Clinical and genetic analysis of childhood-onset myoclonus dystonia syndrome caused by SGCE variants / 中华儿科杂志

Objective@#To explore the clinical characteristics and genotyping results of childhood-onset myoclonus dystonia syndrome caused by SGCE variants.@*Methods@#The clinical data of 9 children with SGCE-related myoclonus dystonia syndrome admitted at either the Department of Neurology, Beijing Children′s Hospital, Capital Medical University or the Department of Pediatrics, Peking University First Hospital from May 2018 to October 2019 were collected and the patients were followed up. The definite diagnosis was made on the basis of whole exome sequencing and multiple ligation-dependent probe amplification. The clinical features and gene test results were analyzed retrospectively.@*Results@#Data of 9 patients (4 boys and 5 girls) diagnosed as myoclonus dystonia syndrome caused by SGCE variants were collected. The onset age ranged from 1 year to 3 years and 2 months. The first symptom was myoclonus in 4 cases, while dystonia in the remaining 5 cases. In the course of the disease, 9 cases had myoclonus and 8 had dystonia. Myoclonic jerks were characterized by involuntary jerks in both upper limbs in 8 patients. Six patients had involuntary jerks of lower limbs, resulting in gait instability or even falling. The myoclonus was exacerbated during the fine motor activities, emotional stress or fatigue. Dystonia was characterized by abnormal gait, including 5 cases with right leg dystonia, and 3 cases with the left leg dystonia. Three probands had a positive family history. Intellectual development was normal in all cases. There was no obvious abnormality in video-electroencephalogram (EEG) during both ictal and interictal periods. Electromyography (EMG) and brain magnetic resonance imaging (MRI) of 9 patients were normal. Nine patients carried SGCE gene variants, including 3 frame shift variants, 2 nonsense variants, 2 missense variants, 1 fragment deletion variant and 1 splice site variant. Seven variants were inherited paternally, and 2 variants were de novo. Madopar was used in 8 patients, and nitrazepam in 4 patients, leading to the decrease in the myoclonus jerks and improvement of gait in 6 and 2 patients, respectively.@*Conclusions@#SGCE gene variants can cause myoclonus dystonia syndrome. The onset of the disease may occur at infancy or preschool age, with either myoclonic jerks or dystonia as the initial symptom. Non-epileptic myoclonus is the prominent symptom, with upper limb mainly involved. Most of the patients have the accompanying symptoms of dystonia, and some of them may have spontaneous symptom relief. SGCE gene is imprinted maternally, and the inherited variants of SGCE are paternal in origin.

Clinical features and laboratory characteristics of eight patients with subacute sclerosing panencephalitis / 中华神经科杂志

Objective:To investigate the clinical and laboratory characteristics of subacute sclerosing panencephalitis (SSPE).Methods:The clinical, laboratory and electroencephalogram (EEG) data of eight patients with SSPE who admitted to the Department of Neurology, Beijing Children's Hospital, Capital Medical University, from May 2014 to February 2019 were retrospectively analyzed and followed up.Results:Four of the patients were male and four were female, who aged from two years and seven months to 13 years and five months with a median onset age of five years and six months. All of the eight cases had disease onset with progressive mental and physical regression, then developed periodic myoclonic seizures at the course of 11 days to 11 months. Video EEG examinations showed persistent generalized periodic complex waves with long interval (3-20 s). The IgG titers of measles virus in blood and cerebrospinal fluid of all cases were significantly increased. There was no significant abnormality in blood/urine metabolism screening nor head magnetic resonance imaging for the first time. Five cases performed head magnetic resonance imaging again, in which two cases with deepening hemispheric sulcus, two cases with cerebral white matter signal abnormalities. Antiepileptic drugs, gamma globulin, adrenocortical hormone and antiviral drugs were used after diagnosis though all were ineffective. All patients presented progressive deterioration. During the follow-up period of three months to two years and seven months, four patients died, of which three patients died at the time of five months, one year and two months, two years and six months after onset respectively, and the other one was unknown.Conclusions:The diagnostic clues of SSPE are progressive mental and physical regression, recurrent myoclonic seizures during period Ⅱ, as well as the extensive periodic complex waves of EEG. It is necessary to detect measles virus IgG antibody in blood and cerebrospinal fluid to make a definite diagnosis. There is no specific treatment for SSPE and its prognosis is very poor.

