Phenotype and genotype features of 11 children with dystonia 28 caused by KMT2B variants / 中华实用儿科临床杂志

Objective:To summarize the clinical characteristics of children with dystonia 28 (DYT28) caused by KMT2B gene variations so as to improve clinicians′ understanding of the disease. Methods:The clinical manifestations, treatment and gene variation data of 11 children with DYT28 caused by KMT2B gene variations were retrospectively collected and analyzed.The subjects were recruited from the Department of Neurology, Beijing Children′s Hospital, Capital Medical University from March 2018 to January 2021.The patients were followed up. Results:There were 8 males and 3 females.The age at onset was ranging from 1 month to 6 years without inducement.Eight cases were gene-ralized dystonia and 3 cases were multifocal dystonia.The initial symptoms of 7 cases were unilateral or bilateral lower limbs tiptoeing.Four cases presented dysarthria, retching or swallowing difficulties at onset.As the disease progressed, all the cases had laryngeal dystonia, 10 cases had lower limbs dystonia, and 8 cases had upper limbs dystonia.Six cases were complicated with other dyskinesia symptoms.Ten cases had varying degrees of short stature, microcephalus, micrognathia, musculoskeletal abnormalities, intellectual disability, endocrinopathies and sleep difficulties.The brain magnetic resonance imaging showed abnormal in only 1 case.Eleven KMT2B gene pathogenic variants were found, including 8 frameshift variants, 1 in-frame variant and 2 missense variants.Four variants were novel.Eleven cases were followed up at the age of 1 year and 7 months to 17 years and 9 months.One case wasn′t given therapy.The dystonia in 3 cases was mildly improved after medication.Dysfunction of urination and defecation was disappeared in 1 case after medication.The symptom of 6 cases had no improvement after drug therapy.Among the above 6 cases, 5 drug refractory cases had deep brain stimulation, and their dystonia symptoms are all obviously improved; 2 cases had normal control of urination and defecation after deep brain stimulation.The motor scores in the Burke-Fahn-Marsden dystonia rating scale were improved by 55.8%-90.7%, and the disability scores were improved by 14.8%-69.6%. Conclusions:DYT28 caused by KMT2B gene variations is one of the most common and early-onset genetic dystonia in children.The dystonia symptom progresses from local parts to the whole body, prominently involving laryngeal muscles and lower limbs.Control of urination and defecation requires attention.Patients with mild dystonia symptoms can be effectively treated by drugs.However, patients with severe dystonia symptoms were drug refractory, and their dystonia symptoms can be effectively improved by deep brain stimulation.

Clinical features and genetic characteristics of children with tyrosine hydroxylase deficiency caused by TH gene variants / 中华实用儿科临床杂志

