Autism with dysphasia accompanied by mental retardation caused by FOXP1 exon deletion:A case report

BACKGROUND Forkhead box protein 1(FOXP1)(OMIM:605515)at chromosomal region 3p14.1 plays an important regulatory role in cell development and functions by regulating genetic expression.Earlier studies have suggested that FOXP1,an oncogene,is capable of initiating tumorigenicity depending on the cell type.FOXP1 also plays an important role in regulating the cell development and functions of the immune system,e.g.,regulating B-cell maturation and mononuclear phagocyte differentiation,and in the occurrence and development of various immune diseases.The mRNA of this gene is widely expressed in humans,and its differential expression is related to numerous diseases.CASE SUMMARY A 5-year-old boy mainly presented with attention deficit and hyperactivity disorder and developmental retardation accompanied by gait instability and abnormal facial features(low-set ears).DNA samples were extracted from the child’s and his parents’peripheral blood to detect whole-exome sequences and whole-genome copy number variations.Results revealed heterozygous deletions of exon 6-21 of FOXP1 gene in the child.Physical examination upon admission showed that the child was generally in good condition,had a moderate nutritional status,a slightly slow response to external stimuli,equally large and equally round bilateral pupils,was sensitive to light reflection,and had poor eye contact and joint attention.He had no meaningful utterance and could not pronounce words properly.He was able to use gestures to simply express his thoughts,to perform simple actions,and to listen to instructions.He had no rash,cafe-au-lait macules,or depigmentation spots.He had thick black hair and low-set ears.He had highly sensitive skin,especially on his face and palms.He had no abnormal palm fingerprint.Cardiopulmonary and abdominal examinations revealed no abnormalities.He had normal limb muscle strength and tension.He showed normal tendon reflexes of both knees.His bilateral Babinski and meningeal irritation signs were negative.He had a normal male vulva.CONCLUSION We report the characteristic features of autism with dysphasia accompanied by mental retardation caused by FOXP1 exon deletion.This study provides a molecular basis for etiological diagnosis and treatment of the child,as well as for genetic counseling for the pedigree.

Autism and Mental Retardation of Young Children in China

To understand the prevalence and rehabilitation status of autism and mental retardation in China. Methods Screening test and clinical assessment were conducted for the diagnosis of autism and mental retardation. The assessment included investigation of the histories of medical conditions and development of these two disorders, utilization and needs for the rehabilitation service, and related intellectual and behavioral appraisal. Results Among the 7345 children investigated, the prevalence of autism disorder was 1.10 cases per 1000 children aged 2-6 years （95% CI=0.34 to 2.54）, and the prevalence of mental retardation was 10.76 cases per 1000 children （95% CI=8.40 to 13.12）. All the children suffering from autistic disorder were intellectually disabled, whereas 31.0% of the non-autism mental retardates had other disabilities. The medical conditions prior to birth and perinatal period were important potential factors for autism. Half of the autistic children and 84% of the children with non-autism mental retardation had never received any rehabilitative service. Conclusions The prevalence of autistic disorder in children aged 2-6 years in Tianjin is rather high. It is urgent to improve the status of the autistic and intelligently disabled young children in China. In order to upgrade the level of early diagnostic and improve the intervention to autism and mental retardation, public awareness and training courses should be heightened.

Correlating fine motor function to cognitive competence in children with mental retardation An analysis of 42 cases

