Aims/hypothesis
Individuals with heterozygous activating mutations of the
KCNJ11
gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea ...(SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications.
Methods
We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to
KCNJ11
mutations identified through the University of Chicago Monogenic Diabetes Registry (
http://monogenicdiabetes.uchicago.edu/registry
). We assessed the influence of age at initiation of SU therapy on treatment outcomes.
Results
HbA
1c
fell from an average of 8.5% (69 mmol/mol) before transition to 6.2% (44 mmol/mol) after SU therapy (
p
< 0.001). Age of initiation of SU correlated with the dose (mg kg
−1
day
−1
) of SU required at follow-up (
r
= 0.80,
p
< 0.001). Similar associations were observed across mutation subtypes. Ten participants required additional glucose-lowering medications and all had initiated SU at age 13 years or older. No serious adverse events were reported.
Conclusions/interpretation
Earlier age at initiation of SU treatment is associated with improved response to SU therapy. Declining sensitivity to SU may be due to loss of beta cell mass over time in those treated with insulin. Our data support the need for early genetic diagnosis and appropriate personalised treatment in all cases of neonatal diabetes.
Display omitted
•Diocleinae is excluded from Phaseoleae and ranked at tribe level.•Phaseoleae is polyphyletic and includes the monophyletic Desmodieae and Psoraleeae.•The reinstated Diocleae includes ...Canavalia (1 genus), Dioclea (4), and Galactia (8) clades.•Bionia, Camptosema, Cratylia, Dioclea, and Galactia are not monophyletic.
Deciphering the phylogenetic relationships within the species-rich Millettioid clade has persisted as one of the major challenges in the systematics and evolutionary history of papilionoid legumes (Leguminosae, Papilionoideae). Historically, the predominantly neotropical lianas of subtribe Diocleinae in the Millettioid legumes have been taxonomically tangled together with the largely heterogeneous tribe Phaseoleae. This work presents a comprehensive molecular phylogenetic analysis based on nuclear and chloroplast markers and includes all genera ever referred to Diocleae except for the monospecific Philippine Luzonia, resolving several key generic relationships within the Millettioid legumes. The first of two separate analyses includes 310 matK accessions and strongly supports the reestablishment of tribe Diocleae as a branch of the Millettioid clade. This work sheds greater light on the higher-level phylogeny of Diocleae and allows the recognition of three major lineages: the Canavalia, Dioclea, and Galactia clades. The second set of phylogenetic analyses utilized nuclear (ITS/5.8S and ETS) and plastid (matK and trnT-Y) DNA sequences to reveal (i) the monophyly of Canavalia and Cleobulia; (ii) the monophyly of Bionia with the exclusion of Bionia bella; (iii) the paraphyly of Dioclea with respect to Cleobulia, Cymbosema, and Macropsychanthus; (iv) the paraphyly of Cratylia with respect to the broadly polyphyletic Camptosema; and (v) the polyphyly of Galactia with species scattered widely across the tree.
Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory ...cell function and mutations are known to cause “immune dysregulation, polyendocrinopathy (including insulin‐requiring diabetes), enteropathy, X‐linked” (IPEX) syndrome. This condition is often fatal unless patients receive a bone‐marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin‐requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole‐exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT‐PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice‐site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT‐PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early‐onset insulin‐requiring diabetes with or without other features of IPEX syndrome.
Background/objective: Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50% of patients diagnosed with diabetes before 6 months of age and in a small ...fraction of those diagnosed between 6 and 12 months. The aim of this study was to identify the genetic cause of diabetes in 77 consecutive patients referred to the University of Chicago with diabetes diagnosed before 1 yr of age.
Methods: We used Oragene™ DNA Self‐Collection kit to obtain a saliva sample for DNA. We sequenced the protein‐coding regions of KCNJ11, ABCC8, and INS using standard methods.
Results: We enrolled 32 patients diagnosed with diabetes before 6 months of age and 45 patients diagnosed between 6 and 12 months. We identified a mutation in KCNJ11 in 14 patients from 12 families and in INS in 7 patients from 4 families. Three of the patients with an INS mutation were diagnosed with diabetes between 6 and 12 months of age. Finally, we found that two patients had an abnormality of chromosome 6q24 associated with transient neonatal diabetes mellitus.
Conclusions: We were able to establish a genetic cause of diabetes in 63% of patients diagnosed with diabetes before 6 months of age and in 7% of patients diagnosed between 6 and 12 months. Genetic testing, which is critical for guiding appropriate management, should be considered in patients diagnosed with diabetes before 1 yr of age, especially if they are autoantibody negative, although the presence of autoantibodies does not rule out a monogenic cause.
Diabetes occurs in 1/90,000–1/160,000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause.
FOXP3
encodes a transcription factor critical for T regulatory ...cell function and mutations are known to cause “Immune dysregulation, Polyendocrinopathy (including insulin-requiring diabetes), Enteropathy, X-linked” (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in
FOXP3
. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have
FOXP3
variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that
FOXP3
mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.
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