Phenotypic heterogeneity associated with defective apolipoprotein B-100 and occurrence of the familial hypercholesterolemia phenotype in the absence of an LDL-receptor defect within a Canadian kindred

Of 163 individuals with a diagnosis of heterozygous familial hypercholesterolemia (FH), only one subject was found to be positive for familial defective apo B-100 (FDB). The eight-member kindred ascertained through this subject who presented with both a clinical phenotype of FH and the FDB apo B-100 (Arg₃₅₀₀→-Gln) mutation was studied. Plasma lipid and lipoprotein profiles, apo E phenotypes, apo B gene markers at the 3′ hypervariable region and LDL-receptor haplotypes (ApaLI, PvuII, NcoI), were determined, together with LDL-receptor activity on freshly isolated blood lymphocytes. The FDB mutation, present in four relatives, was associated with three different phenotypes: FH and severe hypercholesterolemia, moderate hypercholesterolemia and normolipidemia. The FH phenotype occurred in the absence of any functional LDL-receptor defect. In homozygotes for the absence of the PvuII cutting site who had the apo B mutation, LDL-cholesterol levels were low in the presence of the apo E3/2 phenotype and high in the presence of the apo E4/4 phenotype. None of the major known environmental influences accounted for the wide range of variation in LDL-cholesterol among the affected members. Further observations in the spouse and offspring of the normolipidemic FDB subject confirmed the association of apo E4, the FDB mutation and the PvuH(-/-) genotype with high cholesterol levels. It is concluded that the phenotypic expression of the FDB mutation may vary widely as a function of the genetic environment within a family. The presence of phenotypic heterogeneity among individuals with the same apo B mutation may result from epistatic interaction of the apo B locus with genetic factors regulating cholesterol homeostasis, including possible involvement of the apo E and the LDL-receptor gene loci. This study also confirms that the clinical diagnosis of FH is not necessarily associated with an LDL-receptor defect.     

Increased recognition of IgA nephropathy in African-American children

Based upon the percentage of cases of IgA nephropathy (IgAN) in biopsy series, a lower prevalence has been assumed for African-Americans compared with Americans of European descent. This may be due to a racial difference in the basic underlying pathology of IgAN or to racial differences in patterns of referral and biopsy selection practices. Over the past decade (1985 – 1994), we have found similar incidences of IgAN in Caucasian and African-American children from Shelby County, Tennessee. The incidence was 3.0 cases per million per year for Caucasian and 5.7 cases per million per year for African-American children. IgAN may be more common in African-American children than previously appreciated. Population-based incidence studies will be necessary to determine whether or not our experience has become a more widespread phenomenon. Received August 21, 1996; received in revised form and accepted December 18, 1996     

Myocardial injury during standard treatment of an adult with status asthmaticus.

Asthma affects 5%-10% of adults in the United States. Older adults (> 65 years) with asthma have higher rates of fatal asthma than younger adults. The occurrence of a respiratory emergency, such as status asthmaticus, would seem likely to create a situation of cardiopulmonary dysfunction conducive to myocardial ischemia. However, multiple studies of fatal or near-fatal asthma have failed to incriminate myocardial infarction as a contributing factor. We report a patient without underlying coronary artery disease who sustained myocardial injury consistent with myocardial ischemia and infarction during status asthmaticus while receiving recommended treatment without intravenous sympathomimetics or theophylline.     

Pulmonary complications after tricyclic antidepressant overdose

We studied 82 consecutive patients admitted to the ICU with predominant tricyclic antidepressant overdose (mean plasma tricyclic level, 1,025 ng/ml) to determine the nature and incidence of respiratory complications. The majority of patients (80.4 percent) had a decreased arterial to alveolar oxygen tension ratio (PaO2/PAO2) on initial emergency room arterial blood gas analysis (mean, 0.56). Mechanical ventilation was required in 76.8 percent of the patients for a mean duration of 46.2 h. Chest radiograph abnormalities developed during the first 48 h in 32/82 patients (39 percent). The group with radiographic abnormalities had higher mean drug levels than the group without (p less than 0.05). Of 82 patients, nine (11 percent) developed radiographic evidence of bilateral alveolar infiltrates suggestive of acute lung injury. This group had significantly higher mean drug levels than the groups with other types of radiographic abnormalities (p less than 0.001). Charcoal was recovered from the airway of 18/72 patients who received activated charcoal slurry by nasogastric tube in the emergency room after endotracheal intubation. The group who aspirated did not show statistically significant difference in the incidence of chest radiograph abnormalities, gas exchange, or survival compared with the group that did not aspirate.