BACKGROUND： In clinical practice, the degree of cognitive competence damage correlates to fine motor function deficits in children with psychomotor development retardation. Clear correlations between the two can help to develop and perform corresponding functional training for children with mental retardation （MR）. OBJECTIVE： This study was designed to evaluate and analyze the correlation of fine motor function to cognitive competence in MR children using the Peabody Developmental Motor Scale-Fine Motor （PDMS-FM） and Symbolic Play Test. DESIGN： Scale evaluation and correlation analysis. SETTING： Children＇s Rehabilitation Center ＆ Huajing District Hospital, Children＇s Hospital Affiliated to Fudan University. PARTICIPANTS： A total of 42 MR children, 28 males and 14 females, aged 14-69 months, were admitted to the Rehabilitation Center, Children＇s Hospital, Fudan University between June 2003 and April 2006, and were recruited for this study. All children corresponded to MR diagnosis criteria determined by Chinese Neurology and Psychiatry Society in 1989. Written informed consent for participating in the evaluation and for evaluated content was obtained from each child＇s guardian. METHODS： Subsequent to admission and prior to treatment, fine motor function of each MR child was evaluated using PDMS-FM （Chinese version）. The scale captured 98 items that formed the grasping （Gr） and visual-motor integration （Vi） subtests. Cognitive competence was evaluated using the Symbolic Play Test （Chinese version）, which captured four 6-item specific contents. The original score of each subtest was used to evaluate results for statistical analysis. Higher scores from the two evaluations indicated stronger abilities. Pearson correlation analysis was applied for analyzing data correlation. MAIN OUTCOME MEASURES： Fine motor function was evaluated using PDMS-FM. Cognitive competence was measured using the Symbolic Play Test. Correlations between results from the two evaluations were analyzed. RESULTS： All 42 MR children were included in the final analysis. Correlation analysis results demonstrated significant positive correlations of original scores existed between Gr and Vi subtests in the PDMS-FM （r = 0.761, P 〈 0.01）, and between Vi and Gr subtests in PDMS-FM and Symbolic Play Test （r = 0.663, 0.450, P 〈 0.01）. CONCLUSION： Fine motor function closely correlates to cognitive competence in MR children. This indicates fine motor function training should be developed in combination with cognitive competence training.

Molecular Genetic Analysis of Partial 9p Trisomy in Two Chinese Families with Mental Retardation and Facial Anomaly

Mental retardation is defined by significant limitations in intellectual function and adaptive behavior that occur before 18 years of age.Many chromosomal diseases come with mental retardation.We reported two Chinese families with partial trisomy 9p and other chromosome partial monosomy,clinical features of mental retardation and mild facial and pinkie anomalies.In the family 1,we showed that the proband carried a trisomy 9p21.3→pter and monosomy 21q22.3→qter by using fluorescence in situ hybridization analysis.Molecular genetic analysis defined the precise breakpoint on chromosome 9p between markers D9S1846 and D9S171,an interval of about 2.9 Mb on 9p21.3,and the breakpoint on chromosome 21q between markers D21S1897 and D21S1446,a region of about 1.5 Mb on 21q22.3.In the family 2,a patient with trisomy 9p21.3→pter and monosomy 5p15.33→pter,and a de novo maternal balanced translocation between chromosomes 5 and 9 was identified in his mother.Cytogenetic and molecular genetic analysis defined the precise breakpoints on chromosome 9p21.3 and chromosome 5p15.33.Further clinical investigation found that any individual had no refractoriness eczema disease except the proband in this family.These results further implicate that trisomy 9p is associated with mental retardation,and that there may be key gene duplication on chromosome 9p21.3→9pter responsible for mental retardation and mild facial anomaly.This result has been applied successfully in prenatal diagnosis of the second family.

Primed In Situ Labeling Technique for Subtelomeric Rearrangements in 70 Children with Idiopathic Mental Retardation

Subtelomeric rearrangements contribute to idiopathic mental retardation （MR）, but most children with idiopathic MR do not show any chromosome abnormalities with standard cytogenetic analysis. The primed in situ labeling （PRINS） technique, using an oligonucleotide primer complementary to the telemetric repeat sequences （TTAGGG）, can identify chromosome telomeric abnormality （deletion） in idiopathic MR children. In this study, seventy children with idiopathic MR were enrolled and subjected to PR1NS. The results showed normal karyotype in all the children, subtelomeric rearrangements （lq del and 4q del） in 2 cases, which was confirmed by fluorescence in situ hybridization （FISH）. It was concluded that PRINS is effective for the detection of subtelomeric rearrangements and may become a routine technique for cytogenetical abnormality screening.

