Neurological manifestations of SARS-CoV-2 infection in children in Taiwan: A cross-section, multicenter study.

BACKGROUND: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry. METHODS: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry. RESULTS: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement. In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients. CONCLUSIONS: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM.

Psychosocial stress in children with Tourette syndrome and chronic tic disorder.

BACKGROUND: This study aimed to understand the longitudinal relationship between psychosocial stress with tic exacerbation in children with Tourette syndrome (TS) and chronic tic disorder. METHODS: Consecutive ratings of tic severity as well as child and parental reports of psychosocial stress were obtained for 373 children (296 males, 77 females; mean age 9y 5mo; SD 3y 3mo) with TS and chronic tic disorder between January 2018 and December 2020. The Yale Global Tic Severity Scale (YGTSS) global severity score, total tic score, and impairment rating were calculated. The stressful events and YGTSS measurements were used and treated as time-varying variables in the analyses. Models that controlled for non-independence among the repeated observations using a random intercept and random slope model were employed. Each participant was treated as a random factor in the modelling. RESULTS: Family-related stress, personal relationship stress and school-related stress were independently associated with increasing YGTSS global severity, total tic score, and impairment rating over time. An increased number of stressful events were associated with increased severity of tics. CONCLUSION: Family, personal relationships, and school-related stress were consistently associated with the exacerbation of tics. Managing these stressful events is important in the treatment of TS and chronic tic disorder.

Case report: Presentations and cytokine profiles of inflammatory non-pulmonary COVID-19 and related diseases in children.

The coronavirus disease 2019 (COVID-19) pandemic has evolved to dynamic waves of different SARS-CoV-2 variants. Initially, children diagnosed with COVID-19 presented pulmonary involvement characterized by mild diseases. In the later waves of the COVID-19 pandemic, life-threatening non-pulmonary inflammatory diseases such as (1) aseptic meningoencephalitis (ME), (2) acute necrotizing encephalopathies (ANE), and (3) multisystem inflammatory syndrome in children (MIS-C) have been reported, affecting the pediatric population. To alert timely identification and prevention of the life-threatening non-pulmonary COVID-19, we present the cases of ME, ANE, and MIS-C in terms of clinical manifestation, cytokine profile, and follow-up consequences. Based on the immunopathogenesis and risk factors associated with non-pulmonary COVID-19, we delineate strategies for an early diagnosis and treatment to reduce morbidity and mortality in children.

Factors associated with Tourette syndrome among adolescents in Taiwan: A cross-sectional correlational study.

PURPOSE: Adolescents with Tourette syndrome (TS) may suffer from learning difficulties (attention-deficit/hyperactivity disorder), challenges in interpersonal interactions (especially with peers), disruptions of daily routines (disruptive behavior disorders), and increased psychosocial stress, which can result in internalizing and externalizing behavioral problems, such as venting depression and stress through self-harm. The aim of this study was to investigate peer attachment in adolescents with TS and associated risk factors. DESIGN AND METHODS: Adolescents with TS aged 13-18 years were recruited from the outpatient departments of 2 hospitals in Taiwan. Participants completed a basic data sheet, the Beck Depression Inventory-II, the Chinese version of the State-Trait Anxiety Inventory, and the Chinese version of the Youth Self-Report. Descriptive statistics were performed. Structural equation modeling was used to verify the model proposed in this study and to analyze the overall fit and internal structure. RESULTS: A total of 452 adolescents with TS aged 10-19 years participated in this study, which aimed to investigate factors affecting peer attachment, depression, anxiety, and psychosocial maladaptation and to explore causal relationships between these factors. Peer attachment was significantly associated with grade point average (rs = -0.240, p < .001), birth order (rs = -0.118, p = .012), parental marital status (rs = -0.111, p = .018), parenting style (rs = -0.138, p = .003), family monthly income (rs = 0.124, p = .008), and weekly hours on the internet (r = -0.164, p < .001). CONCLUSIONS: These results suggest that depression, anxiety, and peer attachment affect psychosocial development. PRACTICAL IMPLICATIONS: The findings may help clinical staff manage adolescents' severe emotional distress and psychosocial maladaptation.

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.

