Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy.

We have shown in vivo and in vitro previously that psychosine causes dysfunction of autophagy and the ubiquitin-proteasome system underlying the pathogenesis of globoid cell leukodystrophy (GLD), a devastating lysosomal storage disease complicated by global demyelination. Here, we investigated the therapeutic efficacy of the mTOR inhibitor rapamycin in twitcher mice, a murine model of infantile GLD, in biochemical, histochemical, and clinical aspects. Administration of rapamycin to twitcher mice inhibited mTOR signaling in the brains, and significantly reduced the accumulation of insoluble ubiquitinated protein and the formation of ubiquitin aggregates. The astrocytes and microglia reactivity were attenuated in that reactive astrocytes, ameboid microglia, and globoid cells were reduced in the brains of rapamycin-treated twitcher mice. Furthermore, rapamycin improved the cortical myelination, neurite density, and rescued the network complexity in the cortex of twitcher mice. The therapeutic action of rapamycin on the pathology of the twitcher mice's brains prolonged the longevity of treated twitcher mice. Overall, these findings validate the therapeutic efficacy of rapamycin and highlight enhancing degradation of aggregates as a therapeutic strategy to modulate neuroinflammation, demyelination, and disease progression of GLD and other leukodystrophies associated with intracellular aggregates.

Vital Signs Sensing Gown Employing ECG-Based Intelligent Algorithms.

This study presents a long-term vital signs sensing gown consisting of two components: a miniaturized monitoring device and an intelligent computation platform. Vital signs are signs that indicate the functional state of the human body. The general physical health of a person can be assessed by monitoring vital signs, which typically include blood pressure, body temperature, heart rate, and respiration rate. The miniaturized monitoring device is composed of a compact circuit which can acquire two kinds of physiological signals including bioelectrical potentials and skin surface temperature. These two signals were pre-processed in the circuit and transmitted to the intelligent computation platform for further analysis using three algorithms, which incorporate R-wave detection, ECG-derived respiration, and core body temperature estimation. After the processing, the derived vital signs would be displayed on a portable device screen, including ECG signals, heart rate (HR), respiration rate (RR), and core body temperature. An experiment for validating the performance of the intelligent computation platform was conducted in clinical practices. Thirty-one participants were recruited in the study (ten healthy participants and twenty-one clinical patients). The results showed that the relative error of HR is lower than 1.41%, RR is lower than 5.52%, and the bias of core body temperature is lower than 0.04 °C in both healthy participant and clinical patient trials. In this study, a miniaturized monitoring device and three algorithms which derive vital signs including HR, RR, and core body temperature were integrated for developing the vital signs sensing gown. The proposed sensing gown outperformed the commonly used equipment in terms of usability and price in clinical practices. Employing algorithms for estimating vital signs is a continuous and non-invasive approach, and it could be a novel and potential device for home-caring and clinical monitoring, especially during the pandemic.

Pathogenesis and Preventive Tactics of Immune-Mediated Non-Pulmonary COVID-19 in Children and Beyond.

The COVID-19 pandemic has evolved to immune escape and threatened small children and the elderly with a higher severity and fatality of non-pulmonary diseases. These life-threatening non-pulmonary COVID-19 diseases such as acute necrotizing encephalopathies (ANE) and multisystem inflammatory syndrome in children (MIS-C) are more prevalent in children. However, the mortality of multisystem inflammatory syndrome in adults (MIS-A) is much higher than that of MIS-C although the incidence of MIS-A is lower. Clarification of immunopathogenesis and genetic susceptibility of inflammatory non-pulmonary COVID-19 diseases would provide an appropriate guide for the crisis management and prevention of morbidity and fatality in the ongoing pandemic. This review article described three inflammatory non-pulmonary COVID-19 diseases including (1) meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) post-infectious multisystem inflammatory syndrome in children (MIS-C) and in adults (MIS-A). To prevent these life-threatening non-pulmonary COVID-19 diseases, hosts carrying susceptible genetic variants should receive prophylactic vaccines, avoid febrile respiratory tract infection, and institute immunomodulators and mitochondrial cocktails as early as possible.

HIV fragments detected in Kaposi sarcoma tumor cells in HIV-infected patients.