INFLUENCE OF ACUPUNCTURE ("JIN'S SAN ZHEN") ON BRAINSTEM EVOKED POTENTIALS IN MENTAL RETARDATION CHILDREN

Objective: To investigate the effect of acupuncture ("JIN’s San Zhen") on infantile mental retardation (MR). Methods: 44 cases of MR children were attributed to treatment group and 39 normal children to control group. P 3 (event related potential) and brainstem evoked potentials were used as the indexes. Acupoints "Si shen Zhen", "Head Zhi San Zhen", "Hand Zhi San Zhen", "Foot Zhi San Zhen" were punctured with filiform needles, and stimulated by manipulating the needle once every 5 minutes with uniform reinforcing reducing method. The treatment was conducted once daily, 6 times every week, with 4 months being a therapeutic course. Results: In comparison with normal children, the latency of P 3 was longer and its amplitude lower in MR children. After 4 months’ acupuncture treatment, the latency was shortened and the amplitude increased significantly in comparison with pre treatment (P<0.01, 0.05). Results of the total intelligence quotient (TIQ) evaluation showed a 70.3% coincidence rate compared with improvement of P 3. Conclusion: Changes of P 3 and BAEP(brain auditory evoked potential) after acupuncture treatment may be related to the effect of "JIN’s San Zhen" in bettering clinical symptoms and signs of MR infantile patients.

Acupuncture at jing-well point combined with educational training for the treatment of children with severe mental retardation

Objective To observe clinical efficacy of acupuncture at ]ing-well point combined with educational training for the treatment of children with severe mental retardation. Methods Sixty children with severe mental retardation were randomly divided into ]ing-well point acupuncture plus simple special education and language training group （group A） and simple special education and language training group （group B） with 30 child patients in each group according to registration order. All the patients were treated once every other day, 10 times as a course of treatment. There were 20 days of interval between each course of treatment. Curative effect was analyzed after 3 courses of treatment. Gesell Developmental Scale test was conducted for all children before and after treatment. Development quotient at the functional area of social adaptability, large motor, fine motor, language skill and social behavior of individuals was recorded and compared between groups and before and after treatment to evaluate the curative effect. Results Social adaptability and fine motor of children were improved in the group B after treatment. And in the group A, social adaptability, fine motor, language skill and social behavior of individuals were improved after treatment. Meanwhile, the group A was superior to the group B in curative effect of overall social adaptability and language skill （both P〈0.05）. The overall response rate in group B was 23.3% （7/30） and in group A was 46.6% （14/30, P〈0.05）. Conclusion Acupuncture at jing-well point combined with educational training can effectively improve the intelligence level of children with severe mental retardation and its curative effect is better than that of simply education and training.

Acupuncture combined with ear point taping and pressing for sleep disturbance in 30 children with mental retardation

Objective To observe the therapeutic effect of acupuncture combined with ear point taping and pressing on sleep disturbance of the children with mental retardation. Method Thirty children of mental retardation with sleep disturbance were treated with acupuncture combined with ear point taping and pressing therapy, Sìshénzhēn （四神针）, Nǎosānzhēn （脑三针）, Zhìsānzhēn （智三针）, Nièsānzhēn （颞三针）, Shǒuzhìzhēn （手智针） were selected as main acupoints, and adjunct points were used according to symptoms and syndrome differentiation. For ear point taping and pressing, ěrshénmén （耳神门 MA-TF1）, Pízhìxià （皮质下 MA–AT1）, Jiāogǎn （交感 MA-AH7）, Xīn （心, heart）, Shèn （肾 kidney）, Pí （脾 spleen） were selected. The treatment was given two therapeutic courses, thrice each week, 36 sessions constituted one course. Child Sleep Habit Questionnaire （CSHQ） scale was used for assessment of sleep state before and after the treatment. Results After the treatment, among the 30 cases, 11 cases were markedly effective, 16 cases were effective and 3 cases were failed, the total effective rate was 90.0%; after the treatment, the children had significant improvement in the total time of sleep, the time of going to bed for sleep, sleep habit, sleep behavior, awaking state at night, getting-up state in the morning, sleep state in the daytime and the total score （P0.01, P0.001）. Conclusion Acupuncture combined with ear point taping and pressing therapy has a positive therapeutic effect on sleep disturbance and increases sleep quality in varying degrees in children with mental retardation.

