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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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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 summarize the clinical features of leukoencephalopathy with vanishing white matter disease (VWM) in children.@*Methods@#A retrospective cohort study was performed on 54 genetically diagnosed VWM patients in Peking University First Hospital from January 2007 to March 2019. Paper registration form and electronic medical record system were used to collect the data,and the children were divided into five groups according to the age of disease onset:<1 year, 1-<2 years, 2-<4 years, 4-<8 years and 8-<18 years respectively. The progression of motor function, episodic aggravation, epileptic seizures, survival time, brain magnetic resonance imaging (MRI) and genotype features were analyzed and compared. Non-parametric test, χ2 test or Fisher′s exact test were used for comparison among groups; Kaplan-Meier survival curve was adopted to delineate the survival status of the children.@*Results@#Fifty-four VWM patients were included in the study, including 34 males and 20 females.The age of disease onset was 2 years and 8 months (ranged from 6 months to 9 years and 7 months). Onset age was less than 1 year in 5 cases; onset age was 1-<2 years in 12 cases; onset age was 2-<4 years in 25 cases; onset age was 4-<8 years, in 10 cases; onset age was 8-<18 years in 2 cases; 94% (51/54) of patients had complaint of motor regression at the first visit; 87% (47/54) of patients suffered from episodic aggravation. Episodic seizures occurred in 43% (23/54) patients. In survivors with disease durations of 1-3 years, in 38% (9/24) patients the disease was classified as grades Ⅳ-Ⅴ by gross motor function classification system (GMFCS). For the onset age 1-<2 years group, 1 patient was classified as GMFCS Ⅳ among 3 survivors with disease durations of 1-3 years. As for the 2-<4 years group, 6 patients were classified as GMFCS Ⅳ-Ⅴ among 15 patients with disease durations of 1-3 years, whereas 1 patient was classified as GMFCS Ⅳ-Ⅴ among 4 patients with disease durations of 1-3 years in the 4-<8 years group. Lesions, liquefaction and diffusion restriction in brain MRI were compared among different groups, and it was revealed that the earlier the age of disease onset was, the more likely the subcortical white matter (frontal lobe P<0.01,temporal and parieto-occipital lobe both P=0.002), internal capsule (anterior limb P<0.01, posterior limb P=0.00) and brain stem (midbrain P=0.001, pons P<0.01) were to be involved. In addition, internal capsule (anterior limb P=0.002, posterior limb P=0.005) and brain stem (midbrain P=0.001, pons P=0.003) showed more diffuse restricted diffusion. Moreover, the subcortical white matter (frontal and parieto-occipital lobe both P<0.01, temporal lobe P=0.005) showed earlier rarefaction. The 1-year and 2-year survival rates of the overall patients were 81% and 75% respectively, while the 15-year survival rate was 45%. EIF2B5 gene variation was the most common, which accounts for 43% (23/54), followed by EIF2B3 (22%, 12/54).@*Conclusions@#The majority of VWM patients complained of motor regression at the first visit, episodic aggravation and epileptic seizures are common in the course. Earlier age at onset is associated with more rapid clinical progression, shorter survival time as well as more extensive lesions, liquefaction and diffusion restriction in brain MRI. The most common variant gene is EIF2B5, followed by EIF2B3.
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Objective@#To summarize the clinical and genetic characteristics of focal epilepsy in children caused by GATOR1 complex gene variation.@*Methods@#The clinical data, gene variation and treatment outcome of 12 children with focal epilepsy caused by GATOR1 complex gene variation admitted to Beijing Children′s Hospital Affiliated to Capital Medical University from June 2016 to October 2018 were retrospectively analyzed.@*Results@#There were 7 males and 5 females in 12 cases. The epilepsy onset age was 5.5 (3.0, 12.0) months, and from 11 days to 16 months of age. The epileptic seizure types were all focal motor seizures, and one case combined with epileptic spasms. The frequency of seizures in all patients was more than one time per day. Seven cases had frontal lobe epilepsy and two cases had lateral temporal lobe epilepsy. One case had a family history of febrile seizures and two had a family history of suspicious epilepsy. Epileptic form discharges were observed in 9 patients during the interictal phase by electroencephalograms (EEG), and all of them were focal discharges. Eight cases had clinical seizures detected by EEG, in 4 of whom the seizures were originated in frontal region. There were no abnormalities in brain magnetic resonance imaging in 11 cases whereas 1 case had malformation of cortical development of left frontal lobe. Eight patients had DEPDC5 gene variation, one had NPRL2 gene variation, three had NPRL3 gene variation. One case had de novo variation and the other 11 had hereditary variation. There were 11 types of gene variation, including 5 nonsense variations, 3 missense variations, 2 frame shift variations and 1 in frame deletion variation. There was no clear relationship between the clinical phenotype and the genotype. During the follow-up period from 6 months to 2 years and 6 months, 6 cases had seizure control, 3 of them were controlled by oxcarbazepine. The other 6 cases had drug-refractory epilepsy, 2 of them failed with vagus nerve stimulation and ketogenic dietary therapy as well, meanwhile combined with mental retardation.@*Conclusions@#GATOR1 complex gene variation can lead to genetic focal epilepsy, which usually has early onset with frequent seizures. Most of the patients have focal epileptic form discharges on EEG, and there is usually no structural lesion in brain imaging. Most of the patients have hereditary loss-of-function variations. Approximately half of cases are drug-resistant epilepsy.
