Cerebrotendinous xanthomatosis without neurological involvement.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism. Neurological symptoms are considered to be a clinical hallmark of untreated adult patients. We describe a 'milder CTX phenotype', without neurological involvement. METHODS: We performed a retrospective patient file study in 79 genetically confirmed Dutch patients with CTX (55 patients aged ≥ 21 years) to study the clinical heterogeneity of CTX. We studied the frequency of adult patients with CTX without neurological involvement at diagnosis, in our Dutch cohort, and included a family from South Africa and patients from Italy, USA, Chile and Asia from the literature. RESULTS: In total, we describe 19 adult patients with CTX from 16 independent families, without neurological symptoms at diagnosis. A relatively small percentage (21%, n = 4) had a history of cataract. The majority, 84% (n = 16), presented with tendon xanthomas as the sole or predominant feature. The majority of patients showed increased plasma cholesterol levels. No correlation was found between this 'milder phenotype', the cholestanol levels and the CYP27A1 genotype. In addition, we describe three novel mutations in the CYP27A1 gene. CONCLUSIONS: This study shows the clinical heterogeneity of CTX, highlighting the existence of a 'milder phenotype', that is without neurological involvement at diagnosis. Adult patients with CTX may present with tendon xanthomas as the sole or predominant feature, mimicking familial hypercholesterolemia. It is important to realize that the absence of neurological symptoms does not rule out the development of future neurological symptoms. As CTX is a treatable disorder, early diagnosis and initiation of treatment when additional clinical signs occur is therefore essential.

Apolipoprotein E and Atherosclerosis.

PURPOSE OF REVIEW: The functions, genetic variations and impact of apolipoprotein E on lipoprotein metabolism in general are placed in the context of clinical practice dealing with moderate dyslipidaemia as well as dysbetalipoproteinemia, a highly atherogenic disorder and lipoprotein glomerulopathy. RECENT FINDINGS: Additional variants of apolipoprotein E and participation of apolipoprotein E in inflammation are of interest. The mostly favourable effects of apolipoprotein E2 as well as the atherogenic nature of apolipoproteinE4, which has an association with cognitive impairment, are confirmed. The contribution of remnant lipoproteins of triglyceride-rich lipoproteins, of which dysbetalipoproteinemia represents an extreme, is explored in atherosclerosis. Mimetic peptides may present new therapeutic approaches. Apolipoprotein E is an important determinant of the lipid profile and cardiovascular health in the population at large and can precipitate dysbetalipoproteinemia and glomerulopathy. Awareness of apolipoprotein E polymorphisms should improve medical care.

Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Marine and terrestrial foods as a source of brain-selective nutrients for early modern humans in the southwestern Cape, South Africa.

Many attempts have been made to define and reconstruct the most plausible ecological and dietary niche of the earliest members of the human species. While earlier models emphasise big-game hunting in terrestrial, largely savannah environments, more recent scenarios consider the role of marine and aquatic foods as a source of polyunsaturated fatty acids (PUFA) and other brain-selective nutrients. Along the coast of southern Africa, there appears to be an association between the emergence of anatomically modern humans and accumulation of some of the earliest shell middens during the Middle Stone Age (200-40 ka). Fragmentary fossil remains classified as those of anatomically modern humans, along with marine food residues and numerous material cultural indicators of increased social and behavioural complexity have been recovered from coastal sites. In this paper, new information on the nutrient content of marine and terrestrial foods available to early modern humans in the southwestern Cape is presented and compared with existing data on the nutritional value of some wild plant and animal foods in Africa. The results suggest that coastal foraging, particularly the collection of abundant and predictable marine molluscs, would have allowed early modern humans to exploit some of the richest and most accessible sources of protein, micronutrients and longer-chain omega-6 and omega-3 fatty acids. Reliable and accessible sources of omega-3 eicosapentaenoic and docosahexaenoic acid are considerably more restricted in terrestrial foods.

Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E.

Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.

Increased cardiovascular risk in South African patients with Addison's disease.