Phenotypic and genotypic characteristics of fever-induced paroxysmal weakness and encephalopathy caused by ATP1A3 pathogenic variants / 中华儿科杂志

Objective@#To characterize fever-induced paroxysmal weakness and encephalopathy (FIPWE) caused by ATP1A3 gene pathogenic variant.@*Methods@#Phenotypic and genotypic characteristics of 4 FIPWE patients (3 boys and 1 girl), who were ascertained from October 2016 to March 2018 in Beijing Children's Hospital due to ATP1A3 heterozygous variants, were retrospectively analyzed. The whole exsome sequencing was used for genetic testing.@*Results@#The onset ages of 4 patients were 2 years and 9 months, 2 years and 4 months, 8 months, 2 years and 5 months respectively. The episode ranged from 1 to 3 times, and at 3 months to 2 years and 10 months intervals. All 4 patients had symptoms of limb weakness and encephalopathy, accompanied with mild to severe ataxia or athetosis. The tendon reflex was absent in all patients, and the Babinski's sign was positive. Three patients had dysphagia and 3 patients had slurred speech. Three patients had abnormal eye movements, including strabismus and opsoclonus. None of the 4 patients exhibited visual impairment, auditory impairment or talipes cavus. The duration of acute phase ranged from 1 week to 3 months. In 3 relapsing patients, symptoms became progressively worse, with relapses occurring frequently and recovery being more difficult, and various sequelae were found after the last relapse. All patients carried heterozygous variant in ATP1A3 gene. The missense variants result in the substitution of an arginine residue at position 756. Three variants were identified, including C. 2267G > T (p. R756L) (1 case), C. 2266C > T (p. R756C) (2 cases), and C. 2267G > A (p. R756H) (1 case). Three were de novo and one inherited from his father, but the grandparents did not carry the variant. All variants were reported as pathogenic.@*Conclusions@#FIPWE is one of new clinical phenotypes of ATP1A3 spectrum disease and most cases are sporadic. The missense variants result in the substitution of an arginine residue at position 756. This report provided insights into the phenotype-genotype association in patients with FIPWE caused by pathogenic variants of ATP1A3.

Clinical and genetic characteristics of 62 children with mitochondrial epilepsy / 中华儿科杂志