Application of Drug Testing Platforms in Circulating Tumor Cells and Validation of a Patient-Derived Xenograft Mouse Model in Patient with Primary Intracranial Ependymomas with Extraneural Metastases.

Primary intracranial ependymoma is a challenging tumor to treat despite the availability of multidisciplinary therapeutic modalities, including surgical resection, radiotherapy, and adjuvant chemotherapy. After the completion of initial treatment, when resistant tumor cells recur, salvage therapy needs to be carried out with a more precise strategy. Circulating tumor cells (CTCs) have specifically been detected and validated for patients with primary or recurrent diffused glioma. The CTC drug screening platform can be used to perform a mini-invasive liquid biopsy for potential drug selection. The validation of potential drugs in a patient-derived xenograft (PDX) mouse model based on the same patient can serve as a preclinical testing platform. Here, we present the application of a drug testing model in a six-year-old girl with primary ependymoma on the posterior fossa, type A (EPN-PFA). She suffered from tumor recurrence with intracranial and spinal seeding at 2 years after her first operation and extraneural metastases in the pleura, lung, mediastinum, and distant femoral bone at 4 years after initial treatment. The CTC screening platform results showed that everolimus and entrectinib could be used to decrease CTC viability. The therapeutic efficacy of these two therapeutic agents has also been validated in a PDX mouse model from the same patient, and the results showed that these two therapeutic agents significantly decreased tumor growth. After precise drug screening and the combination of focal radiation on the femoral bone with everolimus chemotherapy, the whole-body bone scan showed significant shrinkage of the metastatic tumor on the right femoral bone. This novel approach can combine liquid biopsy, CTC drug testing platforms, and PDX model validation to achieve precision medicine in rare and challenging tumors with extraneural metastases.

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.

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.

Clinical spectrum and the comorbidities of Dravet syndrome in Taiwan and the possible molecular mechanisms.

Dravet syndrome (DS) is an uncommon epilepsy syndrome that may negatively affect the patients and their caregivers. However, reliable and valid measures of its impact on caregivers and the characteristics of patients with DS in Taiwan are lacking. This study aimed to describe the characteristics of patients with DS and concerns of their caregivers and establish a baseline frequency of disease characteristics using a cross-sectional survey in Taiwan. We assessed the caregivers of patients with DS using an online anonymous questionnaire. The seizure frequency decreased with age, although lacking statistical significance. Vaccines show no influence on the condition of patients with DS. Our findings revealed the highest impact on the domains affecting the caregivers' daily life, including additional household tasks, symptom observation, further medical plan, and financial issues. Caregivers also expressed concerns regarding the lack of independence/constant care, seizure control, speech/communication, and impacts on siblings because of long-term care of the patients in parents' absence. Our findings highlight the significant effects of caring for a child with DS on the lives of their caregivers in Taiwan; these findings will help raise awareness regarding the needs of these families. Furthermore, we discussed the possible pathophysiological mechanisms of associated comorbidities.

Natural history in spinal muscular atrophy Type I in Taiwanese population: A longitudinal study.

INTRODUCTION: Spinal muscular atrophy (SMA) is caused by a defect in the survival motor neuron 1 (SMN1) gene. The Cooperative Study of the natural history of SMA Type I in Taiwan is a retrospective, longitudinal, observational study that helps in further understanding SMA disease progression in patients who have not received disease-modifying therapeutic interventions. METHODS: Case report forms were used to collect demographics; genetic confirmation; SMN2 copy number; treatment patterns; and clinical outcomes including ventilator use, endotracheal tube intubation, tracheostomy, gastrostomy, complications, and survival. RESULTS: A total of 111 patients with SMA Type I were identified over the study period (1979-2015). Mean (median) age of onset and age at confirmed diagnosis were 1.3 (0.8) and 4.9 (4.4) months, respectively. SMN1 deletion/mutation was documented in 70 patients and SMN2 copy number in 32 (2 copies, n = 20; 3 copies, n = 12). At 240 months, survival probability for patients born during 1995-2015 versus 1979-1994 was significantly longer (p = 0.0057). Patients with 3 SMN2 copies showed substantially longer 240-month survival versus patients with 2 SMN2 copies. Over the 36-year period, mean (median) age at death was 31.9 (8.8) months. As of December 2015, 95 patients had died, 13 were alive, and 3 were lost to follow-up. The use of supportive measures (tracheostomy and gastrostomy) was associated with improved survival. CONCLUSIONS: These data describe the short survival of patients with SMA Type I in Taiwan in the pretreatment era, emphasizing the positive impact of supportive measures on survival.

