Focal cerebral arteriopathy-inflammatory type in a child - MR diagnosis using vessel wall imaging technique with review of classification and diagnostic evaluation criteria.

Acute ischemic stroke (AIS) in childhood is defined by a stroke occurring after 28 days of life to 18 years of age. This presents a distinct clinical challenge in terms of both diagnosis and treatment. The overlapping clinical presentations of acute ischemic stroke and its mimics such as migraine with aura, seizure with Todd paresis and encephalitis renders early accurate diagnosis of this time-sensitive condition difficult, with a change in the final diagnosis in up to 40% of patients. Identification of the etiology after establishing the diagnosis of ischemic stroke is paramount for prognostication and treatment decisions. These include cardioembolic, arteriopathy, thrombophilia and inflammatory causes. Magnetic resonance imaging (MRI) plays an indispensable role towards tackling the initial diagnostic dilemma and subsequent evaluation of the underlying etiology, particularly in patients with arteriopathy. Here we present the MRI findings including vessel wall imaging with longitudinal follow-up, which support the diagnosis of focal cerebral arteriopathy-inflammatory type (FCAi) in a pediatric patient.

Expansion of the clinical and molecular spectrum of WWOX-related epileptic encephalopathy.

WWOX biallelic loss-of-function pathogenic single nucleotide variants (SNVs) and copy number variants (CNVs) including exonic deletions and duplications cause WWOX-related epileptic encephalopathy (WOREE) syndrome. This disorder is characterized by refractory epilepsy, axial hypotonia, peripheral hypertonia, progressive microcephaly, and premature death. Here we report five patients with WWOX biallelic predicted null variants identified by exome sequencing (ES), genome sequencing (GS), and/or chromosomal microarray analysis (CMA). SNVs and intragenic deletions of one or more exons were commonly reported in WOREE syndrome patients which made the genetic diagnosis challenging and required a combination of different diagnostic technologies. These patients presented with severe, developmental and epileptic encephalopathy (DEE), and other cardinal features consistent with WOREE syndrome. This report expands the clinical phenotype associated with this condition, including failure to thrive in most patients and epilepsy that responded to a ketogenic diet in three patients. Dysmorphic features and abnormal prenatal findings were not commonly observed. Additionally, recurrent pancreatitis and sensorineural hearing loss each were observed in single patients. In summary, these phenotypic features broaden the clinical spectrum of WOREE syndrome.

Deep brain stimulation in a young child with GNAO1 mutation - Feasible and helpful.

Background: GNAO1 is an emerging disorder characterized with hypotonia, developmental delay, epilepsy, and movement disorder, which can be potentially life threatening during acute exacerbation. In the USA, deep brain stimulation (DBS) has been licensed for treating children with chronic, treatment-resistant primary dystonia, who are 7 years old or older. Case Description: A 4-year-old girl diagnosed to have GNAO1-related dyskinesia and severe global developmental delay. She had severe dyskinesia precipitated by intercurrent infection, requiring prolonged intensive care for heavy sedation and related complications. Her dyskinesia improved dramatically after DBS implantation. Technical difficulties and precautions of DBS in preschool children were discussed. Conclusion: DBS should be considered early in the treatment of drug-resistant movement disorders in young children with GNAO1, especially after dyskinetic crisis, as they tend to recur. Presurgical counseling to parents and close monitoring of complications is also important in the process.

Guillain-Barré syndrome in children - High occurrence of Miller Fisher syndrome in East Asian region.