Objective@#To summarize the clinical and genetic characteristics of children with mitochondrial epilepsy.@*Methods@#Clinical data of 62 children who were clinically and genetically diagnosed with mitochondrial epilepsy by the Department of Neurology, Beijing Children′s Hospital from October 2011 to December 2018 were analyzed retrospectively, and the control of epilepsy was followed up. T test or χ2 test were used to analyze the related factors affecting the prognosis of epilepsy between the effective group and the ineffective group.@*Results@#Of the 62 patients, 33 were male and 29 were female. The age of onset was 3.38 (0-12.00) years; for the type of seizures, 68% (42/62) of the patients had focal seizures, generalized or secondary generalized tonic-clonic seizures were seen in 32% (20/62), myoclonic seizures in 23% (14/62), spastic seizures in 7 cases, tonic seizures in 4 cases, absence seizure, atonic seizure and clonic seizure in 1 case each; 16 cases (26%) had status epilepticus, of whom 6 cases had epilepsia partialis continua; 52% (32/62) had 2 or more types of seizures. The clinical phenotypes were mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) in 29 cases, Leigh syndrome (LS) in 11 cases, combined oxidative phosphorylation deficiency in 6 cases, myoclonus epilepsy with ragged-red fibers in 5 cases, Alpers syndrome in 4 cases, pontocerebellar hypoplasia type 6 and mitochondrial DNA depletion syndrome 9 in 2 cases each, mitochondrial complex Ⅰ deficiency nuclear type 20, progressive cavitating leukoencephalopathy, and biotinidase deficiency in 1 case each. Of the 62 cases, 40 cases (65%) had mitochondrial DNA (mtDNA) variations, of which 26 cases had m.3243A>G variants, 6 cases had m.8344A>G variants, and 3 cases had m.8993T>G/C variants, m.3271T>C, m.3481G>A, m.3946G>A, m.13094T>C, m.14487T>C variant was in 1 case each; nuclear DNA (nDNA) variations were identified in 22 cases (35%), of which 7 cases carrying variations in mitochondrial ammonia acyl tRNA synthetase coding gene, mutations in POLG and the gene encoding complex Ⅰ were in 4 cases each, variations in SUCLG1 and SDHA genes were in 2 cases each, and variations in PDHA1, BTD and TRIT1 genes were in 1 case each. Forty-three patients were followed up, and the follow-up time was 20 (3-84) months. According to the follow-up results, the anti-epilepsy treatment was effective in 19 cases (44%) and ineffective in other 24 cases (56%). The onset age of the effective group was 3.42 (0-11.50) years and that of the ineffective group was 0.92 (0-9.50) years. The onset duration of the effective group was 0 (0-7.00) years and that of the ineffective group was 0 (0-4.83) years. There was no significant difference between the effective group and the ineffective group (t=1.662, 0.860; P=0.104, 0.395). In the effective group and the ineffective group, 12 cases and 9 cases used less than 2 kinds of antiepileptic drugs, 7 cases and 15 cases used more than or equal to 2 kinds of antiepileptic drugs, 13 and 15 cases had first epilepsy, 6 and 9 cases had non-first epilepsy, 14 and 11 cases had mtDNA variation, 5 and 13 cases had nDNA variation, respectively. There was no significant difference between the two groups (χ2=2.794, 0.164, 3.380; P=0.095, 0.686, 0.066).@*Conclusions@#The types of seizures with mitochondrial epilepsy in children varied, with focal motor seizures being the most common, followed by generalized or secondary generalized tonic-clonic seizures. Most children have more than two types of seizures. MELAS is the most common clinical phenotype, followed by LS; mtDNA variation is the dominant gene variation, of which m.3243A>G variation is the most common hotspot variation, followed by gene variation encoding mitochondrial aminoacyl tRNA synthase.

Clinical and genetic characteristics of focal epilepsy in children caused by GATOR1 complex gene variation / 中华儿科杂志

Objective@#To summarize the clinical and genetic characteristics of focal epilepsy in children caused by GATOR1 complex gene variation.@*Methods@#The clinical data, gene variation and treatment outcome of 12 children with focal epilepsy caused by GATOR1 complex gene variation admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from June 2016 to October 2018 were retrospectively analyzed.@*Results@#There were 7 males and 5 females in 12 cases. The epilepsy onset age was 5.5 (3.0, 12.0) months, and from 11 days to 16 months of age. The epileptic seizure types were all focal motor seizures, and one case combined with epileptic spasms. The frequency of seizures in all patients was more than one time per day. Seven cases had frontal lobe epilepsy and two cases had lateral temporal lobe epilepsy. One case had a family history of febrile seizures and two had a family history of suspicious epilepsy. Epileptic form discharges were observed in 9 patients during the interictal phase by electroencephalograms (EEG), and all of them were focal discharges. Eight cases had clinical seizures detected by EEG, in 4 of whom the seizures were originated in frontal region. There were no abnormalities in brain magnetic resonance imaging in 11 cases whereas 1 case had malformation of cortical development of left frontal lobe. Eight patients had DEPDC5 gene variation, one had NPRL2 gene variation, three had NPRL3 gene variation. One case had de novo variation and the other 11 had hereditary variation. There were 11 types of gene variation, including 5 nonsense variations, 3 missense variations, 2 frame shift variations and 1 in frame deletion variation. There was no clear relationship between the clinical phenotype and the genotype. During the follow-up period from 6 months to 2 years and 6 months, 6 cases had seizure control, 3 of them were controlled by oxcarbazepine. The other 6 cases had drug-refractory epilepsy, 2 of them failed with vagus nerve stimulation and ketogenic dietary therapy as well, meanwhile combined with mental retardation.@*Conclusions@#GATOR1 complex gene variation can lead to genetic focal epilepsy, which usually has early onset with frequent seizures. Most of the patients have focal epileptic form discharges on EEG, and there is usually no structural lesion in brain imaging. Most of the patients have hereditary loss-of-function variations. Approximately half of cases are drug-resistant epilepsy.

Clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation / 中华儿科杂志

Objective@#To summarize the detailed clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation, in order to improve the understanding of the disease.@*Methods@#The clinical data and genetic results of 40 benign infantile epilepsy patients with PRRT2 mutation who were diagnosed and treated in the neurology department of National Center for Children's Health (Beijing) , Beijing Children's Hospital affiliated to Capital Medical University from January 2002 to October 2017 and their affected family members were analyzed.@*Results@#Forty benign infantile epilepsy patients were recruited for this study, with 18 males and 22 females. The age at onset ranged from 3 to 15 months (median: 4.6 months). All patients presented focal seizures with or without secondary generalization. Decreased responsiveness, eyes stare and cyanosis were commonly observed. A cluster of seizures was observed in 20 patients at the beginning of the disease, but interictal clinical conditions were normal. Interictal electroencephalograms were normal in 32 cases but 8 cases showed small amount scattered spike and spike wave. Two patients developed paroxysmal kinesigenic dyskinesia in 30 months and 12 years respectively after the cessation of the seizure. Thirty-four affected pedigree members had a history of paroxysmal episodes in 24 families, including 19 individuals of infantile afebrile convulsion, 6 individuals of paroxysmal kinesigenic dyskinesia during childhood or adulthood, 8 individuals of infantile convulsion and paroxysmal kinesigenic dyskinesia during adulthood, one individual of infantile febrile convulsion. The follow-up time ranged from 6 months to 15 years. Thirty-six patients were treated with antiepileptic drugs and their seizures were easy to control. Four patients stayed seizure free without medication (all <2 years). Seizure stopped in 24 patients within 1 year of age, in 10 patients stopped during 12-24 months and in 2 patients stopped during 24-36 months. All cases had PRRT2 mutations, 7 cases of a complete PRRT2 deletion, 33 cases of PRRT2 heterozygous mutations consisted of 28 frameshift mutations and 5 missense mutations. Of these heterozygous mutations, 30 cases were hereditary mutations while 3 were de novo mutations. Nine family members harbored the same PRRT2 mutations without any symptom.@*Conclusions@#Benign infantile epilepsy with PRRT2 mutation is characterized by early onset of seizure mostly before 6 months, focal seizures with or without secondary generalization, a high incidence of a cluster of seizures, rapid resolution of seizure by antiepileptic drugs and cessation of seizure mostly before 2 years of age. Partial patients may develop paroxysmal kinesigenic dyskinesia increasing with age. Most PRRT2 gene mutations are heterozygous mutations, and a few are the overall deletion of PRRT2 gene.

Clinical value of ultrasonography in the diagnosis of carotid plaque neovascularization / 中国基层医药

Objective To evaluate the clinical value of ultrasonography in the diagnosis of carotid plaque neovascularization .Methods 32 patients with carotid artery plaques diagnosed by conventional ultrasonography were enrolled.The patients were followed up for contrast-enhanced ultrasonography (CEUS) and ultrasonography micro-vascular imaging(SMI),and the results of the two-dimensional detection of carotid plaque and plaque neovasculariza-tion were compared .Results A total of 63 plaques were detected by SMI , including 39 hypoechoic plaques , 19 episodes of echo patches ,58 of plaques ,and 17 hypoechoic plaques .The diagnostic rate of neovascularization was 10.34％.Among the 113 carotid plaques,48 carotid plaques were detected by SMI ,46 carotid plaques were detected by CEUS.The distribution of neovascularization was similar to that of CEUS ,and the neovascularization of SMI and CEUS was better(Kappa=0.669,P<0.001).Conclusion For the diagnosis of carotid plaques ,ultrasonography can accurately detect the number , location and neovascularization of plaques , and the accuracy of carotid plaques is effective.It provides a radiographic basis for the diagnosis and early intervention of patients ,which has great signifi-cance to the prevention of stroke and cardiovascular and cerebrovascular adverse events .It is worthy of popularizing and application .

