Cerebellar atrophy in genetic epileptic encephalopathies: A cohort study and a systematic review.

OBJECTIVE: To analyze cerebellar atrophy in genetic epileptic encephalopathies (EEs). METHODS: This research included a retrospective cohort study conducted from January 2016 to December 2023 and a systematic review on cerebellar atrophy in genetic EEs. Pediatric individuals who were diagnosed with EEs based on electroclinical features, carried causative gene variants, and exhibited cerebellar atrophy were recruited. Electroclinical features, neuroimaging findings, and causative variants of eligible individuals were analyzed. RESULTS: The cohort study showed 10 of 67 pediatric individuals (10/67; 15 %) who were diagnosed with genetic EEs had cerebellar atrophy; and 6 of the 10 individuals (6/10; 60 %) exhibited cerebellar signs. Diagnostic delay between the detection of cerebellar atrophy and the identification of genetic diagnosis existed in 6 individuals (6/10; 60 %) and the median duration was 4.4 years. A total of 32 genes, including 31 genes from the literature review and a newly identified SCN2A gene in this cohort, were reported associated with cerebellar atrophy in genetic EEs. Twenty-six genes (26/32; 81 %) accounted for cerebellar atrophy associated with other brain anomalies and 6 genes (6/32; 19 %) caused isolated cerebellar atrophy. Twenty-five genes (25/32; 78 %) showed late-onset cerebellar atrophy identified after the age of 1 year old. CONCLUSION: Cerebellar atrophy is not uncommon in genetic EEs and may serve as an indicator for molecular diagnosis in clinical practice. To shorten the diagnostic delay, follow-up neuroimaging study is crucial because of high rate of clinico-radiological dissociation and late-onset cerebellar atrophy in this patient group.

Resolving unsolved whole-genome sequencing data in paediatric neurological disorders: a cohort study.

OBJECTIVE: To resolve unsolved whole-genome sequencing (WGS) data in individuals with paediatric neurological disorders. DESIGN: A cohort study method using updated bioinformatic tools, new analysis targets, clinical information and literature databases was employed to reanalyse existing unsolved genome data. PARTICIPANTS: From January 2016 to September 2023, a total of 615 individuals who aged under 18 years old, exhibited neurological disorders and received singleton WGS were recruited. 364 cases were unsolved during initial WGS analysis, in which 102 consented to reanalyse existing singleton WGS data. RESULTS: Median duration for reanalysis after initial negative WGS results was 2 years and 4 months. The diagnostic yield was 29 of 102 individuals (28.4%) through reanalysis. New disease gene discovery and new target acquisitions contributed to 13 of 29 solved cases (44.8%). The reasons of non-detected causative variants during initial WGS analysis were variant reclassification in 9 individuals (31%), analytical issue in 9 (31%), new emerging disease-gene association in 8 (27.6%) and clinical update in 3 (10.3%). The 29 new diagnoses increased the cumulative diagnostic yield of clinical WGS in the entire study cohort to 45.5% after reanalysis. CONCLUSIONS: Unsolved paediatric WGS individuals with neurological disorders could obtain molecular diagnoses through reanalysis within a timeframe of 2-2.5 years. New disease gene, structural variations and deep intronic splice variants make a significant contribution to diagnostic yield. This approach can provide precise genetic counselling to positive reanalysis results and end a diagnostic odyssey.

Long-Term Outcome of Pediatric Patients with Anti-NMDA Receptor Encephalitis in a Single Center.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is the most common autoimmune encephalitis in children. There is a high probability of recovery if treated promptly. We aimed to analyze the clinical features and long-term outcomes of pediatric patients with anti-NMDA receptor encephalitis. METHOD: We conducted a retrospective study with definite diagnoses of anti-NMDA receptor encephalitis in 11 children treated in a tertiary referral center between March 2012 and March 2022. Clinical features, ancillary tests, treatment, and outcomes were reviewed. RESULTS: The median age at disease onset was 7.9 years. There were eight females (72.7%) and three males (27.3%). Three (27.3%) patients initially presented with focal and/or generalized seizures and eight (72.7%) with behavioral change. Seven patients (63.6%) revealed normal brain MRI scans. Seven (63.6%) had abnormal EEG results. Ten patients (90.1%) received intravenous immunoglobulin, corticosteroid, and/or plasmapheresis. After a median follow-up duration of 3.5 years, one patient was lost to follow-up at the acute stage, nine (90%) had an mRS ≤ 2, and only one had an mRS of 3. CONCLUSIONS: With the early recognition of anti-NMDA receptor encephalitis based on its clinical features and ancillary tests, we were able to treat patients promptly with first-line treatment and achieve favorable neurological outcomes.

