Short-chain acyl-CoA dehydrogenase gene mutation (c.319C>T) presents with clinical heterogeneity and is candidate founder mutation in individuals of Ashkenazi Jewish origin

We report 10 children (7 male, 3 female), 3 homozygous for c.319C>T mutation and 7 heterozygous for c.319C>T on one allele and c.625G>A variant on the other in the short-chain acyl-CoA dehydrogenase (SCAD) gene (ACADS). All were of Ashkenazi Jewish origin in which group we found a c.319C>T heterozygote frequency of 1:15 suggesting the presence of a founder mutation or selective advantage. Phenotype was variable with onset from birth to early childhood. Features included hypotonia (8/10), developmental delay (8/10), myopathy (4/10) with multicore changes in two and lipid storage in one, facial weakness (3/10), lethargy (5/10), feeding difficulties (4/10) and congenital abnormalities (3/7). One female with multiminicore myopathy had progressive external ophthalmoplegia, ptosis and cardiomyopathy with pneumonia and respiratory failure. Two brothers presented with psychosis, pyramidal signs, and multifocal white matter abnormalities on MRI brain suggesting additional genetic factors. Two other infants also had white matter changes. Elevated butyrylcarnitine (4/8), ethylmalonic aciduria (9/9), methylsuccinic aciduria (6/7), decreased butyrate oxidation in lymphoblasts (2/4) and decreased SCAD activity in fibroblasts or muscle (3/3) were shown. Expression studies of c.319C>T in mouse liver mitochondria showed it to be inactivating. c.625G>A is a common variant in ACADS that may confer disease susceptibility. Five healthy parents were heterozygous for c.319C>T and c.625G>A, suggesting reduced penetrance or broad clinical spectrum. We conclude that the c.319C>T mutation can lead to wide clinical and biochemical phenotypic variability, suggesting a complex multifactorial/polygenic condition. This should be screened for in individuals with multicore myopathy, particularly among the Ashkenazim.     

Sleep architecture and glucose and insulin homeostasis in obese adolescents

OBJECTIVE

Sleep deprivation is associated with increased risk of adult type 2 diabetes mellitus (T2DM). It is uncertain whether sleep deprivation and/or altered sleep architecture affects glycemic regulation or insulin sensitivity or secretion. We hypothesized that in obese adolescents, sleep disturbances would associate with altered glucose and insulin homeostasis.

RESEARCH DESIGN AND METHODS

This cross-sectional observational study of 62 obese adolescents took place at the Clinical and Translational Research Center and Sleep Laboratory in a tertiary care children’s hospital. Subjects underwent oral glucose tolerance test (OGTT), anthropometric measurements, overnight polysomnography, and frequently sampled intravenous glucose tolerance test (FSIGT). Hemoglobin A_1c (HbA_1c) and serial insulin and glucose levels were obtained, indices of insulin sensitivity and secretion were calculated, and sleep architecture was assessed. Correlation and regression analyses were performed to assess the association of total sleep and sleep stages with measures of insulin and glucose homeostasis, adjusted for confounding variables.

RESULTS

We found significant U-shaped (quadratic) associations between sleep duration and both HbA_1c and serial glucose levels on OGTT and positive associations between slow-wave sleep (N3) duration and insulin secretory measures, independent of degree of obesity, pubertal stage, sex, and obstructive sleep apnea measures.