Clinical characteristics and follow-up of Hashimoto encephalopathy in children / 临床儿科杂志

Objective To explore the clinical characteristics of Hashimoto encephalopathy (HE) in children. Methods The clinical data of 4 children with HE were analyzed retrospectively. Results All the 4 cases were school-age children and 3 of them were girls. They were physically healthy before onset. The main clinical manifestations were epileptic seizures in 3 cases, mental symptoms in 2 cases, disturbance of consciousness in 2 cases, stroke like symptoms in 1 case, decreased memory and decreased sleep in 1 case. Electroencephalogram showed that the background activity was decreased in 4 cases, and MRI showed abnormal in 3 cases. Serum thyroid antibodies were significantly increased in 4 cases, and were returned to normal in 2 cases when clinical symptoms disappeared, while they were significantly reduced, but not completely back to normal in another 2 cases. Only one out of 4 cases had abnormal thyroid function. All the 4 cases responded well to corticosteroid therapy. One of them relapsed after discontinuation of the therapy, but it was still effective when the therapy was reassumed. Conclusions HE is rare in children. When there are manifestations of unknown cause, such as epileptic seizures, mental disorders, cognitive impairment, movement disorders and disturbance of consciousness, HE should be considered. In addition, the increase of serum thyroid antibody should be considered as a necessary condition for diagnosis.

Rendom Cotrol Study of Peri-operative Application of GLP-1 Analogue and Insulin on Myocardial Perfusion and Prognosis in STEMI Patients With Stress-induced Hyperglycemia / 中国循环杂志

Objective: To explore the peri-operative application of GLP-1 analogue and insulin on myocardial perfusion and clinical prognosis in patients of acute ST segment elevation myocardial infarction (STEMI) with stress-induced hyperglycemia. Methods: Our research was a prospective single center randomized control study. A total of 114 consecutive STEMI patients received percutaneous coronary intervention (PCI) within 12h of onset were enrolled, the patients had no diabetes while blood glucose ≥11.1mmol/L at immediate admission. Based on random number table, the patients were divided into 2 groups: Observation group, the patients received GLP-1 analogue, n=59 and Control group, the patients received insulin, n=55. The post-operative myocardial perfusion, indicators of myocardial damage and cardiac function, myocardial infarct area (MIA) and myocardial salvage index (MSI) were compared between 2 groups. The patients were followed-up for 6 months to record the incidence of major adverse cardiovascular events (MACE). Results: At peri-operative period, compared with Control group, Observation group had decreased peak values of creatine kinase isoenzyme (CK-MB) and troponin T (cTnT), P<0.05. At 6 months post-operation, compared with Control group, Observation group showed increased myocardial perfusion and left ventricular ejection fraction (LVEF), P<0.05, reduced MIA (15±12) g vs (20±14) g, P<0.05 and 12% elevated MSI as (0.64±0.13) vs (0.56±0.12), P<0.001. The MACE incidence was similar between 2 groups, P=0.217. Conclusion: In STEMI patients with stress-induced hyperglycemia, peri-operative application of GLP-1 analogue may safely regulate blood glucose, improve cardiac perfusion and function, reduce MIA; while it had no influence on myocardial perfusion at peri-operative period and no impact on MACE occurrence at 6 months post-operation.

