Onasemnogene Abeparvovec Treatment after Nusinersen in an Infant with Spinal Muscular Atrophy Type 1.

BACKGROUND: Until recently, the treatment of spinal muscular atrophy (SMA) was limited to symptomatic treatment with no cure. Three innovative drugs, nusinersen, onasemnogene abeparvovec (OA), and risdiplam have been developed to treat SMA. Although the clinical trials for these drugs have demonstrated their efficacy, there is limited information on real world treatment strategies. In this study, we present a case of a male infant with SMA type 1 who underwent OA treatment after nusinersen treatment. CASE PRESENTATION: At 4 months of age, the patient was diagnosed with SMA type 1. At 6 months of age, nusinersen treatment was initiated. His motor function improved, but the effect was limited; therefore, his parents requested gene replacement therapy. During the preparation for OA treatment, anti-adeno-associated virus 9 (AAV9) antibody tests repeatedly showed non-specific reactions, which delayed initiation of treatment. The patient was put on ventilator management after he caught a common cold. During this management, the anti-AAV9 antibody test results were negative. Furthermore, the patient showed increased transaminase levels just before OA treatment; however, since these gradually decreased without signs of liver failure, we started OA treatment at 13 months of age. Four months later, the patient began to sit without support and was weaned from non-invasive positive pressure ventilation, although nasogastric tube feeding remained partially necessary. CONCLUSION: We believe that the management of unstable SMA type 1 symptoms, anti-AAV9 antibody testing, and changes in transaminase levels will be helpful for other patients with SMA who require treatment.

Spinal Muscular Atrophy Type I With False Negative in Newborn Screening: A Case Report.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene. The establishment of effective newborn screening (NBS) for SMA is important for early diagnosis so that treatment can be administered in the pre-symptomatic or early disease stages. Polymerase chain reaction (PCR)-based genetic testing with dried blood spots has been used in NBS to detect the homozygous deletion of exon 7 in SMN1, however, this methodology is not able to detect newborn infants with heterozygous deletions and/or point mutations in SMN1. We report the case of a male infant who was diagnosed with SMA despite the NBS being negative for all conditions including SMA. The patient presented with severe hypotonia and muscle weakness from around 14 days of age. SMA was suspected and sequence analysis of SMN1 and SMN2 was conducted using the multiplex ligation-dependent probe amplification (MLPA) method, which revealed compound heterozygous mutations of SMN1. The patient was diagnosed with SMA and started on modulating agents including gene therapy. His motor function improved slightly with treatment, however, his motor development remained prominently retarded by 5 months of age. This case highlights the importance of investigating SMA as a potential diagnosis even when the NBS result is negative.

Comparison of long-term quality of life based on surgical procedure in patients with rectal cancer.

Introduction: Reports on the long-term quality of life (QOL) over 3 years after surgery in patients who have undergone surgery for rectal cancer are limited. Therefore, we aimed to evaluate the long-term QOL of patients who underwent high anterior resection (HAR), low anterior resection (LAR), internal sphincter resection (ISR), or abdominoperineal resection (APR) for rectal cancer. Methods: A questionnaire regarding QOL was sent to 360 patients with rectal cancer who underwent curative resection by HAR, LAR, ISR, or APR between January 2005 and December 2015. QOL was assessed using the short-form 36 (SF-36) and modified fecal incontinence QOL (mFIQL) questionnaire. QOL between surgical procedures was analyzed using a multivariate model adjusted for age, sex, and postoperative time. Results: A total of 144 patients responded with a median follow-up period of 94 months (range 38-233 months). According to surgical procedure, HAR was performed in 26 patients, LAR in 80 patients, ISR in 32 patients, and APR in 6 patients. Patients who underwent HAR had significantly better mFIQL scores than those who underwent LAR and ISR (p=0.013 and p=0004, respectively) and significantly better role/social component summary scores on the SF-36 subscales (p=0.007). No difference was observed in the mFIQL scores between patients who underwent ISR and those who underwent APR (p=0.8423). In addition, postoperative anastomotic leakage sutures did not influence the mFIQL and SF-36 scores after surgery. Conclusion: The QOL of patients who underwent anus-preserving surgery was best in the HAR group, with the QOL of other groups similar to the APR group. These results suggest that anus- preserving surgery is acceptable from a QOL standpoint. However, a colostomy may be a more satisfactory procedure in some patients.

