De novo KCNMA1 mutations in 3 children with paroxysmal nonkinesigenic dyskinesia and developmental delay / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics of 3 unrelated boys with paroxysmal nonkinesigenic dyskinesia and developmental delay caused by de novo mutation in KCNMA1,and to expand the knowledge of clinical phenotype of KCNMA1 mutation.Methods Clinical data of patients were collected,including gender,age,condition of the perinatal period,personal history,and family history.And the features of genotype data were collected including features of attack,developmental milestones,physical examinations,treatments,and responses to treatment.The data including blood biochemical results,results of metabolic screening and genetic testing and the pedigree validation were collected,while the relationship between phenotype and genotype was analyzed.Results (1)Phenotypic features:3 unrelated boys were diagnosed.The ages of disease onset were 20 days,7 months and 13 months,respectively.All the patients manifested paroxysmal nonkinesigenic dyskinesia and were characterized by the episodes that occurred during wakefulness,presented with sudden onset of asymmetric limb dystonic posture,sometimes with nystagmus and strabismus,or sudden decrease of voluntary movement of limbs with hypotonia and occasional esotropia and yawning.There was no loss of awareness during attack.No precipitating factors were observed before attacks.The developmental milestones were delayed.Three children had no response to anti-epilepsy drug before diagnosis.After diagnosis,2 cases used Clonazepam and 1 case showed less attack.There was not any epileptic seizure until the last follow-up at the ages of 3 years and 6 months old,7 years old,and 5 years and 8 months old,respectively.The frequency of attacks was decreased.The episodes were recorded during video-electroencephalogram(EEG) monitoring,which showed normal ictal and interictal EEG.(2)Genotypic features:all 3 children were detected to have KCNMA1 genetic heterozygous missense mutation,while c.2650G>A (p.Glu884Lys) mutation was identified in 1 patient,and c.3158A>G(p.Asn1053Ser)mutation in the other 2 patients,but no such mutation was found in their parents.Conclusion This finding expands the phenotype of KCNMA1mutation.KCNMA1 should be considered as one of the candidate genes for screening in patients with early onset of paroxysmal nonkinesigenic dyskinesia without triggers,or early-onset of developmental delay,with or without epilepsy.

Follow-up and genetic study of 43 Chinese children with type Ⅰ Alexander disease / 中华儿科杂志

Objective@#To identify the clinical and genetic characteristics in 43 Chinese children diagnosed with type Ⅰ Alexander disease (AxD).@*Method@#Forty-three type Ⅰ AxD cases identified by glial fibrillary acidic protein (GFAP) gene mutations in Peking University First Hospital from 2005 to 2016 were followed up. The data of medical history, physical examination and magnetic resonance imaging (MRI) were collected. All these patients were followed up in December 2010, Febury 2012, June 2014 and January 2016, respectively.@*Result@#Forty-three patients were genetically confirmed as type I AxD and the median age at the last visit was 11.71 years (10.27, 13.15). The characteristic clinical manifestations of these type Ⅰ AxD patients were developmental delay (79%, 34/43), seizures (86%, 37/43), macrocephaly (the median percentile of head circumference is 90%), and paroxysmal deterioration (27%, 13/43). All the 43 patients′ brain MRI satisfied typical MRI features proposed by van der Knaap. According to the analysis of the long-term follow-up, patients with type Ⅰ AxD began to have obvious regression in motor function after 7 years of age, and the social life ability was milally impaired 8(6, 10)scores at the last follow-up. Seventeen heterozygous missense mutations of GFAP were identified in 43 genetically confirmed patients, and 4 mutations were novel. The mutations in 41 patients (95%, 41/43) were de novo. Three hot spots of mutation in Chinese patients were found: p. Arg239(35%, 15/34), p. Arg79 (26%, 11/43) and p. R88 (16%, 7/43).@*Conclusion@#The characteristic clinical manifestations of type Ⅰ AxD patients are developmental delay, seizures, macrocephaly and paroxysmal deterioration. Moreover, a few patients may present with brain stem symptoms, mental abnormalities, scoliosis or kyphosis. Patients with type Ⅰ AxD may show significant regression in motor function after 7 years of age.

Clinical research of 4 patients with type Ⅱ Alexander disease and literature review / 中华实用儿科临床杂志

