A fragile X syndrome family with epilepsy / 中国神经精神疾病杂志

Fragile X syndrome(FXS)is caused by abnormal duplication and amplification of the FMR1 gene CGG.This article reports a pair of brothers diagnosed with FXS by genetic testing.Two patients,aged 15 and 14 years old respectively,both had clinical manifestations such as language disorders,intellectual disabilities,attention deficit disorder,autism spectrum disorder,and FXS's characteristic facial features.The proband had a rare late-onset epileptic seizure,which was well treated with levetiracetam,while his younger brother had no electroencephalogram abnormalities after repeated follow-up.This pair of cases suggests that the clinical phenotype of FXS has diversity and heterogeneity.

Fragile X Syndrome in children

Fragile X syndrome is caused by the expansion of CGG triplets in the FMR1 gene, which generates epigenetic changes that silence its expression. The absence of the protein coded by this gene, FMRP, causes cellular dysfunction, leading to impaired brain development and functional abnormalities. The physical and neurologic manifestations of the disease appear early in life and may suggest the diagnosis. However, it must be confirmed by molecular tests. It affects multiple areas of daily living and greatly burdens the affected individuals and their families. Fragile X syndrome is the most common monogenic cause of intellectual disability and autism spectrum disorder; the diagnosis should be suspected in every patient with neurodevelopmental delay. Early interventions could improve the functional prognosis of patients with Fragile X syndrome, significantly impacting their quality of life and daily functioning. Therefore, healthcare for children with Fragile X syndrome should include a multidisciplinary approach.

El síndrome de X frágil es causado por la expansión de tripletas CGG en el gen FMR1, el cual genera cambios epigenéticos que silencian su expresión. La ausencia de la proteína codificada por este gen, la FMRP, causa disfunción celular, llevando a deficiencia en el desarrollo cerebral y anormalidades funcionales. Las manifestaciones físicas y neurológicas de la enfermedad aparecen en edades tempranas y pueden sugerir el diagnóstico. Sin embargo, este debe ser confirmado por pruebas moleculares. El síndrome afecta múltiples aspectos de la vida diaria y representa una alta carga para los individuos afectados y para sus familias. El síndrome de C frágil es la causa monogénica más común de discapacidad intelectual y trastornos del espectro autista; por ende, el diagnóstico debe sospecharse en todo paciente con retraso del neurodesarrollo. Intervenciones tempranas podrían mejorar el pronóstico funcional de pacientes con síndrome de X frágil, impactando significativamente su calidad de vida y funcionamiento. Por lo tanto, la atención en salud de niños con síndrome de X frágil debe incluir un abordaje multidisciplinario.

A Rare Case of Congenital Hypothyroidism

Congenital Hypothyroidism (CH) is a common preventable cause of mental retardation. The incidence of CH is 1 in 2500 to 1 in 3000 newborns. Most common causes are thyroid dysgenesis and dyshormonogenesis. Some disorder like maternal autoantibodies, maternal intake of anti thyroid medication, iodine deficiency or iodine excess can result in transient CH. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. In this case report, A 3 day old baby was admitted to SNCU with chief complain of yellowish discoloration upto abdomen and respiratory distress. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born.

Transcutaneous electrical acupoint stimulation based on electro-oculogram signal regulation for children with mental retardation: a randomized controlled trial / 中国针灸

OBJECTIVE@#To observe the clinical efficacy of transcutaneous electrical acupoint stimulation (TEAS) at Changqiang (GV 1) based on the modulation of electro-oculogram (EOG) signal for children with mental retardation, and explore the evaluation effect of the goal attainment scale (GAS) in children with mental retardation.@*METHODS@#Sixty children with mental retardation were randomly divided into a treatment group and a control group, with 30 cases in each one. The children in the control group were treated with conventional rehabilitation, 5 times a week. On the basis of the control group, TEAS at Changqiang (GV 1) under the modulation of EOG signal was adopted in the treatment group. When the similarity between the collected EOG signal and the template was within the range of EOG threshold, one electric stimulation was triggered at Changqiang (GV 1) for 20 s (continuous wave, 70-100 Hz in frequency, 0.1-0.2 ms in pulse width), lasting 30 min in each treatment, the intervention was given twice a week. One course of treatment was composed of 4 weeks, and 3 courses were required in total in the two groups. The infant-junior high school student's social living ability scale (S-M) and GAS were scored and compared before and after treatment in the two groups.@*RESULTS@#After treatment, the scores of self-living ability in the treatment group and communication ability in the control group were higher than those before treatment (P<0.01, P<0.05). The scores of collective activity and motor ability in the treatment group were higher than those in the control group (P<0.05). After treatment, GAS scores were higher than before treatment in both groups (P<0.001), and the score in the treatment group was higher than the control group (P<0.05).@*CONCLUSION@#TEAS under the modulation of EOG signal is conductive to improving the collective, motor and self-living abilities of the children with mental retardation and promoting children's individual goals. Compared with the standard score of S-M, the T value of GAS can better reflect the subtle progress of individual.

