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.
A ...retrospective study was carried out on paediatric patients diagnosed with anti-NMDAR encephalitis in Hong Kong from January 2009 to December 2015.
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).
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.
With the rapid advancement of medical technologies in genomic and molecular medicine, the number of treatable neurometabolic diseases is quickly expanding. Spastic paraplegia 56 (SPG56), one of the ...severe autosomal recessive forms of neurodegenerative disorders caused by pathogenic variants in the CYP2U1 gene, has no reported specific targeted treatment yet. Here we report 2 Chinese brothers with CYP2U1 bi-allelic pathogenic variants with cerebral folate deficiency who were treated for over a decade with folinic acid supplement. Patients have remained stable under therapy.
Epileptic Encephalopathy (EE) is a heterogeneous condition in which cognitive, sensory and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures ...and/or major interictal paroxysmal activity. There are various causes of EE and they may occur at any age in early childhood. Genetic mutations have been identified to contribute to an increasing number of children with early onset EE which had been previously considered as cryptogenic. We identified 26 patients with Infantile Epileptic Encephalopathy (IEE) of unknown etiology despite extensive workup and without any specific epilepsy syndromic phenotypes. We performed genetic analysis on a panel of 7 genes (ARX, CDKL5, KCNQ2, PCDH19, SCN1A, SCN2A, STXBP1) and identified 10 point mutations ARX (1), CDKL5 (3), KCNQ2 (2), PCDH19 (1), SCN1A (1), STXBP1 (2) as well as one microdeletion involving both SCN1A and SCN2A. The high rate (42%) of mutations suggested that genetic testing of this IEE panel of genes is recommended for cryptogenic IEE with no etiology identified. These 7 genes are associated with channelopathies or synaptic transmission and we recommend early genetic testing if possible to guide the treatment strategy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dravet syndrome is a severe form of epilepsy. Majority of patients have a mutation in SCN1A gene, which encodes a voltage-gated sodium channel. A recent study has demonstrated that 16% of ...SCN1A-negative patients have a mutation in PCDH19, the gene encoding protocadherin-19. Mutations in other genes account for only a very small proportion of families. TSPYL4 is a novel candidate gene within the locus 6q16.3-q22.31 identified by linkage study.
The present study examined the mutations in epileptic Chinese children with emphasis on Dravet syndrome.
A hundred children with severe epilepsy were divided into Dravet syndrome and non-Dravet syndrome groups and screened for SCN1A mutations by direct sequencing. SCN1A-negative Dravet syndrome patients and patients with phenotypes resembling Dravet syndrome were checked for PCDH19 and TSPYL4 mutations.
Eighteen patients (9 males, 9 females) were diagnosed to have Dravet syndrome. Among them, 83% (15/18) had SCN1A mutations including truncating (7), splice site (2) and missense mutations (6). The truncating/splice site mutations were associated with moderate to severe degree of intellectual disability (p<0.05). During the progression of disease, 73% (11/15) had features fitting into the diagnostic criteria of autism spectrum disorder and 53% (8/15) had history of vaccination-induced seizures. A novel PCDH19 p.D377N mutation was identified in one SCN1A-negative female patient with Dravet syndrome and a known PCDH19 p.N340S mutation in a female non-Dravet syndrome patient. The former also inherited a TSPYL4 p.G60R variant.
A high percentage of SCN1A mutations was identified in our Chinese cohort of Dravet syndrome patients but none in the rest of patients. We demonstrated that truncating/splice site mutations were linked to moderate to severe intellectual disability in these patients. A de novo PCDH19 missense mutation together with an inherited TSPYL4 missense variant were identified in a patient with Dravet syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
Dravet syndrome (DS) is a severe and intractable form of epilepsy with prolonged seizures which may evolve to other seizure types and associated with mild‐to‐severe intellectual ...disabilities. Fibroblast growth factor 21 (FGF‐21) is a stress hormone mediating metabolic and oxidative stress and circulating level of FGF‐21 had been shown to increase in some patients with impairment of oxidative phosphorylation in muscles. In DS, FGF‐21 is of interest for further study as mitochondrial oxidative stress was identified previously in patients.
Methods
Plasma FGF‐21 levels were compared between 22 DS patients and 22 normal controls, and their clinical characteristics of DS patients at the time of plasma sampling were studied retrospectively. Besides, the relationships of FGF‐21 level with intellectual development, seizure frequency, valproate treatment, and types of SCN1A mutations were analyzed. Logarithmic transformation of FGF‐21 levels was performed before comparison and statistical analysis.
