Κυριακή 10 Δεκεμβρίου 2017
“Lowe syndrome: A particularly severe phenotype without clinical kidney involvement”
Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23-year-old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.
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Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene
Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.
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A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V: Possible phenotypic expansion
SLC25A1 mutations are associated with combined D,L-2-hydroxyglutaric aciduria (DL- 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal-onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2-OH-glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V-associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.
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A novel truncating variant within exon 7 of KAT6B associated with features of both Say–Barber–Bieseker–Young–Simpson syndrome and genitopatellar syndrome: Further evidence of a continuum in the clinical spectrum of KAT6B-related disorders
KAT6B sequence variants have been identified in both patients with the Say–Barber–Biesecker–Young–Simpson syndrome (SBBYSS) and in the genitopatellar syndrome (GPS). In SBBYSS, they were reported to affect mostly exons 16–18 of KAT6B, and the predicted mechanism of pathogenesis was haploinsufficiency or a partial loss of protein function. Truncating variants in KAT6B leading to GPS appear to cluster within the proximal portion of exon 18, associated with a dominant-negative effect of the mutated protein, most likely. Although SBBYSS and GPS have been initially considered allelic disorders with distinctive genetic and clinical features, there is evidence that they represent two ends of a spectrum of conditions referable as KAT6B-related disorders. We detected a de novo truncating variant within exon 7 of KAT6B in a 8-year-old female who presented with mild intellectual disability, facial dysmorphisms highly consistent with SBBYSS, and skeletal anomalies including exostosis, that are usually considered component manifestations of GPS. Following the clinical diagnosis driven by the striking facial phenotype, we analyzed the KAT6B gene by NGS techniques. The present report highlights the pivotal role of clinical genetics in avoiding clear-cut genotype-phenotype categories in syndromic forms of intellectual disability. In addition, it further supports the evidence that a continuum exists within the clinical spectrum of KAT6B-associated disorders.
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Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia
We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.
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Spontaneously regressing brain lesions in Smith–Lemli–Opitz syndrome
Smith–Lemli–Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.
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A prospective study comparing perioperative anxiety and posthospital behavior in children with autism spectrum disorder vs typically developing children undergoing outpatient surgery
Summary
Background
Research describing the experience of youth with autism spectrum disorders in the perioperative setting is limited. This study compared youth with autism spectrum disorder to typically developing children in the perioperative setting and examined group differences in: child anxiety, parent anxiety, premedication patterns, induction compliance, and changes in behavior postprocedure.
Methods
Participants were 60 youth (32 with autism spectrum disorder, 28 typically developing) of ages 2-19 years undergoing outpatient surgery and their parents. Parents and research assistants rated children's anxiety at 3 time points (waiting room, preoperative holding, separation), and parents rated their own anxiety in the waiting room and at separation. The anesthesiologist rated induction compliance. Postprocedure behavior change was assessed via phone survey 1 and 7 days postprocedure. Analyses examined group differences in anxiety, medication patterns, and behavior.
Results
Children with autism spectrum disorder had higher research assistant reported anxiety than typically developing youth in the holding room only. There were no group differences in parent report of their own anxiety or their child's anxiety across time points. Compared to typically developing youth, children with autism spectrum disorder were more likely to receive a premedication (including nonstandard premedication), and had poorer induction compliance. Groups did not differ on posthospital behavior change 1 or 7 days postsurgery.
Conclusion
Findings revealed ratings of anxiety in youth with and without autism spectrum disorder facing surgery varied by reporter and setting, highlighting the importance of using multiple reporters in research of youth with autism spectrum disorder in the perioperative period. Furthermore, while results showed group differences in premedication patterns and induction compliance, groups did not differ in level of negative behavior change after surgery. Future research can examine how individual differences in youth with autism impact anxiety in the perioperative setting and degree of behavior change postprocedure.
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Exploring the relationship between frontal asymmetry and emotional dampening
Source:International Journal of Psychophysiology
Author(s): James P. Loveless, Alexandra J. Nicoletta, Andrea R. Winters, Robert A. Carels, Karl L. Wuensch, Matthew C. Whited, James A. McCubbin, D. Erik Everhart
Cardiovascular emotional dampening is the term used to describe the inverse relationship between resting blood pressure and emotional responsivity which extends from normotensive to hypertensive ranges. Little is known about its underlying physiological mechanisms, but it is thought to involve some disruption in emotion processing. One area that has yet to be explored in the literature is the relationship between emotional dampening and frontal asymmetry, a psychophysiological indicator for motivational direction and emotional valence bias. The present study explored that relationship using data from a sample of 48 healthy college students. Measures of baseline resting blood pressure and frontal cortical activity were recorded, after which participants completed a series of emotion-related tasks. Results revealed a significant relationship between resting systolic blood pressure and left frontal activity. Likewise, left frontal activity was associated with neutral appraisal of emotionally valenced stimuli within the tasks. The findings from the present study yield support for a link between emotional dampening and left frontal activity. Implications are discussed.
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