Effect of CYFIP2 overexpression on biological function and Wnt/β-catenin signaling pathway of bladder cancer cell line T24 / 国际生物医学工程杂志

Objective:To investigate the effects of cytoplasmic fragile X mental retardation protein 1 binding protein 2 (CYFIP2) overexpression on the biological functions and Wnt/β-catenin signaling pathways of bladder cancer T24 cells.Methods:The control group was T24 cells transfected with the empty pcDNA3 vector, and the overexpression group was T24 cells transfected with the CYFIP2 overexpression vector. The expression of CYFIP2 mRNA and protein was detected by reverse transcriptase, quantitative polymerase chain reaction, and Western Blot. The effect of CYFIP2 overexpression on T24 cell proliferation was detected by CCK-8. The effect of CYFIP2 overexpression on T24 cell migration and invasion was detected by Transwell. The effects of CYFIP2 overexpression on Wnt/β-catenin signaling pathway in T24 cells were detected by Western Blot.Results:Compared with the control group, the expression levels of CYFIP2 mRNA and protein were increased in the overexpression group (all P < 0.001), and the cell proliferation, migration, and invasion abilities were reduced (all P < 0.01). β-catenin, c-Myc, and Cyclin D1 protein expression were down-regulated in CYFIP2 overexpressed T24 cells (all P < 0.05), while the protein levels of p-β-catenin were increased ( P < 0.05). Conclusions:CYFIP2 overexpression can inhibit T24 cell proliferation, migration, and invasion, and its possible molecular mechanism is related to the inhibition of Wnt/β-catenin signaling pathway.

15q11-q13 Duplication syndrome with intractable epilepsy: a case report and literature review / 中华神经科杂志

15q11-q13 Duplication syndrome is a rare genetic disease of the nervous system, characterized by developmental retardation, intellectual impairments, hypotonia, autism, epilepsy and so on. This article reports a 33-year-old male patient, with the clinical manifestation of early-onset intractable epilepsy and mental retardation. The high-throughout whole exome sequencing showed a 10.53 Mb repeat sequence in the 15q11.2-q13.3 region, further confirming the diagnosis of 15q11-q13 duplication syndrome. The literature reports of the pathogenic mechanism, classification, typical clinical manifestation, seizure features,accessory examination and therapy of the 15q11-q13 duplication syndrome are summarized and reviewed, so as to enhance the understanding of the disease, as well as to improve the diagnosis and treatment level of the clinicians.

Clinical analysis of 3 adult-onset patients with genetically diagnosed familial neuronal intranuclear inclusion disease / 中华神经医学杂志

Objective:To analyze the clinical characteristics of adult-onset patients with familial neuronal intranuclear inclusion disease (NIID).Methods:The clinical data of 3 patients with familial NIID genetically diagnosed in Department of Neurology, Sixth Affiliated Hospital of Guangzhou Medical University in August 2021, January 2022, and August 2022 were collected. Their clinical manifestations, imaging features, pathological features, Notch2 N-terminal-like C ( NOTCH2NLC) gene mutation characteristics, treatment methods and prognoses were summarized retrospectively. Results:The age of these 3 patients was 73, 67, and 65 years, and the onset age was 68, 64, and 56 years, respectively. The clinical manifestations are highly heterogeneous. In patient 1, the nervous centralis, peripheral nerves and autonomic nerves were involved, appearing dementia, epilepsy, Parkinson's syndrome, muscle weakness and uremia; in patient 2, only the nervous centralis were involved, presenting symptoms of Parkinson's syndrome; in patient 3, peripheral nerves and autonomic nerves were involved, prominently presenting with repeated vomiting. Skull diffusion weighted imaging (DWI) showed asymmetric high signal at the dermo-medullary junction in 3 patients. Acidophilic inclusion bodies in some sudoriferous duct epithelial cells, and vascular endothelial nucleus were found in the skin biopsy of 2 patients. All 3 patients completed NOTCH2NL gene test, and all had GGC repeat amplification mutations with mutation frequency>134. These 3 patients were mainly treated symptomatically, and the disease was still progressed gradually. Conclusion:The clinical manifestations of familial NIID are highly heterogeneous; skull MRI characteristic changes and skin biopsy can help to diagnose NIID and NOTCH2NL gene detection can diagnose NIID.

Autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations: a report of 8 cases and literature review / 中国当代儿科杂志

OBJECTIVES@#To summarize the clinical phenotype and genetic characteristics of children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations.@*METHODS@#A retrospective analysis was performed on the medical data of 8 children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations who were diagnosed and treated in the Department of Pediatrics, Xiangya Hospital of Central South University.@*RESULTS@#The mean age of onset was 9 months for the 8 children. All children had moderate-to-severe developmental delay (especially delayed language development), among whom 7 children also had seizures. Among these 8 children, 7 had novel heterozygous mutations (3 with frameshift mutations, 2 with nonsense mutations, and 2 with missense mutations) and 1 had 6p21.3 microdeletion. According to the literature review, there were 48 Chinese children with mental retardation caused by SYNGAP1 gene mutations (including the children in this study), among whom 40 had seizures, and the mean age of onset of seizures was 31.4 months. Frameshift mutations (15/48, 31%) and nonsense mutations (19/48, 40%) were relatively common in these children. In terms of treatment, among the 33 children with a history of epileptic medication, 28 (28/33, 85%) showed response to valproic acid antiepileptic treatment and 16 (16/33, 48%) achieved complete seizure control after valproic acid monotherapy or combined therapy.@*CONCLUSIONS@#Children with autosomal dominant mental retardation type 5 caused by SYNGAP1 gene mutations tend to have an early age of onset, and most of them are accompanied by seizures. These children mainly have frameshift and nonsense mutations. Valproic acid is effective for the treatment of seizures in most children.

Hypomagnesemia, seizures, mental retardation caused by heterozygous mutation of CNNM2: a case report and literatures review / 中国医师杂志

Objective:To analyze the clinical characteristics of a case of CNNM2 gene heterozygous mutation causing hypomagnesemia epilepsy mental retardation (HOMGSMR1) [MIM: 616418] in a child, and explore the association between genotype and phenotype.Methods:We followed up and retrospectively analyzed the clinical characteristics of a case of HOMGSMR1 caused by CNNM2 gene heterozygous mutation treated at Maternal and Child Health Care Hospital of Liuyang. Through whole exome sequencing of the family and bioinformatics analysis of the original data, we consulted databases and literature materials such as Online Mendelian Inheritance in Man (OMIM), ClinVar, gnomAD, GeneReviews, Pubmed, and China National Knowledge Infrastructure (CNKI), The American College of Medical Genetics and Genomics (ACMG) guidelines were used to rate heterozygous deletion mutations in the locked CNNM2 gene.Results:Patient, male, 3 months and 18 days old, mother gave birth to 1 child with 1 pregnancy, recurrent convulsions for more than 10 days, and multiple tests showed that blood magnesium levels were below normal, fluctuating between 0.51-0.55 mmol/L; After oral administration of " oxcarbazepine" and " magnesium sulfate", convulsions improved and blood magnesium concentration increased, but remained below normal, with the highest being 0.61 mmol/L. The sequencing results of the whole exome display of the family showed that the child carried a heterozygous deletion mutation in the exon region of the CNNM2 gene (c.838_843delATGGCCp. M280-A281del), which was not detected in their parents, indicating a new mutation. The large-scale population frequency database gnomAD did not include this mutation, and no literature reported this mutation. According to the ACMG guidelines, it was rated as a suspected pathogenic variant. The pathogenic variation of this gene can lead to autosomal dominant HOMGSMR1, which was consistent with genetic patterns.Conclusions:CNNM2 gene c. 838_ 843delATGGCC (p.M280_A281del) is a suspected pathogenic variant in this patient, with genotype and phenotype matching and heterozygous mutations following genetic patterns. Autosomal dominant inheritance is the molecular cause of clinical manifestations in this patient, and it is an unreported novel mutation.

