Familial nephropathic systemic amyloidosis caused by apolipoprotein Al variant Arg26

A point mutation in the apolipoprotein Al (apoAl) gene causingautosomal dominant non-neuropathic systemic amyloidosis is describedin a previously unreported Canadian family of British originwith five affected individuals in three generations. Amyloiddeposits in the renal biopsy from the prob-and, a 31-year-oldfemale presenting with hypertension and renal failure, stainedimmunospecifically with antiserum to apoAl. The plasma of allfamily members with amyloidosis contained both wild-type apoAland a variant bearing one additional positive charge. Sequencingof the apoAl gene demonstrated that the proband was a heterozygotefor a single base substitution in exon 3, changing codon 26from GGC(Gly) to CGC(Arg). Concordance of the mutant allelewith the presence of variant plasma apoAl and clinical featuresof amyloidosis was demonstrated. This is the third family inwhich this amyloidotic mutation has been described, but thedistribution of amyloid deposits and their clinical effectsare clearly determined by other genetic and/or environmentalfactors.     

Familial hypercholesterolaemia: clinical features and management

Coronary heart disease is the leading cause of mortality and morbidity in the UK, for which hypercholesterolaemia is a risk factor. This article concentrates on the management of patients with familial hypercholesterolaemia (FH). It discusses FH, how it is diagnosed, and the treatments that are available.     

Familial defective apolipoprotein B-100: molecular basis, prevalence and clinical features.

Familial defective apo B-100 is an autosomal dominant trait which causes moderate to severe elevation of LDL-cholesterol in the plasma and may predispose the coronary heart disease. The primary defect is a single amino acid change (Arg3500 to Gln), which disrupts the normal binding of LDL to the LDL-receptor. The mutation occurs at an estimated frequency of 1/600 in the normal population and is, therefore one of the most common known single-gene defects causing an inherited abnormality.     

Familial hypertrophic cardiomyopathy: clinical features, molecular genetics and molecular genetic testing

Hypertrophic cardiomyopathy is a Mendelian disease characterized by cardiac hypertrophy. It has a prevalence of 1:500 individuals and is the most common cause of sudden death in the young. Other complications include heart failure and the need for heart transplantation. Hypertrophic cardiomyopathy is due to sarcomeric gene mutations, however, phenocopies with myocardial hypertrophy can be due to triplet-repeat syndromes (Friedreich ataxia and myotonic dystrophy), mitochondrial and metabolic diseases. In a peculiar form associated with Wolf-Parkinson-White syndrome, the disease is caused by mutations in the gamma2 regulatory subunit of the AMP-activated protein kinase gene, leading to a glycogen storage cardiomyopathy. In spite of the growing knowledge about the molecular basis of hypertrophic cardiomyopathy, very little is still known about the genotype-phenotype correlations and their clinical implications. In this review, the clinical and molecular genetics of hypertrophic cardiomyopathy are described.     

国人190例免疫球蛋白轻链型淀粉样变性病临床与病理的相关性分析

目的：探讨免疫球蛋白轻链（AL）型淀粉样变性病肾组织病理改变与肾活检时临床表现的相关性。方法研究对象为1990年1月至2011年12月在北京大学第一医院经肾活检诊断的AL型肾淀粉样变性病患者共190例。对淀粉样物质在肾小球、肾血管和肾间质沉积的程度进行半定量评分,并进行临床病理特点的相关性分析。结果（1）肾小球淀粉样变程度与尿蛋白量呈正相关（rs＝0.298，P＜0.001）；（2）肾小球淀粉样变程度重的患者肾功能不全的发生率高（χ2＝34.027，P＜0.001）；（3）肾血管淀粉样变程度越重，肝脏受累、心脏受累的发生率越高（χ2＝15.916，P＜0.001；χ2＝6.189，P＝0.014）；（4）AL-κ患者肝脏受累的发生率和心脏受累的发生率都显著高于AL-λ患者（75%vs.24.4%，χ2＝16.057，P＜0.001；72.7%vs.34.2%，χ2＝5.757，P＝0.020）；前者的肾血管淀粉样变程度评分亦显著高于后者[3.5（3～4）vs.2（1～3）， Z＝-3.118，P＝0.002]。结论 AL型肾淀粉样变性病患者肾组织中肾小球淀粉样变的程度与确诊时的蛋白尿水平和肾功能相关，肾血管淀粉样变的程度与心脏和肝脏受累相关。AL-κ患者肾血管淀粉样变程度重，容易发生肝脏和心脏受累。     