Cranial ultrasonographic screening findings among healthy neonates and their association with neurodevelopmental outcomes.

BACKGROUND: To analyze the findings of cranial ultrasonographic screening in asymptomatic neonates and to assess the association between abnormal results and neurodevelopment. METHODS: We retrospectively reviewed the cranial ultrasonographic screening results of healthy neonates born between 35 and 42 weeks gestation at our hospital from October 2011 to October 2018. RESULTS: In total, 11,681 neonates underwent cranial ultrasonographic screening during the study period, and 9666 (82.7%) had normal results. Of 2015 neonates with abnormal findings, 294 had more than two abnormalities. The most common minor findings were subependymal cysts (8.99%), choroid plexus cysts (2.43%), lenticulostriate vasculopathy (2.34%), frontal horn cysts (1.80%), and enlarged cisterna magna (1.04%). Then, 33 (0.28%) neonates had major abnormalities, including cerebral hemorrhage, periventricular heterotopia, focal cortical dysplasia, anomalies of the corpus callosum, and vascular malformation. Of 1334 neonates who underwent serial clinical evaluations, 76 (5.69%) had neurodevelopmental disorders, including developmental delay, attention-deficit/hyperactivity disorder, and autistic spectrum disorder. CONCLUSION: The incidence rate of intracranial anomalies in healthy neonates was 17.3%, and about 5.69% had neurodevelopmental disorders. Cranial ultrasonographic screening has its own value in helping early detection of intracranial anomalies in healthy neonates, some of which have prognostic implications.

Is the Yale Global Tic Severity Scale a valid tool for parent-reported assessment in the paediatric population? A prospective observational study in Taiwan.

OBJECTIVE: The Yale Global Tic Severity Scale (YGTSS) is the most commonly used clinician-rated evaluation tool for Tourette syndrome (TS), with established reliability and validity. This study aims to determine whether the YGTSS is a valid parent-reported assessment in the TS population. DESIGN: A prospective cohort study. SETTING: A major medical centre in Taiwan. METHODS: A total of 594 patients were enrolled. A revised traditional Chinese version of the YGTSS was made available to parents via Google docs. Parents were encouraged to complete the YGTSS the day before each outpatient clinic visit. At each visit, a paediatric neurology fellow also administered the YGTSS assessment. We investigated whether differences in scores between physicians and parents changed as the number of parent evaluations increased. The results of the physician assessments were also taken as the expert standard for evaluating the sensitivity and specificity of the parent-reported assessments was conducted for the same visit. RESULTS: The differences in the YGTSS scores between participants and physicians were small. The mean difference in the total assessment score was 4.15 points. As the number of times the parent evaluation was performed increased, the difference between the parent and physician scores decreased. Discrimination of moderate-to-severe attacks was good using the parent-assessed YGTSS (area under the receiver operating characteristic curve, 0.858; 95% CI 0.839 to 0.876). The sensitivity for detecting a moderate-to-severe attack by YGTSS parent assessment was 79.7% (95% CI 76.6 to 82.8), and the specificity was 91.8% (95% CI 89.9 to 93.7). CONCLUSION: The parent-reported YGTSS is a promising tool for TS assessment, demonstrating good discriminative ability for disease severity, with user precision increasing with experience.

Therapeutic effects of children with refractory epilepsy after vagus nerve stimulation in Taiwan.

