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Bruck syndrome is an autosomal recessive disease characterised by the clinical combination of both osteogenesis imperfecta and arthrogryposis multiplex congenita (AMC). It is caused due to collagen miss-folding and cross-linking defect resulting from a deletion in FKBP10 (OMIM #259450) and/or PLOD2

An asymptomatic woman aged 24 years was informed about the presence of a heart murmur by her attending obstetrician while she was hospitalised for a spontaneous abortion 6 months ago and was subsequently referred to us to rule out underlying heart disease. After clinical examination and relevant laboratory evaluation, a diagnosis of severe valvular pulmonary stenosis (PS) was established. Interestingly, our patient had undergone an open thoracotomy for surgical closure of a patent ductus arteriosus (PDA) under general anaesthesia 12 years ago in the absence of any appreciable shunt across the ligated ductus at present. Considering the severe gradient across her pulmonary valve, she underwent a successful percutaneous balloon pulmonary valvuloplasty (PBPV) procedure with excellent haemodynamic outcome. The pertinent literature concerning the rare combination of PDA in association with PS as well as the technicalities of PBPV procedure in an adult are discussed.

Background Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study we used functional near-infrared spectroscopy (fNIRS) to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. Methods Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function and autism symptoms. Functional NIRS was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. Results Compared to the control group, girls with FXS showed significant hyper-activation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition including executive function, autism symptoms, depression and anxiety. Conclusions These findings strongly support a hypothesis of neural hyper-activation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker endpoint for improving treatment trial evaluation in girls with this condition.

Coexistence of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and Turner Syndrome (TS) is rare. We report a 6-year-old Portuguese girl with mosaic TS [45,XO(39)/47,XXX(21)] presented with premature pubarche at the age of 5 years. Laboratory findings showed elevated 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and total testosterone, and sex-determining region Y (SRY) was negative. CYP21A2 gene analysis revealed two mutations (c.[844G>T]; [CYP21A2del]), consistent with the non-classical form of CAH. Complete deletion of CYP21A2 allele occurred de novo. At 6 years and 4 months, she presented accelerated growth velocity and hydrocortisone at the dose of 5 mg/m2/day was initiated. This case highlights the need to perform global examinations looking for virilization signs in TS patients follow-up. It also supports the reported genetic combination of TS and CAH. Therefore, CAH should be kept in mind in TS patients with SRY negative and virilization signs, even in the absence of short stature.

Coarctation of the aorta, a stenotic disease of the juxtaductal aorta, causes upper extremity hypertension, lower extremity hypoperfusion, and various degrees of left ventricular hypertrophy or left ventricular failure depending on the tightness of the coarcted segment, the age at presentation, and associated cardiac lesions. Patients with coarctation of the aorta can be categorized into three major groups: (1) Patients with isolated coarctation (the greater majority), which can be associated with a bicuspid aortic valve; (2) Patients with coarctation and ventricular septal defect (VSD); (3) Patients who have associated complex heart disease, including truncus arteriosus, transposition of the great arteries, double outlet ventricles, or heterotaxy syndrome.

Aims. The relationship of tumour volume, radiotherapy treatment time and other prognostic factors affecting prognosis was evaluated. Methods. 184 patients with locally advanced head and neck cancer were treated with radical intensity modulated radiotherapy (IMRT) and compared retrospectively. Results. In the multivariate analysis the overall survival was dependent on gross tumour volume (GTV), clinical stage (CS), radiotherapy treatment time (RTT) and p16 status. Local control was influenced by GTV, overall RTT and age. DFS was significantly affected by GTV, CS, RTT, p16 status and concomitant chemotherapy (CHT). Conclusions. The tumour volume and the radiotherapy treatment time were the most significant prognostic factors with the best outcomes in patients with GTV ≤ 55 cc and RTT ≤ 48 days (mean LC 8.1, DFS 7.1 and OS 6.4 years) and worst outcomes with GTV > 55 cc and RTT >48 days (mean LC 4.4, mean DFS 3.2 and mean OS 2.6 years).

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

In 1961, K Merendino ‘in pure curiosity’, while tracking the murmur of mitral regurgitation, placed his stethoscope ‘on the vertex of the head’, and ultimately led to a medical curiosity and exam finding that not only bears his name, but awes medical learners at all stages of their careers. Merendino and colleagues collected seven such cases of the ‘Murmur on Top of the Head’ building on the work of others who provided a detailed description of mitral regurgitation and noted murmur radiation to the neck and cervical/lumbosacral spine. The majority of patients suffered from rheumatic heart disease or subacute bacterial endocarditis in native heart valves. Here, we report on a case of the ‘Murmur on Top of the Head’ and provide the reader/listener with a direct recording of the ‘Merendino murmur’ (as well as its spinal correlate) in an elderly woman with a bioprosthetic mitral valve.

