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The CACNA1A gene encodes a voltage-gated calcium channel of the pore-forming protein, which has important functions in the central nervous system.The CACNA1A gene mutation can lead to a variety of neurological diseases, including familial hemiplegic migraine 1, spinocerebellar ataxia 6, episodic ataxia 2 and early infantile epileptic encephalopathy 42.Overlapping phenotypes could be observed in a small number of patients.This review summarized the clinical and genetic characteristics of the CACNA1A gene mutation.
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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.
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Objective:To analyze the clinical and imaging features of influenza associated encephalopathy(IAE) in children, thus contributing to enhance the efficacy of early identification, timely treatment and prognosis.Methods:Clinical data, laboratory examination, imaging data, treatment and outcomes of 40 children with IAE diagnosed and treated in the Beijing Children′s Hospital, Capital Medical University from December 2016 to January 2020 were retrospectively analyzed.Clinical features were summarized and they were further classified according to clinical imaging features.The prognosis was compared and analyzed.Results:A total of 20 boys and 20 girls were recruited, with the age of attending hospital at (4.0±2.3) years (median, 3.2 years). There were 28 children with influenza A and 12 with influenza B. All children initially had fever, and the interval between fever and symptoms of neurological onset was 24 hours (0-120 hours). The most-common symptom of neurological onset was seizures(32 cases), among which 17 patients showed continuous seizures.All children presented encephalopathy at varying degrees, including 33 cases in coma and 7 in drowsiness or cognitive decline.Thirty cases developed central respiratory failure and received mechanical ventilation.Examination results showed 30 cases had elevated aspartate transaminase (AST), 18 cases had elevated alanine transaminase (ALT), 14 cases had elevated creatinine, 31 cases had elevated lactate dehydrogenase, 16 cases had elevated blood glucose and 1 case had significantly lowered blood glucose.Blood ammonia testing was performed in 38 children and 9 cases had elevated level.The whole exon sequencing in 6 cases showed de novo heterozygous mutation of the SCN1A gene in 1 case, and heterozygous mutation of the ATP1A2 gene inherited from the mother in another case.Lumbar puncture was performed in 35 cases, and all of them had a normal range of cerebrospinal fluid leukocyte counts, while 12 cases had elevated cerebrospinal fluid proteins.Abnormal image findings were examined in 33 cases and the acute necrotizing encephalopathy was the most common one (14 cases). All children received Peramivir or Oseltamivir after admission.A total of 28 cases were treated with glucocorticoids, and 29 cases were treated with immunoglobulin.Seventeen cases died, 9 cases had disability at varying degrees, and 14 cases recovered to the baseline.Patients were divided into good prognosis group and poor prognosis group.(1) Patients in good prognosis group presented significantly shorter interval between fever and first neurological symptoms[(22.7±12.2) h vs.(38.6± 30.9) h], higher Glasgow score on admission[(7.6±2.5) points vs.(4.5 ± 1.6) points], lower ALT [15.6 (9.0-1 631.5) U/L vs.140.2 (12.3-3 232.4) U/L] and lower AST [47.6 (25.4-1 721.3) U/L vs.251.8 (21.7-4 991.6) U/L] than those in poor prognosis group (all P<0.05). (2) Glucocorticoids were applied to 17 and 11 cases in good prognosis group and poor prognosis group, while immunoglobulins were applied to 17 and 12 cases, respectively ( P>0.05). (3) Patients were further classified into cytokine storm group, excitotoxicity group and unclassifiable group according to clinical imaging findings.The Glasgow score [ (4.6±1.7) points vs.(7.6±2.2) point vs.(7.3±2.8) points] and median modified Rankin Scale score (6.0 points vs.1.5 points vs.0) were significantly different among 3 groups (all P<0.01). Conclusions:Influenza associated encephalopathy is common in infants and young children.Fever, convulsions and rapidly progressing disturbance of consciousness are the most common clinical manifestations.Acute necrotizing encephalopathy is the most common subtype of clinical imaging syndrome.Acute onset and rapid progression predict the poor prognosis of influenza associated encephalopathy.
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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.
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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.
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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.
