Clinical implications of persistent joint pain after gout flare.

OBJECTIVES: A subset of gout patients developed persistent joint pain after flares. Analysis of this clinical phenomenon may shed further light on the factors related to worsening gout and even provide clues to its pathogenesis. METHODS: We analyzed the clinical, laboratory, and ultrasound data of gout patients to explore the associations of these data with persistent joint pain after gout flares. RESULTS: A total of 1029 gout patients were included: 182 (17.7%) patients with persistent joint pain and 847 (82.3%) patients with nonpersistent joint pain. Patients with persistent joint pain had more total involved joints, more gout flares in the past year, and more joints with simultaneous gout flares (P<0.01). Among the ultrasound-detected lesions, patients with persistent joint pain had a higher incidence of tophus (36.4% vs. 21.1%) and bone erosion (18.6% vs. 8.6%) (P<0.05). Higher UA and lower TBil were found in patients with persistent joint pain (P<0.001). Hypertension (54.9% vs. 38.7%) and metabolic syndrome (58.8% vs. 46.4%) were both more frequent in patients with persistent joint pain (P<0.05). TBil was negatively correlated with the incidence of persistent joint pain (P<0.001, r=-0.190), UA values (P<0.001, r=-0.125), and metabolic syndrome scores (P<0.001, r=-0.192). A correlation curve was fitted using LOESS (locally weighted region). CONCLUSION: Persistent joint pain after gout flares is a marker of increased disease burden in gout. The significance of the level of total bilirubin for the exacerbation of gout deserves further study.

Case Report: Clinical Features of Childhood Leukoencephalopathy With Cerebral Calcifications and Cysts Due to SNORD118 Variants.

Background: Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a rare autosomal recessive cerebral microangiopathy. Recently, biallelic variants in a non-protein-coding gene SNORD118 have been discovered to cause LCC. Case Presentation: We here report a genetically confirmed childhood case of LCC. The patient was a 4-year-and-1-month-old boy with focal seizures. The age at onset of his seizure was 10 days after birth. The seizures were well-controlled by antiepileptic treatment but reoccurred twice due to a head impact accident and a fever, respectively. He suffered from a self-limited esotropia and unsteady running gait during the seizure onset. He had the typical neuroimaging triad of multifocal intracranial calcifications, cysts, and leukoencephalopathy. Genetic analysis indicated that he carried compound heterozygous variants of n.*9C>T and n.3C>T in SNORD118, which were inherited from his parents. Conclusion: We report a childhood LCC case with compound heterozygous variants in SNORD118. To the best of our knowledge, the patient reported in our case had the youngest onset age of LCC with a determined genotype. The triad cerebral-imaging findings of calcifications, cysts, and leukoencephalopathy provide a crucial diagnostic basis. Moreover, the gene assessment, together with the clinical investigations, should be considered for the diagnosis of LCC.

[Clinical effect of tacrolimus in the treatment of myasthenia gravis in children].

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus in the treatment of children with myasthenia gravis (MG). METHODS: A total of 28 children with MG were treated with tacrolimus. MG-Activities of Daily Living (MG-ADL) scale was used to assess clinical outcome and safety after 1, 3, 6, 9, and 12 months of treatment. RESULTS: After tacrolimus treatment, the MG-ADL score at 1, 3, 6, 9 and 12 months was lower than that at baseline (P<0.05), and the MG-ADL score showed a gradually decreasing trend. The response rates to tacrolimus treatment at 1, 3, 6, 9, and 12 months were 59%, 81%, 84%, 88%, and 88% respectively. At 6, 9, 12, and 18 months of treatment, 4, 13, 14, and 15 children respectively were withdrawn from prednisone. No recurrence was observed during treatment. Major adverse reactions/events were asymptomatic reduction in blood magnesium in 5 children and positive urine occult blood in 1 child, which turned negative without special treatment, and tacrolimus was not stopped due to such adverse reactions/events. One child was withdrawn from tacrolimus due to recurrent vomiting. According to CYP3A5 genotypes, all of the patients were divided into two groups: slow metabolic type (n=19) and non-slow metabolic type (fast metabolic type + intermediate type; n=9). The non-slow metabolism group received a higher dose of tacrolimus, but had a lower trough concentration of tacrolimus than the slow metabolism group (P<0.05). The slow metabolism group had a higher response rates to tacrolimus treatment than the non-slow metabolism group (P<0.05). CONCLUSIONS: Tacrolimus appears to be effective and safe in the treatment of children with MG and is thus an option for immunosuppressive therapy. CYP3A5 genotyping has a certain guiding significance for determining the dosage of tacrolimus.