Gene therapy for spinal muscular atrophy is considerably effective when administered as early as possible after birth.

Introduction: Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by muscle atrophy and progressive muscle weakness. Insurance-approved treatments in Japan include antisense oligonucleotide therapy, gene therapy, and small molecule therapy. The efficacy of these therapies varies depending on the timing of treatment initiation. Case presentation: We report the cases of two infants with SMA born in the same region. Patient 1, who had two copies of SMN2, was born before newborn screening (NBS) was started and received onasemnogene abeparvovec therapy at the age of 4 months. Patient 2, who had three copies of SMN2, was born after the start of NBS and was diagnosed and treated with onasemnogene abeparvovec before symptoms appeared. Unfortunately, Patient 1 became bedridden despite receiving gene therapy, while Patient 2 achieved normal motor development. Discussion: Our findings show that treatment timing is an essential factor affecting patients' motor neurodevelopmental outcomes, although our patients did have differences in the number of copies of SMN2. Therefore, a system should be established to allow all newborns to undergo publicly funded NBS for SMA.

Association between cerebrospinal fluid parameters and developmental and neurological status in glucose transporter 1 deficiency syndrome.

OBJECTIVE: In glucose transporter 1 deficiency syndrome (Glut1DS), cerebrospinal fluid glucose (CSFG) and CSFG to blood glucose ratio (CBGR) show significant differences among groups classified by phenotype or genotype. The purpose of this study was to investigate the association between these biochemical parameters and Glut1DS severity. METHODS: The medical records of 45 patients who visited Osaka University Hospital between March 2004 and December 2021 were retrospectively examined. Neurological status was determined using the developmental quotient (DQ), assessed using the Kyoto Scale of Psychological Development 2001, and the Scale for the Assessment and Rating of Ataxia (SARA). CSF parameters included CSFG, CBGR, and CSF lactate (CSFL). RESULTS: CSF was collected from 41 patients, and DQ and SARA were assessed in 24 and 27 patients, respectively. Simple regression analysis showed moderate associations between neurological status and biochemical parameters. CSFG resulted in a higher R2 than CBGR in these analyses. CSF parameters acquired during the first year of life were not comparable to those acquired later. CSFL was measured in 16 patients (DQ and SARA in 11 and 14 patients, respectively). Although simple regression analysis also showed moderate associations between neurological status and CSFG and CSFL, the multiple regression analysis for DQ and SARA resulted in strong associations through the use of a combination of CSFG and CSFL as explanatory variables. CONCLUSION: The severity of Glut1DS can be predicted from CSF parameters. Glucose and lactate are independent contributors to the developmental and neurological status in Glut1DS.

Exploratory evaluation of an eye-tracking system in patients with advanced spinal muscular atrophy type I receiving nusinersen.

Objective: This study evaluated the feasibility of a matching-pair test using eye-tracking technology to assess nusinersen effectiveness in patients with advanced spinal muscular atrophy (SMA) type I. Methods: This prospective, observational study enrolled patients with 5q-SMA type I who had lost gross motor function. Three different levels of matching-pair tests were conducted using the eye-gaze system (My Tobii; TobiiDynavox Inc.) at baseline, and after 9 and 24 weeks of nusinersen treatment. The primary endpoint was the change from baseline in matching-pair test scores and response times (i.e., the time to answer matching-pair test) at 24 weeks from baseline. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Pediatric Quality of Life inventory for patients with Neuromuscular Disease (PedsQL-NM) and Numerical Rating Scale (NRS) scores were also assessed as secondary endpoints. Analysis of ocular fixation was performed as an additional analysis. This study was registered at https://www.umin.ac.jp/ctr/ (UMIN000033935). Results: Seven patients (one male, six female) aged 5-21 years (median 11 years) were enrolled; all patients were bedridden and six patients were ventilated. All seven patients were able to conduct level 1 matching-pair tests at each assessment; five patients were also able to conduct levels 2 and 3. Two patients (those with the highest CHOP-INTEND scores) were able to complete all tests correctly within 60 s. There was a non-significant trend toward improvement in CHOP-INTEND, PedsQL-NM, and NRS scores over the 6-month period. There were no significant differences in the number of actions, errors, correct answers, or response times between baseline and Week 9 or 24 at any level. However, the result of an additional analysis suggests that detection of eye movement would be useful to evaluate for advanced SMA. Conclusions: Eye-tracking systems are possibly feasible for the assessment of treatment efficacy in patients with advanced SMA type I.

