Phenotype and genotype analysis in Chinese patients with Gitelman's syndrome

Inactivation mutations of the luminal thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubules or the basolateral chloride channel (CLCNKB) in the distal nephron are the most common genetic mutations in Gitelman's syndrome (GS) or Bartter's syndrome (BS). We conducted clinical and molecular studies in Chinese patients with GS or BS. Twenty patients with chronic hypokalemia (15 males and five females, age 25 +/- 7 yr) from 15 unrelated Chinese families were investigated. All had renal K+ wasting, metabolic alkalosis, and normotension. The urinary calcium excretion rate was used to distinguish between BS or GS on clinical grounds. Clinical symptoms and biochemical studies were recorded. Molecular analysis included PCR single-strand confirmational polymorphism, direct sequencing of both the NCC and CLCNKB genes, and restriction fragment length polymorphism. Sixteen patients had a clinical diagnosis of GS with hypocalciuria and four BS without hypocalciuria. Four of these 20 patients did not have hypomagnesemia. The males had severe hypokalemia [1.9 +/- 0.4 mEq/liter (mmol/liter)] with paralytic episodes, whereas females had moderate hypokalemia [2.6 +/- 0.2 mEq/liter (mmol/liter)] and less severe symptoms. There were no mutations detected in CLCNKB. Twelve NCC mutations, including six novel mutations and nine recurrent ones, were identified. Allele frequency of the detected NCC mutations was 3% in 100 healthy subjects. Some GS patients with NCC mutations may have normocalciuria and/or normomagnesemia. Gender differences may account for phenotype variability. Screening of these identified NCC mutations remains the gold standard for the diagnosis of GS.     

Cardiac abnormalities in Anderson-Fabry disease and Fabry's cardiomyopathy

Fabry's disease is an X-linked lysosomal storage disease most often associated with renal dysfunction and death due to renal failure in patients' fourth and fifth decades of life. However, cardiac manifestations including arrhythmias, angina and heart failure are common and probably underrecognized. Furthermore, Fabry's disease is now recognised as also affecting female carriers, who manifest signs later than males. A variant of Fabry's has been identified that only affects cardiac tissue, which presents as an unexplained hypertrophy of the left ventricle in middle-aged patients, possibly with women more affected than men. Given that epidemiological studies report a prevalence of Fabry's cardiomyopathy among middle-aged patients with cardiac hypertrophy to be anywhere from one to 12%, it is reasonable to screen these patients for alpha-galactosidase A deficiency. Although mortality data is lacking from randomised, controlled trials of galactosidase replacement therapy, there are some reports of improvement in cardiac endpoints. Therefore patients with known Fabry's disease should be screened early for cardiac involvement, as treatment benefit may not be seen once cardiac fibrosis has developed.     

Phenotype/genotype relationships in sickle cell disease: a pilot twin study

The roles of genetic and non-genetic factors in the haematology, growth and clinical features of sickle cell disease have been studied in nine identical twin pairs (six homozygous sickle cell disease, three sickle cell-haemoglobin C disease). A comparison group of 350 age-gender matched sibling pairs, selected to have an age difference of <5 years, was used for assessing the concordance of numerical data. Attained height, weight at attained height, fetal haemoglobin, total haemoglobin, mean cell volume, mean cell haemoglobin and total bilirubin levels showed significantly greater correlation in identical twins than in siblings. Twins showed similarities in the prevalence and degree of splenomegaly, susceptibility to priapism, and in onset of menarche, but other clinical complications were discordant in prevalence and severity. These findings suggest that physical growth and many haematological characteristics are subject to genetic influences, but that non-genetic factors contribute to the variance in disease manifestations.     

Systolic myocardial mechanics in patients with Anderson-Fabry disease with and without left ventricular hypertrophy and in comparison to nonobstructive hypertrophic cardiomyopathy

Objectives: Anderson–Fabry disease (AFD) is a lysosomal storage disease, which can involve the heart, mimicking hypertrophic cardiomyopathy (HCM). The underlying mechanism of disease in AFD is an infiltrative, diffuse process, whereas HCM is a primary heart muscle condition with patchy distribution, which may prompt differences in myocardial mechanics. The aim of this study was to assess myocardial mechanics in AFD according to the presence of left ventricular hypertrophy (LVH) compared to nonobstructive HCM (NHCM) and healthy controls. Methods and Results: We carried out a single‐center, retrospective study in a small, genetically confirmed AFD cohort, which was divided into a subgroup with LVH (LVH+, n = 19), and without LVH (LVH–, n = 21). Comparison groups were healthy controls (n = 40) and NHCM patients (n = 19). Vector Velocity Imaging was applied to two‐dimensional echocardiography studies for assessment of longitudinal strain (LS), circumferential strain (CS), and base‐to‐apex CS gradients. AFD LVH+ patients had lower global LS than AFD LVH– patients (–14 ± 4% vs –17 ± 3%, P < 0.05), but similarly lowered global CS (–24 ± 5% vs –22 ± 5%, P = ns). AFD LVH+ and NHCM had similarly lowered global LS compared to normals, but significantly lower global CS was observed in AFD LVH+ (–24 ± 5% vs –28 ± 4%, P < 0.05), whereas it was significantly increased in NHCM (–31 ± 2% vs –28 ± 4%, P < 0.05). Unlike NHCM, in both AFD subgroups, patients lost their normal base‐to‐apex CS gradient. Conclusions: AFD patients without LVH already show abnormal systolic myocardial mechanics. Relevant differences in myocardial mechanics between AFD patients with LVH compared to NHCM reflect the different underlying mechanisms of disease.     