Objective To analyze the clinical and MRI features of patients with type Ⅱ Alexander disease (AxD) in order to better understand and diagnose it earlier.Methods Four type Ⅱ AxD patients identified by glial fibrillary acidic protein gene mutations from Peking University First Hospital and 128 type Ⅱ AxD cases from published literatures were collected,and the clinical and MRI features were summarized.Results (1) In 4 type Ⅱ AxD patients,2 adult patients showed abnormal MRI features without clinical manifestation.The other 2 children patients both manifested motor dysfunction of lower limbs,pyramidal signs,paroxysmal deterioration,and seizures during the course of disease,while 1 of them had bulbar paralysis.The MRI of all the cases was abnormal,but only 1 case MRI corresponded with typical MRI features of type Ⅱ AxD.In the other 3 cases MRI showed thc atrophy in the medulla and upper spinal cord,or the brainstem lesions and abnormal signal in the periventricular white matter,and abnormal basal ganglia region.(2) In 128 reported type Ⅱ AxD cases,the age of onset was (32±19) years old.The initial syndromes mainly contained bulbar and/or pseudobulbar paralysis (32.48％,38/117 cases),motor dysfunction of the lower limbs (31.62％,37/117 cases) and autonomic nerve dysfunction (13.67％,16/117 cases).During the course of the disease,the clinical manifestation showed bulbar and/or pseudobulbar paralysis (73.50％,86/117 cases),pyramidal signs (60.68％,71/117 cases) and ataxia (51.28％,60/117 cases).The MRI of all cases was characterized by atrophy or abnormal signals in the brainstem,especially in medulla oblongata,and spinal cord.And abnormal signals in the cerebellar dentate nuclei,white matter,basal ganglia and thalamus were also commonly shown in the MRI.Conclusions The patients with type Ⅱ AxD are late-onsct.The clinical manifestation mainly contains bulbar and/or pseudobulbar paralysis,motor dysfunction of the lower limbs and pyramidal signs.The MRI is characterized by atrophy or abnormal signals in the brainstem (especially in medulla oblongata) and spinal cord.

Clinical and imaging analysis of white matter lesions combined with congenital sensorineural hearing loss in children / 中华实用儿科临床杂志

Objective To analyze the clinical and imaging characteristics of congenital sensorineural hearing loss (CSNHL)children combined with white matter (WM)lesions in order to provide evidence for clinical practice. Methods With referral to the Department of Pediatrics,Peking University First Hospital from November 201 1 to De-cember 201 5,documents of 78 patients of CSNHL combined with WMlesions were collected and analyzed for the clini-cal and imaging characteristics.Results Bilateral severe -profound hearing loss existed in all 78 cases,48.1 %(25 /52 cases)of the patients exhibited gross motor development delay,98.1 %(51 /52 cases)of them had normal cognition development.One hundred percent (61 /61 cases)of patients had abnormal language development.Infection occurring during pregnancy existed in 21 .2%(1 1 /52 cases)of the patients,the premature and smaller for the gestational age in-fants accounted for 28.9% (1 5 /52 cases).The bilateral multiple WMlesions from the brain MRI were in dot to flake sizes with sharp boundary,the intensity of T1 -weighted imaging decreased,T2 -weighted imaging and fluid attenuated inversion recovery increased.Eighty -two point one percent (64 /78 cases)of the patients were found to have the periventricular and subcortical WM involvement.The most frequently affected periventricular region was the posterior horn (91 .9%,68 /74 cases),followed by the anterior horn and temporal horn,and the least with the body involvement. The former three had a combined lesion tendency (55.4% -68.9%).There was an extensive involvement in the sub-cortical WMof parietal,frontal,temporal and occipital lobes respectively(73.5% -88.2%).Subcortical WM involve-ment of multiple lobes was common (accounted for 67.6% -77.9%).The enlargement of bilateral ventricles existed in 37.2%(29 /78 cases)of the patients and cystic changes in the subcortical WM of anterior temporal lobe could be found in 9.0% (7 /78 cases)patients.Calcification in 2 CT cases was reported.Corpus callosum and basal ganglia of all cases were normal.For cases with MRI scans more than once,WMlesions of 96.0%(24 /25 cases)patients became silent or self -restored.Conclusions The clinical presentations of CSNHL combined with WM lesions are mild,not paralleled with their multiple foci.It is considered as demyelination or a delay of myelination.Due to its benign course, it is probably not the contraindication for the cochlear implantation.

Clinical analysis of 13 cases of unrecognized infantile leukoencephalopathy / 中华实用儿科临床杂志

Objective To summarize the phenotypic features of an unrecognized leukoencephalopathy in infants sharing same clinical features,and to better understand the disease and provide new evidence for identification of new leukoencephalopathy. Methods Clinical and follow-up data of 13 patients with unrecognized infantile leukoen-cephalopathy were collected from Peking University First Hospital from January, 2006 to December, 2014. Results (1) There were 7 male and 6 female. The average age of onset was 11 months (4-25 months). Thirty-eight percent (5/13 cases) of patients had incentives before the onset;all of the cases had acute onset and rapid motor function regression. Fifteen percent (2/13 cases) of the patients suffered from seizures in the course of the disease. Patients′condition became stable,and cognition and motor function improved gradually 1 month after onset. No patient died till the last follow-up. (2) Imaging features:magnetic resonance imaging (MRI) of the patients was characterized by im-plicating deep white matter,presenting T1 hypointense,T2 and fluid attenuated inversion recovery ( FLAIR) hyperin-tense in the periventricular area. All of MRI showed massive and symmetric lesions with heterogeneous signal and cystic degeneration. DWI showed patch or massive hyperintense in some of the lesions. The follow-up MRI showed the original lesions decreased in 88% ( 8/9 cases ) of patients, and white matters atrophied in 55% ( 5/9 cases ) of patients;the cystic degeneration still existed and even expanded;DWI showed regional linear or spot hyperintense in 88% (8/9 cases) of patients,which was smaller than before,and distributed around the original lesions. Conclusions The patients with leukoencephalopathy caused by unknown pathogenic gene were much likely to be mitochondrial leukoencephalopathy. This study provided evidence for further exploration of new pathogenic genes causing leu-koence-phalopathy.