Echocardiographic features of primary, secondary and familial amyloidosis

BACKGROUND: Currently recognized types of amyloidosis include primary, familial and secondary, each of which may affect the heart. There may be differences in the heart response to the deposition of amyloid fibrils in these three forms of the disease. MATERIALS AND METHODS: Over a period of 10 years (1985-95), 28 consecutive patients with primary, 11 with secondary and 17 with familial amyloidosis were studied at the Departments of Cardiology of Laiko and Hammersmith Hospitals. The diagnosis of amyloidosis was confirmed by biopsies of subcutaneous fat, rectum, kidney, bone marrow, gum or sural nerve. Diagnosis of cardiac involvement was based on typical electrocardiographic and echocardiographic findings. RESULTS: The left ventricular fractional shortening (%) was reduced in primary compared with familial or secondary amyloidosis (29.8 +/- 10.2 vs. 36.2 +/- 6.5 vs. 36 +/- 5.9, P < 0.05). The transmitral flow velocity pattern was compatible with abnormal relaxation in most patients in the three groups [primary 16 (57%), familial 11 (64. 7%), secondary 6 (54.5%), P = NS]. Right ventricular systolic dysfunction (right ventricular dP/dt < 220 mmHg s-1 or tricuspid annulus systolic excursion < 10 mm) was present in 8 (28.6%), 2 (11. 8%) and 0 patients. Patients with primary amyloidosis were followed up for 15 +/- 6 months. There were 12 deaths, and repeat echocardiography in the survivors revealed a significant deterioration of left ventricular systolic function (fractional shortening = 23.6% +/- 8.8%, P < 0.05 vs. baseline). CONCLUSION: Primary amyloidosis is characterized by more severe cardiac involvement than the familial or secondary amyloidosis and has an ominous course.     

Doppler tissue echocardiographic features of cardiac amyloidosis.

The purpose of the study was to assess whether quantification of myocardial involvement by Doppler tissue echocardiography (DTE) enhances the accuracy of echocardiographic characterization of cardiac amyloidosis (CA). A group of 36 patients with CA (mean age 58 +/- 13 years; 22 male) and 40 age-matched control patients were studied. Patients with CA were divided into CA-1 subgroup with nonrestrictive (n = 22) and CA-2 with restrictive left ventricular (LV) filling pattern (n = 14). Peak lateral and medial mitral annulus velocities by pulsed wave DTE were measured in systole, early diastole, and late diastole. Using color M-mode DTE of the LV posterior wall, mean myocardial velocities (MMV) and myocardial velocity gradient (MVG) were measured during ventricular ejection, early and late isovolumic relaxation (IVR), rapid ventricular filling, and atrial contraction. In both CA-1 and CA-2 groups, mitral annulus velocities, MMV, and all MVG were lower than those measured in control patients, with the exception of peak late diastolic annulus velocities at lateral side and MMV in atrial contraction. MVGs in both early IVR and rapid ventricular filling were lower in the CA-1 as compared with the CA-2 group. Late IVR-MVG was negative in control patients and positive in patients with CA indicating a faster movement of the subendocardium rather than the subepicardium during late IVR in patients with CA (0.88 +/- 0.50 s(-1) vs -0.40 +/- 1.59 s(-1); P <.001). The following parameters: peak early diastolic annulus velocities at lateral side < or = -12 cm/s, peak early diastolic annulus velocities at medial side < or = -10 cm/s, early IVR-MMV < or = -2.5 cm/s, early IVR-MVG < or = -0.7 s(-1), and late IVR-MVG > or = 0.5 s(-1) differentiated patients with CA from control patients with an overall accuracy of 0.82, 0.83, 0.81, 0.87, and 0.81, respectively. In patients with CA, reduction in early IVR-MMV was independent of patients' age and LV mass. DTE indices proved helpful in differentiating patients with CA from control patients including those patients with CA who had borderline conventional echocardiographic features and nonrestrictive LV filling pattern.     

Hyperthyroidism. Causes, clinical features, and diagnosis

The usual patient with hyperthyroidism has Graves' disease: If serum levels of thyroid hormone are clearly elevated, the presence of infiltrative ophthalmopathy or pretibial myxedema is probably sufficient for establishing the diagnosis. However, if the ancillary findings of Graves' are not present, the radioactive iodine uptake should be determined to rule out other possible etiologies of hyperthyroidism. Signs of hyperthyroidism may be subtle or misleading, particularly in the elderly; the well-informed clinician keeps the diagnosis in mind, and if the initial thyroid hormone tests are not definitive, employs additional tests that are cost-effective in the individual clinical situation.     