Progress in the function of IL1RAPL1, an X-linked nonspecific mental retardation-associated gene / 国际儿科学杂志

IL1RAPL1 gene is one of the genes related to X-linked nonspecific mental retardation(MRX), but its pathogenic mechanism has not been fully clarified.Interleukin-1 receptor accessory protein like 1(IL1RAPL1) is a synaptic adhesion molecule located on postsynaptic membrane.The mutation of IL1RAPL1 gene can lead to the deletion or dysfunction of this protein.Recent studies have shown that the IL1RAPL1 protein regulates dendritic formation and mediates the activity of IL-1β molecules on dendritic morphology.This review describes the latest advances in synaptic and neuronal functions of IL1RAPL1, and summarizes some gene mutations that have been found to be associated with mental retardation(MR)and autism spectrum disorder(ASD), to provide evidence for clinical diagnosis and treatment.

A case report of congenital dysplasia caused by the ANK3 gene mutation in the newborn / 中华实用儿科临床杂志

The clinical features, examination findings and gene results of the newborn diagnosed with congenital dysplasia by the ANK3 gene heterozygous mutation in the First Hospital of Jilin University were retrospectively analyzed.A female newborn at 10 minutes presented for postnatal asphyxia and 10 minutes after resuscitation.She had a special appearance, with little spontaneous breathing, no swallowing, extremely low muscular tension, and no primal reflexes.Amplitude integrated electroencephalogram(aEEG) suggested the burst suppression (BS) background activity, BS (+ ), lower boundary at 2 μV, upper boundary at 50 μV, no sleep awakening cycle, no convulsive seizure, and mechanical brush seen in the original electroencephalogram burst.Severe abnormal aEEG was detected.Gene results suggested 2 heterozygous mutations in the ANK3 gene [c.4183(exon33) C >G and c. 8239(exon37) C >T], which have not been previously reported.This case report for the first time reported the clinical phenotype of the ANK3 gene mutation in the newborn with congenital dysplasia.

Diagnosis and treatment of nephroblastoma with WAGR syndrome / 中华泌尿外科杂志

Objective:To discuss the diagnosis and treatment 0f WAGR syndrome.Methods:The clinical data of 10 cases of WAGR syndrome children admitted to our hospital from January 2008 to November 2019 were respectively analyzed including the clinical features, diagnosis, and surgical treatments. There were 6 males and 4 females, aged from 13 to 36 months, with an average of 23.6 months. 9 cases were diagnosed as iris absence due to ocular abnormalities in infancy, and 1 case was diagnosed as iris absence due to ocular abnormalities by physical examination because of renal mass. There were 2 boys with cryptorchidism, and 2 boys with hypospadias, 1 of which did not received operation because of mild hypospadias, and another undergoing surgery. There were no abnormality of genitourinary system in the remaining 5 cases. There were 7 cases of unilateral nephroblastoma, with 1 case at the left and 6 cases at the right, and there were 3 cases of bilateral nephroblastoma. Abdominal doppler ultrasound and enhanced abdominal CT were performed for all patients. Abdominal doppler ultrasound indicated solid mass in renal parenchyma or non-uniform echo zone. Abdominal enhanced CT indicated renal tumor with diameter of 1.8 cm-12.7 cm and locally non-uniform enhanced echo. Among the 7 cases of unilateral nephroblastoma, 4 underwent nephrectomy, 1 underwent tumor enucleation, and 2 underwent tumor enucleation for unilateral tumor complicated with nephrogenic rests. There were 3 cases of bilateral nephroblastoma, 2 cases undergoing unilateral tumor enucleation firstly and contralateral tumor enucleation following chemotherapy. One case underwent unilateral tumor nephrectomy followed by contralateral tumor enucleation. One case of unilateral nephrogenic rests did not undergo renal tumor surgery. Preoperative chemotherapy was performed in 7 patients, including 3 bilateral nephroblastoma, 1 unilateral nephroblastoma combined with contralateral nephroblastoma, and 3 unilateral tumors larger enough to pass the midline. The chemotherapy regimen was VCR+ ACTD in 5 cases, VCR+ ACTD+ CTX+ DOX/CDDP+ VP16 and VCR+ CTX+ DOX in another 2 cases respectively.Results:All 10 cases were diagnosed as nephroblastoma. There were 3 patients without preoperative chemotherapy which belongs to COG stageⅠ(1 case) and STAGEⅢ(2 cases); Preoperative chemotherapy was performed in 2 patients with SIOP stage Ⅱ, 2 patients with SIOP stage Ⅲ, and 3 patients with SIOP stageⅤ. Nine children received regular chemotherapy after surgery, among which 1 child in stage Ⅰ received DD4A chemotherapy regimens, 2 children in stage Ⅱ received DD4A and EE4A regimen respectively, and 3 of the 4 children in stage Ⅲ received regular chemotherapy after surgery, including EE4A(1 case)and DD4A(2 cases). EE4A(1 case)and DD4A(2 cases) chemotherapy were performed in 3 patients with stage Ⅴ according to their unilateral tumor stage. Ten cases were followed up, with 9 of the 10 cases having no tumor recurrence or metastasis, and death in 1 case. At present, abdominal doppler ultrasound of 1 child with nephrogenic rests showed no obvious progress. The renal function of 9 children was not significantly abnormal during the regular follow-up. The results of intelligence screening showed that 6 of the 10 patients were significantly behind their peers, and 4 had no obvious abnormality compared with their peers. Gene tests were performed 3 times after surgery, and the results showed the deletion of 11p13 and adjacent distal genes.Conclusions:WAGR syndrome is rare in clinical practice, and renal ultrasound should be monitored after diagnosis to detect renal tumors in early stage. For bilateral cases, renal function should be preserved as long as possible in order to reduce the probability of renal failure. Long-term follow-up of nephroblastoma with this syndrome is particularly important.