Kaposi sarcoma (KS) is a malignant vascular neoplasm caused by KS-associated herpesvirus (KSHV) infection. HIV plays a major role in KS pathogenesis. KS in HIV usually produces more malignant features than classic KS. Despite the close KS-HIV relationship, no study has reported the existence of HIV in KS tissue. We used ddPCR to detect HIV and KSHV in HIV+ KS samples and classic KS control. We verified KS cell types through immunohistochemistry and applied hypersensitive in situ hybridization (ISH) to detect HIV and KSHV in tumor cells. Furthermore, we co-stained samples with ISH and immunohistochemistry to identify HIV and KSHV in specific cell types. Regarding pathological stages, the KS were nodular (58.3%), plaque (33.3%), and patch (8.3%) tumors. Moreover, ddPCR revealed HIV in 58.3% of the KS samples. ISH revealed positive Pol/Gag mRNA signals in CD34 + tumor cells from HIV + patients (95.8%). HIV signals were absent in macrophages and other inflammatory cells. Most HIV + KS cells showed scattered reactive particles of HIV and KSHV. We demonstrated that HIV could infect CD34 + tumor cells and coexist with KSHV in KS, constituting a novel finding. We hypothesized that the direct KSHV-HIV interaction at the cellular level contributes to KS oncogenesis.

Neurological state changes indicative of ADHD in children learned via EEG-based LSTM networks.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that pervasively interferes with the lives of individuals starting in childhood.Objective. To address the subjectivity of current diagnostic approaches, many studies have been dedicated to efforts to identify the differences between ADHD and neurotypical (NT) individuals using electroencephalography (EEG) and continuous performance tests (CPT).Approach. In this study, we proposed EEG-based long short-term memory (LSTM) networks that utilize deep learning techniques with learning the cognitive state transition to discriminate between ADHD and NT children via EEG signal processing. A total of 30 neurotypical children and 30 ADHD children participated in CPT tests while being monitored with EEG. Several architectures of deep and machine learning were applied to three EEG data segments including resting state, cognitive execution, and a period containing a fusion of those.Main results. The experimental results indicated that EEG-based LSTM networks produced the best performance with an average accuracy of 90.50 ± 0.81% in comparison with the deep neural networks, the convolutional neural networks, and the support vector machines with learning the cognitive state transition of EEG data. Novel observations of individual neural markers showed that the beta power activity of the O1 and O2 sites contributed the most to the classifications, subjects exhibited decreased beta power in the ADHD group, and had larger decreases during cognitive execution.Significance. These findings showed that the proposed EEG-based LSTM networks are capable of extracting the varied temporal characteristics of high-resolution electrophysiological signals to differentiate between ADHD and NT children, and brought a new insight to facilitate the diagnosis of ADHD. The registration numbers of the institutional review boards are 16MMHIS021 and EC1070401-F.

Impact of Mitochondrial A3243G Heteroplasmy on Mitochondrial Bioenergetics and Dynamics of Directly Reprogrammed MELAS Neurons.

The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (>95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases.

Neural Dynamics for Facilitating ADHD Diagnosis in Preschoolers: Central and Parietal Delta Synchronization in the Kiddie Continuous Performance Test.

The present study aimed to characterize children at risk of attention-deficit/hyperactivity disorder (ADHD) during preschool age and provide early intervention. The continuous performance test (CPT) and electroencephalography (EEG) can contribute additional valuable information to facilitate diagnosis. This study measured brain dynamics at slow and fast task rates in the CPT using a wireless wearable EEG and identified correlations between the EEG and CPT data in preschool children with ADHD. Forty-nine preschool children participated in this study, of which 29 were diagnosed with ADHD and 20 exhibited typical development (TD). The Conners Kiddie Continuous Performance Test (K-CPT) and wireless wearable EEG recordings were employed simultaneously. Significant differences were observed between the groups with ADHD and TD in task-related EEG spectral powers (central as well as parietal delta, P < 0.01), which were distinct only in the slow-rate task condition. A shift from resting to the CPT task condition induced overall alpha powers decrease in the ADHD group. In the task condition, the delta powers were positively correlated with the CPT perseveration scores, whereas the alpha powers were negatively correlated with specific CPT scores mainly on perseveration and detectability (P < 0.05). These results, which complement the findings of other sparse studies that have investigated within-task-related brain dynamics, particularly in preschool children, can assist specialists working in early intervention to plan training and educational programs for preschoolers with ADHD.

