Research progress on neurodevelopmental disorders in children with Duchenne muscular dystrophy / 中华实用儿科临床杂志

Duchenne muscular dystrophy (DMD) is a disease inherited in an X-linked recessive pattern, which is caused by the pathogenic mutation of the gene encoding Dystrophin.An increasing number of studies have confirmed the high risk of neurodevelopmental disorders in children with DMD, and that related comorbidities have distinct clinical characteristics.In this article, the research progress on neurodevelopmental disorders in children with DMD was reviewed to clarify the prevalence, clinical characteristics and high-risk factors of neurodevelopmental disorders in children with DMD.DMD therapy teams should pay attention to the evaluation, interpretation and early intervention of neurodevelopmental disorders in clinic practice, so as to improve the life quality of DMD children and help them to be-tter integrate into the society.

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 13 cases with acute pandysautonomia / 中华实用儿科临床杂志

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.

Large-single scale mitochondrial DNA deletions in different tissues in Kearns-Sayre syndrome / 中华实用儿科临床杂志

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.

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

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

Large-single scale mitochondrial DNA deletions in different tissues in Kearns-Sayre syndrome / 中华实用儿科临床杂志

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.

Feasibility study on the control of clonic symptoms in children with neuroblastoma based on systemic chemotherapy combined with high-dose of immunoglobulin and prednisone / 中华实用儿科临床杂志

Objective To explore the feasibility of immunotherapy intermittently with high dose intravenous immunoglobulin(HD-IVIG)impact therapy combined with prednisone on the basis of systematic chemotherapy to control the clonic symptoms of children with neuroblastoma(NB).Methods A retrospective analysis was made based on the clinical data of 8 NB children with combined clonus,who were admitted in Beijing Children's Hospital,Capital Medical University from May 2011 to February 2017.And analysis and summary were also made according to patients' clinical data,neurological symptoms,therapy methods and prognosis.The follow-up visiting was ended on March 1,2017.Results Eight patients were investigated,3 male and 5 female,with onset age ranged from 10.0 to 35.5 months (the median age was 17.5 months),and the period from occurrence of clonic symptoms to a definite diagnosis and starting treatment was 1.25 to 6.50 months (the median time was 3.60 months).All patients developed kinds of neurological syndrome clinically,such as clonus on the trunk and limbs,and 5 cases of them were involved in combined opsoclonus-myoclonus syndrome (OMS).All patients went for their first-time consultancy at the Neurology Department of Beijing Children's Hospital,Capital Medical University or local hospitals.The primary tumor focus was found in unilateral adrenal gland in 2 cases,1 case in bilateral adrenal glands,2 case in retroperitoneal region,2 cases in mediastinum and 1 cases in presacral region.The image examination indicated 1 case with a tumor focus,the diameter of it more than 5 cm.Except for 1 case involved in the local invasion of tumor in vertebral body,the images examination of all other patients showed the focus in the primary location,without visible distant metastasis or no abnormality was seen by head magnetic resonance imaging (MRI) examination.Initially,four cases had normal neuronal specific enolase (NSE) and 4 had higher NSE;one case had higher urine vanillylmandelic acid (VMA) and 7 normal;3 cases had higher urine homovanillic acid(HVA) and 5 normal.Among 8 patients,the pathological pattern of 6 cases was NB,in which 4 cases were of differentiated type and 2 cases of poorly differentiated type;the pathological pattern of 2 cases was ganglion cell NB,in which 1 case was of nodular type and 1 case of mixed type.N-MYC was not amplified.Clinical staging:5 cases of stage Ⅱ and 3 cases of stage Ⅲ.Clinical grouping:7 cases of intermediate risk group and 1 case of low risk group.So far,1 case lost follow-up in that the child didn't receive regular diagnosis and treatment due to economic problem,so significant improvement of clonic symptoms was not seen,all other patients were given the immunotherapy with intermittent HD-IVIG impact therapy and oral administration of prednisone based on systematic chemotherapy:immunoglobulin was applied respectively before,during and after chemotherapy in multiple impact treatments;3 cases received 4 courses of treatment,2 cases received 3 courses of treatment and 2 cases received 2 courses of treatment.Prednisone was given orally during the application of immunoglobulin,from the full dose and with the course of treatment of 1.0 to 5.5 months,3 months on average;then the dose was gradually reduced.With the follow-up up to now,hormone was discontinued in 4 cases and the total course of treatment was 8 to 12 months,10 months on average.One month after the treatment of patients in 4 cases,the clonic symptoms were improved or disappeared in 5 to 12 months;the clonus of patients in 2 cases was improved respectively 3 months after treatment and half a year after drug withdrawal,in which the symptoms of 1 case disappeared completely 1 year after treatment and the slight clonic symptoms of 1 case still existed by the update follow-up.Except for 1 case of patient lost to follow-up,the regular primary tumor focus of all patients indicated that the disease conditions were in a stable state.Conclusions The immunotherapy intermittently applied with HD-IVIG impact therapy in combination with prednisone based on regular systematic chemotherapy can effectively control the clonic symptoms of children with NB.The earlier the intervene treatment for clonic symptoms is recommended,so that the faster recovery of symptoms can be achieved.Early diagnosis and early treatment play a helpful role in the recovery of children with neurological symptoms.

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 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 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>

A case report and literature review of myocardial hypertrophy in children's acute rhabdomyolysis / 中华实用儿科临床杂志

Objective To report one case of the children's acute rhabdomyolysis(RM) with myocardial hypertrophy for the first time and the related data in order to improve the clinical diagnose and the treatment efficacy.Methods Clinical data of the patient with myocardial hypertrophy and pericardial effusion treated in the Heart Center of Beijing Children's Hospital Affiliated to Capital Medical University were retrospectively analyzed.According to the symptoms,signs,laboratory examination,the diagnosis was made and related literature was reviewed.Results A 7-years-old girl was characterized by myalgia,weakness,and dark urine.Physical examination showed extremity swelling,clammy skin,lower extremity muscle tenderness positive.Creatine kinase (CK) and myoglobin levels increased.So she was clearly diagnosed of acute RM undoubtedly.Without physical,metabolic and autoimmune factors,the patient was only had positive mycoplasma antibodies and might be coursed by mycoplasma infection.The muscular involvement was so severe that the patient had the heart failure,myocardial hypertrophy and pericardial effusion was conformed to ultrasound cardiogram(UCG).After treatment with hydration,alkalization,anti-infection,support and symptomatic therapy for a few days,the clinical symptoms improved obviously,CK returned to normal,myocardial hypertrophy and pericardial effusion disappeared.One-year-follow-up study indicated that the child's animal force and body movements were norrmal,and CK and UCG were negative.Conclusions Acute RM is a rare disorder and less recognized in children,and myocardial hypertrophy and pericardial effusion may be caused by acute RM.If the diagnosis and treatment are done earlier,the prognosis will be good,without permanent complications.

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>

Function disability evaluation in hereditary motor and sensory neuropathy pediatric patients / 中华实用儿科临床杂志

Hereditary motor and sensory neuropathy is the most common peripheral neuropathy.It is slowly progressive,proximal limb weakness and muscular dystrophy and severe foot deformity can cause function disability.For most patients were diagnosed in early children,so function disability evaluation and effective treatment from children is significant to their prognosis.