Biallelic SHQ1 variants in early infantile hypotonia and paroxysmal dystonia as the leading manifestation.

Biallelic SHQ1 variant-related neurodevelopmental disorder is extremely rare. To date, only six affected individuals, from four families, have been reported. Here, we report eight individuals, from seven unrelated families, who exhibited neurodevelopmental disorder and/or dystonia, received whole-genome sequencing, and had inherited biallelic SHQ1 variants. The median age at disease onset was 3.5 months old. All eight individuals exhibited normal eye contact, profound hypotonia, paroxysmal dystonia, and brisk deep tendon reflexes at the first visit. Varying degrees of autonomic dysfunction were observed. One individual had cerebellar atrophy at the initial neuroimaging study, however, three individuals showed cerebellar atrophy at follow-up. Seven individuals who underwent cerebral spinal fluid analysis all had a low level of homovanillic acid in neurotransmitter metabolites. Four individuals who received 99mTc-TRODAT-1 scan had moderate to severe decreased uptake of dopamine in the striatum. Four novel SHQ1 variants in 16 alleles were identified: 9 alleles (56%) were c.997C > G (p.L333V); 4 (25%) were c.195T > A (p.Y65X); 2 (13%) were c.812T > A (p.V271E); and 1 (6%) was c.146T > C (p.L49S). The four novel SHQ1 variants transfected into human SH-SY5Y neuronal cells resulted in a retardation in neuronal migration, suggestive of SHQ1 variant correlated with neurodevelopmental disorders. During the follow-up period, five individuals still exhibited hypotonia and paroxysmal dystonia; two showed dystonia; and one had hypotonia only. The complex interactions among movement disorders, dopaminergic pathways, and the neuroanatomic circuit needs further study to clarify the roles of the SHQ1 gene and protein in neurodevelopment.

Clinico-Radiological Phenotype of UBTF c.628G>A Pathogenic Variant-Related Neurodegeneration in Childhood: A Case Report and Literature Review

Background: This work aims to describe the clinico-radiological phenotype of UBTF c.628G>A (p.Glu210Lys) pathogenic variant-related neurodegeneration in childhood. Methods: We describe the progress of clinical and neuroimaging features in a male individual who had childhood-onset neuroregression and carried the heterozygous UBTF c.628G>A (p.Glu210Lys) pathogenic variant. Clinical cases reported in the literature are reviewed. Results: Fifteen individuals, from 14 reported cases and the index case, were noted. The median age at onset of neurodegeneration was 3 years. Clinical phenotype was consistent among the affected individuals, with progressive motor, speech, cognitive, and social−emotional regression together with ataxia and prominent pyramidal and extrapyramidal symptoms and signs in early to middle childhood. All individuals had the same brain MRI features in terms of symmetric and diffuse T2 high signal intensity over the bilateral subcortical, periventricular, and peritrigonal white matter and progressive cortical and subcortical supratentorial atrophy. Two individuals were reported to have bilateral thalamic involvement. All individuals had profound intellectual disability with loss of verbal and/or ambulatory functions during follow-up. Conclusions: Individuals with the heterozygous UBTF c.628G>A (p.Glu210Lys) pathogenic variant had consistent clinical progress and neuroimaging features. Familiarity with this clinico-radiological phenotype may allow earlier diagnosis of this rare disease.

Intrafamilial phenotypic variability in TBC1D24-TLDc homozygous pathogenic variant-related developmental and epileptic encephalopathy.

