Geographic distribution of French-Canadian low-density lipoprotein receptor gene mutations in the Province of Quebec.

A total of 35 homozygous and 1320 heterozygous patients with familial hypercholesterolemia (FH) was screened for the presence of six low-density lipoprotein receptor (LDLR) gene mutations previously reported among French-Canadians. The geographic distribution of patients' birthplaces and the relative prevalence of these six mutations in the LDLR gene in the province of Quebec were compared. For this purpose, the 16 administrative regions of the province of Quebec were grouped into seven geographic regions. The relative frequency of the six mutations differed in the seven regions: the > 15 kb deletion (delta > 15 kb) had the highest relative frequency in the Bas St-Laurent/Gaspésie region, and the point mutation in exon 3 had the highest relative frequency in the Saguenay-Lac-St-Jean/Côte-Nord region. In the Montreal area, the delta > 15 kb and the mutation in exon 3 had prevalence rates of 71.2% and 13.0%, respectively, whereas the relative frequencies of the delta > 15 kb and the point mutation in exon 3 in the Quebec city region were 57.5 and 21.8%, respectively. Finally, in Saguenay-Lac-St-Jean/Côte-Nord, the relative frequency of the delta > 15 kb only reached 31.5% and the point mutation in exon 3, 59.2%. Thus, on the north shore of the St. Lawrence River, the prevalence of the delta > 15 kb decreases from west to north-east, whereas the relative frequency of the mutation in exon 3 appears to increase. These observations provide a better characterization of FH among French-Canadians of Quebec, a Canadian province with a high prevalence of this inherited disease.

Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Canadian Lovastatin in Children Study Group.

OBJECTIVE: Familial hypercholesterolemia (FH), an inherited autosomal dominant disorder of lipoprotein metabolism, is associated with premature atherosclerosis. The recommended pediatric therapy consists of dietary intervention and, when necessary, treatment with bile acid-binding resins. However, compliance has been poor in many children. Therefore, our objectives were to determine the efficacy, safety, and tolerance of the short-term use of lovastatin, a 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitor, in the control of severe FH in a male pediatric population and to evaluate the dose-response relationship. METHODS: Sixty-nine male patients with FH 12.9 +/- 2.4 years of age (mean +/- SD) participated in this multicenter, randomized, double-blind trial. After a 4-week placebo period, the patients were allocated to four treatment groups (lovastatin 10, 20, 30, 40 mg/d) for 8 weeks. Plasma lipid and apolipoprotein (Apo) concentrations were measured every 2 weeks. Clinical and laboratory evidence of adverse events was monitored periodically throughout the study. RESULTS: All lovastatin doses reduced total cholesterol (-17% to -29%), low density lipoprotein cholesterol (-21% to -36%), and ApoB (-19% to -28%) concentrations. A dose-response relationship was seen, and between-group comparisons showed that results were significantly improved up to a dose of 30 mg/d. We observed a 7% increase in high-density lipoprotein cholesterol and a 4% increase in ApoA1 concentrations. The medication was well tolerated by all patients. No serious clinical adverse experience was reported. Lovastatin increased aspartate aminotransferase concentrations, but there was no evidence of a dose-response relationship, and no value exceeded two times the upper limit of normal. No significant change in alanine aminotransferase was observed. Three patients had marked (more than three times the upper limit of normal) asymptomatic elevations in their creatine kinase values, which returned spontaneously to normal, and no action was required regarding the drug.

Translocation between chromosomes 6 and 15 (45,XX,t(6;15)(q25;q11.2)) with further evidence for lack of imprinting of the insulin-like growth factor II/mannose-6-phosphate receptor in humans.

We report a 24 year old female with growth retardation, microcephaly, and congenital abnormalities who has an unbalanced de novo translocation between chromosomes 16 and 6: 45,XX,t(6;15)(q25;q11.2). FISH analysis confirmed that the deletion on chromosome 15 is proximal to the Prader-Willi locus. Several genes have been assigned to the 6q25-qter region including the insulin-like growth factor II/mannose-6-phosphate (IGF-II/M6P) receptor. DNA analysis from our patient documented the loss of one IGF2R gene copy. These data confirm the localisation of the IGF2R receptor to distal 6q25. We also showed reduced expression of the soluble and membrane bound IGF-II receptor, a gene dosage effect incompatible with imprinting. The IGF2R gene has been shown to be imprinted in the mouse but not in humans. Our data provide further evidence for lack of imprinting of this gene in humans.

Unilateral radio-ulnar synostosis, generalized hypotonia, developmental retardation, and a characteristic facial appearance in sibs: a new syndrome.

We report on 2 sibs with generalized hypotonia, developmental retardation, unilateral radio-ulnar synostosis, and a characteristic facial appearance. We propose that they have a new autosomal recessive syndrome.

Syndrome of mental retardation and distal arthrogryposis in sibs.

Two sisters presented with a syndrome of characteristic facial anomalies and distal arthrogryposis. The older sister is now 4 years old and is severely mentally retarded. Her sister died of respiratory failure due to hypoplastic lungs shortly after birth. The occurrence of this potentially lethal syndrome in 2 sisters with unaffected parents suggests autosomal recessive inheritance.

Costello syndrome.

In 1971, Costello described a new syndrome in 2 patients. The major clinical findings comprise short stature; redundant skin of the neck, palms, soles, and fingers; curly hair; relative macrocephaly; depressed nasal bridge; papillomata around the mouth and nares; distinct facial gestalt; hyperextensible joints; and mental retardation. We present a third patient and review the manifestations of this condition.

Homozygous familial hypercholesterolemia among French Canadians in Québec Province.

Nineteen patients with homozygous familial hypercholesterolemia (FH) living at the time of the 1981 Canada census are the subject of this report. Their mean age at that time was 15, with a range of 1 to 26 years. All patients had extensive xanthomatosis but showed variable clinical manifestations of coronary heart disease (CHD); five (mean age, 21; range, 11 to 27 years) died from sudden death due to CHD. Plasma cholesterol levels varied more than twofold (557 to 1532 mg/dl). Variation in the concentrations of both plasma and low density lipoprotein cholesterol, as well as apolipoprotein B, were related neither to age at death from CHD nor to the clinical course of CHD. The mean high density lipoprotein cholesterol concentration (37 mg/dl) was lower than the mean value (49 mg/dl) in the control population (p less than 0.001). Both the clinical and biochemical features of this cohort are typical of homozygous FH. The prevalence of homozygotes among French Canadians in Québec was approximately 1:275,000, and the minimum estimated frequency of heterozygotes was 1:270. In northeastern Québec, the frequency of homozygotes was approximately 1:100,000, and the minimum estimated frequency of heterozygotes was 1:154. Only Afrikaaners in South Africa have correspondingly higher frequencies.