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Objective:To summarize the clinical data of patients with acute pandysautonomia (APD) and discuss the treatment and prognosis of them.Methods:A total of 13 patients with APD in the Department of Neurology, Beijing Children′s Hospital, Capital Medical University, from January 2010 to December 2019, were investigated retrospectively.The general data, clinical symptoms, autonomic nerve examination and function test, laboratory examination, treatment and follow-up were collected and analyzed.Results:There were 4 males and 9 females in 13 patients with APD, with an average age was 8 years and 5 months (3 years and 8 months to 12 years and 5 months ). The average course of disease was 94.5 d (14-410 d). The common initial symptoms were gastrointestinal motility disorder (11 cases), dysuria (3 cases), and upright syncope/vertigo (3 cases). During the course of the disease, all the patients manifested with gastrointestinal motility disfunction and dyshidrosis, glands involvement and orthostatic hypotension in 12 cases, abnormal pupil in 9 case and urinary retention in 7 case.Other symptoms included fatigue in 9 cases, emotional disorder in 4 cases, limb weakness in 2 cases, and sensory disturbance in 2 cases.All the patients were treated with intravenous immunoglobulin (IVIG), and 3 cases combined with glucocorticoid.Six patients with severe gastrointestinal symptoms were treated with intravenous nutrition; 4 patients were fed with jejunum, 3 cases of whom returned to normal diet within 1-12 months, and 1 patient was followed up for 5 years and 2 months.Hyponatremia was found in 7 cases, which recovered in 2-30 d. Nine cases were followed up for 1 month to 9 years.Seven cases were normal in daily work and study, with satisfactory nutritional status, stable mood and no relapse.Conclusions:The clinical manifestations of APD are varied.The initial symptoms are gastrointestinal motility disorders, orthostatic hypotension, urinary retention and hyponatremia.Individualized multi-disciplinary comprehensive management for symptoms, especially the comprehensive treatment of gastrointestinal motility disorders, management of postural hypotension, and the urinary system diagnosis and individualized treatment of can shorten the length of hospital stay and improve the prognosis effectively.
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Children′s status dystonicus is a nervous system emergency with high mortality and lacking clinical knowledge.Trigger avoiding as well as early recognition and treatment is important for improvement of symptoms and reducing mortality.In this article, the etiology, diagnosis, antidiastole, treatment and prognosis of status dystonicus in children were reviewed.
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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.
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Objective@#To summarize the clinical features of Bickerstaff brainstem encephalitis (BBE) in children.@*Methods@#In this retrospective study, data of 19 patients with BBE (11 males and 8 females) were collected from Department of Neurology, Beijing Children′s Hospital from October 2015 to January 2018. The clinical features, treatment and prognosis were analyzed.@*Results@#The onset age of BBE ranged from 1 year and 8 months to 12 years and 11 months. There were 18 cases with preceding infection. The most common infection was upper respiratory tract infection (9 cases), followed by simple fever (5 cases). The most common initial neurological symptoms were lethargy or disturbance of consciousness (8 cases), followed by limb weakness (5 cases). There were 6 cases of simple BBE and 13 cases of BBE overlapping Guillain-Barré syndrome (GBS). Besides the characteristic triad of altered mental status, ataxia, and ophthalmoplegia, there were other symptoms including convulsion (5 cases), diplopia (3 cases), nystagmus (7 cases), facial muscular weakness (7 cases),bulbar palsy (13 cases) and autonomic nerve symptoms (9 cases). Hypo or areflexia was seen in 16 cases. Positive Babinski′s signs were seen in 8 cases. Hyponatremia was present in 10 cases in whom 4 showed severe hyponatremia. Albumin-cytological dissociation of cerebrospinal fluid was seen in 10 cases. The autoimmune antibodies were examined in all 19 patients. Anti-ganglioside antibodies including anti-GM1 IgG antibody was positive in 2 patients and one of whom was also found with positive anti-GD1b IgG antibody. Anti-GQ1b IgG antibody was present in 2 patients. Electromyography was performed in 14 cases and 8 cases, who were all BBE overlapping GBS, showed neurological damage. A total of 16 cases were monitored by video electroencephalography and 8 cases showed slow waves of background. In addition to, interictal focal discharge was detected in 2 cases. T2 fluid-attenuated inversion recovery (FLAIR) sequence abnormal signals were detected in 3 of 18 cases performed brain magnetic resonance imaging (MRI), and lesions involved with brainstem, basal ganglia, thalamus, cerebellum, corpus callosum and cerebral cortex. Lesions involved cervical and thoracic spinal cord were found in 1 out of 11 cases for whom spinal cord MRI was performed. All of the 4 cases who underwent enhanced MRI of spinal had partial nerve roots enhancement. All of the 19 patients received 1 to 2 courses of intravenous immunoglobulin therapy, and 2 cases also received plasma exchange. Fifteen cases received steroid therapy. The following-up period ranged from 3 months to 2.5 years. Two cases were lost to follow-up. Twelve cases achieved a full recovery within 3 months. Three cases recovered within 6 months. One case still had slight limb weakness and ataxia after 1 year and 8 months of follow-up, and another case had left autonomic nerve symptoms in the follow-up of 2 years and 3 months. Both of them were BBE overlapping GBS.@*Conclusions@#Children′s BBE is similar to that in adults, and is frequently found overlapped with GBS. Furthermore, it is sometimes accompanied by central nervous system demyelination disease. The antiganglioside antibodies are not often detectable. Immunoglobulin therapy could usually achieve good response. The prognosis of simple BBE is good in most situations. For BBE overlapping GBS, the more severe the limb weakness during the peak of disease is, the slower the recovery would be.
