Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance.

The frequencies of low-activity alleles of glucose-6-phosphate dehydrogenase in humans are highly correlated with the prevalence of malaria. These "deficiency" alleles are thought to provide reduced risk from infection by the Plasmodium parasite and are maintained at high frequency despite the hemopathologies that they cause. Haplotype analysis of "A-" and "Med" mutations at this locus indicates that they have evolved independently and have increased in frequency at a rate that is too rapid to be explained by random genetic drift. Statistical modeling indicates that the A- allele arose within the past 3840 to 11,760 years and the Med allele arose within the past 1600 to 6640 years. These results support the hypothesis that malaria has had a major impact on humans only since the introduction of agriculture within the past 10,000 years and provide a striking example of the signature of selection on the human genome.

Unusual presentation of Kearns-Sayre syndrome in early childhood.

Congenital glaucoma and insulin-dependent diabetes mellitus were the predominant presenting signs in a patient with Kearns-Sayre syndrome. Thereafter, he developed short stature, pigmentary retinopathy, progressive external ophthalmoplegia, and ataxia. The diagnosis was confirmed by detecting a deletion of mitochondrial DNA in muscle, thus demonstrating that Kearns-Sayre syndrome can have the unusual presenting signs described above.

Medium chain acyl-CoA dehydrogenase deficiency.

From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.

A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency.

A patient with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is reported. He had a severe neonatal presentation and cardiomyopathy. He was found to be homozygous for a severe mutation with no residual enzyme activity. Tandem mass spectrometry on dried blood spots revealed increased long chain acylcarnitines. VLCAD enzyme activity was severely decreased to 2% of control levels. Dietary management consisted of skimmed milk supplemented with medium chain triglycerides and L-carnitine. Outcome was good and there was no acute recurrence.