OBJECTIVE: To describe intrafamilial phenotypic variability in rare TBC1D24-TLDc homozygous pathogenic variant-related developmental and epileptic encephalopathy (DEE). METHODS: Four individuals from two unrelated families who had been diagnosed with DEE caused by TBC1D24-TLDc homozygous c.1499C>T (p.A500V) pathogenic variant were recruited. RESULTS: The age of seizure onset ranged from 1 to 7 months. All four individuals exhibited very prolonged multifocal myoclonus or focal clonic fits, and the interictal EEGs were prone to dissociation with clinical seizures. The common precipitating factors for seizures were viral infection and fever. Two individuals from family II had progressive cerebellar atrophy: one had ataxia and the other one had no cerebellar signs clinically. All individuals had pharmaco-resistant epilepsy. However, the younger siblings of the two sibling pairs had normal neurodevelopmental outcomes. CONCLUSION: Intrafamilial phenotypic variability of cerebellar neurodegeneration on neuroimages and neurodevelopmental outcomes might be noted in individuals with TBC1D24-TLDc homozygous c.1499C>T (p.A500V) pathogenic variant-related DEE.

Genotype-Phenotype Dissociation in Two Taiwanese Children with Molybdenum Cofactor Deficiency Caused by MOCS2 Mutation.

BACKGROUND: To describe the genotype-phenotype dissociation in two Taiwanese patients with molybdenum cofactor deficiency (MoCoD) caused by MOCS2 gene mutations. PATIENT DESCRIPTION: Patient 1 exhibited early-onset neurological symptoms soon after birth, followed by subsequent myoclonic seizures and movement disorder. The brain magnetic resonance imaging (MRI) showed diffuse brain injury with cystic encephalomalacia along with bilateral globus pallidi involvement, hypoplasia of corpus callosum, and cerebellar atrophy. Patient 2 had a mild phenotype with prominent movement disorder after intercurrent illness, and the brain MRI showed selective injury of the bilateral globus pallidi and the cerebellum. Both patients had markedly low levels of plasma uric acid and harbored the same MOCS2 homozygous c.16C > T mutation. Patient 1 showed chronic regression of developmental milestones and died of respiratory failure at the age of 8 years, whereas patient 2 demonstrated improvement in motor function. CONCLUSION: Genotype-phenotype dissociation could be noted in patients with MoCoD due to MOCS2 mutation. Patients with neonatal seizures, developmental delay, movement disorder, and motor regression after an illness, as well as focal or bilateral involvement of the globus pallidi on the neuroimages, should undergo biochemical testing of plasma uric acid. A pronounced plasma uric acid level is a good indicator of MoCoD. Early diagnosis can allow early provision of adequate genetic counseling.

Frasier Syndrome: A Rare Cause of Refractory Steroid-Resistant Nephrotic Syndrome.

Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental glomerulosclerosis (FSGS) that is resistant to steroid treatment in early childhood. Male patients can have female external genitalia (pseudo-hermaphroditism) at birth and develop gonado-blastoma in their adolescence. Frasier syndrome is caused by mutations in the splice donor site at intron 9 of the Wilms' tumor WT1 gene; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect the development of the urogenital tract, podocyte function, and tumor suppression. Here, we report on a patient with long-term refractory NS who developed a malignant mixed germ cell tumor arising in a gonado-blastoma of the ovary 8 years after the onset of proteinuria.

Diagnostic yield and treatment impact of whole-genome sequencing in paediatric neurological disorders.

AIM: To investigate the diagnostic yield and treatment impact of whole-genome sequencing (WGS) in patients with paediatric neurological disorders. METHOD: From January 2016 to December 2019, paediatric patients who had suspected genetic neurological disorders were assessed using WGS. The phenotypes of eligible patients were divided into four groups: patients with neurodevelopmental disorders; patients with epilepsy; patients with neuromuscular disorders; and patients with movement disorders. RESULTS: A total of 214 consecutive patients (128 males, 86 females) underwent WGS. The mean (SD) age of disease onset was 13.8 (27.6) months (range 1d-15y 5mo). The mean (SD) age at which WGS was performed was 71.7 (58.9) months (range 8d-18y). A molecular diagnosis was reported in 43.9% of patients. The highest diagnostic rate was achieved in 62.5% of patients with neuromuscular disorders, 47.5% of patients with epilepsy, 41.1% of patients with neurodevelopment disorders, and 15.4% of patients with movement disorders. All 94 patients with a WGS diagnosis were given access to genetic counselling and 23.4% of patients had immediate changes in treatment strategies after undergoing WGS. INTERPRETATION: WGS allows paediatric neurologists to integrate genomic data into their diagnosis and adjust management strategies for a range of clinical and genetically heterogeneous disease entities to improve the clinical outcomes of patients. In our cohort, the diagnosis of a significant proportion of patients was reached through WGS (43.9%). Clinicians could use these results to directly guide the management of their patients and improve their clinical outcomes (23.4%). What this paper adds For selected children in our cohort, the diagnostic yield of whole-genome sequencing (WGS) was 43.9%. WGS can be used to expand our knowledge of phenotype-genotype variations.