Towards a reference genome that captures global genetic diversity.

The current human reference genome is predominantly derived from a single individual and it does not adequately reflect human genetic diversity. Here, we analyze 338 high-quality human assemblies of genetically divergent human populations to identify missing sequences in the human reference genome with breakpoint resolution. We identify 127,727 recurrent non-reference unique insertions spanning 18,048,877 bp, some of which disrupt exons and known regulatory elements. To improve genome annotations, we linearly integrate these sequences into the chromosomal assemblies and construct a Human Diversity Reference. Leveraging this reference, an average of 402,573 previously unmapped reads can be recovered for a given genome sequenced to ~40X coverage. Transcriptomic diversity among these non-reference sequences can also be directly assessed. We successfully map tens of thousands of previously discarded RNA-Seq reads to this reference and identify transcription evidence in 4781 gene loci, underlining the importance of these non-reference sequences in functional genomics. Our extensive datasets are important advances toward a comprehensive reference representation of global human genetic diversity.

Impairment of Proteasome and Autophagy Underlying the Pathogenesis of Leukodystrophy.

Impairment of the ubiquitin-proteasome-system (UPS) and autophagy causing cytoplasmic aggregation of ubiquitin andp62 have been implicated in the pathogenesis of most neurodegenerative disorders, yet, they have not been fully elucidated in leukodystrophies. The relationship among impairment of UPS, autophagy, and globoid cell leukodystrophy (GLD), one of the most common demyelinating leukodystrophies, is clarified in this study. We examined the ubiquitin and autophagy markers in the brains of twitcher mice, a murine model of infantile GLD, and in human oligodendrocytes incubated with psychosine. Immunohistochemical examinations showed spatiotemporal accumulation of ubiquitin- and p62-aggregates mainly in the white matter of brain and spinal cord at disease progression. Western blot analysis demonstrated a significant accumulation of ubiquitin, p62, and LC3-II in insoluble fraction in parallel with progressive demyelination and neuroinflammation in twitcher brains. In vitro study validated a dose- and time-dependent cytotoxicity of psychosine upon autophagy and UPS machinery. Inhibition of autophagy and UPS exacerbated the accumulation of insoluble ubiquitin, p62, and LC3-II proteins mediated by psychosine cytotoxicity as well as increased cytoplasmic deposition of ubiquitin- and p62-aggregates, and accumulation of autophagosomes and autolysosomes. Further, the subsequent accumulation of reactive oxygen species and reduction of mitochondrial respiration led to cell death. Our studies validate the impairment of proteasome and autophagy underlying the pathogenesis of GLD. These findings provide a novel insight into pathogenesis of GLD and suggest a specific pathomechanism as an ideal target for therapeutic approaches.

Zebrafish Carrying pycr1 Gene Deficiency Display Aging and Multiple Behavioral Abnormalities.

Aging is a natural process that internal gene control and external stimuli mediate. Clinical data pointed out that homozygotic or heterozygotic mutation in the pyrroline-5-carboxylate reductase 1 (PYCR1) gene in humans caused cutis laxa (ARCL) disease, with progeroid appearance, lax and wrinkled skin, joint laxity, osteopenia, and mental retardation phenotypes. In this study, we aimed to generate pycr1 knockout (KO) zebrafish and carried out biochemical characterizations and behavior analyses. Marked apoptosis and senescence were detected in pycr1 KO zebrafish, which started from embryos/larvae stage. Biochemical assays showed that adult pycr1 KO fish have significantly reduced proline and extracellular matrix contents, lowered energy, and diminished superoxide dismutase (SOD) and telomerase activity when compared to the wild type fish, which suggested the pycr1 KO fish may have dysfunction in mitochondria. The pycr1 KO fish were viable; however, displayed progeria-like phenotype from the 4 months old and reach 50% mortality around six months old. In adult stage, we found that pycr1 KO fish showed reduced locomotion activity, aggression, predator avoidance, social interaction interest, as well as dysregulated color preference and circadian rhythm. In summary, we have identified multiple behavioral alterations in a novel fish model for aging with pycr1 gene loss-of-function by behavioral tests. This animal model may not only provide a unique vertebrate model to screen potential anti-aging drugs in the future, but also be an excellent in vivo model towards a better understanding of the corresponding behavioral alterations that accompany aging.

