Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic ...contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom‐designed gene panel. We selected 55 leukoencephalopathy‐related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically.
About 13.3% of adult patients with leukoencephalopathy were definitively disgnosed with known, apparently pathological or novel mutations.
We present the first measurement of the planet frequency beyond the "snow line," for the planet-to-star mass-ratio interval –4.5 < log q < –2, corresponding to the range of ice giants to gas giants. ...We find \endgraf\vbox{\begin{center}$\displaystyle{d^2 N{_{\rm pl}}\over d\log q\, d\log s} = (0.36\pm 0.15)\;{\rm dex}^{-2}$\end{center}}\noindentat the mean mass ratio q = 5 × 10 –4 with no discernible deviation from a flat (Öpik's law) distribution in log-projected separation s. The determination is based on a sample of six planets detected from intensive follow-up observations of high-magnification ( A>200) microlensing events during 2005-2008. The sampled host stars have a typical mass M host ~ 0.5 M sun
The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, ...biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non‐syndromic intellectual disabilities. In this study, we identified by whole‐exome sequencing compound heterozygous SZT2 mutations in 3 patients with early‐onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice‐site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.
Pedigrees of families (upper) and schematic presentation of recessive mutations in SZT2 (lower). Eight previously reported mutations and the 6 mutations found in this study are shown above and below SZT2, respectively.
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, ...plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Eight mutations have been reported in 13 unrelated families. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. One recurrent missense mutation (p.Asp106Asn) was previously reported in Turkish and Italian families, while the other 2 mutations (p.Leu18Serfs*8 and p.Cys180*) are novel. We also show that mutant PRUNE1 mRNA can be subject to nonsense‐mediated mRNA decay. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) (OMIM #617481) is an autosomal recessive disease characterized by progressive microcephaly, plagiocephaly, hypotonia, spastic quadriparesis, global developmental delay, intellectual disability, optic features and abnormal brain magnetic resonance imaging (MRI). NMIHBA was recently reported to be caused by PRUNE1 mutations. Here, we report 3 PRUNE1 mutations in 1 Caucasian and 3 Japanese families. The patients presented in this study showed atypical NMIHBA phenotypes with no progressive microcephaly. Furthermore, one Caucasian case had significant macrocephaly; therefore, patients with PRUNE1 mutations can exhibit a broad and heterogeneous spectrum of phenotypes.
Objective
To assess insulin sensitivity in patients with systemic lupus erythematosus (SLE) in response to a meal tolerance test (MTT).
Methods
In this cross‐sectional study, 33 adult females with ...mild/inactive SLE (SLE group) and 16 age‐ and body mass index–matched female healthy controls (CTRL group) underwent an MTT and were assessed for insulin sensitivity and beta cell function. Skeletal muscle protein expressions of total and membrane insulin‐dependent glucose transporter 4 (GLUT‐4) were also evaluated (SLE group: n = 10, CTRL group: n = 5); muscle biopsies were performed after MTT. Further measurements included inflammatory cytokines, adipocytokines, physical activity level, body composition, and food intake.
Results
SLE and CTRL groups showed similar fasting glucose, glucose response, and skeletal muscle GLUT‐4 translocation after MTT. However, the SLE group demonstrated higher fasting insulin levels (P = 0.01; effect size ES 1.2), homeostatic model assessment insulin resistance (IR) (P = 0.03; ES 1.1), insulin‐to‐glucose ratio response to MTT (P = 0.02; ES 1.2), fasting glucagon levels (P = 0.002; ES 2.7), glucagon response to MTT (P = 0.0001; ES 2.6), and a tendency toward lower Matsuda index of whole‐body insulin sensitivity (P = 0.06; ES −0.5) when compared with the CTRL group. Fasting proinsulin‐to‐insulin ratio and proinsulin‐to‐insulin ratio response to MTT were similar between groups (P > 0.05), while the SLE group showed a higher insulinogenic index when compared with the CTRL group (P = 0.02; ES = 0.9).
Conclusion
We have identified that SLE patients had a bi‐hormone metabolic abnormality characterized by increased IR and hyperglucagonemia despite normal glucose tolerance and preserved beta cell function and skeletal muscle GLUT‐4 translocation. Strategies capable of ameliorating insulin sensitivity to reduce the risk of type 2 diabetes mellitus and cardiovascular disease in SLE may require more than targeting IR alone.