Electroclinical variability of pyridoxine-dependent epilepsy caused by ALDH7A1 gene mutations in four Taiwanese children.

BACKGROUND: The aim of this study was to describe the electroclinical variability of four Taiwanese patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 gene mutations. METHODS: Demographic data, case histories, clinical seizure patterns, EEG features, neuroimaging findings, ALDH7A1 gene mutations, treatments, and neurodevelopmental outcomes of the four patients were collected and analyzed. RESULTS: The four patients exhibited the first symptom between the ages of 6 days and 11 months. The age of diagnosis was between 2 months and 13 years 8 months. Patient 1 exhibited classical phenotype of PDE, neonatal onset epileptic encephalopathy. Patient 2 showed atypical phenotypes of intractable epilepsy with additional neurological and abdominal symptoms. Patients 3 and 4, who had normal neurodevelopment, had familial epilepsy with fever sensitivity. Patients 2, 3, and 4 had atypical phenotypes and showed seizure exacerbation during febrile infections. EEG features of patient 1 revealed alternating rhythmic discharges followed by electrodecremental episodes; while those of patients 2, 3, and 4 disclosed nonspecific findings or normal results. Administration of oral pyridoxine hydrochloride resulted in seizure cessation in patients 1, 3, and 4, and they achieved normal neurodevelopmental outcomes, but intractable epilepsy and profound mental retardation occurred in patient 2 as he was not diagnosed until he was 13 years and 8 months old. CONCLUSION: Electroclinical features of PDE vary widely, including patients with normal neurodevelopment and normal or nonspecific EEG findings. To avoid delay in treatment, a therapeutic trial with pyridoxine hydrochloride should be performed in all cases of neonatal, infantile, and childhood refractory epilepsy until ALDH7A1 gene mutation-related PDE has been excluded. Pyridoxine treatment may show clinical effectiveness even in a relatively late stage, i.e., age older than one year.

Respiratory presentation of patients infected with enterovirus D68 in Taiwan.

BACKGROUND: Enterovirus-D68 (EV-D68) has been endemic in Taiwan for some years with a small number of positive cases. Detailed information about respiratory presentation is lacking. This study characterized the clinical course in children admitted to the medical center and regional hospital in Taichung during 2015. METHODS: Retrospective chart review of patients with confirmed EV-D68 infection admitted to the medical center and regional hospital in Taichung with respiratory symptoms in the second half of 2015. Past medical history, clinical presentation, management, and course in hospital were collected and analyzed. Simple demographic data and clinical symptoms were also collected from patients confirmed with EV-D68 infection who visited clinics in Taichung. RESULTS: Six children were included. Two patients had a prior history of asthma or recurrent dyspnea, and one had other preexisting medical comorbidities. One child was admitted to the pediatric intensive care unit. All the patients were cured. Cough, rhinorrhea, tachypnea and fever were the most common clinical symptoms among inpatients, while influenza-like illness (ILI) was prevalent in outpatients. CONCLUSION: EV-D68 infection resulted in respiratory presentations of asthma-like illness in the hospitalized pediatric population. Patients with a prior history of asthma or recurrent dyspnea appear to be more severely affected.

Antisense oligonucleotides modulate dopa decarboxylase function in aromatic l-amino acid decarboxylase deficiency.