BRPF1 gene mutation caused intellectual developmental disorder with dysmorphic facies and ptosis: a case report and literature review / 中华实用儿科临床杂志

The clinical data of a child with intellectual developmental disorder with dysmorphic facies and ptosis (IDDDFP) admitted to the Department of Pediatrics of Gansu Provincial People′s Hospital in December 2020 were retrospectively analyzed and related literatures were reviewed.The female child was at the age of 6 months, with birth weight of 2.8 kg, hypodystonia, underdevelopment, blepharophimosis, slightly ptosis and six fingers deformity.Whole exome sequencing showed that the patient′s BRPF1 gene c. 1631G>A (p.Trp544Ter) heterozygous pathogenic variant was a novel IDDDFP-related mutation, which was consistent with the phenotype and inheritance pattern of the subject.A total of 27 patients with IDDDFP were found in 6 articles, including 4 pedigrees.The patients displayed different degrees of mental disability and facial deformities, psychomotor and language retardation, epilepsy and other clinical features.When the clinical manifestations of children are mental retardation, ptosis, psychomotor and language retardation, and epilepsy, IDDDFP should be considered, and gene sequencing can make a clear diagnosis.

Chiropractic plus plum-blossom needling combined with flexibility training on attention deficit in mentally-retarded adolescents / 中国针灸

OBJECTIVE@#To observe the clinical efficacy of chiropractic plus plum-blossom needling combined with flexibility training for attention deficit in mentally-retarded adolescents.@*METHODS@#Thirty adolescents with mild mental retardation were randomly divided into a medical rehabilitation plus flexibility training group (10 cases, 2 cases dropped off), a flexibility training group (10 cases, 1 case dropped off) and a control group (10 cases). The patients in the flexibility training group received flexibility training, once every other day, 3 times a week for 12 weeks. The patients in the medical rehabilitation plus flexibility training group received chiropractic and plum-blossom needling at Baihui (GV 20) and Sishencong (EX-HN 1) on the basis of the treatment in the flexibility training group, once every other day, 3 times a week for 12 weeks. The patients in the control group did not receive any targeted physical training and medical rehabilitation. Tobii Pro Spectrum eye movement instrument was used to test the attention concentration (T), attention span (M), attention transfer (γ%) and attention distribution (η).@*RESULTS@#Compared before treatment, T and M in the medical rehabilitation plus flexibility training group and the flexibility training group were increased after treatment (P<0.01, P<0.05), and γ% in the medical rehabilitation plus flexibility training group was increased after treatment (P<0.05). The increasing range of T, M and γ% in the medical rehabilitation plus flexibility training group and the flexibility training group was greater than that in the control group (P<0.01), and the increasing range of T and γ% in the medical rehabilitation plus flexibility training group was greater than that in the flexibility training group (P<0.05).@*CONCLUSION@#The chiropractic plus plum blossom needling combined with flexibility training can improve the attention deficit in mentally-retarded adolescents.

