Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency.

AIMS: Recessive PDX1 (IPF1) mutations are a rare cause of pancreatic agenesis, with three cases reported worldwide. A recent report described two cousins with a homozygous hypomorphic PDX1 mutation causing permanent neonatal diabetes with subclinical exocrine insufficiency. The aim of our study was to investigate the possibility of hypomorphic PDX1 mutations in a large cohort of patients with permanent neonatal diabetes and no reported pancreatic hypoplasia or exocrine insufficiency. METHODS: PDX1 was sequenced in 103 probands with isolated permanent neonatal diabetes in whom ABCC8, KCNJ11 and INS mutations had been excluded. RESULTS: Sequencing analysis identified biallelic PDX1 mutations in three of the 103 probands with permanent neonatal diabetes (2.9%). One proband and his affected brother were compound heterozygotes for a frameshift and a novel missense mutation (p.A34fsX191; c.98dupC and p.P87L; c.260C>T). The other two probands were homozygous for novel PDX1 missense mutations (p.A152G; c.455C>G and p.R176Q; c.527G>A). Both mutations affect highly conserved residues located within the homeobox domain. None of the four cases showed any evidence of exocrine pancreatic insufficiency, either clinically, or, where data were available, biochemically. In addition a heterozygous nonsense mutation (p.C18X; c.54C>A) was identified in a fourth case. CONCLUSIONS: This study demonstrates that recessive PDX1 mutations are a rare but important cause of isolated permanent neonatal diabetes in patients without pancreatic hypoplasia/agenesis. Inclusion of the PDX1 gene in mutation screening for permanent neonatal diabetes is recommended as a genetic diagnosis reveals the mode of inheritance, allows accurate estimation of recurrence risks and confirms the requirement for insulin treatment.

Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden.

All newly diagnosed diabetes in Kronoberg during 3 years was registered, with blood samples from 1630/1666 (97.8%) adults. Those positive for GADab and/or ICA and/or C-peptide<0.25nmol/L (0.7%) were classified as type 1 diabetes, the remaining as type 2. Incidence of type 1 in 0-19-year-olds was 37.8(36.1-39.6, 95%CI) and in 20-100 year-olds 27.1(25.6-27.4) per 100 000 and year, it was bimodal with equal peaks in 0-9 year-olds and in 50-80-year-olds. Adults had type 2 incidence 378 (375-380), children 3.1 (2.6-3.6). Among adults 6.9% had type 1 and 93.1% type 2. Among antibodypositive adults (n=101), GADab were present in 90%, ICA in 71%, both GADab and ICA in 61%. Ophthalmology contact as second source was confirmed for 98%. There were no gender differences in type 1 in any age group, small ones in pediatric subgroups. In type 2 men predominated in ages above 40 years. Incidences of type 1 diabetes in both children and adults were very high and as high above age 50 years as in children. Incidence of type 2 was the highest reported from Sweden, to which new diagnostic criteria, a high degree of case-finding, and many elders, may have contributed, but results may also reflect a true increase in incidence of both types of diabetes.

Origin of magnetic anisotropy of Gd metal.

Using first-principles theory, we have calculated the energy of Gd as a function of spin direction, theta, between the c and a axes and found good agreement with experiment for both the total magnetic anisotropy energy and its angular dependence. The calculated low temperature direction of the magnetic moment lies at an angle of 20 degrees to the c axis. The calculated magnetic anisotropy energy of Gd metal is due to a unique mechanism involving a contribution of 7.5 microeV from the classical dipole-dipole interaction between spins plus a contribution of 16 microeV due to the spin-orbit interaction of the conduction electrons. The 4f spin polarizes the conduction electrons via exchange interaction, which transfers the magnetic anisotropy of the conduction electrons to the 4f spin.