Aromatic l-amino acid decarboxylase deficiency (AADCD), attributed to mutations in the dopa decarboxylase (DDC) gene, is a rare neurometabolic disease resulting from a defect in the biosynthesis of dopamine and serotonin. The DDC c.714+4A>T mutation is the most prevalent mutation among patients with AADCD, and is also a founder mutation among Taiwanese patients. In this study, the molecular consequences and function of this mutation were examined in AADCD patient-derived lymphoblastoid cells. We identified novel DDC mRNA isoforms spliced with a new exon (exon 6a) in normal and c.714+4A>T lymphoblastoid cells. In addition, we identified the SR proteins (SRSF9 and SRSF6), as well as cis-elements involved in modulating the splicing of this mutated transcript. Notably, we demonstrated that antisense oligonucleotides (ASOs) were able to restore the normal mRNA splicing and increase the level of DDC protein, as well as its downstream product serotonin, in lymphoblastoid cells derived from the patient with AADCD, suggesting that these ASOs might represent a feasible alternative strategy for gene therapy of AADCD in patients with the common c.714+4A>T mutation.

Prenatal brain disruption in isolated sulfite oxidase deficiency.

BACKGROUND: Isolated sulfite oxidase deficiency (ISOD) is a very rare autosomal recessive inherited neurometabolic disease. The most striking postnatal neuroimaging finding is multicystic encephalomalacia, which occurs rapidly within days to weeks after birth and mimics severe hypoxic-ischemic encephalopathy. The aim of this study was to describe the prenatal neuroimaging features in a neonate and a fetus diagnosed with ISOD. RESULTS: We report an 11-day-old female neonate who presented with feeding difficulties, decreased activity, neonatal seizures, and movement disorders within a few days after birth. Brain MRI at 9 days of age showed cystic lesions over the left frontal and temporal areas, diffuse and evident T2 high signal intensity of bilateral cerebral cortex, and increased T2 signal intensity of the globus pallidi. A pronounced low level of plasma cysteine and normal level of plasma uric acid were noted. Mutation analysis of SUOX revealed homozygous c.1200C > G mutations, resulting in an amino acid substitution of tyrosine to a stop codon (Y400X). The diagnosis of ISOD was made. The brain MRI of a prenatally diagnosed ISOD fetus of the second pregnancy of the mother of the index case showed poor gyration and differentiation of cortical layers without formation of cystic lesions at gestational age 21 weeks. CONCLUSION: Cystic brain destruction might occur prenatally and neurodevelopment of gyration and differentiation of the cortical layers in the developing brain could be affected by sulfite accumulation early during the second trimester in ISOD patients. This is the first description of the prenatal neurodevelopment of brain disruption in ISOD.

Early cardiac involvement in an infantile Sandhoff disease case with novel mutations.

INTRODUCTION: Hepatosplenomegaly is often present in infantile Sanshoff disease. However, cardiac involvement is extremely uncommon. CASE REPORT: We describe a 14-month-old female baby who exhibited mitral regurgitation and cardiomegaly at the age of 2months, dilation of the left atrium and left ventricle at age of 6months, followed by regression of developmental milestones after an episode of minor infection at age of 14months. Brain magnetic resonance imaging revealed signal changes over the bilateral thalami, bilateral cerebral white matter and left putamen. An examination of the fundus showed presence of cherry-red spots in both macular areas. The lysosomal enzymatic activities showed a marked reduction of ß-hexosaminidase B (HEXB) activity. Two novel mutations of HEXB gene were identified. One of the mutations was a c.1538 T>C mutation, which predicted a p.L513P amino acid substitution of leucine to proline; the other was a c.299+5 G>A mutation, which was a splice site mutation. CONCLUSION: Cardiac involvement might occur prior to neurological symptoms in infantile Sandhoff disease, and it should be included in the differential diagnoses of metabolic cardiomyopathies in the infantile stage.

Higher frequency but random distribution of EGFR mutation subtypes in familial lung cancer patients.