BACKGROUND: Vagus nerve stimulation (VNS) is used as an add-on treatment for epilepsy. This study aimed to use Taiwanese nationwide registry data to analyze the therapeutic effects of VNS in children with refractory epilepsy (RE) and try to explore predictive factors of VNS treatment effectiveness. METHODS: This retrospective study collected data from December 2007 to December 2014. Patient variables included gender, age, VNS implantation date, epilepsy duration, seizure frequency, seizure type, etiology, and antiepileptic drug (AED) history. We divided patients into three groups: Group I as seizure frequency >80 times per month, Group II as seizure frequency 24-80 times per month, and Group III as seizure frequency <24 times per month. Multivariate regression analysis was performed to determine predictors of seizure frequency reduction after VNS treatment. RESULTS: A total of 80 patients were included in this study. Three or more AED types were prescribed for 61 (77.1%) patients. Seizure frequency decreased significantly at 12 and 24 months after VNS treatment. The mean seizure reduction rates were 44.6% and 50.1% at 12 and 24 months after VNS treatment, with the difference between them reaching statistical significance (p = 0.001). In multivariate linear regression, high seizure frequency (Group I) was a positive predictor of seizure frequency reduction (p < 0.001). The most common complication was coughing (eight patients, 10%) and no patient had early withdrawal or premature termination of VNS use due to complications. CONCLUSION: VNS is an effective palliative treatment for children with RE for different seizure types. Seizure reduction rate at 24 months after VNS was better than at 12 months after VNS. High seizure frequency can be regarded as a positive predictor for seizure frequency reduction in children with RE treated with VNS.

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.

Application of Sonography in the Diagnosis and Follow-Up of Trapped Temporal Horn of Lateral Ventricle: Two Case Reports.

Trapped temporal horn of lateral ventricle (TTHLV) is a rare condition of isolated focal hydrocephalus. We report two cases with different presentations, etiologies, and surgical managements. The first case involved an extremely preterm male baby with a history of ventriculitis and intraventricular hemorrhage; he received external ventricle drainage twice due to obstructive hydrocephalus. TTHLV was detected by sonography. He received a ventriculoperitoneal shunt involving two catheters to bypass the adhesion site. There was no ventricular dilatation during 2 years of follow-up. The second case involved a term baby with an enlarged head; brain sonography revealed left focal hydrocephalus with TTHLV and mild midline shift. Neuroendoscopic cystoventriculostomy with fenestration from the left trigone to the frontal horn was performed and serial follow-up brain sonography for 3 months showed decreased ventricle size. The suitable surgical techniques for the management of TTHLV should be adjusted according to the patients' condition to obtain more favorable outcomes. Brain sonography can be a useful tool for the diagnosis and for following up the surgical outcomes in infants with TTHLV.

Effects of preferred music therapy on peer attachment, depression, and salivary cortisol among early adolescents in Taiwan.

AIMS: To explore the effects of preferred music therapy on peer attachment, depression, and salivary cortisol among early adolescents. BACKGROUND: As adolescents enter puberty, they start to seek partnering relationships among peers. Peer attachment is central for adolescents and greatly influences their physical and psychological development. DESIGN: A pre-test-posttest control group design. METHODS: The data were collected from July - October 2016. A total of 65 individuals were included. The treatment group received 40 min of music therapy twice per week over the course of 10 weeks. The control group maintained its typical routine. The research data were collected using structured questionnaires, including basic information, the Inventory of Peer Attachment, the Beck Depression Inventory-II questionnaires, and salivary cortisol concentrations. Statistical analysis methods included percentages, chi-square tests, t tests, analyses of covariance, and the Johnson-Neyman technique. RESULTS: There were statistically significant differences in peer attachment, depression, and salivary cortisol levels in the music group compared to the control group (p < 0.05). Additionally, the findings showed that early adolescents with more severe depression experienced greater improvement through preferred music therapy. CONCLUSION: The results allude to the beneficial effects of receiving preferred music therapy in terms of the peer attachment, depression, and salivary cortisol levels of early adolescents. Adjustments should be made based on the characteristics of student groups to develop suitable and safe music therapy and to reduce the risks of poor mental health.

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.

Posterior Fossa Hemorrhage in a Term Neonate with Hemophilia A.

Posterior fossa hemorrhage is rare in term baby and difficult to assess. The clinical signs are nonspecific and usually delay the diagnosis. We present a 5-day-old male neonate of posterior fossa hemorrhage with the initial presentations of fever and seizure and early deduced by cranial ultrasonography findings as hyperechoic, asymmetric, ill-defined density and complicated with hydrocephalus. Magnetic resonance imaging of the head verified the diagnosis. Hemophilia A was confirmed thereafter by serology.