Oxidative Insults and Mitochondrial DNA Mutation Promote Enhanced Autophagy and Mitophagy Compromising Cell Viability in Pluripotent Cell Model of Mitochondrial Disease.

Dysfunction of mitochondria causes defects in oxidative phosphorylation system (OXPHOS) and increased production of reactive oxygen species (ROS) triggering the activation of the cell death pathway that underlies the pathogenesis of aging and various diseases. The process of autophagy to degrade damaged cytoplasmic components as well as dysfunctional mitochondria is essential for ensuring cell survival. We analyzed the role of autophagy inpatient-specific induced pluripotent stem (iPS) cells generated from fibroblasts of patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with well-characterized mitochondrial DNA mutations and distinct OXPHOS defects. MELAS iPS cells recapitulated the pathogenesis of MELAS syndrome, and showed an increase of autophagy in comparison with its isogenic normal counterpart, whereas mitophagy is very scarce at the basal condition. Our results indicated that the existence of pathogenic mtDNA alone in mitochondrial disease was not sufficient to elicit the degradation of dysfunctional mitochondria. Nonetheless, oxidative insults induced bulk macroautophagy with the accumulation of autophagosomes and autolysosomes upon marked elevation of ROS, overload of intracellular calcium, and robust depolarization of mitochondrial membrane potential, while mitochondria respiratory function was impaired and widespread mitophagy compromised cell viability. Collectively, our studies provide insights into the dysfunction of autophagy and activation of mitophagy contributing to the pathological mechanism of mitochondrial disease.

A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder.

Aging is a complex biological process. A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may not only shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) but also help elucidate the functional mechanisms associated with aging. In this study, we used RNA-Seq technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with PYCR1 mutations. Approximately 22 and 32 candidate genes were found to be up- and downregulated, respectively, in fibroblasts from patients. Among the downregulated candidates in fibroblasts with PYCR1 mutations, a strong reduction in the expression of 17 genes (53.1%) which protein products are localized in the extracellular space was detected. These proteins included several important ECM components, periostin (POSTN), elastin (ELN), and decorin (DCN); genetic mutations in these proteins are associated with different phenotypes of aging, such as cutis laxa and joint and dermal manifestations. The differential expression of ten selected extracellular space genes was further validated using quantitative RT-PCR. Ingenuity Pathway Analysis revealed that some of the affected genes may be associated with cardiovascular system development and function, dermatological diseases and conditions, and cardiovascular disease. POSTN, one of the most downregulated gene candidates in affected individuals, is a matricellular protein with pivotal functions in heart valvulogenesis, skin wound healing, and brain development. Perturbation of PYCR1 expression revealed that it is positively correlated with the POSTN levels. Taken together, POSTN might be one of the key molecules that deserves further investigation for its role in this progeroid neurocutaneous syndrome.

Monetary Reward and Punishment to Response Inhibition Modulate Activation and Synchronization Within the Inhibitory Brain Network.

A reward or punishment can modulate motivation and emotions, which in turn affect cognitive processing. The present simultaneous functional magnetic resonance imaging-electroencephalography study examines neural mechanisms of response inhibition under the influence of a monetary reward or punishment by implementing a modified stop-signal task in a virtual battlefield scenario. The participants were instructed to play as snipers who open fire at a terrorist target but withhold shooting in the presence of a hostage. The participants performed the task under three different feedback conditions in counterbalanced order: a reward condition where each successfully withheld response added a bonus (i.e., positive feedback) to the startup credit, a punishment condition where each failure in stopping deduced a penalty (i.e., negative feedback), and a no-feedback condition where response outcome had no consequences and served as a control setting. Behaviorally both reward and punishment conditions led to significantly down-regulated inhibitory function in terms of the critical stop-signal delay. As for the neuroimaging results, increased activities were found for the no-feedback condition in regions previously reported to be associated with response inhibition, including the right inferior frontal gyrus and the pre-supplementary motor area. Moreover, higher activation of the lingual gyrus, posterior cingulate gyrus (PCG) and inferior parietal lobule were found in the reward condition, while stronger activation of the precuneus gyrus was found in the punishment condition. The positive feedback was also associated with stronger changes of delta, theta, and alpha synchronization in the PCG than were the negative or no-feedback conditions. These findings depicted the intertwining relationship between response inhibition and motivation networks.

