Jiao Xue

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.

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 cohort study of pyridoxine-dependent epilepsy and high prevalence of splice site IVS11+1G>A mutation in Chinese patients

PURPOSE Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder caused by mutations of the ALDH7A1 gene. We aimed to analyze the relations between the clinical diagnosis and treatment of PDE and ALDH7A1 gene mutations in Chinese PDE patients. METHODS The clinical manifestations, diagnosis and treatment were observed in a cohort of PDE patients with early onset of seizure. Video-electroencephalogram (VEEG) and magnetic resonance imaging (MRI) were performed. The mutation of ALDH7A1 gene was analyzed. RESULTS Of eight patients, six were males and two were females. Age of seizure onset ranged from 1 to 100 days and 75% patients presented with seizures in the neonatal period. All patients showed different degrees of developmental delay. EEGs showed focal or multifocal discharges, or were normal. Molecular analysis revealed 10 ALDH7A1 mutations, including 2 splice site mutations. Five patients had mutation at IVS11+1G>A site, six patients had missense mutations, one with nonsense mutation and another patient had 9-bp genomic deletion mutation. Among them, two mutations were first time reported. CONCLUSIONS Seizure onset was in neonatal or early infantile period in our PDE patients. Early recognition and diagnosis of the disease is necessary for early intervention and improve cognitive development in the later life. In this study, on the molecular level, we also identified the splice site mutation IVS11+1G>A as a high prevalence mutation site with a frequency of 31.25% (5 of 16 alleles) in Chinese PDE patients.

Early childhood myoclonic epilepsy: An independent genetic generalized epilepsy with myoclonic seizures as the main seizure type

OBJECTIVE To elucidate the characteristics of the myoclonic seizures alone, or predominant myoclonus combined with generalized tonic-clonic seizures (GTCS) and/or absences, in early childhood, and discuss its classification. METHODS Forty-two children were retrospectively recruited between January 2006 and June 2015. RESULTS The mean age of seizure onset was 40.5months. They were divided into 4 groups: myoclonic seizures alone; predominant myoclonus combined with GTCS; predominant myoclonus combined with absences; predominant myoclonus combined with both GTCS and absences. Interictal EEG showed generalized spike- or polyspike-wave discharges at 2-4Hz. Seizures were controlled in 22 patients at a mean age of 60.5months. The psychomotor development was normal (30/37) or mildly delayed (7/37). CONCLUSIONS We reported a cohort of patients with early childhood myoclonic epilepsy (ECME), with the following characteristics: Seizures started below 5years old in otherwise normal children; Seizure types included myoclonic seizures alone or combined with GTCS and/or absences; Febrile or afebrile GTCS might appear firstly; Interictal EEG showed generalized spike- or polyspike-wave; Seizures usually were in remission before adolescence with normal development or mild cognitive or behavioral deficits in most. SIGNIFICANCE ECME might be an independent epileptic syndrome not established by International League Against Epilepsy (ILAE) previously.

Electro-clinical-etiological associations of epilepsia partialis continua in 57 Chinese children

OBJECTIVE Epilepsia partialis continua (EPC) was one type of focal status epilepticus. The aim of this study was to analyze the clinical and electroencephalography (EEG) characteristics, and outcome of 57 child-onset patients with EPC according to different etiologies, and further explore the electro-clinical-etiological associations. METHODS We retrospectively reviewed 57 children diagnosed with EPC in our department over last ten years. Etiology, clinical and EEG data, and outcome were categorized and analyzed. RESULTS For the 57 child-onset patients, EPC was caused by different etiologies, including immune-related disease (43.9%), focal lesions (17.5%), inborn errors of metabolism (24.6%), and unknown (14.0%). EEG background abnormalities showed generalized slowing in 45 patients (78.9%) and focal slowing in two patients (3.5%). Nineteen patients (33.3%) presented clear correlation of ictal EEG/EMG and the remaining 38 patients (66.7%) showed no clear correlation of ictal EEG/EMG. Both EEG background activity and ictal EEG/EMG correspondence among different etiologies had statistical significance (P<0.05). The ictal patterns without clear EEG/EMG correspondence in immune-related disease and the ictal patterns with clear EEG/EMG correspondence in focal lesions were more prominent (P<0.05). CONCLUSION This is the first study of child-onset EPC with a large series in a pediatric epilepsy center in China. The most common cause for EPC was immune-related disease. The EEG background activity and the EEG/EMG correspondence might be influenced by the etiologies of EPC to some degree. These findings might guide the direction of EPC diagnosis in conjunction with other examinations.