Acupuncture for Promoting Intelligence of Children—An Observation on 37 Cases with Mental Retardation

Objective: To observe the effect of acupuncture on intelligence quotient (IQ) in children with mental retardation (MR). Methods: One hundred children with MR were randomly divided into an acupuncture group and a control group, 50 in each. There were 37 and 36 cases with complete data in the former and latter group respectively. Four-week treatment constituted a course, the comprehensive therapeutic effect of two groups was compared after 3 courses of treatment, and the influence of acupuncture on IQ was estimated. Results: The total effective rate in the acupuncture group was 78.4%, better than 30.56% in the control group, the difference being significant (P<0.01). Both groups were improved in IQ but the effect of the former group was better than that of the latter group (P<0.05). Conclusion: Acupuncture can obviously improve IQ of children suffering from MR.

Bidirectional regulation of fragile X mental retardation protein phosphorylation controls rhodopsin hornoeostasis

Homoeostatic regulation of the light sensor, rhodopsin, is critical for the maintenance of light sensitivity and survival of photore- ceptors. The major fly rhodopsin, Rhl, undergoes light-induced endocytosis and degradation, but its protein and mRNA levels remain constant during light/dark cycles. It is not clear how translation of Rhl is regulated. Here, we show that adult photorecep- tors maintain a constant, abundant quantity of ninaE mRNA, which encodes Rhl. We demonstrate that the Fmrl protein associ- ates with ninaE mRNA and represses its translation. Further, light exposure triggers a calcium-dependent dephosphorylation of Fmrl, which relieves suppression of Rhl translation. We demonstrate that Mts, the catalytic subunit of protein phosphatase 2A （PP2A）, mediates light-induced Fmrl dephosphorylation in a regulatory B subunit of PP2A （CKa）-dependent manner. Finally, we show that blocking light-induced Rhl translation results in reduced light sensitivity. Our results reveal the molecular mechanism of Rhl homoeostasis and physiological consequence of Rhl dysregulation.

SUMOylation of Fragile X Mental Retardation Protein: A Critical Mechanism of FMRP-Mediated Neuronal Function

Recently, Khayachi et al.;showed that fragile X mental retardation protein （FMRP） is an active substrate of the small ubiquitin-like modifier （SUMO） pathway in neurons.FMRP SUMOylation is induced by the activation of metabotropic glutamate receptors （mGlu5Rs）. FMRP

Analysis of the Fragile X Mental Retardation 1 Premutation in Han Chinese Women Presenting with Primary Ovarian Insufficiency

Background: The aim of this study is to investigate the prevalence of the fragile X mental retardation 1(FMR1) gene premutation in Han Chinese women with primary ovarian insufficiency(POI) using a rapid and cost-effective method. Methods: A total of 153 Han Chinese women with sporadic POI were systematically analyzed for trinucleotide repeats within the FMR1 gene. We employed an improved strategy to screen for cytosine-guanine-guanine repeats in the 5’ untranslated region of the FMR1 gene. Before using the previously reported Fragil Ease polymerase chain reaction(PCR) method for premutation identification, we developed a new cost-effective PCR-based method to exclude most of the normal allele carriers during the initial screening stage. Results: In our initial screening, 62.1% of women with POI were found to carry heterozygous normal alleles of FMR1, which were recognized by our sensitive and cost-effective method. The remaining women were further screened for the presence of the FMR1 premutation. We identified a Han Chinese woman with a premutation allele of FMR1 out of 153 sporadic POI women(0.7%). Conclusions: The frequent FMR1 premutation in Caucasian individuals with POI may not be a common genetic cause of sporadic POI in the Han Chinese population.