CONCLUSIONS

Insufficient and excessive sleep was associated with short-term and long-term hyperglycemia in our obese adolescents. Decreased N3 was associated with decreased insulin secretion. These effects may be related, with reduced insulin secretory capacity leading to hyperglycemia. We speculate that optimizing sleep may stave off the development of T2DM in obese adolescents.Sleep deprivation is endemic; 9.3% of U.S. adults sleep <6 h per night (1), and 75% of high-school seniors report getting insufficient sleep (2). This cumulative societal sleep curtailment is significant, as sleep deprivation is associated with a number of metabolic consequences: increased predisposition to obesity (3) and insulin resistance (IR) (4) in both adults and children, increased risk of type 2 diabetes mellitus (T2DM) in adults (5), and higher fasting glucose in young adults with preexisting diabetes (6). The metabolic consequences of insufficient sleep may be the result of a lack of total sleep or insufficiency of a certain sleep component. The American Academy of Sleep Medicine recognizes four different sleep stages indicated as follows: stage 1 (N1), a brief transition between wake and sleep; stage 2 (N2); stage 3 (N3), “slow-wave” or “deep” sleep; and rapid eye movement (REM) (dream) sleep. In adult studies, cerebral glucose utilization declines (7) and plasma glucose rises (8) in N3 sleep. One pediatric study found a negative association between REM sleep duration and obesity (9), but there is little pediatric data on sleep architecture and glucose and insulin homeostasis. A potential confounding factor is obstructive sleep apnea (OSA), a syndrome more common in obesity in which upper airway obstruction leads to sleep fragmentation and desaturation (10). OSA has been associated with T2DM risk in adults (10) and with IR in children (11,12). We hypothesized that in obese adolescents (who are at risk for T2DM), altered sleep architecture is associated with abnormalities of insulin secretion and sensitivity and of glucose homeostasis independently of confounding factors (e.g., degree of obesity, presence of OSA, sex, and pubertal stage). Therefore, the aim of our study was to investigate the relationship between sleep architecture and insulin secretion and sensitivity and overall glycemia in this population.     

A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms

Norrie disease (ND) is a rare X-linked recessive disorder characterized by congenital blindness and in some cases, mental retardation and deafness. Other neurological complications, particularly epilepsy, are rare. We report on a novel mutation identified in a patient with ND and profound mental retardation. The patient was diagnosed at the age of 6 months due to congenital blindness. At the age of 8 months he developed infantile spasms, which were diagnosed at 11 months as his EEG demonstrated hypsarrhythmia. Mutation analysis of the ND gene (NDP) of the affected child and his mother revealed a novel missense mutation at position c.134T > A resulting in amino acid change at codon V45E. To the best of our knowledge, such severe neurological involvement has not been previously reported in ND patients. The severity of the phenotype may suggest the functional importance of this site of the NDP gene.     

Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer

Anaplastic thyroid carcinoma is an aggressive form of cancer with no treatment. Angiogenesis inhibitors, such as TNP-470, a synthetic derivative of fumagillin, have been shown to reduce tumor size and increase survival in heterotopic animal models of thyroid cancer. Our goals were to determine the effect of TNP-470 on anaplastic thyroid cancer using an orthotopic murine model, to identify the molecular pathways of TNP-470 actions on endothelial cells, and to determine the non-endothelial tumor effects of TNP-470. We injected human anaplastic thyroid carcinoma cells (DRO'90) into the thyroid glands of nude mice. Mice received TNP-470 (30 mg/kg) s.c. for 6 weeks. TNP-470 prolonged survival and reduced liver metastases. TNP-470 had direct cytotoxic effects on anaplastic thyroid carcinoma cells in vitro and in vivo. Paradoxically, TNP-470 increased vascular endothelial growth factor secretion from tumor cells in vitro and in vivo. However, there was no associated increase in tumor microvessel density. In endothelial cells, TNP-470 prevented vascular endothelial growth factor-induced endothelial permeability, intercellular gap formation, and ruffle formation by preventing Rac1 activation.     

How voluntary actions modulate time perception

Distortions of time perception are generally explained either by variations in the rate of pacing signals of an “internal clock”, or by lag-adaptation mechanisms that recalibrate the perceived time of one event relative to another. This study compares these accounts directly for one temporal illusion: the subjective compression of the interval between voluntary actions and their effects, known as ‘intentional binding’. Participants discriminated whether two cutaneous stimuli presented after voluntary or passive movements were simultaneous or successive. In other trials, they judged the temporal interval between their movement and an ensuing tone. Temporal discrimination was impaired following voluntary movements compared to passive movements early in the action-tone interval. In a control experiment, active movements without subsequent tones produced no impairment in temporal discrimination. These results suggest that voluntary actions transiently slow down an internal clock during the action-effect interval. This in turn leads to intentional binding, and links the effects of voluntary actions to the self.

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Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease

PURPOSE: Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS: A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4(+/-) mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS: Although the level of Elovl4 mRNA was reduced in Elovl4(+/-) retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4(+/-) retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4(+/-) mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4(+/-) retinas, particularly the monounsaturated fatty acids. CONCLUSIONS: The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.