Losartan in combination with propranolol slows the aortic root dilatation in neonatal Marfan syndrome.

Neonatal Marfan syndrome, in contrast to classical Marfan syndrome, is characterized by rapidly progressive multi-valvular cardiac disease and death from congestive heart failure, typically within the first year of life. Due to the rarity of this condition, treatment for neonatal Marfan syndrome has not been well studied. In this report, a combination of losartan and propranolol reduced the aortic root dilatation rate after three months of losartan therapy. Genetic analysis in this patient revealed a mutation in exon 25 of the FBN1 gene, which typically results in a shorter life expectancy. However, the patient's heart failure was controlled by losartan, propranolol and other anti-congestive medications, which may have prolonged his survival.

Inflexibility of AMPK-mediated metabolic reprogramming in mitochondrial disease.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is most commonly caused by the A3243G mutation of mitochondrial DNA. The capacity to utilize fatty acid or glucose as a fuel source and how such dynamic switches of metabolic fuel preferences and transcriptional modulation of adaptive mechanism in response to energy deficiency in MELAS syndrome have not been fully elucidated. The fibroblasts from patients with MELAS syndrome demonstrated a remarkable deficiency of electron transport chain complexes I and IV, an impaired cellular biogenesis under glucose deprivation, and a decreased ATP synthesis. In situ analysis of the bioenergetic properties of MELAS cells demonstrated an attenuated fatty acid oxidation that concomitantly occurred with impaired mitochondrial respiration, while energy production was mostly dependent on glycolysis. Furthermore, the transcriptional modulation was mediated by the AMP-activated protein kinase (AMPK) signaling pathway, which activated its downstream modulators leading to a subsequent increase in glycolytic flux through activation of pyruvate dehydrogenase. In contrast, the activities of carnitine palmitoyltransferase for fatty acid oxidation and acetyl-CoA carboxylase-1 for fatty acid synthesis were reduced and transcriptional regulation factors for biogenesis were not altered. These results provide novel information that MELAS cells lack the adaptive mechanism to switch fuel source from glucose to fatty acid, as glycolysis rates increase in response to energy deficiency. The aberrant secondary cellular responses to disrupted metabolic homeostasis mediated by AMPK signaling pathway may contribute to the development of the clinical phenotype.

Mitigation of cerebellar neuropathy in globoid cell leukodystrophy mice by AAV-mediated gene therapy.

Globoid cell leukodystrophy (GLD) is an autosomal recessive, lysosomal storage disease caused by deficiency of the enzyme galactocerebrosidase (GALC). The absence of GALC activity leads to the accumulation of the toxic substance psychosine and the preferential loss of myelinating cells in the central and peripheral nervous systems. Profound demyelination, astrogliosis and axonopathy are the hallmarks of the pathogenesis of GLD, and cerebellar ataxia is one of the dominant manifestations in adolescents and adults affected with GLD. To date, studies regarding cerebellar degeneration in GLD are limited. In this study, the efficacy of cerebellum-targeted gene therapy on the cerebellar neuropathology in twitcher mice (a murine model of GLD) has been validated. We observed degeneration of Purkinje cells, Bergmann glia, and granule cells in addition to astrocytosis and demyelination in the cerebellum of the twitcher mice. Ultrastructural analysis revealed dark cell degeneration and disintegration of the cellular composition of Purkinje cells in untreated twitcher mice. In addition, the expressions of neurotrophic factors CNTF, GDNF and IGF-I were up-regulated and the expression of BDNF was down-regulated. Intracerebellar-mediated gene therapy efficiently corrected enzymatic deficiency by direct transduction to Purkinje cells and cross-correction in other cell types in the cerebellum, leading to the amelioration of both neuroinflammation and demyelination. The population, dendritic territory, and axonal processes of Purkinje cells remained normal in the cerebellum of treated twitcher mice, where radial fibers of Bergmann glia spanned the molecular layer and collateral branches ensheathed the dendritic processes of Purkinje cells. Moreover, the aberrant expressions of neurotrophic factors were mitigated in the cerebellum of treated twitcher mice, indicating the preservation of cellular function in addition to maintaining the neuronal architecture. The life span of the treated twitcher mice was significantly prolonged and their neurobehavioral performance was improved. Taken together, our findings underscore the complexity of cerebellar neurodegeneration in GLD and highlight the potential effectiveness of gene therapy in mitigating neuropathological deficits in GLD and other neurodegenerative disorders in which Purkinje cells are involved.