High-grade serous carcinoma of the fallopian tube in a young woman with chromosomal 4q abnormality:A case report

BACKGROUND Few studies have reported an association between an increased risk of acquiring cancers and survival in patients with 4q deletion syndrome.This study presents a rare association between chromosome 4q abnormalities and fallopian tube highgrade serous carcinoma(HGSC)in a young woman.CASE SUMMARY A 35-year-old woman presented with acute dull abdominal pain and a known chromosomal abnormality involving 4q13.3 duplication and 4q23q24 deletion.Upon arrival at the emergency room,her abdomen appeared ovoid and distended with palpable shifting dullness.Ascites were identified through abdominal ultrasound,and computed tomography revealed an omentum cake and an enlarged bilateral adnexa.Blood tests showed elevated CA-125 levels.Paracentesis was conducted,and immunohistochemistry indicated that the cancer cells favored an ovarian origin,making us suspect ovarian cancer.The patient underwent debulking surgery,which led to a diagnosis of stage IIIC HGSC of the fallopian tube.Subsequently,the patient received adjuvant chemotherapy with carboplatin and paclitaxel,resulting in stable current condition.CONCLUSION This study demonstrates a rare correlation between a chromosome 4q abnormality and HGSC.UBE2D3 may affect crucial cancer-related pathways,including P53,BRCA,cyclin D,and tyrosine kinase receptors,thereby possibly contributing to cancer development.In addition,ADH1 and DDIT4 may be potential influencers of both carcinogenic and therapeutic responses.

Missense mutation in DYNC1H1 gene caused psychomotor developmental delay and muscle weakness:A case report

BACKGROUND The DYNC1H1 gene encodes a part of the dynamic protein,and the protein mutations may further affect the growth and development of neurons,resulting in degeneration of anterior horn cells of the spinal cord,and a variety of clinical phenotypes finally resulting in axonal Charcot-Marie-Tooth disease type 20(CMT20),mental retardation 13(MRD13)and spinal muscular atrophy with lower extremity predominant 1(SMA-LED).The incidence of the disease is low,and it is difficult to diagnose,especially in children.Here,we report a case of DYNC1H1 gene mutation and review the related literature to improve the pediatrician’s understanding of DYNC1H1 gene-related disease to make an early correct diagnosis and provide better services for children.CASE SUMMARY A 4-mo-old Chinese female child with adducted thumbs,high arch feet,and epileptic seizure presented slow response,delayed development,and low limb muscle strength.Electroencephalogram showed abnormal waves,a large number of multifocal sharp waves,sharp slow waves,and multiple spasms with a series of attacks.High-throughput sequencing and Sanger sequencing identified a heterozygous mutation,c.5885 G>A(p.R1962H),in the DYNC1H1 gene(NM 001376)of the proband,which was not identified in her parents.Combined with the clinical manifestations and pedigree of this family,this mutation is likely pathogenic based on the American Academy of Medical Genetics and Genomics guidelines.The child was followed when she was 1 year and 2 mo old.The magnetic resonance imaging result was consistent with the findings of white matter myelinated dysplasia and congenital giant gyrus.The extensive neurogenic damage to the extremities was considered,as the results of electromyography showed that the motor conduction velocity and sensory conduction of the nerves of the extremities were not abnormal,and the degree of fit of the children with severe contraction was poor.At present,the child is 80 cm in length and 9 kg in weight,with slender limbs and low muscle strength,and still does not raise her head.She cannot sit or speak.Speech,motor,and mental development was significantly delayed.There is still no effective treatment for this disease.CONCLUSION We herein report a de novo variant of DYNC1H1 gene,c.5885 G>A(p.R1962H),leading to overlapping phenotypes(seizure,general growth retardation,and muscle weakness)of CMT20,MRD13,and SMA-LED,but there is no effective treatment for such condition.Our case enriches the DYNC1H1 gene mutation spectrum and provides an important basis for clinical diagnosis and treatment and genetic counseling.