BACKGROUND: Guillain-Barré syndrome (GBS) is a rare acquired immune-mediated polyneuropathy. Updated population-based data concerning paediatric GBS is needed. METHODS: Paediatric patients aged below 18 years diagnosed with GBS between 2009 and 2018 in all 11 paediatric departments in Hong Kong were identified from the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System. The collected data from medical health records were reviewed by paediatric neurologist from each department. Estimated incidence of paediatric GBS was calculated. We also compared our findings with other paediatric GBS studies in Asia. RESULTS: 63 subjects of paediatric GBS were identified, giving an estimated annual incidence of 0.62 per 100,000 population. Half of the subjects had acute inflammatory demyelinating polyneuropathy (AIDP) (n = 31; 49.2%), one quarter had Miller Fisher Syndrome (MFS) (n = 16; 25.4%), one-fifth had axonal types of GBS (n = 12; 19.0%), and four were unclassified. Paediatric subjects with axonal subtypes of GBS compared to the other 2 subtypes, had significantly higher intensive care unit (ICU) admission rates (p = 0.001) and longest length of stay (p = 0.009). With immunomodulating therapy, complete recovery was highest in those with MFS (100%), followed by AIDP (87.1%) and axonal GBS (75%). Our study also confirms a higher MFS rate for paediatric GBS in East Asia region and our study has the highest MFS rate (25.4%). CONCLUSION: Our population-based 10-year paediatric GBS study provides updated evidence on estimated incidence, healthcare burden and motor outcome of each subtype of paediatric GBS and confirmed a higher occurrence of paediatric MFS in East Asia.

Improving Consistency and Accuracy of Neonatal Amplitude-Integrated Electroencephalography.

OBJECTIVE: This study aimed to improve the utilization of amplitude-integrated electroencephalography (aEEG) in a neonatal unit by improving aEEG documentation, aEEG knowledge, and pattern recognition ability of neonatal staff. METHODS: A quality improvement (QI) program comprising the two Plan-Do-Study-Act (PDSA) cycles was conducted in a level-3 neonatal intensive care unit. The first cycle was focused on improving aEEG documentation with the primary outcome indicator being compliance with aEEG documentation. The second cycle was focused on aEEG interpretation in a health care professional education program with the outcome indicators being accuracy of seizure identification on aEEG and change in conventional EEGs (cEEG) performed. Other outcome indicators included accuracy in identification of background pattern, sleep-wake cycles and artifacts. Process indicators included improvement in aEEG-related knowledge. RESULTS: First PDSA cycle includes lectures on aEEG interpretation, a bedside key, and documentation form. Second PDSA cycle includes online aEEG education pack and detailed aEEG guideline. There was a significant improvement in aEEG documentation after the implementation of both PDSA cycles. Seven of the 46 patients (15.2%) had isolated electrographic seizures which would not have been identified in the pre-aEEG monitoring era. There was an increase in the number of patients with cEEGs done but a steady decrease in number of cEEGs per patient. CONCLUSION: With the successful application of standardized QI methods, improvements in outcome indicators, such as correct aEEG pattern recognition and improved coverage of at risk infants with cEEGs, were observed. Our QI measures were associated with improvement in aEEG pattern recognition. KEY POINTS: · Consistent and accurate use of aEEG is challenging.. · Standardized forms and guidelines improve aEEG interpretation consistency and documentation.. · Interactive self-paced online education packs can improve aEEG knowledge and pattern recognition..

TPI1-reduced extracellular vesicles mediated by Rab20 downregulation promotes aerobic glycolysis to drive hepatocarcinogenesis.

Rab GTPases are major mediators that ensure the proper spatiotemporal regulation of intracellular trafficking. Functional impairment and altered expression of Rab proteins have been revealed in various human cancers. There is an emerging evidence about the role of Rab proteins in the biogenesis of extracellular vesicles (EVs). In hepatocellular carcinoma (HCC), using RNA sequencing comparing expression profiles of adjacent non-tumorous tissues and HCC, Rab20 is identified to be the most frequently downregulated Rab member in HCC. Functionally, restoration of Rab20 in metastatic HCC cells results in the release of EVs with a diminished activity to promote cell growth, motility and metastasis. Conversely, EVs released from normal liver cells with Rab20 knockdown loses suppressive effect on HCC cell growth and motility. Proteomic profiling revealed the level of triosephosphate isomerase 1 (TPI1), a glycolytic enzyme, in EVs to be positively associated with Rab20 expression of the releasing cells. TPI1 targeted to be expressed in EVs released by Rab20 knockdown cells compromises the oncogenic activity of EVs. Besides, EVs released by TPI1 knockdown cells recapitulates the promoting effect of EVs derived from HCC cells with Rab20 underexpression. Aerobic glycolysis is beneficial to the survival and proliferation of tumour cells. Here, we observed that the enhanced cell growth and motility are driven by the enhanced aerobic glycolysis induced by EVs with reduced TPI1. The addition of glycolytic inhibitor blocks the promoting effect of EVs with reduced TPI1. Taken together, our study provides a mechanistic link among tumour cell-derived EVs and glucose metabolism in HCC with Rab20 deregulation.

