (93%), pyramidal (93%), or cerebellar (53%). All patients had walking difficulties, with falls in 27%. Systemic features were common: cataracts (93%) or tendon xanthomata (87%). Frequent MRI abnormalities included cerebellar atrophy (100%), cerebral atrophy (80%), and dentate nuclei signal changes (80%). Functional dopaminergic imaging often demonstrated presynaptic denervation. Improvement with levodopa was frequent (91%) but mild. Progressive neurological decline occurred in 92% of patients despite treatment with chenodeoxycholic acid. Cerebrotendinous xanthomatosis should be considered in the differential diagnosis of atypical parkinsonism, including corticobasal syndrome, particularly with early age of onset and in the context of a complex neurological phenotype. Tendon xanthomata, early-onset cataracts, and radiological findings of cerebellar atrophy with lesions of the dentate nuclei are useful clinical clues. Symptomatic treatment with levodopa may help, but progressive neurological decline is frequent despite treatment with chenodeoxycholic acid.

(2) The role of improved phenotypic confirmation of familial hypercholesterolemia in enhancing the use of genetic testing

Genetic diagnosis of familial hypercholesterolemia (FH) allows definitive identification of the index case and cascade testing of their family. However the decreasing population rates of coronary artery disease (CAD), and a reduction in the incidence of tendon xanthomata, suggests that existing clinical criteria for phenotypic identification of FH index cases, such as Simon Broome and Dutch Lipid Clinic Network, may be becoming less reliable.