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Objective@#To describe the clinical manifestations of central nerve system inflammatory demyelinating disease associated with anti-myelin oligodendrocyte glycoprotein antibody (MOG-IDD) in children, and to explore the clinical characteristics of the children.@*Methods@#The clinical and laboratory characteristics of the patients diagnosed in Beijing Children′s Hospital, Capital Medical University, from October 2016 to August 2018 were described, and the clinical data of the patients with unipolar and recurrent diseases were compared.@*Results@#A total of 50 patients were included, among whom the ratio of male to female was 24:26, and the average age of onset was (6.7±3.1) years old (0.4-12.6 years old). There was no significant difference in the age of onset between boys and girls(t=0.712, P=0.480). The main symptoms included fever (31/50 cases), encephalopathy (26/50 cases) and optic neuritis (22/50 cases), etc.In the last follow-up, 26 patients (52.0%) had a monophasic course and 24 patients (48.0%) had a recurrent course.There were age differences in encephalopathy and ataxia in the first episode of [(5.7±2.8) years old vs.(8.1±3.0) years old, (5.0±2.5) years old vs. (7.7±3.0) years old](t=2.746, P=0.009; t=2.837, P=0.007). The average number of recurrence was (2.1±1.4) times (1-7 times), in which 17 cases (70.8%) of recurrence presented within 12 months and 20 cases (83.3%) of recurrence presented within 24 months after onset.Convulsion incidences of recurrent cases were 10 cases and 13 cases respectively in the first episode and recurrent courses, which were significantly higher than those of monophasic cases (4 cases, 4 cases)(χ2=7.912, P=0.005; χ2=8.365, P=0.004). All patients were sensitive to first-line immunotherapy.Seven patients with recu-rrence were treated with mycophenolatemofetil, and 17 patients with repeated first-line therapy.In the last follow-up, all patients were in remission and 2 patients had mild neurological dysfunction.@*Conclusions@#MOG-IDD can occur in childhood.Encephalopathy and optic neuritis are the most common symptoms.Encephalopathy and ataxia are more common in young children.Convulsions may indicate the course of recurrence.
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Objective@#To investigate the clinical significance of different samples (the peripheral blood, urine and skeletal muscle) that could be detected the large-scale single deletions directly by using next-generation sequencing in the diagnosis of Kearns-Sayre syndrome (KSS) by concluding the clinical and genetic features of KSS, in order to explore a non-invasive method for diagnosis.@*Methods@#The clinical data, skeletal muscle′s pathology and enzymology and genetic results of individuals with KSS, who were hospitalized from October 2016 to October 2017 in Department of Neurology, Beijing Children′s Hospital, Capital Medical University, were collected.The gene tests were performed by using next generation sequencing technology and long-PCR technology of mitochondrial DNA(mtDNA) and the whole exon in the peripheral blood, urine and skeletal muscle.@*Results@#Four patients were all consistent with the diagnosis criteria of KSS, among whom the age of onset was 8.2 years old on average, and the initial symptoms were statue, ptosis, headache and vomiting, and visual impairment.The common symptoms of the 4 cases were ophthalmoplegia, exercise intolerance, development delay, loss of appetite, hypotonia, muscle weakness, with cerebrospinal fluid protein concentration over 1 000 mg/L, the cerebral magnetic resonance imaging showed that abnormal signals in the brainstem, in addition, white matter, thalamus, basal ganglia, cerebrum and cerebellum atrophy could be found.Moreover, 3 cases had cardiac conduction block.Two cases had maternal family history.Molecular analysis of the 4 cases revealed the large-scale single deletions of mtDNA from the peripheral blood, the urine, the skeletal muscle through the next-generation sequencing, which were m. 6460-15590(9 131 bp del), m.8482-13446(4 964 bp del), m.6831-14981(8 151 bp del), m.7983-15495(7 513 bp del), respectively.Among 3 cases who did pedigree analysis, only the mother of case 4 was detected with the same variation of the proband.@*Conclusions@#KSS is a rare mitochondrial disease, which could be detected with the single large scale mtDNA deletions in the peripheral blood, urine and skeletal muscle.With the development of the methodology, the diagnosis of KSS maybe no longer than depends on the muscle biopsy with the next-generation sequencing.And the possibility to get the positive results in the peripheral blood and urine by the non-invasive method could improve the molecular diagnosis of KSS.
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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.