Perampanel markedly improved clinical seizures in a patient with a Rett-like phenotype and 960-kb deletion on chromosome 9q34.11 including the STXBP1.

Intractable epilepsy was successfully controlled using perampanel, an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor antagonist, in a 27-year-old woman who presented with a Rett syndrome-like phenotype and novel 960-kb deletion involving syntaxin-binding protein 1 on chromosome 9q34.11. Perampanel may be an effective antiepileptic drug for intractable epilepsy associated with STXBP1 mutations.

Investigation of clinicopathological characters and gene expression features in colorectal signet-ring cell carcinoma utilizing CMS classification.

Signet ring cell carcinoma (SRCC) is a rare pathological type of colorectal cancer, of which the clinicopathological features and genetic background have not yet been fully investigated. Previous research has focused on the optimization of colorectal cancer treatment utilizing consensus molecular subtyping (CMS). However, it is not known what type of CMS would be designated to SRCC treatment. In the current study, of 1,350 patients diagnosed with colorectal cancer who underwent surgery, 14 were diagnosed with SRCC. The case-control cohort that fit the clinical background of the SRCC case was constructed. Statistical comparison between the SRCC group and the case-control cohort was performed among clinicopathological variables. SRCC and well to moderately adenocarcinoma case mRNA were submitted to microarray analysis and CMS analysis. Compared with the case-control cohort, the SRCC group was located more in the right-sided colon, the lymphatic invasion was more severe and the peritoneal dissemination was more frequent. The cancer-specific survival and the progression-free survival were significantly worse in the SRCC group compared with the case-control cohort. Microarray and CMS analysis identified that one SRCC case was significantly well assigned in the CMS 4 group and the other case was assigned in the CMS 1 group. Gene set analysis revealed the upregulation of EMT related genes and the downregulation of fatty acid, glycolysis, differentiation, MYC, HNF4A, DNA repair genes. In conclusion, the clinical characteristics of SRCC are severe but there is a possibility of the presence of different phenotypes according to CMS analysis.

Trifluridine/tipiracil plus bevacizumab as a first-line treatment for elderly patients with metastatic colorectal cancer (KSCC1602): A multicenter phase II trial.

BACKGROUND: A previous Phase I/II study demonstrated that TAS-102 (trifluridine/tipiracil [FTD/TPI]) plus bevacizumab (Bev) has encouraging efficacy and controllable safety for patients with previously treated metastatic colorectal cancer. Therefore, we designed for assessing the efficacy and safety of FTD/TPI plus Bev in elderly patients with previously untreated metastatic colorectal cancer. METHODS: This is a multicenter, single-arm Phase II study included patients ≥70 years old with previously untreated, unresectable metastatic colorectal cancer. Treatment consisted of FTD/TPI plus Bev given every 4 weeks. The primary endpoint was progression-free survival (PFS), assuming a null hypothesis of a PFS of 5 months. The secondary endpoints were the overall survival (OS), overall response rate (ORR), and adverse events (AEs). RESULTS: Between 5 January 2017 and 13 March 2018, 39 patients were enrolled from 18 institutions. The median patient age was 76.0 years (range, 70-88); the ECOG-PS was 0 in 24 patients and 1 in 15 patients. The median PFS was 9.4 months as a primary endpoint, and the median OS was 22.4 months. The ORR was 40.5% and the disease control rate was 86.5%. Grade 3-4 AEs included neutropenia (71.8%), leukopenia (51.3%), anorexia (15.4%), febrile neutropenia (10.3%), and fatigue (10.3%). CONCLUSIONS: FTD/TPI plus Bev is an effective and well-tolerated regimen for elderly patients with previously untreated metastatic colorectal cancer. Capecitabine/bevacizumab can be selected as a subsequent maintenance therapy without irinotecan and oxaliplatin because FTD/TPI has no cross-resistance with 5-fluorouracil. CLINICAL TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000025241).

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome.

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH ), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5-/-Aldh2 E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.

Long-term melatonin treatment for the sleep problems and aberrant behaviors of children with neurodevelopmental disorders.