Phenotype and genotype report on homozygous and heterozygous patients with congenital factor X deficiency

Factor X deficiency is a severe rare hemorrhagic condition inherited as an autosomal recessive trait. It is one of the most severe recessive inherited coagulation disorders. We analyzed the clinical manifestations, laboratory phenotype and genotype in 10 patients with severe Factor X deficiency and in their heterozygous relatives. The most frequent bleeding episodes were hematomas (70%) and gum bleeding (60%). Fifty percent of the homozygous patients required blood transfusion and one-third of heterozygotes required treatment after surgery or delivery. The genetic characterization revealed six different missense mutations, two of which were novel: p.Glu69Lys and p.Asp103His. Haplotype analysis, performed with intra- and extra- FX gene polymorphic markers in Indian, Iranian and Italian patients with the same mutations failed to establish identity by descent, despite the same Caucasian origin. In conclusion, factor X deficiency was confirmed to be one of the most serious among rare bleeding disorders and genetically heterogeneous in different populations.     

Molecular characterization of Portuguese patients with dilated cardiomyopathy

Introduction

Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by ventricular dilatation and impaired systolic function. Familial forms account for 30-50% of cases. Autosomal dominant inheritance is the predominant pattern of transmission. Causal genetic variants have been identified in several genes and molecular diagnosis has implications for genetic counseling and risk stratification.

Exhaled nitric oxide in patients with asthma: association with NOS1 genotype

An increased concentration of nitric oxide (NO) in exhaled air (FENO) is now recognized as a critical component of the asthmatic phenotype. When we identified patients with asthma on the basis of a standard case definition alone, we found that they were remarkably heterogeneous with respect to their FENO. However, when we included genotype at a prominent asthma candidate gene (i.e., NOS1) in the case definition, and determined the number of AAT repeats in intron 20, we identified a remarkably homogeneous cohort of patients with respect to FENO. Both mean FENO (p = 0.00008) and variability around the mean (p = 0.000002) were significantly lower in asthmatic individuals with a high number (> or = 12) of AAT repeats at this locus than in those with fewer repeats. These data provide a biologically tenable link between genotype at a candidate gene in a region of linkage, NOS1, and an important component of the asthmatic phenotype, FENO. We show that addition of NOS1 genotype to the case definition of asthma allows the identification of a uniform cohort of patients, with respect to FENO, that would have been indistinguishable by other physiologic criteria. Our isolation of this homogeneous cohort of patients ties together the well-established associations among asthma, increased concentrations of NO in the exhaled air of asthmatic individuals, and variations of trinucleotide repeat sequences as identified in several neurologic conditions.     

The association of methamphetamine use and cardiomyopathy in young patients

Purpose

Methamphetamine is the most widespread illegally used stimulant in the United States. Previously published case reports and series suggest a potential association between methamphetamine exposure and cardiomyopathy. The objective of this study is to demonstrate an association between methamphetamine use and cardiomyopathy.

Subject and Methods

Case-control study based on chart review of discharges from a tertiary care medical center from January 2001 to June 2004. Patients were ≤45 years old. Cases included patients with a discharge diagnosis of either cardiomyopathy or heart failure. Controls included hospitalized patients who had an echocardiographic assessment of left ventricular function with ejection fraction ≥55% and no wall motion abnormalities.

Results

One hundred and seven cases and 114 controls were identified. Both groups had similar gender distribution, length of hospital stay, rates of health insurance, prevalence of coronary artery disease, diabetes mellitus, hypertension, cigarette smoking, alcohol abuse, and marijuana and cocaine use. Cases were older than controls (mean age: 38 vs 35 years; P=.008), had higher body mass index (BMI) (mean BMI: 37 vs 30 kg/m²; P<.001), and higher prevalence of renal failure (13% vs 4.4%; P=.03). Methamphetamine users had a 3.7-fold increased odds ratio [95% confidence interval, 1.8-7.8] for cardiomyopathy, adjusting for age, body mass index, and renal failure.

Conclusions

Methamphetamine use was associated with cardiomyopathy in young patients.     

Prevalence of hypertrophic cardiomyopathy and its association with mitral anular calcium in elderly patients

We investigated the prevalence of hypertrophic cardiomyopathy (HC) and its association with mitral anular calcium (MAC) detected by Doppler echocardiography in 379 unselected elderly patients in a long-term health care facility. HC was present in 17 of 379 patients (4 percent). Of 17 patients with HC, ten (59 percent) had asymmetric septal hypertrophy, and seven (41 percent) had idiopathic hypertrophic subaortic stenosis with resting gradients of 20 to 110 mm Hg across the left ventricular outflow tract. The mean age of patients with HC was 85 +/- 7 years compared with 82 +/- 8 years in patients without HC (difference not significant). MAC was present in 13 of 17 patients (76 percent) with HC and in 176 of 362 (49 percent) without HC (p less than 0.025).     

Phenotype analysis of mononuclear cells from endomyocardial biopsy specimens in patients with viral myocarditis and dilated cardiomyopathy]

The distribution and phenotype of mononuclear cells from endomyocardial biopsy (EMB) specimens in patients with viral myocarditis (VMC, 25 cases) and dilated cardiomyopathy (DCM, 10 cases) were studied. T-lymphocytes, including T-h/i (T-helper/induced) cells in VMC and T-c/s (T-cytotoxic/suppressor) cells in DCM, were predominated in the infiltrating mononuclear cells within these specimens. The morphological relationship between infiltration of T-lymphocytes and pathological changes of myocardium was also observed, but both macrophages and B-lymphocytes were absent.