Objective:To summarize the clinical characteristics and genetic features of tyrosine hydroxylase deficiency(THD) caused by TH gene variants for the improvement of the understanding of the disease. Methods:The clinical and genetic data of 33 children with THD caused by TH gene variants were diagnosed in the Department of Neurology of Beijing Children′s Hospital, Capital Medical University from May 2011 to January 2020 and their data were retrospectively collected and analyzed. Results:There were 19 females and 14 males.The age at onset was ranged from 0 to 6.3 years.13 patients developed diseases, accompanied with fever after infection, and 1 patient suffered from hypoxia, 19 patients suffered from no predisposing factors.There were 7 mild TH-deficient dopa-responsive dystonia cases, 16 severe TH-deficient infantile parkinsonism with motor delay cases and 10 very severe TH-deficient progressive infantile encephalopathy cases.Clinical symptoms were fluctuating, including 26 cases of diurnal fluctuation, 22 cases of infection aggravation, and 30 cases of fatigue aggravation.The initial symptoms included tiptoeing and numbness in the limbs(7 cases), motor development retardation or degression (26 cases), fremitus (8 cases), ptosis (2 cases), and status dystonicus (3 cases). Other clinical features had hypermyotonia (23 cases), hypomyotonia (27 cases), decreased movement (27 cases), decreased facial expression (24 cases), fremitus (18 cases), tiptoeing (20 cases), talipes equinovarus (7 cases), ptosis (8 cases), oculogyric crisis (10 cases), salivation (21 cases), dysphagia (12 cases), dysarthria (16 cases), dyspnea (3 cases), increased sleep (10 cases), decreased sleep (5 cases), irritable mood (15 cases), apathetic mood (2 cases), profuse sweating (8 cases), and status dystonicus (6 cases). A total of 6 patients′ right limbs were more severe, and 14 patients′ lower limbs were more severe.Eight patients had family history, and Levodopa treatment was effective for all patients.Ten patients suffered side effects, including dyskinesia and irritability.Four patients were lost follow-up, and 29 patients were followed up between 0.8 and 13.2 years old until Ja-nuary 2020.Totally, 22 patients almost had no such symptoms.Twenty-five TH gene pathogenic variants were discovered in 33 patients.There were 13 novel variants (c.1160T>C, c.1303T>C, c.887G>A, c.1084G>A, c.1097A>T, c.734G>T, c.907C>G, c.588G>T, c.992T>G, c.755G>A, c.184-6C>T, c.1510C>T, c.910G>A) and 2 patients had c. 910G>A variant.Meanwhile, there were 5 hot variants [c.698G>A(13 cases), c.457C>T(9 cases), c.739G>A(6 cases), c.1481C>T(4 cases), c.694C>T(3 cases)]. c.910G>A(2 cases) may be the foun-der variant of Chinese population. Conclusions:THD caused by TH gene variant mostly onsets from infant, with complex clinical features.Most of these patients were severe, and only a few were very severe and mild.Very severe and mild symptoms were easily misdiagnosed.Levodopa treatment was obviously effective.A possible founder variant of Chinese population (c.910G>A) was found.c.698G>A and c. 457C>T mutations mainly appeared in patients with severe and extremely severe THD, while c. 739G>A mainly appeared in patients with mild THD.

Clinical analysis of 20 cases of paraneoplastic syndrome with prominent osteoarticular involvement / 中华风湿病学杂志

Objective To investigate the clinical characteristics of paraneoplastic syndrome with prominent osteoarticular involvement. Methods The clinical materials of 20 patients with paraneoplastic syndrome with prominent osteoarticular involvement were collected. The characteristics of clinical manifest-ations, laboratory tests and imagines were analyzed. Results Among the 20 patients, 16 were male and 4 were female, with a mean age of 44.5 years and a median course of 6 months. Ten cases were associated with hematological tumor and 10 cases were associated with solid tumor. Eleven cases presented as peripheral arthritis (7 cases of polyarthritis, 4 cases of oligoarthritis/monoarthritis), 5 cases presented with hypertrophic osteoarthropathy (HOA) and 4 cases presented with tumor-induced osteomalacia (TIO). Three cases were acute lymphocytic leukemia, 2 cases were multiple myeloma, 1 case was lymphoma, and 1 case was bone tumor in polyarthritis. Four oligoarthritis cases were all associated with acute lymphocytic leukemia. All 5 cases of HOA were associated with lung cancer. All 4 cases of TIO were associated with tumor of mesenchymal tissue. Extra-articular manifestations presented in 14 cases and inflammatory markers increased in 15 cases. anti-cyclic cirullinated peptide (anti-CCP) antibodies was low titer positive in only 1 case and other parameters including rheumatoid factor (RF), anti-CCP antibodies, antinuclear antibodies spectrum (ANAs) and human leukocyte antigen (HLA)-B27 were negative. Multiple bone imaging abnormalities appeared in 15 cases. Conclusion Osteoarticular manifestations may be the first symptom of malignancy and difficult to diagnose. It is necessary to be highly aware of potential malignancy.