BACKGROUND: Clinical evidence is required about the long-term efficacy and safety of melatonin treatment for sleep problems in children with neurodevelopmental disorders (NDDs) who underwent adequate sleep hygiene interventions. METHODS: We conducted a 26-week, multicenter, collaborative, uncontrolled, open-label, phase III clinical trial of melatonin granules in children 6 to 15 years of age who had NDDs and sleep problems. The study consisted of the 2-week screening phase, the 26-week medication phases I and II, and the 2-week follow-up phase. Children received 1, 2, or 4 mg melatonin granules orally in the medication phases. Variables of sleep status including sleep onset latency (SOL), aberrant behaviors listed on the Aberrant Behavior Check List-Japanese version (ABC-J), and safety were examined. The primary endpoint was SOL in the medication phase I. RESULTS: Between June 2016 and July 2018, 99 children (80 males and 19 females, 10.4 years in mean age) were enrolled at 17 medical institutions in Japan-74, 60, 22, 9, 6, and 1 of whom had autism spectrum disorder, attention-deficit/hyperactivity disorder, intellectual disabilities, motor disorders, specific learning disorder, and communication disorders, respectively, at baseline. Fifteen children received the maximal dose of 4 mg among the prespecified dose levels. SOL recorded with the electronic sleep diary shortened significantly (mean ± standard deviation [SD], - 36.7 ± 46.1 min; 95% confidence interval [CI], - 45.9 to - 27.5; P <  0.0001) in the medication phase I from baseline, and the SOL-shortening effect of melatonin persisted in the medication phase II and the follow-up phase. Temper upon wakening and sleepiness after awakening improved significantly (P <  0.0001 each) in the medication phase I from baseline and persisted in the follow-up phase. The following subscales of the ABC-J improved significantly: stereotypic behavior (P = 0.0322) in the medication phase I; and irritability, hyperactivity, and inappropriate speech (P <  0.0001) in the medication phase II. Treatment-emergent adverse events did not occur subsequent to week 16 after medication onset, and NDDs did not deteriorate in the follow-up phase. CONCLUSIONS: Long-term melatonin treatment in combination with adequate sleep hygiene interventions may afford clinical benefits to children with NDDs and potentially elevates their well-being. TRIAL REGISTRATION: ClinicalTrils.gov , NCT02757066 . Registered April 27, 2016.

Meaningful word acquisition is associated with walking ability over 10 years in Rett syndrome.

PURPOSE: To investigate walking ability in Japanese patients with Rett syndrome (RTT). METHODS: Walking ability was assessed in 100 female Japanese patients with RTT using univariate and multivariate analysis in all age groups, and in patients over 10 years of age. We analyzed walking ability and confounding factors including prenatal-perinatal histories, developmental milestones, somatic and head growth, anthropometric data, body mass index, age of loss of purposeful hand use, age at onset of stereotypic hand movement, history of autistic behavior, age at regression, presence or absence of seizures, and the results of MECP2 genetic examination from the Japanese Rett syndrome database. RESULTS: Univariate analysis revealed that acquisition of walking in all age groups was significantly correlated with the acquisition of meaningful words, microcephaly, and crawling (P < 0.0001, P = 0.005, P < 0.0001, respectively). Univariate analysis revealed that walking ability over 10 years of age was significantly correlated with acquisition of meaningful words, microcephaly, and body mass index (P < 0,0001, P = 0.005, P = 0.0018, respectively). MECP2 mutations R306C, R133C, and R294X were significantly associated with different acquisition of crawling (P = 0.004) and walking (P = 0.01). Multivariate analysis revealed that only acquisition of meaningful words was significantly correlated with walking ability over 10 years of age. This trend excluded the genetic effects of R306C, R133C, and R294X. CONCLUSIONS: Meaningful word acquisition was robustly associated with walking ability over 10 years. Prognosis of walking ability may be predicted by the acquisition of meaningful words. This information is potentially useful for early intervention and the planning of comprehensive treatment for young children with RTT.

Association between children's sleep patterns and problematic behaviors at age 5.