Flexible Wolf Pack Algorithm for Dynamic Multidimensional Knapsack Problems.

Optimization problems especially in a dynamic environment is a hot research area that has attracted notable attention in the past decades. It is clear from the dynamic optimization literatures that most of the efforts have been devoted to continuous dynamic optimization problems although the majority of the real-life problems are combinatorial. Moreover, many algorithms shown to be successful in stationary combinatorial optimization problems commonly have mediocre performance in a dynamic environment. In this study, based on binary wolf pack algorithm (BWPA), combining with flexible population updating strategy, a flexible binary wolf pack algorithm (FWPA) is proposed. Then, FWPA is used to solve a set of static multidimensional knapsack benchmarks and several dynamic multidimensional knapsack problems, which have numerous practical applications. To the best of our knowledge, this paper constitutes the first study on the performance of WPA on a dynamic combinatorial problem. By comparing two state-of-the-art algorithms with the basic BWPA, the simulation experimental results demonstrate that FWPA can be considered as a feasibility and competitive algorithm for dynamic optimization problems.

Prevalence of psychological disorders, sleep disturbance and stressful life events and their relationships with disease parameters in Chinese patients with ankylosing spondylitis.

Our aim was to investigate the prevalence of psychological disorders, sleep disturbance, and stressful life events in Chinese patients with ankylosing spondylitis (AS) and healthy controls, to assess the correlation between psychological and disease-related variables, and finally to detect powerful factors in predicting anxiety and depression. AS patients diagnosed with the modified New York criteria and healthy controls were enrolled from China. Participants completed a set of questionnaires, including demographic and disease parameters, Zung self-rating anxiety scale (SAS), Zung self-rating depression scale (SDS), the Pittsburgh Sleep Quality Index questionnaire (PSQI), and the Social Readjustment Rating Scale (SRRS). The relationship between psychological and other variables was explored. Stepwise multiple regression was used to determine the contributors to each disorder. Of all the 2772 AS patients, 79.1% were male. Mean age was 28.99 ± 8.87 years. Prevalence of anxiety, depression, and sleep disturbance was 31.6% (95% CI, 29.9, to 33.4), 59.3% (95% CI, 57.5, to 61.2), and 31.0% (95% CI, 29.3, to 36.7), respectively. 35.3% had stimulus of psychological and social elements (SPSE). Compared with healthy controls, AS patients had more severe psychological disorders, sleep disturbance, and stressful life events (P < 0.01). SDS, overall pain, BASFI, and sleep disturbance were significant contributors of the SAS scores (P < 0.03). SAS, less years of education, and sleep duration were significant contributors of SDS (P < 0.01). AS patients had more anxiety, depression, stressful life events, and sleep disturbance than healthy controls. Pain, functional limitation, sleep disturbance, and education were major contributors to psychological disorders.

[Diagnosis of mitochondrial disorders in children with next generation sequencing].

OBJECTIVE: To explore the application value of next generation sequencing (NGS) in the diagnosis of mitochondrial disorders. METHOD: 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. RESULT: 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. CONCLUSION: NGS has a certain application value in the diagnosis of mitochondrial diseases, especially in Leigh syndrome atypical mitochondrial syndrome and rare mitochondrial disorders.

[Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy].