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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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<p><b>OBJECTIVE</b>To investigate the clinical and genetic features of a Chinese girl with Schwartz-Jampel syndrome (SJS).</p><p><b>METHOD</b>To analyze the clinical and genetic data of a girl with Schwartz-Jampel syndrome who was sent to neurology outpatient department of Beijing Children's Hospital in Auguest of 2010. Reports on Schwartz-Jampel syndrome published until July of 2015 were searched and the clinical and genetic characteristics of reported cases were summarized.</p><p><b>RESULT</b>At 8 months after birth, the girl showed myotonia; at 1 year old when she was walking alone she had myotonia of lower limbs, both feet evaginated, walked slowly and was prone to fall. At 2 years of age, she could not climb up stairs, at 3 years she could not jump continuously. At 3 years and 7 months of age when the girl was taken to neurology outpatient department, on examination, she had a dull facial expression, rigid lips and could not fully open her mouth, a micromandible, low-set and prominent ears, systemic muscle rigidity, there were muscular nodes formation on the limbs and gait stiffness. She had high level of creatine kinase and atlanto-axial joint subluxation on cervical CT reconstruction. She also had spontaneous myotonia-like discharges on needle electromyography (NEMG). X-ray of limbs showed metaphyseal dysplasia. The patient was treated with neurologic rehabilitation and carbamazepine. The myotonia at the last follow-up at her 8 years of age was the same as at the onset. On her HSPG2 gene, two novel heterozygous mutations c.10776delT on exon 78 and c.5702-5G>A on intron 45 were found. c.10776delT resulted in the amino acid change on p.Ala3592fsX6 and c.5702-5G>A maybe changed protein splicing. No reports were found among Chinese journals, while 7 reports were found in English literature. The total 34 mutations were known in reviewed reports, which included eleven deletion or insertion, twelve splice site, eight missense, and three nonsense mutations. Four patients had a single mutation. No definite genotype-phenotype correlation was identified.</p><p><b>CONCLUSION</b>Schwartz-Jampel syndrome is a rare autosomal-recessive hereditary disease appears to be slowly progressive, in which distinctive clinical features were induced by HSPG2 gene mutation. We reported the c.10776delT on exon 78 and c.5702-5G>A on intron 45 which were not reported previously. This is the first report of Schwartz-Jampel syndrome of which genetic mutations was identified in a Chinese child.</p>
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Child , Child, Preschool , Female , Humans , Infant , Asian People , Carbamazepine , Therapeutic Uses , Exons , Heterozygote , Introns , Mutation , Osteochondrodysplasias , Diagnosis , GeneticsABSTRACT
<p><b>OBJECTIVE</b>To analyze the clinical and PMM2 gene mutation features of congenital disturbance of glycosylation caused by PMM2 gene mutation (PMM2-CDG, previously known as CDG 1a).</p><p><b>METHOD</b>The clinical data of two Chinese patients who were clinically diagnosed as PMM2-CDG at neurology department of Beijing Children's Hospital in 2012 were retrospectively collected. The gene mutations were identified by Sanger sequencing.</p><p><b>RESULT</b>Both patients were female, aged 1 year and 1 month and 8 months respectively. The main clinical features of the two cases were developmental delay after birth, chronic diarrhea and metabolic acidosis, associated with elevated serum transaminases, and decreased antithrombin III activity. Physical examination showed esotropia, inverted nipples, and abnormal subcutaneous fat pads. The cranial MRI showed cerebellar atrophy. Both cases were treated with occupational therapy, physical therapy and speech therapy. The development was gradually improved but also delayed as compared with normal peers during follow-up for more than 3 years. Genetic analysis showed that patient 1 was compound heterozygous for c. 422G>A(p.Arg141His), which was reported for known pathogenic mutation, and c. 669C>A(p.Asp223Glu), was a new mutation. The patient 2 showed compound heterozygous mutation for c. 634A>G (p.Met212Val)and c. 713G>C(p.Arg238Pro), which were both new mutations.</p><p><b>CONCLUSION</b>PMM2-CDG is a rare metabolic disease, and the diagnosis should be considered in a child with developmental delay, elevated serum transaminases, decreased antithrombin III activity, inverted nipples, abnormal subcutaneous fat pads, esotropia, and cerebellar atrophy on MRI. It can be confirmed by PMM2 gene analysis.</p>