Cdc6 cooperates with c-Myc to promote genome instability and epithelial to mesenchymal transition EMT in zebrafish.

Aberration in DNA replication is a major cause to genome instability that is a hallmark of cancer cells. Cell division cycle 6 (Cdc6) and c-Myc have a critical role in the initiation of DNA replication. However, whether their interaction induces epithelial-mesenchymal transition (EMT) and promotes tumorigenesis in in vivo animal model remains unclear. Since using zebrafish as a cancer model has been restricted by the late onset of tumorigenesis and extreme difficulty in transformation on skin, we tried to establish a novel non-melanoma skin model in zebrafish to study their role in tumorigenesis. A stable transgenic zebrafish was created by using tol2 transposon, in which cdc6 and c-myc were co-overexpressed in epidermis driven by a skin-specific krt4 promoter. Intriguingly, co-overexpression of cdc6 and c-myc in transgenic zebrafish skin triggered tumor-like transformation, apoptosis attenuation, genomic instability, and EMT, hallmarks of malignant tumorigenesis. Our findings and other characteristics of zebrafish, including optical clarity and small molecule treatment, provide the future utility of this model for easy and non-invasive detection and for identification of new anti-cancer drug.

De novo MECP2 duplication derived from paternal germ line result in dysmorphism and developmental delay.

Xq28 duplications encompassing the methyl CpG binding protein 2 (MECP2) in males exhibit a distinct phenotype, including developmental delay, facial dysmorphism, muscular hypotonia, intellectual disability, poor or absent speech, recurrent infections and early death. The vast majority of affected males inherit the MECP2 duplication from their usually asymptomatic carrier mothers. Only a few cases with Xq28 duplication originating from de novo unbalanced X/Y translocation have been reported and the paternal origin of the aberration has only been validated in three males in the related literature. Here we present a karyotypically normal male with features characteristic of the MECP2 duplication syndrome. The genome-wide SNP genotyping shows a de novo 2.26-Mb duplication from Xq28 to the terminus. The genotypes of the SNPs within the duplicated region indicated a paternal origin. Furthermore, the results of fluorescence in situ hybridization (FISH) indicated a novel Xq:Yp translocation, characterized as der(Y)t(Y;X)(p11.32;q28), which suggests an aberrant that occurred during spermatogenesis. The phenotype is compared to the previously reported cases with Xq28 duplication originated from an unbalanced X/Y translocation, and there was no specific part of the phenotype that could be contributed to the origin of parental imbalances. This report further highlights the capacity of high-molecular cytogenetic methods, such as SNP array and FISH, in the identification of submicroscopic rearrangement, structural configuration and parental origin of aberrant while in the evaluation of children with idiopathic developmental delay and intellectual disability.

99mTc-ethyl cysteinate dimer cranial single-photon emission computed tomography and serial cranial magnetic resonance imaging in a girl with isolated sulfite oxidase deficiency.

Isolated sulfite oxidase deficiency, a rare autosomal recessive inherited disorder, is easily misdiagnosed as the more common hypoxic-ischemic encephalopathy. A female term infant was diagnosed with isolated sulfite oxidase deficiency. Magnetic resonance imaging at ages 13 days, 2 months, and 10 months indicated diffuse edema with posterior predominance, followed by progressive multicystic encephalomalacia and brain atrophy with relatively sparing of the thalami. Single-photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer at 2 months revealed decreased uptake in the frontal lobes. The characteristic neuroimaging findings in isolated sulfite oxidase deficiency help differentiate it from hypoxic insult. The correct diagnosis is helpful in genetic counseling for parents.