OBJECTIVE: To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy. METHOD: Totally 66 patients with narcolepsy who were conformed international classification of sleep disturbances (ICSD-2) diagnostic criteria treated with atomoxetine hydrochloride seen from November 2010 to December 2014 were enrolled into this study, 42 of them were male and 24 female, mean age of onset was 7.5 years (3.75-13.00 years), mean duration before diagnosis was 1.75 years (0.25-5.00 years). Complete blood count, liver and kidney function, multiple sleep latency test (MSLT), polysomnography (PGS), neuroimaging and electroencephalography (EEG) were performed for each patient. For some of the children HLA-DR2 gene and serum markers of infection were tested. The 66 cases were followed up from 2 to 49 months (average 18 months) to observe the clinical efficacy and adverse reactions. RESULTS: In 62 cases excessive daytime sleepiness was improved, in 11 cases (16.7%) it was controlled (16.7%), in 29 cases (43.9%) the treatment was obviously effective and in 22 (33.3%) it was effective; cataplexy occurred in 54 cases, in 18 (33.3%) it was controlled, in 19 (35.2%) the treatment was obviously effective and in 10 (18.5%) effective; night sleep disorders existed in 55 cases, in 47 cases it was improved, in 14 (25.5%) it was controlled, in 20 (36.4%) the treatment was obviously effective and in 13 (23.6%) effective; hypnagogic or hypnopompic hallucination was present in 13 cases, in only 4 these symptoms were controlled. Sleep paralysis existed in 4 cases, it was controlled in only 1 case. In 18 cases attention and learning efficiency improved.Anorexia occurred in 18 cases, mood disorder in 5 cases, depression in 2 cases, nocturia, muscle tremors, involuntary tongue movement each occurred in 1 case. P-R interval prolongation and atrial premature contraction were found in 1 case. CONCLUSION: Atomoxetine hydrochloride showed good effects in patients with narcolepsy on excessive daytime sleepiness, cataplexy and night sleep disorders, the effects on hallucinations and sleep paralysis were not significant. Adverse reactions were slight, anorexia and mood disorder were common. As a non-central nervous system stimulant, atomoxetine hydrochloride does not induce drug dependence and has no prescription limits; it has good tolerability, safety and effectiveness, it can be a good alternative in treatment of children with narcolepsy.

The relationship between disease activity measured by the BASDAI and psychological status, stressful life events, and sleep quality in ankylosing spondylitis.

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a standard instrument regularly used to assess disease activity of patients with ankylosing spondylitis (AS). However, the well-being of a patient is also affected by impairment of function as well as psychological status and other factors. The objective of this study was to evaluate if psychological status, stressful life events, and sleep quality contribute significantly to BASDAI. Six hundred eighty-three AS patients satisfying the Modified New York Criteria for AS were recruited from the rheumatology clinics of seven hospitals in China. Patients with other concomitant disorders were excluded. Participants were requested to complete a set of clinical examinations and the following questionnaires: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Zung Self-Rating Anxiety Scale (SAS), Zung Self-Rating Depression Scale (SDS), Pittsburgh Sleep Quality Index Questionnaire (PSQI), Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S), and Social Readjustment Rating Scale (SRRS). Spearman correlation analysis showed that BASDAI was highly associated with degree and duration of morning stiffness, overall pain, nocturnal back pain, overall back pain, anxiety, and BASFI (all P < 0.001), but were not associated with education, HAQ-S, and sleep medication in PSQI (P > 0.05). Multiple stepwise regression analysis indicated that overall pain was the maximal statistical contribution in predicting disease activity (standardized coefficient, 0.335). In hierarchic multiple regression analysis, psychological variables added an only additional 2.7% to the overall R(2) beyond that accounted for by demographic and medical variables, resulting in a final R(2) of 53.5%. Although BASDAI is a very good measurement of pain and stiffness and to a certain extent effect of functional impairment in AS, it barely takes into account psychological status, stress life events, and sleep quality These factors should be evaluated by other modalities.

[SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature].

OBJECTIVE: To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient, and review the latest clinical research reports. METHOD: Clinical, laboratory and genetic data of one case of SUCLA2-related encephalomyopathic MDS diagnosed by department of Neurology, Beijing Children's Hospital in November, 2013 were reported, and through taking "SUCLA2" as key words to search at CNKI, Wanfang, PubMed and the Human Gene Mutation Database (HGMD) professional to date, the clinical characteristics of 24 reported cases of SUCLA2-related encephalomyopathic MDS in international literature in combination with our case were analyzed. RESULT: (1) The patient was 5 years and 9 months old, born as a term small for gestational age infant whose birth weight was 2 400 g, and presented since birth with severe muscular hypotonia, feeding difficulties, failure to thrive, psychomotor retardation and hearing impairment. Until now, he still showed severe developmental retardation, together with muscular atrophy, thoracocyllosis and scoliosis, and facial features. The patient is the first born from consanguineous healthy parents, whose relationship is cousins. Laboratory tests showed urinary excretion of mild methylmalonic acid (MMA), elevated plasma lactate concentration, and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling. MRI showed brain atrophy-like and bilateral T2 hyperintensities in bilateral caudate nuclei and putamen. By Next-Generation Sequencing (NGS), we identified a novel homozygous missense mutation (c.970G > A) in the SUCLA2 in a highly conserved amino acid residue. (2) The total number was only 25 with a male to female ratio of 14: 11, and age of onset of 23 was 0-4 months. The most common clinical features in patients with SUCLA2 mutation were permanent hypotonia, muscle atrophy, psychomotor retardation and scoliosis or kyphosis. Frequent signs included hearing impairment, hyperkinesia, dystonia or athetoid movements, feeding difficulties, growth retardation and ptosis or ophthalmoplegia. Epilepsy was occasionally observed. The combination of lactic acidemia, mild MMA-uria and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling were characteristic markers. MRI showed brain atrophy-like and bilateral basal ganglia involvement (mainly the putamen and caudate nuclei). Nineteen patients originated from Europe, with 13 of whom originated from Faroe Islands that carry a homozygous mutation (c.534+1G>A) in SUCLA2. CONCLUSION: SUCLA2-related encephalomyopathic MDS is characterized by onset of severe hypotonia in early infancy, feeding difficulties, growth retardation, psychomotor retardation and hearing impairment. Metabolic findings usually include lactic acidemia, mild MMA-uria and increased C3-carnitine and C4-dicarboxylic-carnitine in plasma carnitine ester profiling. MRI showed brain atrophy-like and bilateral basal ganglia involvement (mainly the putamen and caudate nuclei). SUCLA2 pathogenic mutations would confirm the diagnosis.