Progressive cavitating leukoencephalopathy: four cases and literatures review / 中华儿科杂志

Objective@#To analyze the clinical and genetic features of progressive cavitating leukoencephalopathy (PCL).@*Method@#The data of clinical and genetic features of 4 PCL patients diagnosed by Beijing Children′s Hospital between January 2015 and January 2016 were analyzed. The cases with complete clinical data retrieved on literature search at China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform and PubMed (up to August 2016) by using search terms of"NDUFV1" ,"NDUFS1" , or"leukoencephalopathy" , were summarized.@*Result@#There were three females and one male, two of which were compatriots. The age of onset ranged from 6 months to 15 months. All four children′s first symptoms were motor development regression, and the developmental milestones were almost normal before the onset. Of the 4 patients, 3 had cognitive impairment, 1 had seizures, 4 had dystonia and pyramidal impairment, 2 had emaciation, and 1 had nystagmus. The lactate concentrations of 4 patients were normal in blood. One patient had lactaciduria in the urinary organic acid analysis. Cranial magnetic resonance imaging (MRI) of all patients showed leukoencephalopathy, involved in the corpus callosum, and three patients accompanied by cystic lesions. Follow up for 2-13 years showed that the physical and language development were improved. Genetic analysis revealed that mutations in NDUFS1 were found in three patients and NDUFV1 mutation was found in one patient. All six mutations (p.Arg377Cys and p. Arg377His in NDUFV1; p. Arg482Glyfs*5, p.Thr368Pro, p.Tyr454X and p. Asp565Gly in NDUFS1) are novel. Five English case reports including 10 PCL patients were collected. Together with this group of 4 cases, a total of 14 cases were involved. All 14 children patients had motor development regression, 11 cases had cognitive impairment and dystonia, 6 cases had pyramidal impairment, 5 cases had irritability, 4 cases had epilepsy and nystagmus, 3 cases had strabismus and swallowing difficulty. Cranial MRI showed patchy leukoencephalopathy with cavities, involved in the corpus callosum. Follow up for 19 months-15 years that the neurology development were improved slowly in all patients.@*Conclusion@#NDUFS1 and NDUFV1 gene mutation screening should be performed firstly in patients with PCL clinical and imaging feature.

Diagnosis of mitochondrial disorders in children with next generation sequencing / 中华儿科杂志

<p><b>OBJECTIVE</b>To explore the application value of next generation sequencing (NGS) in the diagnosis of mitochondrial disorders.</p><p><b>METHOD</b>According to mitochondrial disease criteria, genomic DNA was extracted using standard procedure from peripheral venous blood of patients with suspected mitochondrial disease collected from neurological department of Beijing Children's Hospital Affiliated to Capital Medical University between October 2012 and February 2014. Targeted NGS to capture and sequence the entire mtDNA and exons of the 1 000 nuclear genes related to mitochondrial structure and function. Clinical data were collected from patients diagnosed at a molecular level, then clinical features and the relationship between genotype and phenotype were analyzed.</p><p><b>RESULT</b>Mutation was detected in 21 of 70 patients with suspected mitochondrial disease, in whom 10 harbored mtDNA mutation, while 11 nuclear DNA (nDNA) mutation. In 21 patients, 1 was diagnosed congenital myasthenic syndrome with episodic apnea due to CHAT gene p.I187T homozygous mutation, and 20 were diagnosed mitochondrial disease, in which 10 were Leigh syndrome, 4 were mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes syndrome, 3 were Leber hereditary optic neuropathy (LHON) and LHON plus, 2 were mitochondrial DNA depletion syndrome and 1 was unknown. All the mtDNA mutations were point mutations, which contained A3243G, G3460A, G11778A, T14484C, T14502C and T14487C. Ten mitochondrial disease patients harbored homozygous or compound heterozygous mutations in 5 genes previously shown to cause disease: SURF1, PDHA1, NDUFV1, SUCLA2 and SUCLG1, which had 14 mutations, and 7 of the 14 mutations have not been reported.</p><p><b>CONCLUSION</b>NGS has a certain application value in the diagnosis of mitochondrial diseases, especially in Leigh syndrome atypical mitochondrial syndrome and rare mitochondrial disorders.</p>