Despite the advancement of epidermal growth factor receptor (EGFR) inhibitors in lung cancer therapy, it remains unclear whether EGFR mutation status in familial lung cancers is different from that of sporadic cases. In this multicenter retrospective study, we compared both the EGFR mutation frequency and patterns between familial and sporadic cases. The results explored that family history of lung cancer is an independent predictor for higher EGFR mutation rate in 1713 lung adenocarcinoma patients (Odd ratio 1.68, 95% CI 1.06-2.67, P = 0.028). However, the distribution of EGFR mutation subtypes was similar to that of sporadic cases. Part of our study involved 40 lung cancer families with at least 2 tumor tissues available within each single family (n = 88) and there was no familial aggregation pattern in EGFR mutation subtypes. There were two families harboring the YAP1 R331W germline risk allele and EGFR mutation statuses among YAP1 family members also varied. These phenomena may hint at the direction of future research into lung carcinogenesis and EGFR mutagenesis.

The emergence of T790M mutation in EGFR-mutant lung adenocarcinoma patients having a history of acquired resistance to EGFR-TKI: focus on rebiopsy timing and long-term existence of T790M.

Different growth kinetics occurring between the sensitive and T790M-containing cells may result in the repopulation of tumor cells over time. Little information has yet been uncovered on whether rebiopsy timing influences the T790M detection rate. We enrolled a total of 98 epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients, who had a history of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI) and available rebiopsy tumor specimens for reassessment of EGFR mutations. Rebiopsy was performed at the time of first EGFR-TKI progression in 54 patients (55.1%); for the other 44 patients (44.9%), rebiopsy was done with an interval from first EGFR-TKI progression (median 470.5 days, range 46-1742 days). Our results indicated that rebiopsy timing did not influence the detection rate of T790M and that the mutation could be identified in patients with a long EGFR-TKI-free interval. For patients without suitable lesions for rebiopsy at the time of EGFR-TKI progression, an attempt to rebiopsy should be considered during the subsequent treatment courses.

Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and Genetic features in Asia.

BACKGROUND: This study was conducted to describe the clinical and genetic features of patients with late infantile metachromatic leukodystrophy. METHODS: Clinical and genetic manifestations of five Taiwanese patients with late infantile metachromatic leukodystrophy from January 2003 to April 2014 were reviewed. The genetic features of such patients reported in Asian countries during a period of 20 years were also analyzed. RESULTS: The median age at disease onset was 1 year and 3 months with the first clinical symptom being gait disturbance. All five patients became bed-ridden at a median age of 2 years and 5 months. Nerve conduction velocity revealed demyelinating polyneuropathy and brain MRI disclosed tigroid and leopard skin pattern of dysmyelination in all 5 patients. All patients had decreased ARSA activities in leukocytes accounting for 15.88% to 30.75% of controls. Five novel mutations, p.A316D, p.G303R, p.Q176X, p.R293X, and c.749 insGCGGGCCA, were identified in our case series. Eighteen patients, including our 5 patients, were reported in Asian countries. A total of 22 different disease-causing alleles were found, in which p.W320X was identified in Taiwan and China, and p.G101V was found in Taiwan and Korea. CONCLUSIONS: Patients with late infantile metachromatic leukodystrophy exhibited a rapid and devastating clinical course. The pattern of dysmyelination on brain MRI together with peripheral demyelination polyneuropathy indicates that evaluation of ARSA activity in leukocytes is warranted. A wide diversity of ARSA gene mutations was noted in Asia.

Divergent epidermal growth factor receptor mutation patterns between smokers and non-smokers with lung adenocarcinoma.

INTRODUCTION: Smoking status is an important determinant of the prevalence of epidermal growth factor receptor (EGFR) mutations in lung cancer patients. However, it is unclear whether smoking status could also influence the spectrum of EGFR mutations. METHODS: We enrolled patients with lung adenocarcinoma from three medical centers in Taiwan. EGFR mutations were assessed by Sanger direct sequencing. The objective of this study was to evaluate the influence of smoking status on both the frequency and patterns of EGFR mutations. RESULTS: From 2001 to 2013, a total of 1175 patients with lung adenocarcinoma were enrolled for EGFR mutation analysis. The overall EGFR mutation rate was 59.6%, which was significantly higher in females than males (69.1% vs. 49.8%) and in non-smokers than current/former smokers (73.8% vs. 29.8%) (both P<0.001). Among patients harboring EGFR mutations, smokers expressed L858R mutation less frequently (35.2% vs. 50.2%, P=0.005) and exon 19 deletions more frequently (52.8% vs 38.8%, P=0.008) than non-smokers. Smokers and non-smokers also had divergent exon 19 deletions subtypes (Del E746-A750 82.5% vs. 57.6%, respectively, P<0.001). Among subgroup patients harboring the L858R mutation, smokers were associated with a higher rate of complex mutations than non-smokers (34.2% vs. 8.4%, P<0.001). CONCLUSIONS: Our results suggested that smoking status could influence not only the frequency but also the spectrum of EGFR mutations. These findings provide a clue for further investigation of EGFR mutagenesis.