[Phenotype and SCN1A gene mutation screening in 39 families with generalized epilepsy with febrile seizures plus].

OBJECTIVE: To summarize the phenotypes and identify SCN1A mutations in families with generalized epilepsy with febrile seizures plus (GEFS(+)), and analyze the genotype- phenotype correlations in GEFS(+) families. METHOD: Genomic DNA was extracted from peripheral blood lymphocytes of the proband and other available members in the GEFS(+) families. The phenotypes of the affected members were analyzed. The coding regions and flanking intronic regions of the SCN1A gene were screened for mutations using PCR and direct DNA sequencing. RESULT: In 39 GEFS(+) families, there were 196 affected members, ranging from 2 to 22 affected members in each family. Their phenotypes included febrile seizures (FS) in 92(46.9%), febrile seizures plus (FS(+)) in 62(31.6%), FS or FS(+) with partial seizures in 12(6.1%), afebrile generalized tonic-clonic seizures (AGTCS) in 11(5.6%), myoclonic atonic epilepsy in 8(4.1%), Dravet syndrome in 2(1.0%), childhood absence epilepsy in 1 (0.5%), FS(+) with myoclonic seizures in 1(0.5%), AGTCS and myoclonic seizures in 1 (0.5%), partial seizures in 1 (0.5%), unclassified seizures in 5 (2.6%). Four families were found with SCN1A mutations, including three families with missense mutation (N935H, R101Q, G1382R) and one family with truncation mutation (C373fsx378). In three families with missense mutations, the phenotypes include FS, FS(+), FS(+) with partial seizures, and AGTCS. In one family with truncation mutation, the phenotypes included FS, FS(+), and Dravet syndrome. The mother of proband in the family with missense mutation (R101Q) and the father of proband in the family with truncation mutation (C373fsx378) were both somatic mosaicism. Both of their phenotypes were FS(+). CONCLUSION: The most common phenotypes of GEFS(+) were FS and FS(+), followed by the FS/FS(+) with partial seizures and AGTCS. The most severe phenotype was Dravet syndrome. SCN1A mutation rate in GEFS(+) was about 10%. Missense mutation was common in GEFS(+) families, few with truncation mutation. Few members of GEFS(+) families had somatic mosaicism of SCN1A mutations and their phenotypes were relatively mild.

[Clinical analysis of four patients with Schwartz-Jampel syndrome].