Mental retardation autosomal dominant 35 caused by de novo missense variants in PPP2R5D gene: a case report and literature review / 中华神经科杂志

Objective:To enhance understanding of mental retardation autosomal dominant 35 (MRD35) by analyzing the clinical and genetic characteristics of the disease.Methods:Clinical and genetic data of 1 case of MRD35 in Beijing Children′s Hospital in July 2018 were reported, and literature review was conducted.Results:The male proband, 1 year and 3 months old, was admitted with the clinical manifestations including mental retardation, low-grade fever, a large forehead, flat nose, open mouth, and hypomyotonia. The brain magnetic resonance imaging showed enlarged lateral ventricles, cavum septum, cavum verge and cavum velum interpositum cyst. The whole exome sequencing test showed that the proband carried a missense mutation c.1258 G>A, (p.E420K) in the PPP2R5D gene, and the mutation was de novo confirmed by Sanger sequencing. There were ten literatures reported, including a total number of 31 cases. Counting on this case, totally 32 cases were included. Among the 32 patients, 32 cases (100.0%) had mental retardation, 26 cases (81.3%) with motor retardation, 26 cases (81.3%) with macrocephaly, 8 cases (25.0%) with epilepsy. Facial dysmorphic features, ocular abnormalities, skeletal abnormalities, and cardiac malformations were also reported. All reported individuals had missense mutations of PPP2R5D gene and were autosomal dominantly inherited. Conclusions:The main clinical manifestations of MRD35 include growth retardation/mental retardation, severe speech impairment, macrocephaly, hypomyotonia, seizures and dysmorphic facial features. A novel missense mutation in the PPP2R5D gene is the cause of MRD35.

Síndrome X frágil y otras patologías asociadas al gen FMR1 / Fragile X Syndrome and Other Pathologies Associated with the FMR1 Gene / Síndrome do X frágil e outras patologias associadas ao gene FMR1

Resumen: el síndrome X frágil es la causa más frecuente de retraso psicomotor vinculado al cromosoma X en niños, con una prevalencia de 1 : 5.000 en hombres y 1 : 4.000 - 8.000 en mujeres. Además, es la causa hereditaria más asociada al síndrome del espectro autista. Esta patología posee como base etiológica la expansión del triplete CGG en el extremo distal del gen FMR1, lo que causa su silenciamiento. Los pacientes afectados con este síndrome suelen padecer de problemas conductuales, neurológicos, cardíacos y ortopédicos. Este síndrome también se relaciona con la insuficiencia ovárica primaria asociada al X frágil, y el síndrome de temblor y ataxia asociado al X frágil que afectan a la madre y al abuelo materno, y que, por su reciente descripción, podrían ser desconocidos por el personal sanitario, lo que retrasa su diagnóstico y tratamiento. El objetivo de este artículo es analizar estas enfermedades, con el fin de describir el conocimiento actual sobre su etiología, las manifestaciones clínicas, el diagnóstico y el tratamiento. Esto se realizó mediante la recopilación de artículos en Pubmed, con algunas contribuciones de las bases de datos Scielo, Redalyc, Europe PMC, Science Direct, Google Académico y Genetics Home Reference. Entre las conclusiones principales se destaca que los fenotipos asociados a la premutación del gen FMR1 contemplan mecanismos fisiopatológicos diferentes al síndrome X frágil, a pesar de estar íntimamente relacionados.

Abstract: fragile X syndrome is the most common cause of X-linked psychomotor retardation in children, with a prevalence of 1 : 5.000 in males and 1 : 4.000 -8.000 in females. It is also the hereditary cause most associated with autism spectrum syndrome. The etiological basis of this pathology is the expansion of the CGG triplet at the distal end of the FMR1 gene, which causes its silencing. Patients affected with this syndrome usually suffer from behavioral, neurological, cardiac and orthopedic problems. This syndrome is also related to Fragile X-associated primary ovarian insufficiency, and Fragile X-associated tremor and ataxia syndrome affecting the mother and maternal grandfather, which, because of their recent description, may be unknown to health care providers, delaying their diagnosis and treatment. The objective of this article is to analyze these diseases, in order to describe the current knowledge about their etiology, clinical manifestations, diagnosis and treatment. This was done by collecting articles in Pubmed, with some contributions from Scielo, Redalyc, Europe PMC, Science Direct, Google Scholar and Genetics Home Reference databases. Among the main conclusions, it is highlighted that the phenotypes associated with FMR1 gene premutation involve different pathophysiological mechanisms to Fragile X syndrome, despite being closely related.