Clinical and laboratory characteristics and genetic diagnosis of Kabuki syndrome / 中华儿科杂志

Objective@#To investigate the clinical features, laboratory characteristics and genetic diagnosis of Kabuki syndrome (KS).@*Methods@#Between September 2014 and September 2016, seven children with clinically diagnosed KS from the neurology department, Beijing Children Hospital, Capital Medical University were included in this study. Three of them were male and 4 were female aged from 19 days to 6 years and 4 months with a median age of 3 years and 1 month. The clinical features, laboratory and imaging materials, gene tests were analyzed prospectively.@*Results@#Clinical manifestation: cephalofacial anomaly: all seven cases had unusual facies presented as long palpebral fissures, eversion of the lateral third of lower eyelids, arched eyebrow with brow sparse, epicanthus, orbital hypertelorism, short columella with broad and depressed nasal tip; six cases presented with palatal arch deformity; four cases presented with ptosis; three cases presented with dental abnormalities and hearing impairment respectively; two cases presented with strabismus and earlap malformation respectively; one case presented with amblyopia. Six cases presented with skeletal anomalies. Six cases presented with dermatoglyphic anomalies. All cases presented with mild to moderate mental retardation. Three cases presented with short stature. Four cases presented with cardiac abnormalities. Three cases presented with epileptic seizures. Others: three cases presented with dystonia and neonatal hyperbilirubinemia respectively; two cases presented with feeding problem and hypoglycemia respectively; one case presented with micropenis and fetal finger pads respectively. All seven patients received magnetic resonance imaging (MRI) tests, and none demonstrated an abnormal finding. Five patients received electroencephalogram (EEG) tests, and three of them presented with seizures and EEG abnormalities. Five patients received genetic testing and all presented with KMT2D heterozygous mutations which were new mutations proved by parents validation (three cases were nonsense mutations, one was frameshift mutation, one was missense mutation). All patients received rehabilitation training and symptomatic treatments. Three patients presented with epileptic seizures received antiepileptic therapy. At a median follow-up of 11 months (from 4 months to 2 years), one patient died, one lost to follow-up and five had improved intellectual and physical development. Epileptic seizures were controlled or reduced significantly in three patients presented with epileptic seizures.@*Conclusions@#KS is a multisystem disease with complicated manifestations, which needs a combination of various diagnosis and treatments. Genetic testing can help determine the diagnosis. Unusual facies and mental retardation are the main clinical features and diagnostic clue. It is important to improve prognosis through increasing the knowledge of KS, early diagnosis, and treatment.

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 features and diagnosis of childhood leukoencephalopathy with cerebral calcifications and cysts in four cases / 中华儿科杂志

Objective@#To investigate the clinical features and diagnostic bases of childhood leukoencephalopathy with cerebral calcifications and cysts (LCC).@*Methods@#The clinical data involving manifestations and laboratory examinations of 4 children with LCC admitted to Beijing Children's Hospital Affiliated to Capital Medical University from 2012 to 2017 were retrospectively summarized. Each patient had a follow-up visit ranging from 4 months to 5 years and 9 months after initial examination.@*Results@#Patients consisted of 2 males and 2 females, whose age of onset was respectively 2 years and 9 months, 6 years and 2 months, 7 years and 10 months, and 5 years and 1 month. The main clinical symptoms of these cases included headache, dizziness, partial seizure and claudication, and two of these cases had insidious onset. Cerebral calcifications and cysts with leukoencephalopathy were detected by neuroimaging in all patients. In addition, multifocal microhemorrhages and calcifications were observed by magnetic susceptibility-weighted imaging (SWI) series in 3 patients. Brain biopsy performed on 1 case disclosed a neuronal reduction in the cerebral cortex, loosening of focal white matter, multifocal lymphocyte infiltration, fresh hemorrhages, and gliosis, as well as angiomatous changes of blood vessels with hyalinized thicken-wall, stenotic or occlusive lumina and calcification deposits. The compound heterozygous mutations of n.*10G>A and n.82A>G in SNORD118 were identified in 1 case by target-capture next-generation sequencing. Sanger sequencing verified that the variant n.*10G>A was a novel mutation and it was of paternal-origin, while the variant n.82A>G was of maternal-origin, which had already been reported to be pathogenic to LCC. Follow-up study had shown continued partial seizure in 1 case and remissive claudication in another, while the remaining 2 cases had a relatively favorable outcome without obvious neurological symptoms at present time.@*Conclusions@#The clinical manifestations of LCC are nonspecific, and the onset of the disease tends to be insidious. The triad neuroimaging findings of cerebral calcifications, cysts and leukoencephalopathy are essential to the diagnosis of the disease, and the signals of microhemorrhages revealed by SWI series provide another eloquent reference for the diagnosis. As biopsy is invasive and usually unavailable in the early stage, gene assessment, instead of pathological data, should be the gold standard in the diagnosis of LCC.