OBJECTIVE: To analyze the clinical manifestation, diagnosis and treatment of Schwartz-Jampel syndrome (SJS). METHOD: The clinical data, including demographic, laboratory tests (creatase, creatine kinase, etc.) and electromyography of 4 children with SJS were analyzed. RESULT: All the 4 patients were male. The age of onset was from 0.5 to 1.25 years (average 0.83 years). The onset of 4 patients was insidious, the age to see doctor was from 2.17 to 10 years (average 5.92 years), body height was less than the third percentile rank in the children of same age and gender, they presented with facial expression stiffness, microstomia, difficult in opening mouth, blepharophimosis, limbs stiffness and, so formed a characteristic phenotype. Investigations showed the creatase in serum increased, creatine kinase (CK): 229 - 1039 U/L (normal value < 200 U/L), Creatine Kinase MB (CK-MB): 30 - 45 U/L (normal value < 25 U/L), lactate dehydrogenase (LDH): 455 - 716 U/L (normal value < 240 U/L). General myotonia potential was found in electromyography, osteoarticular deformities in medical imaging, and muscle biopsy in 2 patients showed type I muscle fibers differed in size and were disproportionate. All the patients took oral vitamin B, and received rehabilitation training, 1 patient took carbamazepine for 1 month, blepharophimosis and limbs stiffness was improved. CONCLUSION: SJS is a rare autosomal recessive inherited disease. Clinical manifestations of SJS are characteristic facies, skeletal abnormalities, generous myotonia and short stature. Carbamazepine is effective for treatment.

NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.

While pathogenic copy number variations (CNVs) in 15q11.2 were recently identified in Caucasian patients with idiopathic generalized epilepsies (IGEs), the epilepsy-associated gene(s) in this region is/are still unknown. Our study investigated whether the CNVs in 15q11.2 are associated with childhood absence epilepsy (CAE) in Chinese patients and whether the selective magnesium transporter NIPA2 gene affected by 15q11.2 microdeletions is a susceptive gene for CAE. We assessed IGE-related CNVs by Affymetrix SNP 5.0 microarrays in 198 patients with CAE and 198 controls from northern China, and verified the identified CNVs by high-density oligonucleotide-based CGH microarrays. The coding region and exon-intron boundaries of NIPA2 were sequenced in all 380 patients with CAE and 400 controls. 15q11.2 microdeletions were detected in 3 of 198 (1.5%) patients and in no controls. Furthermore, we identified point mutations or indel in a heterozygous state of the NIPA2 gene in 3 out of 380 patients, whereas they were absent in 700 controls (P = 0.043). These mutations included two novel missense mutations (c.532A>T, p.I178F; c.731A>G, p.N244S) and one small novel insertion (c.1002_1003insGAT, p.N334_335EinsD). No NIPA2 mutation was found in 400 normal controls. We first identified that NIPA2, encoding a selective magnesium transporter, is a susceptible gene of CAE, and 15q11.2 microdeletions are important pathogenic CNVs for CAE with higher frequency in Chinese populations than that previously reported in Caucasians. The haploinsufficiency of NIPA2 may be a mechanism underlying the neurological phenotypes of 15q11.2 microdeletions.

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis.

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.

[Follow-up study on the clinical characteristics and treatment effect of the different types of Guillain-Barré syndrome in children].

OBJECTIVE: To study the clinical characteristics and effects of immunoglobulin treatment in children with the different types of Guillain-Barré syndrome (GBS). METHOD: Data of 108 patients hospitalized for GBS were retrospectively analyzed; 75 cases in this group were given acute high dose of gamma globulin (IVIG) 400 mg/(kg·d) intravenously for 5 d. Clinical and electrophysiological data and information on treatment and recovery of the children were collected during the follow-up and were analyzed. RESULT: According to the clinical and electrophysiologic findings, 32 patients manifested acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 34 had acute motor axonal neuropathy (AMAN), 3 had acute motor and sensory axonal neuropathy (AMSAN), 4 were inexcitable, 2 were unclassified. The clinical progress of the AMAN was faster than the AIDP group. Except for sensory nerve involvement, there was no significant difference in the clinical feature and severity. The mean time of the muscle strength began to recover was (5.59±3.63) days in the AIDP group and (7.21±4.68) days in the AMAN group after IVIG treatment. The time of the AIDP group was shorter than the AMAN group, but the difference was not statistically significant (t=-1.5702, P>0.05). The mean time of the muscle strength increased one grade was (8.88±4.39) days in the AIDP group and (12.67±8.35) days in the AMAN group. The difference was statistically significant (t=-2.3689, P<0.05). No patients in this group died. Follow-up data showed that the complete recovery time was not significantly different (t=0.2041, P>0.05). CONCLUSION: The clinical progress of the AMAN was faster than the AIDP group. Besides sensory nerve involvement, there was no significant difference in the clinical feature and severity. The AIDP group's clinical recovery was faster than AMAN's after the immunoglobulin treatment. The two groups were not significantly different in long-term prognosis.

[Clinical manifestation and EEG characteristics of Angelman syndrome].