On the Lawful Rights and Interests of Mentally Retarded Children——A case study of a rehabilitation center in Liaoning Province

Mentally retarded children are the most disadvan- taged among disabled children. Since the reform and opening up, with sup- port from the Communist Party of China, the government and the public, the legitimate rights and interests of mentally retarded children have greatly improved. But problems in this respect remain serious, and vari- ous levels of government, relevant departments and the public should attach much importance to these problems. This paper, taking a reha- bilitation center in Liaoning Province for mentally retarded children as a single case, studies the protection of these children＇s lawful rights and in- terests in a systematic manner.

Expression changes of microtubule associated protein 1B in the brain of Fmr1 knockout mice

Objective To explore the regulatory effect of fragile X mental retardation protein （FMRP） on the translation of microtubule associated protein 1B （MAP1B）. Methods The expressions of MAP1B protein and MAP1B mRNA in the brains of 1-week and 6-week old fragile X mental retardation-1 （FmrI） knockout （KO） mice were investigated by immunohistochemistry, Western blot, and in situ hybridization, with the age-matched wild type mice （WT） as controls. Results The mean optical density （MOD） of MAP1B was significantly decreased in each brain region in KO6W compared with WT6W, whereas in KO1W, this decrease was only found in the hippocampus and cerebellum. MAP1B in 6-week mice was much less than that in 1-week mice of the same genotype. The results of Western blot and in situ hybridization showed that MAP1B protein and MAP1B mRNA were significantly decreased in the hippocampus of both KO1W and KO6W. Conclusion The decreased MAP1B protein and MAP1B mRNA in the Fmrl knockout mice indicate that FMRP may positively regulate the expression of MAP1B.

Fragile X syndrome and epilepsy

Fragile X syndrome （FXS） is one of the most prevalent mental retardations. It is mainly caused by the loss of fragile X mental retardation protein （FMRP）. FMRP is an RNA binding protein and can regulate the translation of its binding RNA, thus regulate several signaling pathways. Many FXS patients show high susceptibility to epilepsy. Epilepsy is a chronic neurological disorder which is characterized by the recurrent appearance of spontaneous seizures due to neuronal hyperactivity in the brain. Both the abnormal activation of several signaling pathway and morphological abnormality that are caused by the loss of FMRP can lead to a high susceptibility to epilepsy. Combining with the research progresses on both FXS and epilepsy, we outlined the possible mechanisms of high susceptibility to epilepsy in FXS and tried to give a prospect on the future research on the mechanism of epilepsy that happened in other mental retardations.

Structural insights into a novel histone demethylase PHF8

Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain （PHD） finger protein 8 （PHF8） are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate （α-KG） at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 （H3K9me2/1）, but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.

Neonatal isovaleric acidemia in China: A case report and review of literature

BACKGROUND Isovaleric acidemia(IVA)is a rare autosomal recessive inherited organic acidemia caused by a genetic deficiency of isovaleryl-CoA dehydrogenase(IVD).Its morbidity is low,but mortality is high.There is no effective cure for this disease.Early identification of IVA using clinical features can significantly slow disease progression and reduce mortality.Here we report a Chinese neonate with two mutations of IVD and share valuable information on this disease.CASE SUMMARY A 12-day-old male neonate with“poor response for 1 d and repeated convulsions accompanied by high muscle tension for 6 h”was hospitalized.The patient was the first child of nonconsanguineous ethnic Chinese parents.He was delivered by cesarean section due to breech position at 39+1 wk of gestation with a birth weight of 3.27 kg.Initially,he suffered from dyspnea and rhinobyon,and at 10 d after birth the patient suddenly developed poor feeding,low response,lethargy and seizures.Organic acid analysis of blood and urine by tandem mass spectrometry and gas chromatography mass spectrometry showed extremely high concentrations of isovaleryl glycine.The patient had an acute episode of IVA causing severe metabolic stress and eventually died.CONCLUSION A new case of an IVA patient carrying c.1193G>A(p.Arg398Gln)and c.1208A>G(p.Try403Cys)mutations is reported in China.