BACKGROUND: Night-shift lifestyles affect children as well as adults, and are associated with sleep and behavioral problems among children. This study aimed to investigate associations among sleep patterns, individual/environmental factors, and problematic behaviors in children at age 5 years. METHODS: Data for sleep patterns, individual / environmental factors, and problematic behaviors for 8,689 5-year-old children were collected from health-checkup records. Problematic behaviors investigated were anxious behavior (being afraid, difficulty being separated from the mother), developmental behavior (violence, restlessness, rebellious behavior, restrictive diet, stereotypic play), personal habits (thumb-sucking, nail-biting, tic, masturbation), and excretory problems. The relationships between sleep patterns (bedtime, sleep duration) and the presence of these behaviors were analyzed. Individual / environmental factors that affected problematic behaviors were statistically identified using a tree-form model. RESULTS: Late bedtime and short sleep duration showed significant adverse effects on children's problematic behaviors - odds ratio (OR): 1.07, 95% confidence interval (CI): 1.03-1.11 and OR: 0.92, 95% CI: 0.87-0.97, respectively. Long television watching time, abnormality at birth, and lack of father's support also showed significant adverse effects on problematic behaviors (OR: 2.34, 95% CI: 1.87-2.94), and significantly affected late bedtime and short sleep duration. CONCLUSIONS: There were significant associations among sleep patterns, individual / environmental factors, and problematic behaviors in 5-year-old children. Improving children's sleep patterns, reducing the duration of television watching, and improving support from fathers may reduce problematic behaviors.

Association between problematic behaviors and individual/environmental factors in difficult children.

BACKGROUND: Difficult children are ones whose behavior deviates from the norm, which manifests as restlessness, violence, and difficulty in separating from the mother. Such problematic behaviors usually exhaust their parents during child rearing. This study aimed to identify individual and environmental factors that influence children's problematic behavior, which could be helpful in supporting parents' child rearing. METHODS: Records of children's problematic behaviors and their individual or environmental information were collected from 8691 children at their 5-year-old health checks. Problematic behaviors were divided into three categories; anxious behaviors, developmental behaviors, and personal habits. Individual factors included sex, parental age, birth order, birth weight, and birth abnormalities. The environmental factors were mother's smoking during pregnancy or currently, partner's cooperation in child rearing, having someone to consult about child rearing, and television viewing time. Using logistic regression, we identified the association between such behaviors and aggravating factors. RESULTS: Problematic behavior was identified in 2.2%, 11.5%, and 16.1% of cases, respectively, with regard to anxious behaviors, developmental behaviors, and personal habits. The individual factors (including birth order and birth abnormality), and the environmental factors (including mothers currently smoking, lack of someone to consult about child rearing, and long television-watching time) were associated with the odd ratio of increased risk for some problematic behaviors. CONCLUSION: Behaviors in difficult children are not influenced by individual factors but by several environmental factors. To reduce the parental child rearing burden, health providers should be aware of these aggravating factors.

Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing.

BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

Resting energy expenditure prediction using bioelectrical impedance analysis in patients with severe motor and intellectual disabilities.

INTRODUCTION: Resting energy expenditure (REE) is expected to be lower in with severe motor and intellectual disabilities (SMID) patients than in healthy subjects because of their relatively low fat-free mass (FFM). Therefore, an REE predictive equation for SMID patients may be required. The aim of this study was to validate existing REE predictive weight-based equations (Harris-Benedict, WHO, Mifflin, Owen, Schofield) and FFM-based REE equations (Mifflin, Owen and Cunningham) and to develop a new SMID patient-specific FFM-based REE equation. METHODS: Twenty-eight (22 males, 6 females) SMID patients over 18 years of age were included. The REE was measured using indirect calorimetry. FFM were measured using bioelectrical impedance analysis. A multiple linear regression analysis was used to develop a new FFM-based REE predictive equation. The accurate predictions compared the measured REE and root mean square error. RESULTS: The median measured REE was 950 (25th,75th percentile:712.75, 1102.75) kcal/day. The new FFM-based equation was as follows: REE (kcal/day) = 550.62 + 16.62 FFM (kg). The new FFM-based REE resulted in the highest percentage of accurate predictions within 10% of measured REE (42.9%). The root mean square errors were the smallest for the new FFM-based REE and largest for Harris-Benedict (91.00 and 185.22 kcal/day). CONCLUSION: For SMID patients, the REE cannot accurately be predicted using the existing weight-based REE equations. Furthermore, the existing FFM-based REE equations are less accurate with regard to the measured REE than the new FFM-based REE equation. The new FFM-based equation is advised for use in SMID patients.

Mina53 nuclear localization is an important indicator of prognosis in patients with colorectal cancer after adjuvant chemotherapy.