Resumo: a síndrome do X frágil é a causa mais comum de retardo psicomotor ligado ao cromossomo X em crianças, com prevalência de 1 : 5.000 em homens e 1 : 4.000 a 8.000 em mulheres. Além disso, é a causa mais hereditária associada à síndrome do espectro do autismo. Essa patologia tem como base etiológica a expansão do trigêmeo CGG na extremidade distal do gene FMR1, o que causa seu silenciamento. Pacientes com essa síndrome geralmente sofrem de problemas comportamentais, neurológicos, cardíacos e ortopédicos. Essa síndrome também está relacionada à insuficiência ovariana primária associada ao X frágil, à síndrome do tremor e à ataxia associada ao X frágil, que acometem a mãe e o avô materno, e que, devido à sua descrição recente, poderiam ser desconhecidas pelos profissionais de saúde, o que atrasa seu diagnóstico e tratamento. O objetivo deste artigo é analisar essas doenças, a fim de descrever o conhecimento atual sobre sua etiologia, manifestações clínicas, diagnóstico e tratamento. Isso foi feito através da recopilação de artigos no Pubmed, com algumas contribuições das bases de dados Scielo, Redalyc, Europe PMC, Science Direct, Google Academic e Genetics Home Reference. Dentre as principais conclusões, destaca-se que os fenotipos associados à premutação do gene FMR1 incluem outros mecanismos fisiopatológicos além da síndrome do X frágil, apesar de eles estarem intimamente relacionados.

Analysis of clinical phenotype and genotype of Jansen-de Vries syndrome caused by PPM1D gene mutation / 中华神经科杂志

Objective:To investigate the clinical phenotype of a child with Jansen-de Vries syndrome, to clarify its genetic diagnosis and genetic characteristics, and to improve the understanding of this disease.Methods:Clinical data from a child with Jansen-de Vries syndrome diagnosed in the Children′s Affiliated Hospital of Zhengzhou University in October 2019 were collected, using core family-complete exon genomics detection (Trio-WES) and chromosome copy number variation (CNV) analysis techniques for genetic testing for the child and her parents, generation Sanger sequencing for family member verification for possible pathogenic mutations, and clinical and molecular genetic analysis. The relevant reports of PPM1D gene mutation in patients with mental retardation were reviewed.Results:The proband was a 11-month-old girl, presenting with mental retardation, lagging speech and motor development, autistic behavior, gastrointestinal dysfunction, and short stature, low flat nose bridge, low ear, short finger syndrome.Trio-WES results of the core family of the child suggested that PPM1D was a new transcoding heterozygous mutation, PPM1D (NM-003620): c.1216delA (p.Thr406Profs *3), and the karyotype and CNV analysis of the chromosome were normal. Literature retrieval showed currently a total of 18 cases were reported PPM1D gene mutation of mental disorders, described in the online human Mendel database for developmental disorder associated with gastrointestinal dysfunction and pain threshold increases, the age distribution in the seven months to 21 years of age, clinical manifestation of mental retardation, increased pain threshold, abnormal behavior, feeding difficulties, visual impairment, short finger syndrome, a group of syndromes associated with short stature, fever or vomiting, and congenital deformities. Conclusions:Jansen-de Vries syndrome clinically presents mainly with overall retardation (mental retardation/backward delayed motor development, language development, low muscle tone), abnormal behavior (lonely sample behavior, autism), craniofacial malformations (broad forehead, low ear nose bridge, thin upper lip), short finger syndrome (short feet, pinky stubby), gastrointestinal dysfunction (milk overflow, feeding difficulties, constipation). The child was diagnosed as a newly transcoding heterozygous mutation of the PPM1D gene. The current treatment is mainly rehabilitation training, and growth hormone replacement therapy can be given to part of the short height disease. The PPM1D gene [PPM1D(NM-003620): c.1216delA(p.Thr406Profs *3)] is the genetic cause of the child.