Exome sequencing in paediatric patients with movement disorders.

BACKGROUND: Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. RESULTS: We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. CONCLUSIONS: A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.

OBJECTIVE: To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants. METHODS: A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed. RESULTS: Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified. CONCLUSIONS: This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.

Anti-N-methyl-d-aspartate receptor encephalitis in children: Incidence and experience in Hong Kong.

AIM: The study aims to analyze the incidence, clinical features, investigation findings and treatment outcomes of anti-N-methyl-d-aspartate receptor encephalitis in children from Hong Kong. METHOD: A retrospective study was carried out on paediatric patients diagnosed with anti-NMDAR encephalitis in Hong Kong from January 2009 to December 2015. RESULTS: Fifteen patients (67% female, 93% Chinese) were identified over seven years and the estimated incidence in Hong Kong was 2.2/million children per year (95% CI 1.2-3.6). The median age of presentation was 12 years (range 1-17 years). The most common symptom groups observed were abnormal psychiatric behavior or cognitive dysfunction (14/15, 93%) and seizures (14/15, 93%), followed by speech dysfunction (13/15, 87%), movement disorders (12/15, 80%), decreased level of consciousness (10/15, 67%) and autonomic dysfunction or central hypoventilation (5/15, 33%). The median number of symptom groups developed in each patient was 5 (range 3-6). All patients were treated with intravenous immunoglobulin and/or steroids. Three patients (20%) with more severe presentation required additional plasmapheresis and rituximab. Outcome was assessable in 14 patients. Among those eleven patients who had only received intravenous immunoglobulin and/or steroids, nine patients (82%) achieved full recovery. One patient (9%) had residual behavioral problem, while another one (9%) who developed anti-NMDAR encephalitis after herpes simplex virus encephalitis was complicated with dyskinetic cerebral palsy and epilepsy. Among those three patients who required plasmapheresis and rituximab, one (33%) had full recovery and two (66%) had substantial recovery. The median duration of follow up was 20.5 months (range 3-84 months). CONCLUSION: Anti-NMDAR encephalitis is an acquired, severe, but potentially treatable disorder. Ethnicity may play a role in the incidence of anti-NMDAR encephalitis and we have provided a local incidence with the majority of patients being Chinese. The diagnosis of anti-NMDAR encephalitis should be considered in children presenting with a constellation of symptoms including psychiatric and neurological manifestations. Patients may respond to first line immunotherapy. For those who do not, second line therapy is indicated in order to achieve a better outcome.

Traceless and Chemoselective Amine Bioconjugation via Phthalimidine Formation in Native Protein Modification.

ortho-Phthalaldehyde (OPA) and its derivatives are found to react chemoselectively with amino groups on peptides and proteins rapidly and tracelessly under the physiological condition via formation of phthalimidines, which provides a novel and promising approach when performing bioconjugation on native proteins. The notable advantages of this method over the existing native protein lysine-labeling approaches include a traceless process, a self-reacting, specific and fast reaction, ease of operation, and the ability to use nonhydrolyzable reagents. Its applications have been effectively demonstrated including conjugation of peptides and proteins, and generation of an active PEGlyated l-asparaginase.