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Objective To investigate the clinical significance of different samples (the peripheral blood,urine and skeletal muscle) that could be detected the large-scale single deletions directly by using next-generation sequencing in the diagnosis of Kearns-Sayre syndrome (KSS) by concluding the clinical and genetic features of KSS,in order to explore a non-invasive method for diagnosis.Methods The clinical data,skeletal muscle's pathology and enzymology and genetic results of individuals with KSS,who were hospitalized from October 2016 to October 2017 in Department of Neurology,Beijing Children's Hospital,Capital Medical University,were collected.The gene tests were performed by using next generation sequencing technology and long-PCR technology of mitochondrial DNA(mtDNA) and the whole exon in the peripheral blood,urine and skeletal muscle.Results Four patients were all consistent with the diagnosis criteria of KSS,among whom the age of onset was 8.2 years old on average,and the initial symptoms were statue,ptosis,headache and vomiting,and visual impairment.The common symptoms of the 4 cases were ophthalmoplegia,exercise intolerance,development delay,loss of appetite,hypotonia,muscle weakness,with cerebrospinal fluid protein concentration over 1 000 mg/L,the cerebral magnetic resonance imaging showed that abnormal signals in the brainstem,in addition,white matter,thalamus,basal ganglia,cerebrum and cerebellum atrophy could be found.Moreover,3 cases had cardiac conduction block.Two cases had maternal family history.Molecular analysis of the 4 cases revealed the large-scale single deletions of mtDNA from the peripheral blood,the urine,the skeletal muscle through the nextgeneration sequencing,which were m.6460-15590(9 131 bp del),m.8482-13446(4 964 bp del),m.6831-14981 (8 151 bp del),m.7983-15495 (7 513 bp del),respectively.Among 3 cases who did pedigree analysis,only the mother of case 4 was detected with the same variation of the proband.Conclusions KSS is a rare mitochondrial disease,which could be detected with the single large scale mtDNA deletions in the peripheral blood,urine and skeletal muscle.With the development of the methodology,the diagnosis of KSS maybe no longer than depends on the muscle biopsy with the next-generation sequencing.And the possibility to get the positive results in the peripheral blood and urine by the non-invasive method could improve the molecular diagnosis of KSS.
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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.
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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.
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Objective To discuss the clinical manifestations,imaging features and prognosis of children with mild encephalitis/encephalopathy with a reversible splenial lesion(MERS).Methods Twenty-five patients with MERS admitted to Beijing Children′s Hospital,Capital Medical University,between November 2013 and March 2016 were enrolled and their clinical and imaging data were retrospectively analyzed.Ages of onset of these 25 cases were from 6 months to 13 years old.Because of different clinical manifestations in different onset ages,these 25 cases were divided into 2 groups:≤6 years old group (20 cases),with the onset age of 6 months to 3 years and 9 months old(average 2 years and 2 months);>6 years old group(5 cases),with the onset age of 9 years 3 months to 13 years old (average 10 years and 10 months).Results Nineteen cases among the 25 patients had infection history before onset,including 10 cases of digestive tract infection(all were ≤6 years old children),9 cases of respiratory tract infection(6 children ≤6 years old and 3 children >6 years old).The main clinical manifestations included convulsion (18/25 cases,72.0%),fever (17/25 cases,68.0%),vomiting (11/25 cases,44.0%),and disturbance of consciousness (11/25 cases,44.0%).The main clinical manifestation of ≤6 years old group was convulsion (18/20 cases,90.0%),while the main clinical manifestations of the>6 years old group were fever(3/5 cases,60.0%),headache and dizziness(2/5 cases,40.0%),and none of the patients in >6 years old group had convulsion.Eight cases had liver function injury,myocardial enzymes increased in 10 cases,and hyponatremia occurred in 9 cases.Magnetic resonance imaging (MRI) showed 21 cases were type Ⅰ MERS(only involving corpus callosum),and 4 cases of type Ⅱ MERS which involved corpus callosum as well as deep brain white matter,subcortical white matter (centrum semiovale).MRI lesions disappeared after 8-56 days (average 16.5 days) of anti-infection and reducing intracranial pressure treatment.Conclusion MERS is more common in ≤6 years old children,and digestive tract infection is common in ≤6 years old children,while respiratory tract infection is common in >6 years old children.The symptoms in children are mainly manifested as fever,convulsion,vomiting,conscious disturbance,and so on.Infection and hyponatremia are the main causes of MERS in children.MRI is the first choice of imaging examination methods.
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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.
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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.
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The numerous noxious reactions caused by misusing medicinal plant ingredients have been widely concerned at home and abroad. The problems of safe drug use needed to be solved. DNA barcode is a powerful molecular identification method, which can cover the shortage of tradditional morphological and chemical identification. In recent years, DNA barcode provided new aspects for the identification of Chinese herbal medicines and have obtained outstanding achievement. Several popular DNA regions ( ITS, ITS2, ps-bA-trnH, rbcL and matK) have been used for the identification of Chinese herbs.