New progress in diagnosis and treatment of Rubinstein-Taybi syndrome / 中华实用儿科临床杂志

Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental retardation disease involving multiple organ and system abnormalities.The main manifestations include broad thumbs and big toes, specific facial characteristics, developmental and mental retardation.In addition, it is also manifested as ocular abnormalities, hearing loss, repeated respiratory infection and dyspnea, gastrointestinal disorders, urogenital system disorders and severe constipation.It can be classified into 2 types: RSTS1 (OMIM#180849) caused by the CREBBP gene mutation and RSTS2 (OMIM#613684) caused by the EP300 gene mutation, and most of them are found in the de novo truncated variation.Up to now, a clear diagnosis criterion for RSTS is lacked, which is mainly based on the comprehensive analysis of clinical and genetic results.The main treatment of RSTS is symptomatic and individualized treatment, while early intervention is helpful to improve the prognosis and the quality of life.This study aims to introduce the disease comprehensively, thus enhancing the recognition in RSTS.

Two cases of female-restricted X-linked syndromic mental retardation-99 caused by USP9X gene variations / 中华实用儿科临床杂志

Objective:To summarize and analyze the clinical and genotype features of female-restricted X-linked syndromic mental retardation-99(MRXS99F, OMIM: 300968)caused by USP9 X gene mutation, and to improve the clinicians′ understanding of the disease. Methods:Clinical data and genotypes of 2 children with MRXS99F treated in the Children′s Hospital of Nanjing Medical University in March 2020 (case 1) and June 2020 (case 2) were analyzed, and the relevant databases at home and abroad were reviewed to summarize the clinical characteristics and gene variation characteristics of the disease.Results:The 2 cases were 6 months old (case 1) and 5 years old (case 2), both showed psychomotor retardation.Case 1 presented a short stature, pigment abnormality, characteristic facial features, hypotonia, recurrent respiratory tract infections, laryngeal cartilage hypoplasia, atrial septal defect, feeding difficulty, hearing loss and brain hypoplasia.Case 2 had abnormal electroencephalogram.As confirmed by whole-exome sequencing, two children carried c. 6972+ 1G>A, c.6437C>T of USP9 X, respectively.Neither of the 2 variations was previously reported.Twenty-two cases of MRXS99F caused by USP9 X gene mutation were reported in 4 literatures globally, and 24 cases were combined with this study.The clinical manifestations of 20/22 children had special faces.All of them accompanied mental retardation combined with motor and language retardation, and carried neonatal variation. Conclusions:This is the first case report of MRXS99F induced by USP9 X gene variation in China.MRXS99F caused by functional deletion and variation of USP9 X gene is mainly characterized by psychomotor retardation, language disorder, special face and multiple congenital malformations.For children with unexplained growth retardation, special face and multiple congenital malformations, genetic testing like high-throughput sequencing should be carried out as early as possible to determine the etiology.

A single-centre observational study of 124 surgically managed glioma patients: molecular subtyping and its correlation with clinico-radiological profile

Background: The World Health Organization (WHO) 2016 classification incorporated molecular subtyping in glioma, highlighting the diagnostic and prognostic significance. The study aims to determine the isocitrate dehydrogenase (IDH-1) gene, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene, and tumor suppressor gene-53 (p53) mutation in glioma and their correlation with various clinical and radiological parameters.Methods: In this prospective observational study, histopathological slides of glioma (2017-2018), were analyzed for IDH-1, ATRX and p53 mutations and their correlation with various clinical and radiological parameters.Results: IDH-1 mutation was found in 48 (38.7%), ATRX loss in 38 (30.6%) and p53 mutation in 40 (32.5%) patients. The expression of IDH-1 was significantly higher (43.7%) in adults; however, no significant difference was seen with gender. Also 51.2% of patients, who presented with seizures, showed IDH-1 expression; and 27.7% of patients, who had neurological deficit also showed IDH-1 expression. IDH-1 expression was high in glioma located at insula (73.3%) and parietal lobe (71.4%); while ATRX loss was seen in glioma located at insula (80%). Intraventricular glioma characteristically lacks all three markers: IDH-1 expression, p53 overexpression and ATRX loss. IDH-1 expression and p53 overexpression was seen mainly in diffuse fibrillary astrocytoma, oligodendroglioma, anaplastic astrocytoma and glioblastoma.Conclusions: Molecular subtyping is of paramount importance in glioma management. IDH-1 mutation is commonly observed in adults and patients presenting with seizures. The duration of symptoms correlates with IDH-1 and ATRX mutations. Hypothalamic tumors lack all three mutations.