Clinical features and gene diagnosis of L-2-hydroxyglutaric aciduria in 4 children / 中华实用儿科临床杂志

Objective To investigate the clinical features and gene diagnostic bases of childhood L-2 -hydroxyglutaric aciduria (L-2-HGA). Methods The clinical data involving manifestations,laboratory examinations of 4 children with L-2-HGA admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from April 2015 to March 2018 were retrospectively analyzed. Each patient had a follow-up visit ranging from 3 months to 3 years and 2 months after initial examination. Results The 4 patients,of whom 2 were siblings,consisted of 1 male and 3 females,whose age of onset ranged from 8 months old to 3 years old. All of them presented with seizures as their initial symptom. The developmental milestones were all normal before onset,while 3 cases gradually became mentally stagnant. Other symptoms included unsteady gait in 3 cases,slight hand trembling when holding items in 2 cases,and pyramidal impairment in 2 cases. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus were detected by cranial magnetic resonance imaging (MRI)in all patients,and cerebral and cerebellar atrophy was ob-served in 1 case. Organic acid analysis by gas chromatography/ mass spectrometry (GC/ MS)demonstrated notable ele-vation of urinary 2-hydroxyglutaric acid in 3 cases. Pathogenic mutations on L2HGDH gene were detected by target -capture high-throughput sequencing in all 4 patients. The compound heterozygous mutations of c. 845G > A (p. Arg282Gln)and c. 800_801delCA (p. Ser267Ter)were identified in case 1,the homozygous missense mutation of c. 584A > G (p. Tyr195Cys ) in case 2 and case 3,and the homozygous frameshift mutation of c. 407delA (p. Lys136SerfsTer3)in case 4. The variants of c. 800_801delCA and c. 407delA were novel mutations firstly reported in this study. Sanger sequencing verified that parents of the 4 cases were all heterozygous carriers. The follow-up study in 2 cases who were put on high dosage of vitamin B2 and L-carnitine had shown a relatively favorable outcome of mild remission in ataxia and absence of mental degradation and further seizures,while the other 2 cases without specific therapy remained relatively stable. Conclusions The main clinical manifestations of L-2-HGA are mental retarda-tion,seizures and ataxia. Bilateral symmetric abnormalities in subcortical white matter,basal ganglia and dentate nucleus are specific neuroimaging findings. Significant elevation of urinary 2-hydroxyglutaric acid is the basic feature of the disease,while gene assessment should be the gold standard in the diagnosis of L-2-HGA. Treatment with high dosage of vitamin B2 and L-carnitine might be effective to partial patients.