Eukaryotic elongation factor 1, alpha‐2 (eEF1A2) protein is involved in protein synthesis, suppression of apoptosis, and regulation of actin function and cytoskeletal structure. EEF1A2 gene is highly ...expressed in the central nervous system and Eef1a2 knockout mice show the neuronal degeneration. Until now, only one missense mutation (c.208G > A, p.Gly70Ser) in EEF1A2 has been reported in two independent patients with neurological disease. In this report, we described two patients with de novo mutations (c.754G > C, p.Asp252His and c.364G > A, p.Glu122Lys) in EEF1A2 found by whole‐exome sequencing. Common clinical features are shared by all four individuals: severe intellectual disability, autistic behavior, absent speech, neonatal hypotonia, epilepsy and progressive microcephaly. Furthermore, the two patients share the similar characteristic facial features including a depressed nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth. These data strongly indicate that a new recognizable disorder is caused by EEF1A2 mutations.
The skeletal ciliopathies are a heterogeneous group of disorders with a significant clinical and genetic variability and the main clinical features are thoracic hypoplasia and short tubular bones. To ...date, 25 genes have been identified in association with skeletal ciliopathies. Mutations in the KIAA0753 gene have recently been associated with Joubert syndrome (JBTS) and orofaciodigital (OFD) syndrome. We report biallelic pathogenic variants in KIAA0753 in four patients with short-rib type skeletal dysplasia. The manifestations in our patients are variable and ranging from fetal lethal to viable and moderate skeletal dysplasia with narrow thorax and abnormal metaphyses. We demonstrate that KIAA0753 is expressed in normal fetal human growth plate and show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by our findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning.
We present the discovery of a Neptune-mass planet OGLE-2007-BLG-368Lb with a planet-star mass ratio of q = 9.5 +- 2.1 x 10{sup -5} via gravitational microlensing. The planetary deviation was detected ...in real-time thanks to the high cadence of the Microlensing Observations in Astrophysics survey, real-time light-curve monitoring and intensive follow-up observations. A Bayesian analysis returns the stellar mass and distance at M{sub l} = 0.64{sup +0.21}{sub -0.26} M{sub sun} and D{sub l} = 5.9{sup +0.9}{sub -1.4} kpc, respectively, so the mass and separation of the planet are M{sub p} = 20{sup +7}{sub -8} M{sub +} and a = 3.3{sup +1.4}{sub -0.8} AU, respectively. This discovery adds another cold Neptune-mass planet to the planetary sample discovered by microlensing, which now comprises four cold Neptune/super-Earths, five gas giant planets, and another sub-Saturn mass planet whose nature is unclear. The discovery of these 10 cold exoplanets by the microlensing method implies that the mass ratio function of cold exoplanets scales as dN{sub pl}/dlog q {proportional_to} q {sup -0.7+}-{sup 0.2} with a 95% confidence level upper limit of n < -0.35 (where dN{sub pl}/dlog q {proportional_to} q{sup n} ). As microlensing is most sensitive to planets beyond the snow-line, this implies that Neptune-mass planets are at least three times more common than Jupiters in this region at the 95% confidence level.
Objective
To compare aerobic capacity and health‐related quality of life (HRQOL) in physically inactive adult systemic lupus erythematosus (A‐SLE) and childhood‐onset systemic lupus erythematosus ...(C‐SLE) patients with mild/inactive disease versus healthy controls.
Methods
In a cross‐sectional study, 39 patients (C‐SLE: n = 18, ages 9–18 years; and A‐SLE: n = 21, ages 23–45 years) with inactive disease activity (Systemic Lupus Erythematosus Disease Activity Index ≤4) and low cumulative damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index ≤2) and 30 healthy controls (15 children and adolescents C‐CTRL, 15 adults A‐CTRL) matched by physical inactivity, age, sex, and body mass index (BMI) were assessed for aerobic capacity and HRQOL.
Results
All participants were considered physically inactive according to physical activity guidelines. C‐SLE and A‐SLE patients showed lower
VO2peak (95% CI confidence interval 95% CI −10.5, −1.2 and −11.1, −3.8, respectively) and higher time‐to‐exhaustion when compared with C‐CTRL and A‐CTRL (95% CI −2.8, 0.1 and −3.9, −1.7, respectively). C‐SLE patients showed significantly lower scores in scholar functioning from the Pediatric Quality of Life Inventory questionnaire (P < 0.05) whereas A‐SLE patients showed lower scores in most domains of the Short Form 36 health survey questionnaire (physical function, role‐physical, bodily pain, general health, vitality, social function, and mental health) when compared with healthy controls (P < 0.05 for all).
Conclusion
Our study provides novel data suggesting that A‐SLE and C‐SLE patients with mild/inactive disease have impaired aerobic capacity and HRQOL when compared with controls matched by physical inactivity, age, sex, and BMI. These findings reinforce the recommendation of physical activity in SLE treatment.
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