14-3-3σ confers cisplatin resistance in esophageal squamous cell carcinoma cells via regulating DNA repair molecules.

Esophageal squamous cell carcinoma (ESCC) is the predominant type of esophageal cancer in Asia. Cisplatin is commonly used in chemoradiation for unresectable ESCC patients. However, the treatment efficacy is diminished in patients with established cisplatin resistance. To understand the mechanism leading to the development of cisplatin resistance in ESCC, we compared the proteomes from a cisplatin-resistant HKESC-2R cell line with its parental-sensitive counterpart HKESC-2 to identify key molecule involved in this process. Mass spectrometry analysis detected 14-3-3σ as the most abundant molecule expressed exclusively in HKESC-2R cells, while western blot result further validated it to be highly expressed in HKESC-2R cells when compared to HKESC-2 cells. Ectopic expression of 14-3-3σ increased cisplatin resistance in HKESC-2 cells, while its suppression sensitized SLMT-1 cells to cisplatin. Among the molecules involved in drug detoxification, drug transportation, and DNA repair, the examined DNA repair molecules HMGB1 and XPA were found to be highly expressed in HKESC-2R cells with high 14-3-3σ expression. Subsequent manipulation of 14-3-3σ by both overexpression and knockdown approaches concurrently altered the expression of HMGB1 and XPA. 14-3-3σ, HMGB1, and XPA were preferentially expressed in cisplatin-resistant SLMT-1 cells when compared to those more sensitive to cisplatin. In ESCC patients with poor response to cisplatin-based chemoradiation, their pre-treatment tumors expressed higher expression of HMGB1 than those with response to such treatment. In summary, our results demonstrate that 14-3-3σ induces cisplatin resistance in ESCC cells and that 14-3-3σ-mediated cisplatin resistance involves DNA repair molecules HMGB1 and XPA. Results from this study provide evidences for further work in researching the potential use of 14-3-3σ and DNA repair molecules HMGB1 and XPA as biomarkers and therapeutic targets for ESCC.

Response of levetiracetam in neonatal seizures.

AIM: To review the clinical response to levetiracetam (LEV) in neonatal seizure management in intensive care unit. METHODS: Medical records of neonates who received LEV from January 2009 to August 2014 were reviewed. Their demographic data, clinical characteristics, etiology, seizures, electroencephalograms, response to treatment and outcome were noted. Literature review of use of LEV in neonates were also performed via PubMed and EMBASE with keywords - "neonates", "seizures", "epilepsy" and "LEV" up to Sep 2014 and retrieved the publications. The response rate to LEV was compared. RESULTS: Twelve neonates were identified during the study period. All patients received phenobarbitone loading prior to consideration of LEV. Seven (58%) and nine (75%) achieved seizure freedom 24 h and 72 h after LEV was added, both clinically and electrographically. No serious adverse effects were associated with LEV use. From the literature, there are total 144 neonates reported to have used LEV. The overall results suggested that LEV could control up to 90% of neonatal seizures. CONCLUSION: LEV was found to be relatively safe and efficacious in treating neonatal seizures, but might not work well in the most severe hypoxic ischemic encephalopathy.

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.

Dysregulation of clathrin promotes thyroid cell growth and contributes to multinodular goiter pathogenesis.