OBJECTIVE: To investigate the clinical manifestations and EEG characteristics of Angelman syndrome in children, and to strengthen the recognition of this disease. METHOD: Fourteen children with Angelman syndrome received video EEG monitoring, head MRI/CT and gene test, 11 patients received the metabolic investigations (e.g., lactic acid, ammonia, GC/MS and MS/MS). Eight patients received Gesell test. The patients were followed up for 1-3 years. RESULT: Of the 14 cases, 4 were male and 10 female, their age was from 8 months to 3 years and 7 months. The clinical characteristics included prominent lower jaw and wide mouth, fair skin and yellow hair, light-colored iris, paroxysmal laughter, astasia and language backward. Twelve patients had epileptic seizures; 10 patients displayed non-convulsive status epilepticus (NCSE), 9 patients displayed myoclonic, atypical absence, and non-convulsive seizure simultaneously; myoclonic, generalized tonic-clonic seizure and complex partial seizure in 1 each; 4 patients had fever in early seizures. The EEG showed paroxysmal middle-high amplitude 2-3 Hz spike and spinous slow-wave in 8 patients. Four patients showed paroxysmal frequently middle-high amplitude 2-3 Hz slow waves mixed with sharps. The other 2 patients showed a normal EEG. All the patients were diagnosed with genetics testing. The results included maternal deletion of chromosome 15q11-13 in 12, paternal uniparental disomy in 1 and imprinting defects in 1. CONCLUSION: There are characteristic clinical manifestation and craniofacial features in Angelman syndrome patients. Some patients have specific EEG patterns. Abnormal region of chromosome 15q11-13 is the basis of diagnosis.

[Clinical characteristics and diagnosis of acute pandysautonomia in childhood].

OBJECTIVE: To summarize the clinical characteristics of acute pandysautonomia in childhood, to gain better understanding of the diagnosis and differential diagnosis. METHODS: The clinical data of 6 children with acute pandysautonomia were analyzed and followed-up. All the 6 patients had routine blood and cerebrospinal fluid (CSF), electrocardiography (ECG), electromyography (EMG), cranial magnetic resonance imaging (MRI) and autonomic nerve function tests (head upright tilt test, dermatography test, and thermal/sympathetic sweat response). Other laboratory examinations such as immunologic markers of CSF, electroencephalography (EEG), spinal cord MRI and somatosensory evoked potential (SEP) were also performed in some patients. RESULTS: Of the 6 patients, 1 was male, and 5 were female. The age of onset was from 2.3 to 14.5 years (average 8.2 years). The initial symptoms were gastrointestinal dysfunction in 3 patients and somatic motor dysfunction as their initial symptoms, one had irritability in 1 case, pain in 1 and dysphagia in 1, respectively. Autonomic nerve signs and symptoms: (1) Skin and mucosa are rough and dry, there was no or little perspiration, alacrimia or little tear in all patients. (2) Vision problem appeared in 1 patient, blepharoptosis in 3 patients, pupillary abnormality existed in all patients. (3) Gastrointestinal symptoms were present in all patients. Vomiting and constipation were present in 4 patients, diarrhea and constipation were alternatively present in 1 patient, abdominal distention and abdominal pain were present in 2 patients. (4) Cardiovascular system manifestations included postural dizziness or syncope in 3 patients, tightness and palpitation in 2 patients. (5) Urinary dysfunction was present in 4 patients. In addition, mild to moderate somatic motor dysfunction was present in 5 patients, sensory dysfunction in 3 patients. Autonomic nerve function tests were abnormal in all patients. Laboratory findings included serum IgM antibody to herpes simplex virus and antistreptolysin "O" (ASO) test were positive respectively in 1 patient. The immunological markers in CSF were abnormal in 3 patients and the protein level in CSF was slightly elevated in 3 patients. Cranial MRI was slightly abnormal in 4 patients. ECG was slightly abnormal in all patients. EMG was abnormal in 5 patients. SEP was abnormal in 3 patients. Five patients received IVIG therapy. Five patients were followed-up. One patient died, one lost to follow up and one had slight improvement. Significant improvement was seen in 2 patients. CONCLUSION: Acute pandysautonomia in children usually had non-specific symptoms and could affect multiple organs. Heterotropia, cardiovascular dysfunction and gastrointestinal dysfunction were commonly seen in these patients. In acute pandysautonomia patients, IVIG seemed to be effective and the prognosis was poor in severe cases.