Patients with Addison's disease (AD) are believed to be at risk for cardiovascular disease (CVD). South Africa, like the rest of the developing world is experiencing an increase in CVD and patients with AD may be at double the risk of their peers. We wished to explore AD patients' CVD risk factors. A cross-sectional nationwide study in South Africa of patients with AD was conducted. A cohort of 147 patients with AD and 147 healthy control subjects were matched by age, gender, ethnicity, and BMI as far as was possible. Lipoproteins and highly-sensitive C-reactive-protein (hs-CRP) were the main outcome measures. AD patients had significantly higher triglycerides; (p=0.001), lower HDLC (p<0.001), higher hs-CRP (p<0.001), and more small dense LDL; (p=0.002) than controls. Nonesterified fatty acids were lower in patients (p<0.001). Approximately 65% [95% confidence interval (CI 55.6-72.4%)] had hypercholesterolaemia, 75% (CI 64.8-81.2%) had low HDLC, and 75% (CI 68.0-84.1%) had a higher LDLC. Thirteen percent of AD patients had diabetes mellitus, but none of the risk factors differed from the nondiabetics. Only HDLC correlated positively with daily hydrocortisone dose (r=0.32; p=0.005). In conclusion dyslipidaemia is common in South African AD patients; CVD risk assessment and intervention are probably warranted in the management of these patients.

[An abnormal lipid profile: when to perform additional research for a genetic cause?] / Een afwijkend lipidenprofiel.

Abnormalities in the lipid profile are common, but it is often not easy to determine their cause. After exclusion of secondary causes, a primary (genetic) cause of dyslipidaemia should be considered. The most common monogenic dyslipidaemia is familial hypercholesterolemia (FH), but there are other clinically relevant genetic dyslipidaemias, including familial dysbetalipoproteinaemia (FD), monogenic chylomicronaemia and hypoalphalipoproteinemia. It is important to make a genetic diagnosis because it may influence the prognosis of the patient, for determining appropriate treatment goals and because it is relevant for family members. This clinical viewpoint explains the diagnostic process of genetic dyslipidaemias using two cases.

Hypertriglyceridaemia in adolescents may have serious complications.

Acute pancreatitis is an often-overlooked cause of acute abdominal pain in children and adolescents. Severe hypertriglyceridaemia is an important cause of recurrent acute pancreatitis. Monogenic causes of hypertriglyceridaemia, such as familial chylomicronaemia caused by lipoprotein lipase deficiency, are more frequently encountered in children and adolescents, but remain rare. Polygenic hypertriglyceridaemia is more common, but may require a precipitant before manifesting. With the global increase in obesity and type 2 diabetes, secondary causes of hypertriglyceridaemia in children and adolescents are increasing. We report two cases of severe hypertriglyceridaemia and pancreatitis in adolescent females. Hypertriglyceridaemia improved markedly with restriction of dietary fat. An inhibitor to lipoprotein lipase was found to be the cause in one patient, while in the other limited genetic investigation excluded chylomicronaemia owing to deficiency of lipoprotein lipase, its activators and processing proteins.

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.

Extensively hydrolysed infant formulas: Need for aligned definition of peptide size characteristics and standardisation of analytical methods.

Letter by Nutten et al. on article by Levin et al. (Levin ME, Blackhurst DM, Kirstein F, Kok D, van der Watt GF, Marais AD. Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas. S Afr Med J 2017;107(9):763-767. S Afr Med J 2017;107(3):258-263. https://doi.org/10.7196/SAMJ.2017.v107i9.12137); and response by Levin et al.

South African dyslipidaemia guideline consensus statement: 2018 update A joint statement from the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA).

South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: <3 mmol/L in low- and moderate risk cases; <2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and <1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.

Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin.

Studies on the molecular biology of lipoprotein lipase (LPL) deficiency have been facilitated by the availability of LPL gene probes and the recent characterization of gene mutations underlying human LPL deficiency. Typically, missense mutations have predominated and show a preferential localization to exons 4 and 5. This distribution supports earlier studies attributing functional significance to residues encoded by these exons. We now report a further missense mutation within exon 5 of the LPL gene in three unrelated patients. Amplification of individual exons by the polymerase chain reaction and direct sequencing revealed a T----C transition at codon 194 of the LPL cDNA which results in a substitution of threonine for isoleucine at this residue. The catalytic abnormality induced by this mutation was confirmed through in vitro mutagenesis studies in COS-1 cells. Transfection with a LPL cDNA containing the codon 194 transition resulted in the synthesis and secretion of a catalytically defective protein. The Thr194 substitution was associated with two different DNA haplotypes, consistent with a multicentric origin for this mutation.

