Zhixian Yang

Clinical and electrophysiological characteristics of startle epilepsy in childhood.

OBJECTIVE Startle epilepsy is one syndrome of reflex epilepsies. We studied its clinical and EEG characteristics. METHODS Analysis of the clinical and EEG characteristics of startle epilepsy. RESULTS Of 11 patients, five were female. Age of onset ranged from 5 months to 7.5 years. Abnormal etiologies were found in seven patients, as a result of perinatal and postnatal factors. Neuroimaging showed abnormalities, commonly focal atrophy, in nine patients. Spontaneous seizures preceded or followed the startle seizures and were present in all patients. Startle seizures experienced included tonic, myoclonic, tonic-myoclonic, tonic-atypical absence, asymmetric tonic motor seizure and tonic-clonic seizure. Diffuse electrodecremental pattern was the most common ictal EEG pattern seen. The triggering stimuli of the startle seizures were sound in seven patients, touch in three and both sound and touch in one. Interictal EEG revealed abnormalities in 10 patients including generalized, multifocal or focal discharges. Many different anti-epileptic drugs were often unsatisfactory. CONCLUSION Startle epilepsies were often symptomatic reflex epilepsies and there were several types of startle seizure. The ictal EEG often showed a diffuse electrodecremental pattern. This disease has a bad prognosis. SIGNIFICANCE We delineated the clinical and EEG characteristics of startle epilepsy in childhood.

Analysis of SCN1A mutation and parental origin in patients with Dravet syndrome

Dravet syndrome (DS) or severe myoclonic epilepsy of infancy is an intractable epileptic syndrome that is caused by mutations in the neuronal voltage-gated sodium channel α1 subunit gene SCN1A. We investigated SCN1A mutations in 63 Chinese patients with DS and analyzed its inheritance. Genomic DNA was extracted from peripheral blood lymphocytes of DS patients and their available parents. The SCN1A open reading frame sequence was analyzed by PCR–DNA sequencing and multiple ligation-dependent probe amplication (MLPA). If the mutation was de novo, we used allele-specific PCR (AS-PCR) to determine the parental origin. Of the 63 patients examined, 49 unrelated patients had SCN1A mutations. The mutation rate was 77.8% (49 of 63), in which 61.2% (30 of 49) were truncation mutations. The mutations included 19 missense mutations, 14 frame-shift mutations, 6 nonsense mutations, 8 splice-site mutations. Through MLPA analysis, deletions or duplications of large fragments accounted for 12.5% (2 of 16) in PCR-sequencing-negative patients. By testing parents for the mutation, 40 mutations were found to be de novo and one mutation was inherited from a mother who was mosaic for a mutation. By AS-PCR analysis in 12 patients with de novo mutations, 10 were confirmed paternal in origin and 2 were maternal in origin. Thirty of the SCN1A mutations reported here have not been previously reported. Approximately 80% of Chinese DS patients have SCN1A mutations. MLPA analysis was essential for PCR-sequencing-negative patients. The majority of SCN1A mutations were de novo, most of which were paternal origin.

Early clinical features and diagnosis of Dravet syndrome in 138 Chinese patients with SCN1A mutations.

OBJECTIVE To summarize the early clinical features of Dravet syndrome (DS) patients with SCN1A gene mutations before the age of one. METHODS SCN1A gene mutation screening was performed by PCR-DNA sequencing and multiple ligation-dependent probe amplication (MLPA). The early clinical features of DS patients with SCN1A mutations were reviewed with attention to the seizures induced by fever and other precipitating factors before the first year of life. RESULTS The clinical data of 138 DS patients with SCN1A gene mutations were reviewed. The median seizure onset age was 5.3 months. Ninety-nine patients (71.7%) experienced seizures with duration more than 15 min in the first year of life. Two or more seizures induced by fever within 24h or the same febrile illness were observed in 93 patients (67.4%). 111 patients (80.4%) had hemi-clonic and (or) focal seizures. Seizures had been triggered by fever of low degree (T<38 °C) in 62.3% (86/138) before the first year of life. Vaccine-related seizures were observed in 34.8% (48/138). Seizures in 22.5% (31/138) of patients were triggered by hot bath. Carbamazepine, oxcarbazepine, lamotrigine, phenobarbital and phenytoin showed either no effect or exacerbating the seizures in our group. CONCLUSION The seizure onset age in DS patients was earlier than that was in common febrile seizures. When a baby exhibits two or more features of complex febrile seizures in the first year of life, a diagnosis of DS should be considered, and SCN1A gene mutation screening should be performed as early as possible. Early diagnosis of DS will help clinicians more effectively prescribe antiepileptic drugs for stronger prognosis.