[Clinical and laboratory features of the Menkes disease].

OBJECTIVE: To study the clinical and laboratory features of the patients with Menkes disease. METHOD: Three infants were diagnosed as Menkes disease. Their clinical feature, laboratory findings, radiological manifestation and genes were reviewed. RESULT: All the three cases were male infants. Their clinical manifestations began at the 3, 5 and 6 months after birth. They all had light complexion, sparse fuzzy woolly hair. The main clinical manifestation was severe mental retardation. The first and the third case also had focal clonus seizures. The second case had feeding difficulty after birth. Their hair showed pili torti and trichorrhexis nodosa microscopically. Their ceruloplasmin in plasma were 32.3 mg/L, 72.5 mg/L and 60.7 mg/L, which were significantly lower as compared with the normal values. Their neuroimaging findings were cortical atrophy, delayed myelination of the white matter and tortuosity of the intracranial vessels. The gene examination of the first and the second case showed deletion and nonsense mutation on exon 14 respectively. CONCLUSION: Menkes disease is an X-linked recessive disorder characterized by a copper-transporting ATPase defect. The main clinical manifestation is progressive nerve damage. Patients with the disease have special face and hair abnormality, and have morphological changes of brain blood vessels and cerebral atrophy.

[Mutation analysis of the SCN1A gene in severe myoclonic epilepsy of infancy].

OBJECTIVE: To investigate the mutations of the sodium channel alpha 1 subunit gene SCN1A in severe myoclonic epilepsy of infancy (SMEI) patients and analyze its inheritance. METHODS: Twenty-three patients consistent with the diagnosis of SMEI were selected for SCN1A mutation analysis. Genomic DNA was extracted from peripheral blood lymphocytes of these patients and their parents. All the twenty-six exons of the SCN1A gene were amplified by PCR and sequenced. RESULTS: In the 23 SMEI patients, 17 mutations were identified in 17 unrelated SMEI patients. The SCN1A mutation rate was 73.9% (17/23). The mutations included 8 missense mutations (F90S, I91T, A239T, W952G, T1210K, V1335M, V1390M and G1433E), 3 nonsense mutations (R612X, W768X and W1408X), 3 deletion mutations (A395fsX400, L556fsX557 and V1778fsX1800), 1 insertion mutation (Y1241fsX1270), 1 splice-site mutation (IVS10+3 A to G) and 1 synonymous mutation (K1492K), of which 47.1% (8/17) were truncation mutations. Thirteen mutations (F90S, I91T, T1210K, V1335M, G1433E, R612X, W768X, A395fsX400, L556fsX557, V1778fsX1800, Y1241fsX1270, IVS10+3A to G and K1492K) have not been reported previously. Except for F90S, L556fsX557 and V1778fsX1800, the other 14 mutations were de novo. CONCLUSION: SCN1A is a major pathogenic gene for SMEI. About a half of the SCN1A mutations in SMEI cause truncation. There were no hotspots of SCN1A mutations in SMEI patients, and most mutations were de novo.

[Analysis of the GABRG2 gene mutation in a Chinese family with generalized epilepsy with febrile seizures plus].

OBJECTIVE: To identify the mutation of the GABA(A)-receptor gamma 2 subunit gene (GABRG2) in a Chinese family with generalized epilepsy with febrile seizures plus (GEFS+ ) and analyze the genotype-phenotype correlations and its inheritance. METHODS: Genomic DNA was extracted from peripheral blood lymphocytes of the proband and other available members in the GEFS+ family. The coding regions and flanking intronic regions of the GABRG2 gene were screened for mutations using polymerase chain reaction (PCR) and direct DNA sequencing. RESULTS: There were 7 affected members in the three-generation family, in which one with febrile seizures (FS) and six with febrile seizures plus (FS+ ). This family was consistent with the diagnostic criteria of GEFS+ . The nonsense mutation c.1287G to A (p.W390X) in the GABRG2 gene was initially identified in the proband. Seven affected members (6 FS+ and 1 FS) and one unaffected member carried the mutation. The nonsense mutation c.1287G to A/p.W390X in the GABRG2 gene was co-segregated with the GEFS+ family. The penetrance rate was about 87.5%(7/8). CONCLUSION: This GEFS+ family was consistent with autosomal dominant inheritance with incomplete penetrance. GABRG2 mutation is also a disease-causing mutation in Chinese GEFS+ patients. The p.W390X mutation has not been reported previously.