The clinical features and outcomes of systemic light chain amyloidosis with hepatic involvement

ObjectivesTo evaluate the clinical characteristics and prognostic factors of hepatic systemic light chain (AL) amyloidosis.MethodsEighty-eight patients diagnosed AL amyloidosis with hepatic involvement between June 2004 and January 2019 were analysed retrospectively.ResultsThe median age of the patients was 55 years old, and the male to female ratio was 2.8:1.The main clinical manifestations include edema, digestive symptoms, weight loss, fatigue and ascites. Fifty-one patients received treatment, 42 patients were suitable for therapeutic efficacy evaluation and 25 (59.5%) achieved haematologic response. The median survival time was nine months, and the survival rates at one year, three years and five years were 33.0%, 11.4% and 6.8%, respectively. The risk of death was 6.6 times that of those who did not achieve haematologic response. Multivariate analysis showed that baseline NT-proBNP ≥ 1800 pg/ml and total bilirubin ≥ 34.2 umol/L were predictive of all-cause death.ConclusionsSystemic light chain amyloidosis with hepatic involvement is associated with poor survival but rarely has specific manifestations. The significant increase of NT-proBNP and hyperbilirubinemia indicate a poor prognosis. Vigilance should be raised to the relevant clinical manifestations, early diagnosis and timely treatment can improve the prognosis.

KEY MESSAGES

• Systemic light chain amyloidosis with hepatic involvement is associated with poor survival but rarely has specific manifestations.
• The significant increase of NT-proBNP and hyperbilirubinemia indicate a poor prognosis.

     

Gammopathy interference in clinical chemistry assays: mechanisms, detection and prevention.

Monoclonal gammopathy is characterized by the presence of an M-protein in serum or urine that has homogeneous structural and functional properties. It can occur in very high concentrations and may cause significant interference in clinical chemistry assays. Examples of gammopathy interference for the analytes glucose, bilirubin, gamma-glutamyltransferase, urea and ferritin are presented. Various mechanisms of interference are described, such as the production of turbidity by the M-protein and the binding of the M-protein to a component of the test system or analyte. In immunoglobulin tests, the M-protein is the analyte itself and may not be completely bound by the test antibody owing to its structural properties. Modern analyzers can detect unusual changes in absorption during the course of a reaction, and thus the formation of turbidity due to M-proteins. This interference may be prevented by optimizing the buffering conditions of the reagents to avoid the formation of turbidity or by removal of the M-protein prior to analysis of the sample. Owing to the unique properties of each M-protein, it is impossible to protect common clinical chemistry test systems completely from gammopathy interference. Therefore, efficient ways for the detection of such interference are needed.     

Sonographic features of dialysis-related amyloidosis of the shoulder.

This study evaluated the diagnostic role of ultrasonography in dialysis-related amyloidosis in shoulders of chronically hemodialyzed patients. Fourteen shoulders of 12 long-term hemodialysis patients were examined. All patients had been on dialysis for at least 10 years. All patients had varying degrees of pain and limitations of movement in the studied shoulders. Dialysis-related amyloidosis was the presumed diagnosis in all patients. Any patient with a history of any disease, other than dialysis-related amyloidosis, capable of producing a pathologic shoulder condition was excluded. The following parameters were studied: supraspinatus and biceps tendon thickness, tendon tears, synovial thickening, and the presence of hypoechoic material around tendons and within bursae. All shoulders had a nonhomogeneous thickening, greater than 7 mm, of the supraspinatus tendon. Seven shoulders (50%) had abnormal thickening of the biceps tendon (4 mm or greater), and two shoulders had abnormal thickening of the subscapularis tendon. Hypoechoic deposits were seen in the subdeltoid bursae and biceps sheaths in five and six shoulders, respectively. Three shoulders showed partial tears of the supraspinatus tendon, one shoulder showed a tear in the biceps tendon, and one shoulder had a tear in the subscapularis tendon. Ultrasonography is an excellent imaging modality in diagnosing the presence of dialysis-related amyloidosis in symptomatic shoulders of long-term hemodialysis patients, without having to resort to invasive procedures. The results of previous studies have been confirmed and new ultrasonographic findings described. Of particular interest is the involvement of the subscapularis tendon in dialysis-related amyloidosis. Repeat ultrasonography can become an important way to follow-up progression of shoulder dialysis-related amyloidosis in hemodialyzed patients.     

Drug-induced lupus. Genetic, clinical, and laboratory features

Drug-induced lupus is a disorder similar to idiopathic systemic lupus erythematosus in terms of manifestations. However, these entities have significant serologic and clinical differences, which call into question the concept that they represent an identical disease process. Nonetheless, further research into the drug-induced disease will enhance our understanding and management of this clinically significant iatrogenic disease and will likely contribute to our comprehension of the pathogenesis of autoimmunity.     

Familial Mediterranean fever and systemic amyloidosis in untreated Turkish patients

We compared the frequencies of seven MEFV mutations (M694V, M680I, V726A, M694I, K695R, R761H, E148Q) and the clinical findings in 20 Turkish FMF patients who had not developed amyloidosis by the age of 40 years in the absence of colchicine therapy, with those in 27 Turkish amyloidosis patients. No mutation frequency, including that of M694V, was different between the two groups. Family history of amyloidosis and parental consanguinity were noted to be higher in the amyloidosis group. The seven mutations do not appear to be sufficient to explain the development of amyloidosis in Turkish FMF patients. Other genetic factors may be important for this association.