The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations.

Investigation of seven patients from three families suspected of a fatty acid oxidation defect showed mean CPT-I enzyme activity of 5.9+/-4.9 percent of normal controls. The families, two Inuit, one First Nation, live in areas of Canada geographically very distant from each other. The CPT1 and CPT2 genes were fully sequenced in 5 of the patients. All were homozygous for the same P479L mutation in a highly conserved region of the CPT1 gene. Two patients from the first family were also homozygous for the CPT2 F352C polymorphism in the CPT2 gene. Genotyping the patients and their family members confirmed that all seven patients were homozygous for the P479L variant allele in the CPT1 gene, as were 27 of 32 family members. Three of the seven patients and two cousins had hypoketotic hypoglycemia attributable to CPT-Ia deficiency, but adults homozygous for the variant denied hypoglycemia. We screened 422 consecutive newborns from the region of one of the Inuit families for this variant; 294 were homozygous, 103 heterozygous, and only 25 homozygous normal; thus the frequency of this variant allele is 0.81. There was an infant death in one family and at least 10 more deaths in those infants (7 homozygous, 3 heterozygous) consecutively tested for the mutation at birth. Thus there is an astonishingly high frequency of CPT1 P479L variant and, judging from the enzyme analysis in the seven patients, also CPT-I deficiency in the areas of Canada inhabited by these families. Despite the deficiency of CPT-Ia which is the major rate-limiting enzyme for long chain fatty acid oxidation, clinical effects, with few exceptions, were slight or absent. One clue to explaining this paradox is that, judging from the fatty acid oxidation studies in whole blood and fibroblasts, the low residual activity of CPT-Ia is sufficient to allow a reasonable flux through the mitochondrial oxidation system. It is likely that the P479L variant is of ancient origin and presumably its preservation must have conveyed some advantage.

Congenital rickets caused by maternal vitamin D deficiency.

The cases of four newborn infants with congenital rickets are reported. All infants were native Canadian: three were Cree and one was Inuit. One had a narrow chest and pulmonary hypoplasia, two had clinical and radiological signs of rickets with craniotabes, thickened wrists, and prominent costochondral junctions, and one had perinatal asphyxia and hydrops. All had hypocalcemia, hypophosphatemia and secondary hyperparathyroidism. Serum 25-hydroxyvitamin D levels were low in three of the infants. The four mothers had evidence of vitamin D deficiency. All infants recovered following treatment with 5000 IU oral vitamin D daily.

Mutations in the proenteropeptidase gene are the molecular cause of congenital enteropeptidase deficiency.

Enteropeptidase (enterokinase [E.C.3.4.21.9]) is a serine protease of the intestinal brush border in the proximal small intestine. It activates the pancreatic proenzyme trypsinogen, which, in turn, releases active digestive enzymes from their inactive pancreatic precursors. Congenital enteropeptidase deficiency is a rare recessively inherited disorder leading, in affected infants, to severe failure to thrive. The genomic structure of the proenteropeptidase gene (25 exons, total gene size 88 kb) was characterized in order to perform DNA sequencing in three clinically and biochemically proved patients with congenital enteropeptidase deficiency who were from two families. We found compound heterozygosity for nonsense mutations (S712X/R857X) in two affected siblings and found compound heterozygosity for a nonsense mutation (Q261X) and a frameshift mutation (FsQ902) in the third patient. In accordance with the biochemical findings, all four defective alleles identified are predicted null alleles leading to a gene product not containing the active site of the enzyme. These data provide first evidence that proenteropeptidase-gene mutations are the primary cause of congenital enteropeptidase deficiency.