A germline mutation (A339V) in thyroid transcription factor-1 (TITF1/NKX2.1) was shown to be associated with multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) pathogenesis. The overexpression of A339V TTF1 significantly promoted hormone-independent growth of the normal thyroid cells, representing a cause of MNG and/or PTC. Nevertheless, the underlying mechanism still remains unclear. In this study, we used liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based shotgun proteomics comparing the global protein expression profiles of normal thyroid cells (PCCL3) that overexpressed the wild-type or A339V TTF1 to identify key proteins implicated in this process. Proteomic pathway analysis revealed that the aberrant activation of epidermal growth factor (EGF) signaling is significantly associated with the overexpression of A339V TTF1 in PCCL3, and clathrin heavy chain (Chc) is the most significantly up-regulated protein of the pathway. Intriguingly, dysregulated Chc expression facilitated a nuclear accumulation of pStat3, leading to an enhanced cell proliferation of the A339V clones. Down-regulation and abrogation of Chc-mediated cellular trafficking, respectively, by knocking-down Chc and ectopic expression of a dominant-negative (DN) form of Chc could significantly reduce the nuclear pStat3 and rescue the aberrant cell proliferation of the A339V clones. Subsequent expression analysis further revealed that CHC and pSTAT3 are co-overexpressed in 66.7% (10/15) MNG. Taken together, our results suggest that the A339V TTF1 mutant protein up-regulates the cellular expression of Chc, resulting in a constitutive activation of Stat3 pathway, and prompting the aberrant growth of thyroid cells. This extensive growth signal may promote the development of MNG.

Prevalence and Characteristics of Chinese Patients With Duchenne and Becker Muscular Dystrophy: A Territory Wide Collaborative Study in Hong Kong.

The aim of this collaborative study on Duchenne muscular dystrophy and Becker muscular dystrophy is to determine the prevalence and to develop data on such patients as a prelude to the development of registry in Hong Kong. Information on clinical and molecular findings, and patient care, was systematically collected in 2011 and 2012 from all Pediatric Neurology Units in Hong Kong. Ninety patients with dystrophinopathy were identified, and 83% has Duchenne muscular dystrophy. The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per 10 000 males aged 0 to 24 years. Among the Duchenne group, we observed a higher percentage (40.6%) of point mutations with a lower percentage (45.3%) of exon deletions in our patients when compared with overseas studies. Although we observed similar percentage of Duchenne group received scoliosis surgery, ventilation support, and cardiac treatment when compared with other countries, the percentage (25%) of steroid use is lower.

Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations.

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.

Growth charts for Chinese Down syndrome children from birth to 14 years.

OBJECTIVE: To establish Down syndrome (DS)-specific growth charts for Hong Kong Chinese children. DESIGN AND SETTING: Growth data were collected from (1) members of the Hong Kong Down Syndrome Association (cross-sectional); (2) DS children attending special schools or living in residential homes (cross-sectional); and (3) the paediatric departments of seven public hospitals (retrospective). PATIENTS: 425 DS children (57% males and 43% females) born in 1977-2000, yielding 4987 observations. MAIN OUTCOME MEASURES: The LMS method was used to construct reference centile curves of weight, height, body mass index (BMI) from birth until 14 years and head circumference for the first 4 years. RESULTS: The median birth length was 49.8 cm and height at age 14 was 146.7 cm for DS boys. Corresponding figures for DS girls were 49.5 and 142.1 cm. The median birth weight was 3.0 kg for DS boys and 2.9 kg for DS girls. At age 14, 26% DS boys (BMI >22.6 kg/m(2)) and 12% DS girls (BMI >23.3 kg/m(2)) were overweight. The median head circumference at birth was 32.8 cm for boys and 32.0 cm for girls. CONCLUSIONS: Chinese DS children had a shorter stature, lower weight and tendency to be overweight than local non-DS children. Their growth patterns differed from those of Chinese DS children in Taiwan, and DS children in the USA and Sweden. Growth retardation was most salient during the first year of life.

Early consideration of anti-NMDAR encephalitis in unexplained encephalopathy.

With the identification of anti-NMDAR (N-methyl-D-aspartate receptor) antibody, the spectrum of anti-NMDAR encephalitis has been expanding. The condition is also increasingly recognised in children, though younger patients are less likely to have tumours, while behavioural and speech problems, seizures, and abnormal movements are common early presenting features. Here we present yet another case with subtle, non-specific clinical symptoms that responded promptly to intravenous immunoglobulin. We believe this illustrates the importance of considering this uncommon differential diagnosis in the management of unexplained neurological conditions.