The aim of this study was to investigate the status of the c­Myc­related molecule Mina53 and the clinical impact of Mina53 nuclear localization in patients with stage II and III colorectal cancer (CRC). Patients (n=250) who underwent complete resection of CRC at our department were enrolled in this study, and tissue microarray samples were constructed from resected specimens. Mina53 expression in the nuclei of tumor cells was analyzed using immunohistochemistry (IHC). Patients were classified into Mina53 nuclear localization­-positive and ­negative groups, and statistical correlations with clinicopathological factors were investigated. Relapse­free survival (RFS) was compared using the Kaplan­Meier method and the Cox proportional hazard model. Tumor recurrence was significantly higher in the Mina53­positive group than in the Mina53­negative group. Moreover, in RFS analysis, patients in the Mina53­positive group exhibited significantly poorer prognosis than patients in the Mina53­negative group. In the univariate analysis, histological type, adjuvant chemotherapy status, carcinoembryonic antigen (CEA) status, and Mina53 status were prognostic factors for RFS. Furthermore, in the subgroup analysis, patients in the Mina53­positive group with stage III disease treated with adjuvant chemotherapy exhibited significantly poorer prognosis in RFS than patients in the Mina53­negative group. In the univariate and multivariate analyses, histological type and Mina53 status were significantly associated with RFS. Thus, our findings revealed that Mina53 was an important indicator of prognosis in patients with stage III CRC treated with adjuvant chemotherapy.

De novo HDAC8 mutation causes Rett-related disorder with distinctive facial features and multiple congenital anomalies.

We present a unique 11-year-old girl showing clinical features of Rett-related disorder with distinctive facial features and multiple congenital anomalies including ocular hypertelorism, arched eyebrows, a broad nose, dental anomalies, congenital heart disease, truncal obesity, and epilepsy. A novel de novo mutation in histone deacetylase 8 (HDAC8) (c.652G > T, p.Gly218Cys) was confirmed by whole exome sequencing and Sanger sequencing. X-chromosome inactivation analysis on DNA isolated from peripheral blood lymphocytes revealed a completely skewed pattern associated with an inactive maternal allele. Late clinical loss of acquired purposeful hand movements and psychomotor deterioration may be a feature of Rett-related disorder, while distinctive facial features and multiple congenital anomalies are reminiscent of Cornelia de Lange syndrome.

A novel STXBP1 mutation causes typical Rett syndrome in a Japanese girl.

Rett syndrome (RTT) is a neurodevelopmental disorder mostly caused by mutations in Methyl-CpG-binding protein 2 (MECP2); however, mutations in various other genes may lead to RTT-like phenotypes. Here, we report the first case of a Japanese girl with RTT caused by a novel syntaxin-binding protein 1 (STXBP1) frameshift mutation (c.60delG, p.Lys21Argfs*16). She showed epilepsy at one year of age, regression of acquired psychomotor abilities thereafter, and exhibited stereotypic hand and limb movements at 3 years of age. Her epilepsy onset was earlier than is typical for RTT patients. However, she fully met the 2010 diagnostic criteria of typical RTT. STXBP1 mutations cause early infantile epileptic encephalopathy (EIEE), various intractable epilepsies, and neurodevelopmental disorders. However, the case described here presented a unique clinical presentation of typical RTT without EIEE and a novel STXBP1 mutation.

Ghrelin improves dystonia and tremor in patients with Rett syndrome: A pilot study.

BACKGROUND: Dystonia occurs in approximately 60% of patients with Rett syndrome (RTT) and severely impairs their quality of life. However, an effective standard therapy has not been established. In a previous study, ghrelin levels were significantly decreased in patients with RTT, in particular, among patients over 10years old. This prompted speculation that ghrelin may play an important role in RTT. OBJECTIVES: Four patients, including two adults, with severe dystonia and tremor, were recruited. METHODS: Ghrelin was intravenously administered at a dose of 3µg/kg, once-daily for 3days, followed by once every 3weeks. Objective evaluation was performed, including scoring for different clinical features (SDCF), the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Visual Analog Scale (VAS). RESULTS: The SDCF, BFMDRS, autonomic dysfunction and VAS scores were markedly improved in two patients with severe dystonia and head tremor. CONCLUSION: Ghrelin may improve extrapyramidal symptoms in patients with RTT.