Variable expression of familial dysbetalipoproteinemia in apolipoprotein E*2 (Lys146-->Gln) Allele carriers.

Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with familial dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2 (Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89 +/- 0.37 vs 0.30 +/- 0.27 and 1.86 +/- 0.37 vs 0.68 +/- 0.27 mmol/liter, respectively) and plasma apolipoprotein (apo) E levels (28.1 +/- 1.6 vs 4.6 +/- 1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2 (Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.

Residual allergenicity of amino acid-based and extensively hydrolysed cow's milk formulas.

BACKGROUND: Criteria for labelling infant feeds as suitable for the dietary management of cow's milk protein allergy (CMPA) rely on proving the hypoallergenicity of such feeds or clinical studies showing that the feeds are tolerated by 90% of children with proven CMPA. South African (SA) labelling legislation does not indicate what testing is necessary to prove hypoallergenicity. OBJECTIVES: To evaluate all extensively hydrolysed cow's milk formulas and amino acid-based formulas available in SA for residual allergen content, protein size and amino-acid content. RESULTS: All amino-acid and extensively hydrolysed formulas were found to be similar in composition, with no residual cow's milk allergens detectable by enzyme-linked immunosorbent assay. Furthermore, proteins were absent and only small molecules in the size range of amino acids and possibly of very small oligopeptides were detected. CONCLUSIONS: These findings indicate that the formulas are extremely likely to be compliant with the definition of hypoallergenicity as tolerance in 90% of proven sufferers from cow's milk allergy. The formulas may therefore be labelled as suitable for the dietary management of infants with CMPA.

Concomitant consumption of red wine and polyunsaturated fatty acids in edible oil does not influence the peroxidation status of chylomicron lipids despite increasing plasma catechin concentration.

BACKGROUND AND AIMS: Atherosclerosis may be ameliorated by red wine consumption possibly by providing antioxidants. The effects of red wine on the peroxidation status of chylomicrons (CM) are unknown. The aims were to compare the lipid peroxidation status of oil rich in polyunsaturated fatty acids (PUFA) from a standardised high-fat meal with that of the CM at peak concentrations following ingestion of the meal with and without wine, and to examine the contribution of wine to the antioxidant content of the plasma. METHODS AND RESULTS: Fasted subjects ingested the meal randomly with and without red wine. The peroxidation status was described by conjugated dienes (CD), lipid hydroperoxides (LOOH) and thiobarbituric acid reactive substances (TBARS). CM lag times and the area under the curve (AUC) of CD were determined under oxidative stress. Plasma catechin concentrations and oxygen radical absorbance capacity (ORAC) values were determined. The CM produced with and without wine did not differ in their concentration of CD, LOOH and TBARS. Lag times of CM with and without wine were not significantly different, nor were the AUC. Plasma catechin values increased significantly after consumption of wine with the meal, whereas ORAC values did not. CONCLUSION: Red wine consumption increases plasma catechins, but does not influence lipid peroxidation in postprandial CM.

The diagnosis and management of familial hypercholesterolaemia.

Familial hypercholesterolaemia is a clinical entity comprising high concentrations of low density lipoproteins, tendinous deposition of cholesterol in a large proportion of affected subjects, and a propensity for the development of atherosclerosis and its complications in the coronary arteries. The aim of this review is to integrate publications with clinical experience into a concise profile of the disorder and its management. In less than a century this disease has been recognised, its lipoprotein derangement identified and numerous causal mutations have been detected. Although the phenotype is most commonly due to the occurrence of mutations in the low density lipoprotein receptor, defects in the apolipoprotein B100 may result in a similar phenotype. The same phenotype has also been linked to a gene and its product, PCSK9 and NARC1, that may be involved in the regulation of cholesterol in the cell. In the past few decades statins, by inhibiting cholesterol synthesis at the rate-limiting enzyme (hydroxymethylglutaryl coenzyme A reductase) have been developed and proven safe and effective in reducing the low density lipoprotein cholesterol, promoting regression and reducing mortality and morbidity. Additionally, advances in imaging techniques are allowing non-invasive insights into the impact of the disease on atherosclerosis. For these reasons there should be a high index of suspicion for this treatable condition in which genetic therapy and further modulation of atherosclerosis can be expected in the future.