Clinical and genetic analysis of two Chinese infants with Mabry syndrome

OBJECTIVE Hyperphosphatasia mental retardation syndrome (Mabry syndrome) is an autosomal recessive disorder. We aim to analyze two Chinese patients diagnosed as Mabry syndrome. METHODS The clinical manifestations, diagnosis and treatment were observed in two patients. Genetic analysis including PIGV and PIGO was examined. RESULTS Two patients were diagnosed as Mabry syndrome clinically and genetically. Developmental delay, hyperphosphatasia and seizures were presented in both of them. Typical facial dysmorphism and hypoplastic terminal phalanges were only found in one. Some novel presentations including congenital laryngeal cartilage softening, inguinal hernia, broken palmprint, optic atrophy and skeleton dysplasia such as carpal age delay and metaphysis anomalies were observed in two patients. Molecular genetic analysis revealed compound heterozygous mutations of PIGV or PIGO in our patients, including c.615C>G (p.Asn205Lys) and c.854A>G (p.Tyr285Cys) of PIGV in patient 1, and c.458T>C (p.Phe153Ser) and c.1355_1356del (p.Ala452Glyfs*52) of PIGO in patient 2. Additionally, a heterozygous c.2926G>A (Asp976Asn) of PCDH19 was identified in patient with PIGV mutations, the causative gene of Epilepsy and mental retardation limited to females (EFMR). CONCLUSION To our best knowledge, this is the first time to report Chinese patients diagnosed as Mabry syndrome. For the PCDH19 mutation in our patient carrying PIGV mutations, due to lacking characteristics of EFMR and the ambiguity results in pathogenicity analysis, we were not sure how much pathogenic role PCDH19 mutation shared with PIGV mutations in this disease. The novel mutations of PIGV and PIGO, and novel clinical manifestations reported here might expand the genotype and phenotype spectrum of Mabry syndrome.

Clinical Diagnosis, Treatment, and ALDH7A1 Mutations in Pyridoxine-Dependent Epilepsy in Three Chinese Infants

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder that causes seizures in neonates and infants. Mutations of the ALDH7A1 gene are now recognized as the molecular basis PDE and help to define this disease. Three Chinese children with PDE were clinically analyzed, followed by treatment and examination of the ALDH7A1 mutations. The seizures of the 3 patients were all resistant to multiple anticonvulsants (2 to 7 types). For case 1, onset of seizures was at the age of 2 months. His seizures were well controlled by intravenous pyridoxine for several days at the age of 3 months 20 days and recurred at intervals of 13, 14 and 38 days after pyridoxine withdrawn for 3 times. At the age of 7 months, symptoms of PDE appeared and uninterrupted oral pyridoxine started. For case 2, her seizures occurred at 8 days after birth. After administration of multiple antiepileptic drugs observed ineffective, high-dose pyridoxine continuous therapy was taken at the age of 10 months and the significant treatment effect induced a diagnostic PDE. Seizure onset in case 3 was at the first day of birth. He experienced inadvertently pyridoxine therapy several times (first time at 2 days after birth) and achieved good therapeutic effect, which was confirmed by physicians until 4 months 10 days. The treatment process in our 3 patients suggested that pyridoxine should be early and purposefully used in patients with early onset seizures. ALDH7A1 gene mutation analysis revealed compound heterozygous mutations in each case: heterozygous c.410G>A (p.G137E) and IVS11+1G>A in case 1, heterozygous c.952G>C (p.A318P) and heterozygous c.965C>T (p.A322V) in case 2, and heterozygous c.902A>T (p.N301I) and IVS11+1G>A in case 3. Only p.N301I was reported previously, all other mutations were novel. This is the first time to report cases of Chinese patients diagnosed with PDE by molecular genetic analysis.