Electroencephalographic features of patients with SCN1A-positive Dravet syndrome.

OBJECTIVE: The aim of this study was to characterize the awake EEG features of patients with SCN1A-positive Dravet syndrome. METHODS: Between January 2002 and December 2012, clinical data of 37 SCN1A-positive Dravet syndrome patients were collected. The first interictal awake EEG features, hot water bath test induced ictal seizure patterns and the concomitant EEG results, as well as follow-up interictal awake EEG recordings were analyzed. RESULTS: Thirty-seven interictal awake EEG recordings showed 43.2% had normal features, 43.2% had nonspecific findings, and 13.5% had abnormal epileptiform discharges. Ictal pleomorphic seizure types with a median number of three were recorded in 26 patients. In total, 42.3% exhibited myoclonic seizures as their first recognizable seizure type with simultaneous EEG findings characterized by generalized or focal spikes, generalized 2-3.5Hz spike and wave discharges, or generalized 2-3Hz high voltage slow waves, and 30.8% manifested atypical absence seizures with concomitant EEG results showing generalized or focal spikes. Fifteen patients had 45 follow-up interictal awake EEGs during a period of six years. The follow-up awake EEG recordings revealed 42.2% had normal features, 42.2% showed nonspecific findings, and 15.6% disclosed epileptiform discharges. CONCLUSIONS: The initial and follow-up interictal awake EEG recordings showed normal results and nonspecific features in the majority of SCN1A-positive Dravet syndrome patients. Ictal electroencephalographic seizure types and concomitant EEG pictures were quite diverse and polymorphous. A low detection rate of interictal epileptiform abnormalities at awake stage might make patient management more challenging.

Dynamic plasma EGFR mutation status as a predictor of EGFR-TKI efficacy in patients with EGFR-mutant lung adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status in lung cancer can effectively predict EGFR-tyrosine kinase inhibitor (TKI) efficacy. We evaluated the role of dynamic plasma cell-free DNA EGFR mutation status in outcome prediction. METHODS: Advanced lung adenocarcinoma patients were enrolled and prospectively observed for outcomes of EGFR-TKI treatment. Peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method was developed to assess EGFR mutations in matched tumor and serial plasma cell-free DNA specimens. RESULTS: A total of 72 patients were enrolled in this study, of which 62 patients (86.1%) had EGFR-mutant tumors (34 patients with exon 19 deletions, and 28 patients with L858R). Pretreatment plasma used for EGFR mutation testing showed a sensitivity of 59.7% and a specificity of 100%. Detection sensitivity was significantly higher in stage IV-M1b patients compared with stage IIIb and IV-M1a patients (78.0% versus 23.8%, p < 0.001). All patients who presented with EGFR-mutant tumors received first-line EGFR-TKI therapy. The objective response rate and disease control rate were 74.2% and 82.3%, respectively. Median progression-free survival and overall survival were 8.8 months (95% CI: 6.6-11.0) and 20.5 months (95% CI 15.1-26.0), respectively. Failure to clear plasma EGFR mutations after EGFR-TKI treatment was an independent predictor of lower disease control rate (odds ratio 5.26 [95% CI: 1.13-24.44]; p = 0.034), shorter progression-free survival (hazard ratio: 1.97 [95% CI: 1.33-2.91]; p = 0.001), and shorter overall survival (hazard ratio: 1.82 [95% CI: 1.04-3.18], p = 0.036). CONCLUSION: Changes in plasma EGFR mutation status can be successfully assessed using the peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method and can serve as an independent outcome predictor.