Genetic (idiopathic) epilepsy with photosensitive seizures includes features of both focal and generalized seizures

Clinically, some patients having genetic (idiopathic) epilepsy with photosensitive seizures were difficult to be diagnosed. We aimed to discuss whether the genetic (idiopathic) epilepsy with photosensitive seizures is a focal entity, a generalized entity or a continuum. Twenty-two patients with idiopathic epilepsies and photoconvulsive response (PCR) were retrospectively recruited. In the medical records, the seizure types included “generalized tonic-clonic seizures (GTCS)” in 15, “partial secondarily GTCS (PGTCS)” in 3, partial seizures (PS) in 3, myoclonic seizures in 2, eyelid myoclonus in one, and only febrile seizures in one. Seizure types of PCR included GTCS (1/22), PGTCS (6/22), PS (9/22), electrical seizures (ES) (3/22) and GTCS/PGTCS (3/22). Combined the medical history with PCR results, they were diagnosed as: idiopathic (photosensitive) occipital lobe epilepsy (I(P)OE) in 12, genetic (idiopathic) generalized epilepsy (GGE) in one, GGE/I(P)OE in 5, pure photosensitive seizure in one, and epilepsy with undetermined generalized or focal seizure in 3. So, the dichotomy between generalized and focal seizures might have been out of date regarding to pathophysiological advances in epileptology. To some extent, it would be better to recognize the idiopathic epilepsy with photosensitive seizures as a continuum between focal and generalized seizures.

Scalp-recorded high-frequency oscillations in childhood epileptic encephalopathy with continuous spike-and-wave during sleep with different etiologies

OBJECTIVE To investigate high-frequency oscillations (HFOs) in epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) with different etiologies. METHODS Twenty-one CSWS patients treated with methylprednisolone were divided into structural group and genetic/unknown group. Comparisons were made between the two etiological groups: selected clinical variables including gender, age parameters, seizure frequencies and antiepileptic drugs; distribution of HFOs in pre-methylprednisolone electroencephalography (EEG) and percentage changes of HFOs and spikes after methylprednisolone treatment. RESULTS There were 7 patients (33%) in structural group and 14 patients (68%) in genetic/unknown group. No significant difference was found between the two groups regarding selected clinical variables. HFOs were found in 12 patients in pre-methylprednisolone EEG. The distribution of HFOs was focal and accordant with lesions in 5 of structural group, and it was also focal but in different brain regions in 7 of genetic/unknown group. The percentage reduction of total HFOs and spikes was 81% (158/195) and 19% (1956/10,037) in structural group, while 98% (315/323) and 55% (6658/12,258) in genetic/unknown group after methylprednisolone treatment. CONCLUSION The etiologies had no distinct correlation with some clinical characteristics in CSWS. HFOs recorded on scalp EEG might not only be used as makers of seizure-onset zone (SOZ), but also have association with functional disruption of brain networks. Both HFOs and spikes reduced more in genetic/unknown patients than that in structural patients after methylprednisolone treatment and HFOs were more sensitive to treatment than spikes.

Atonic elements combined or uncombined with epileptic spasms in infantile spasms

OBJECTIVE To study the atonic elements combined or uncombined with epileptic spasms in infantile spasms. METHODS The demographic data, clinical characteristics, electroencephalogram (EEG), and polyelectromyography (PEMG) features were analyzed in 12 infantile spasm patients with atonic elements. RESULTS A total of 29 EEGs were recorded. Hypsarrhythmia or hypsarrhythmia variants were identified during interictal EEG. Insular or clustered epileptic spasms occurred in all. Three subtypes of atonic elements combined or uncombined with epileptic spasms (spasm-atonic, pure atonic, and atonic-spasm seizures) were observed electroclinically, which could present insularly or in cluster or altered with epileptic spasms in the same cluster. The ictal EEG showed generalized high-amplitude slow waves presenting alone or combined with other patterns. The corresponding PEMG showed an obvious electrical silence alone or preceding or following a crescendo-decrescendo pattern generated from myoelectric burst. CONCLUSIONS Atonic elements combined or uncombined with epileptic spasms was a newly noticed phenomenon in infantile spasms, which was artificially divided into three subtypes here. It might be a variant of epileptic spasms or a unique seizure type. SIGNIFICANCE Atonic elements combined or uncombined with epileptic spasms was a previously ignored phenomenon in infantile spasms, which should be seriously considered in clinical practice.

Myoclonic epilepsy in infancy with preceding or concurrent afebrile generalized tonic-clonic seizures in Chinese children

OBJECTIVE To investigate the general characteristics and the category of myoclonic epilepsy in infancy (MEI) with or without afebrile generalized tonic-clonic seizures (GTCS). METHODS Thirty-three children were retrospectively recruited from approximately 42,814 video-electroencephalogram (VEEG) recordings monitored in our department over last nearly 10years. Myoclonic seizures (MS) must be identified by VEEG in all patients. The clinical, EEG features and outcome were analyzed among these patients. RESULTS The 33 patients (25 boys and 8 girls) were divided into three groups: 11 patients with typical MEI; 16 patients with MEI experienced afebrile GTCS before MS onset; and 6 patients with MEI presented afebrile GTCS occurring concurrently with MS. No significant differences were found among the three groups, including gender distribution, family history, personal history of febrile seizures, the age at seizure onset and control, the duration of MS, the interval between age at onset and seizure control, the age at EEG normalization, the interval between seizure onset age and EEG normalization age and normal psychomotor development at the end of follow-up. More patients in group two and group three were controlled by two or three kinds of antiepileptic drugs compared with those in group one. CONCLUSIONS In this study, three groups of patients had similar clinical, EEG features and outcome. Afebrile GTCS was associated with a stronger cortical hyperexcitability. It was worth considering whether MEI with preceding or concurrent afebrile GTCS should be recognized as subgroups or different epileptic syndromes independent of MEI.