Results
Mean of log10 FGF‐21 level was significantly higher in DS patients when comparing with normal controls (P = .0042). Mean of log10 FGF‐21 level was significantly higher in DS patients with normal‐to‐mild ID versus mild‐to‐severe ID (P = .0193) and with valproate treatment versus without valproate treatment (P = .015). No significant difference was shown in FGF‐21 level in DS patients with missense versus truncating SCN1A variants, and no correlation could be demonstrated between seizure frequency and FGF‐21 level.
Significance
Significantly higher level of plasma FGF‐21 was identified in DS patients. The high FGF‐21 levels were shown to be associated with developmental outcome and valproate treatment. These results support further investigation on the relationship of FGF‐21 with the clinical outcomes of DS and other related mechanism which is important for possible therapeutic development for this epileptic encephalopathy.
Abstract A Chinese boy presented at 18 months with intractable epilepsy, developmental delay and autistic features. He had multiple seizure types, including absence, myoclonic seizures, limb spasm ...and tonic seizures. His seizures were finally controlled at 3 years of age with clonazepam and a short course of chloral hydrate incidentally given for his insomnia. Subsequently, he had improvement in his communication skills. Result: A novel hemizygous missense variant (c.1649G>A; p.R550Q) in exon 12 of CDKL5 gene was detected for him, his asymptomatic mother and elder sister. His phenotype is less severe than other male cases. Conclusion: We recommend screening CDKL5 for boys with pharmarco-resistant epilepsy and a trial of benzodiazepines for Infantile Epileptic Encephalopathy (IEE).
Pediatric myasthenia gravis (P‐MG) is an autoimmune disease affecting the neuromuscular junction (NMJ), and is rare in children. The roadmap of the research carried out for P‐MG in Hong Kong over the ...past 30 years was reviewed. Currently, there is a lack of epidemiological studies in comparing clinical data or the outcome for people of different ethnic origins. P‐MG is more common in Asians, especially Chinese and Japanese. Because of the lack of comparison studies for P‐MG worldwide, the author initiated collaboration with international colleagues in 2008, and set up “The International Paediatric Myasthenia Gravis Registry Focus Group (FG)” in 2009. We then established an “International Pediatric Myasthenia Gravis Registry (IPMGR)” to review the current knowledge of P‐MG in children. We designed an e‐MG questionnaire for “Myasthenia Syndromes in Children,” and launched through the website (ICNAPaedia) of the International Child Neurology Association (ICNA) in 2009–2010. As of 2014, we had collected 121 replies from clinicians–researchers in 43 countries. In 2013, we started a Delphi process for obtaining a consensus for diagnosis, management and treatment of P‐MG. Despite the lack of research funding support as a result of the rarity of P‐MG, and the lack of innovative pharmaceutical research and development, we still stress that we set up a foundation as a small step towards consolidating international collaboration to carry out epidemiological studies, genetic studies and randomized controlled trials of all the current available treatments, especially steroids for ocular P‐MG, and indications for thymectomy.
Epileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the ...most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE).
We have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work-up, were negative. Using NGS, we distinguished a panel of 430 epilepsy-associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as "pathogenic," "likely pathogenic" and "uncertain significance," according to the American College of Medical Genetics (ACMG) guidelines.
Pathogenic or likely pathogenic variants were identified in six genes (
1,
2
2
1
1
2) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in
and
in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases.
The diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early-onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in
and
.
Abstract Background Dravet syndrome (DS) is a rare epileptic encephalopathy characterized by treatment resistant polymorphic seizures. Seizures onset usually occurs in the first year of life and are ...often associated with heat related triggering factors (e.g. fever, photosensitivity or hot bath). It is previously reported that children with DS often present with recurrent febrile seizures and vaccination-related seizures. Methods In the present study, we retrospectively studied the occurrence of vaccination-related seizures (defined as the development of a seizure within 48 hours post vaccination) in 54 patients with Dravet syndrome. Patients were divided into two groups according to whether seizures occurred within 48 hours of vaccination (ie vaccination-proximate group) or not (vaccination-distant group). Results There was no significance difference in the vaccination-proximate group and vaccination-distant group for the presence of SCN1A mutation. In our DS cohort, the vaccination-proximate group consisted of 17 (31.5%) DS patients. Thus, vaccination-related seizures are a common triggering factor in DS, reported in up to one-third of our patients. Conclusion As vaccination-related seizures may act as the triggering factor for the onset of seizures in DS patients; especially before the definitive diagnosis of DS can be made within the first year of life. We, therefore, suggest that guidelines and protocols for the prevention and management of vaccination-related seizures in children with recurrent febrile seizures pending a definitive diagnosis of DS in the first 12 months of life should be further studied.
Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be ...challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD.
DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature.
Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of
(arrGRCh37 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases.
The
duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings.
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