Scalp-recorded high-frequency oscillations in atypical benign partial epilepsy.

OBJECTIVE To investigate how high-frequency oscillations (HFOs) were affected by methylprednisolone treatment and the clinical significance of HFOs in patients with atypical benign partial epilepsy (ABPE). METHODS In 14 ABPE patients with methylprednisolone treatment, we measured interictal HFOs and spikes during sleep in pre- and post-methylprednisolone scalp electroencephalography (EEG). Patients with benign childhood epilepsy with centrotemporal spikes (BECTS) were taken as control. RESULTS Before methylprednisolone treatment, 10/14 ABPE patients had HFOs, with a mean value of 85.79 per 60s per patient, while 2/14 BECTS patients had HFOs with a mean value of 1.86 per 60s per patient (p=0.006). The 10 ABPE patients with HFOs tended to have more frequent epileptic negative myoclonus/atypical absences than the other 4 ABPE patients without HFOs. Rates reduced by methylprednisolone treatment were statistically significant for both spikes (p=0.027) and HFOs (p=0.005). The percentage of reduction was 41.8% (4653/11,133) and 95% (1141/1202) for spikes and HFOs, respectively. CONCLUSION Proportion and rates of HFOs in ABPE were more prevalent than in BECTS. HFO rates reduced by methylprednisolone treatment might be more significant than spike rates. SIGNIFICANCE Prevalence of HFOs reflected at least some aspect of epileptic severity of ABPE. HFOs were more sensitive to methylprednisolone treatment than spikes.

A study on epileptic negative myoclonus in atypical benign partial epilepsy of childhood

OBJECTIVE To investigate the clinical and neurophysiological characteristics, particularly therapeutic considerations, of epileptic negative myoclonus (ENM) in atypical benign partial epilepsy (ABPE) of childhood. METHODS From 1998 to 2006, 14/242 patients with benign children epilepsy with centrotemporal spikes (BECTS) were diagnosed as having ABPE with ENM. In all 14 patients, we performed video-EEG monitoring along with tests with the patients arms outstretched; 6/14 patients were also simultaneously underwent surface electromyogram (EMG). ENM manifestations, electrophysiological features, and responses to antiepileptic drugs were analyzed. RESULTS In all cases, ENM developed after the onset of epilepsy and during antiepileptic drug therapy, and the appearance of ENM were corresponding to EEG findings of high-amplitude spikes followed by a slow wave in the contralateral motor areas with secondary generalization. This was further confirmed by time-locked silent EMG. During ENM occurrence or recurrence, habitual seizures and interictal discharges were exaggerated. In some patients, the changes in antiepileptic drug regimens in relation to ENM appearance included add-on therapy with carbamazepine, oxcarbazepine, and phenobarbital or withdrawal of valproate. ENM was controlled in most cases by administration of various combinations of valproate, clonazepam, and corticosteroids. CONCLUSION The incidence of ENM or ABPE in our center was approximately 5.79%. A combination of video-EEG monitoring with the patients arms outstretched and EMG is essential to identify ENM. The aggravation of habitual seizures and interictal discharges indicate ENM. Some antiepileptic drugs, such as carbamazepine, oxcarbazepine, and phenobarbital, may be related to ENM occurrence during spontaneous aggravation of ABPE. Various combinations of valproate, benzodiazepines, and corticosteroids are relatively effective for treating ENM that occurs in ABPE.

The clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population

Mutations in PCDH19, which encodes protocadherin 19, have been identified in epilepsy, mainly in affected females. We summarized the clinical spectrum of female epilepsy patients with PCDH19 mutations in a Chinese population. We screened for PCDH19 mutations in 75 girls diagnosed with Dravet syndrome (DS) without a SCN1A mutation and 29 girls with fever‐sensitive and cluster seizures. We identified 11 novel and 7 reported mutations in 21 of 104 probands (20.2%), including 6 (6/75, 8%) DS girls and 15 (15/29, 51.7%) girls with fever‐sensitive epilepsy. The mutations were inherited in 9 probands, de novo in 11, and undetermined in the remaining patient. Shared clinical features included early onset seizures (5–18 months), seizures sensitive to fever, focal seizures or generalized tonic–clonic seizures in clusters and brief seizures. Mental retardation was present in 17 probands. Three patients had autistic features. Two of the nine probands with inherited mutations had no family history of epilepsy, one inherited the mutation from her transmitting father and the other inherited from her asymptomatic mother. Our results confirmed that the clinical spectrum of PCDH19 mutations includes female DS patients, epilepsy and mental retardation limited to females, epilepsy with normal development and asymptomatic female carriers.

Epilepsy and Narcolepsy-Cataplexy in a Child

We report a 5-year-old boy with epilepsy and narcolepsy-cataplexy. He developed myoclonic seizures at the age of 4 years, which manifested as head shaking to the left. Approximately 6 months later, narcolepsy-cataplexy with excessive daytime sleepiness occurred. Although a short-time electroencephalography (EEG) and 24-hour ambulatory EEG monitoring found epileptiform discharges, no seizures were determined. Oxcarbazepine was used and led to increased attacks. Video EEG testing finally confirmed the diagnosis of epilepsy; therefore, valproate was given and seizures were controlled completely. Typical cataplexy triggered by laughing, together with the positive multiple sleep latency tests confirmed a diagnosis of narcolepsy-cataplexy. Human leukocyte antigens DQB1*0602 was positive, and the hypocretin level in cerebrospinal fluid was found to be decreased. Combination of valproate, methylphenidate, and clomipramine treatment improved the symptoms of both narcolepsy-cataplexy and seizure. The coexistence of both disorders in this single patient indicated that there might be a common mechanism between epilepsy and narcolepsy-cataplexy.

Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients

Objective Hypomyelinating disorders are a group of clinically and genetically heterogeneous diseases characterized by neurological deterioration with hypomyelination visible on brain MRI scans. This study was aimed to clarify the clinical and genetic features of HMDs in Chinese population. Methods 119 patients with hypomyelinating disorders in Chinese population were enrolled and evaluated based on their history, clinical manifestation, laboratory examinations, series of brain MRI with follow-up, genetic etiological tests including chromosomal analysis, multiplex ligation probe amplification, Sanger sequencing, targeted enrichment-based next-generation sequencing and whole exome sequencing. Results Clinical and genetic features of hypomyelinating disorders were revealed. Nine different hypomyelinating disorders were identified in 119 patients: Pelizaeus-Merzbacher disease (94, 79%), Pelizaeus-Merzbacher-like disease (10, 8%), hypomyelination with atrophy of the basal ganglia and cerebellum (3, 3%), GM1 gangliosidosis (5, 4%), GM2 gangliosidosis (3, 3%), trichothiodystrophy (1, 1%), Pol III-related leukodystrophy (1, 1%), hypomyelinating leukodystrophy type 9 (1, 1%), and chromosome 18q deletion syndrome (1, 1%). Of the sample, 94% (112/119) of the patients were genetically diagnosed, including 111 with mutations distributing across 9 genes including PLP1, GJC2, TUBB4A, GLB1, HEXA, HEXB, ERCC2, POLR3A, and RARS and 1 with mosaic chromosomal change of 46, XX,del(18)(q21.3)/46,XX,r(18)(p11.32q21.3)/45,XX,-18. Eighteen novel mutations were discovered. Mutations in POLR3A and RARS were first identified in Chinese patients with Pol III-related leukodystrophy and hypomyelinating leukodystrophy, respectively. Significance This is the first report on clinical and genetic features of hypomyelinating disorders with a large sample of patients in Chinese population, identifying 18 novel mutations especially mutations in POLR3A and RARS in Chinese patients, expanding clinical and genetic spectrums of hypomyelinating disorders.