Clinical and genetic characteristics of children with Leigh syndrome / 中华儿科杂志

Objective@#To investigate the clinically and genetic characteristics of children with Leigh syndrome.@*Method@#Patients with clinically diagnosed Leigh syndrome(LS)in the department of Neurology, Beijing Children′s Hospital from January 2013 to February 2016 underwent the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) detecting with next generation sequencing (NGS) technology. The clinical data of gene confirmed cases were retrospectively collected and analyzed. The differences in the onset age, clinical manifestations, lactic acid level and MRI results between the mtDNA variation and nDNA variation were compared and analyzed.t test, Chi-square test and Fisher′s exact test were used for statistical analysis.@*Result@#Thirty-five cases were diagnosed by gene detection, including 20 males and 15 females. The median onset age was 1 year (ranging from the neonatal period to 4.4 years old). The age of onset within 2 years accounted for 74%(26 cases). The onset age of initial symptoms, including developmental delay, developmental regression, and seizures, were 6 (4, 12) months, 12 (8, 14) months, and 6 (1, 23) months respectively. The onset age of ptosis, extrapyramidal symptoms and ataxia were 26 (18, 44) months, 28 (23, 40) months and 28 (19, 35) months, respectively. There were significant differences in the onset age between the three groups (H=21.919, P=0.01). Within the 35 cases, 29 were manifested with developmental delay (83%), 26 with dystonia (74%), 18 with growth retardation, 15 with myasthenia, 13 with developmental regression, 11 with dysphagia, 10 with feeding difficulties, 4 with skeletal dysplasia, and 2 with digestive tract symptoms; nystagmus and respiratory abnormalities were observed in 9 cases respectively; extrapyramidal symptoms, peripheral nerve injury, ptosis, seizures were observed in 8 cases respectively; and ataxia, ophthalmoplegia and hypertrichiasis were found in 5 cases respectively.The blood lactic acid was measured in 32 LS patients, within which 23 cases (72%) had increased results; 8 out of 11 cases who underwent were cerebrospinal fluid lactic acid test had increased results. The results of neuroimaging revealed that all the patients were involved in the brainstem and (or) basal ganglia, of whom 27 (77%) had brainstem involvement, 24 (69%) had basal ganglia involvement. Thirteen out of 14 patients who had medulla oblongata involvement had nDNA variation; while 7 out of 8 patients with cerebellar involvement had nDNA variation. Genetic etiology was confirmed in all patients, among whom there were 17 cases (49%) with mtDNA mutation, including 8993T>C/G (n=5), 14487T>C (n=4), 13513G>A (n=2), 9176T>C, 10158T>C, 3697G>A, 10191T>C, 14459A>G and 11777C>A (n=1) respectively. Remaining 18 cases(51%) had nDNA mutation, including SURF1 gene(n=10), PDHA1 gene(n=3) and one case each of NDUFV1, NDUFAF6, NDUFAF5, NDUFS1 and COQ7 genes. In this study, 27 types of mutations were founded, 15 of which had not been previously reported. Respiratory chain gene mutations have been found in 31 cases(89%); 3 cases had PDHc gene mutations, and 1 case had other mutation.@*Conclusion@#LS usually occurs in infants. The most common primary symptoms are age-dependent abnormal movements, ocular symptoms, and seizures. Respiratory chain defects is the most common causes of LS.SURF1 is the most common variation, followed by 8993T>C/G, 14487 T>C and 13513G>A mutation.

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>

Clinical effect of atomoxetine hydrochloride in 66 children with narcolepsy / 中华儿科杂志

<p><b>OBJECTIVE</b>To observe the efficacy and safety of atomoxetine hydrochloride in children with narcolepsy.</p><p><b>METHOD</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>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.</p>

SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome: a case report and review of literature / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics of SUCLA2-related encephalomyopathic mitochondrial DNA depletion syndrome (MDS) in one patient, and review the latest clinical research reports.</p><p><b>METHOD</b>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.</p><p><b>RESULT</b>(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.</p><p><b>CONCLUSION</b>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.</p>

A multicenter, randomized, double-blind, controlled study on the injection of two kinds of dexamethasone palmitate in the treatment of rheumatoid arthritis / 中华风湿病学杂志

Objective To evaluate the efficacy and safety of two forms of preparations of dexamethasone palmitate in the treatment of rheumatoid arthritis (RA).Methods A multicenter,double-blind,randomized,parallel-group clinical trial was carried out according to good clinical practice (GCP).A total of 237cases of RA patients with mild to moderate knee swelling were randomly divided into the treatment group (n=118 ) or the control group (n=119) and were treated with two kinds of dexamethasone palmitate 8 mg injection respectively.The primary efficacy endpoints were the circumference of the knee joint at the upper and the lower edge after the intra-articular injection.The secondary efficacy endpoints were joint tenderness index and patients general assessment.The adveme events were recorded.Analysis of covariance,t test or Wilcoxon test,x2 test or Fisher exact test were used for statistical analysis.Results The upper edges of the treatment group and the control group after treatment were (37.2±3.3) cm and (36.4±3.9) cm respectively,and the lower edges of the two groups were (34.4±2.9) cm and (33.9±3.4) cm respectively.They were all significantly smaller than the edges before treatment [(38.1± 3.3) cm and (37.3±4.0) cm of the upper edges,(35.1±3.0)cm and (34.6±3.6) cm of the lower edges respectively ) (P＜0.O1)].After treatment,the joint tenderness index were improved (P＜0.01).A total ratio of great improvement and improvement of patients general assessment of the two group patients were 67.5％ (79/117) and 74.8％ (86/115) respectively.No statistical significant difference was found in all primary and secondary efficacy endpoints between the two groups (P＞0.05).During the clinical trial,the incidence of adverse events related to the treatment of two groups were 4.2％ and 6.8％,without any significant difference (P＞0.05).Conclusion New preparation of dexamethasone palmitate has the same efficacy and safety as the imported producted in the treatment of RA.The circumference of the knee joints at the upper and the lower edge may be used to assess the effects of intra-articular injections.

The clinical analysis of patients with Turner syndrome and spondyloarthropathy / 中华风湿病学杂志

Objective To investigate the clinical characteristics of Turner syndrome in patients with spondyloarthropathy.MethodsSix patients from our hospital were included and the clinical manifestations,laboratory parameters and imaging presentations were analyzed retrospectively and the relevant literature were reviewed.ResultsThe mean age of these 6 cases was (27±5) years.Two cases were spondyloarthropathy,3 cases were ankylosing spondylitis,1 was psoriatic arthritis.Five cases were complicated with peripheral arthriris,2 cases were complicated with inflammatory back pain,4 cases had vertebral activity limitation,3 cases had joint deformity.The karyotype of 6 cases was 45,XO.Six cases were complicated with osteoporosis.Conclusion Turner syndrome can be presented with spondyloarthropathy,arthritis,osteoporosis.Dysplasia of bone is common.

Mutation analysis of the SCN1A gene in severe myoclonic epilepsy of infancy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSION</b>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.</p>

Analysis of the GABRG2 gene mutation in a Chinese family with generalized epilepsy with febrile seizures plus / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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).</p><p><b>CONCLUSION</b>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.</p>

Clinical verification of classified standards for undifferentiated spondyloarthropathy / 中华风湿病学杂志

0 05).Conclusion The standards of Amor and ESSG have higher sensitivity and specificity to diagnose spondyloarthropathy in China.The two standards have no difference in statistics.

Case-control study and transmission/disequilibrium test of childhood absence epilepsy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate whether or not the gamma-aminobutyric acid (GABA) receptor subtype A genes GABRA5 and GABRB3 are associated with childhood absence epilepsy (CAE).</p><p><b>METHODS</b>Two microsatellite DNA, GABRA5 and GABRB3, adjoining to chromosome 15q11.2-q12 were used as genetic markers. Both case-control study and transmission/disequilibrium test (TDT) as well as fluorescence-based semi-automated genotyping technique were used in 90 trios with CAE and 100 controls to conduct association analysis.</p><p><b>RESULTS</b>The allele frequencies of the 2 microsatellite DNA in Chinese normal population are in good agreement with Hardy-Weinberg equilibrium. The polymorphism information content of microsatellite DNA GABRA5 and GABRB3, are 0.80 and 0.66 respectively. The allele 2 frequency of microsatellite DNA GABRA5 and the allele 5 frequency of microsatellite DNA GABRB3 are significantly higher in CAE patients than those in normal controls(P<0.001).</p><p><b>CONCLUSION</b>Both microsatellite DNA GABRA5 and GABRB3 are good genetic markers. The gamma-aminobutyric acid receptor subtype A genes GABRA5 and GABRB3 may be directly involved either in the etiology of CAE or in linkage disequilibrium with disease-predisposing sites.</p>

Liver damage in primary Sjgren′s syndrome / 中华风湿病学杂志

0 05).Among the 13 patients with liver damage,AKP and ? GT were raised in 6,and AKP,? GT,TBIL and DBIL all elevated in 4 In 8 patients anti SMA and AMA were detected,and 5 showed AMA positive.Liver biopsy in 6 patients showed 3 with chronic active hepatitis among which 2 were complicated with liver cirrhosis,1 chronic persistent hepatitis and 2 cholangitis.Of the 6 patients 5 showed different degrees of infiltration of mononuclear cells in the portal tracts.Conclusion The occurrence of liver damage in pSS is rather high.The liver damage may be related to primary biliary cirrhosis (PBC).Patients′ response to corticosteroid treatment is favourable and their prognosis appears good.