Background Patients with Fontan circulation may develop heart failure resulting in atrial fibrillation during the late phase. Inotropic effects to ameliorate hemodynamics on the Fontan circulation are not well understood, especially when in atrial fibrillation. This study was performed to determine whether dobutamine therapy in patients with Fontan circulation has limited effects on improving hemodynamics. Methods Lumped computational models (sinus and atrial fibrillation) were employed including biventricular, atriopulmonary connection (APC), and extracardiac total cavopulmonary connection (TCPC) Fontan models. The condition of atrial fibrillation including lack of atrial beat, irregular ventricular contraction, and time-varying elastance for the ventricle was introduced. A different dose of dobutamine was given by varying the elastance of the ventricle, heart rate, and peripheral resistance. Results In all models, the cardiac output decreased by 22.5% to 25.8% in atrial fibrillation. At 10 μg/kg/min of dobutamine in sinus rhythm, the cardiac output increased by 32.3% in the biventricular model but by only 9.2% (p Conclusions In the Fontan circulation, atrial fibrillation itself reduced the cardiac output by approximately 25%, and dobutamine had a limited effect on increasing the cardiac output, especially when in atrial fibrillation. Maintaining sinus rhythm in patients with Fontan circulation is very important.

Objective To develop an insight scale for Prader-Willi Syndrome (PWS), a genetically determined neurodevelopmental disorder with different psychopathological and behavioural problems. Methodology A sample of 36 PWS patients (58.3% women) attended at the Endocrinological Department of the Corporacio Sanitaria Parc Tauli (Sabadell, Barcelona) was evaluated. Insight was assessed by means of an adapted version of the Scale of Unawareness of Mental Disorder (SUMD), including three general insight dimensions: awareness of having a PWS, awareness of the effects of psychopharmacological medication and awareness of the social consequences, as well as three items that assess awareness of each particular symptom of the disease (obesity/overweight, excessive appetite and excessive food intake). Results The final Scale included six items and demonstrated an adequate internal consistency (Cronbach Alfa of 0.857 for Caregivers and 0.798 for Clinicians) but a high inter-rate variability. External validation using an Analytical-Visual Insight Scale was adequate. Conclusions The Adapted version for Prader-Willi patients of the Scale of Unawareness of Mental Disorder (APW-SUD) showed adequate psychometric properties and it is an easy to administer means to assess insight in this population.

Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease characterised by systemic hamartomas or benign tumours which affects multiple organs including brains, kidneys, heart, liver, eyes, lungs and skin due to inappropriate activation of mammalian target of rapamycin (mTOR)

To report a sporadic case of a familial adenomatous polyposis (FAP) discovered in a patient with bilateral retinal pigment epithelial lesions.Case report.A 30-year-old Asian woman presented for evaluation of bilateral pigmented lesions at the level of the retinal pigment epithelium. She had no personal or family history of colonic polyps or colon cancer. Colonoscopy revealed innumerable adenomatous polyps and genetic testing revealed a mutation in the adenomatous polyposis coli gene consistent with FAP. She subsequently underwent prophylactic total colectomy.The pigmented retinal pigment epithelium lesions of FAP have a characteristic appearance and it is vital for the retinal specialist to be familiar with them. De novo mutations in the APC gene are responsible for 20% to 30% of FAP cases. In the presence of the characteristic retinal pigment epithelium lesions, it is important to send the patient for work up of FAP even in the absence of family history of FAP.

The quality of care for patients admitted with a primary diagnosis of gout, both before and after admission, has not been systematically examined.To understand national trends in hospital admission for a primary diagnosis of gout in Aotearoa New Zealand over the past 10 years and the quality of care for gout received by these patients before and after the admission.Data from the Aotearoa New Zealand National Collections from 1 January 2007 to 31 December 2019 were analysed to determine rates of hospital admission for a primary diagnosis of gout. Admission data include cost-weight analysis, as well as quality of care data including gout-specific medication dispensing in the year prior and year after admission.There were 13 721 admissions with a primary diagnosis of gout over the analysis period, with an average cost per admission in 2019 of NZ$4301. The rate of admission per 100 000 population was highest in Pacific peoples followed by Māori. Although dispensing of any allopurinol increased in the year after admission, rates of regular allopurinol dispensing remained low; 38.1% for admissions in 2018. Patients who were younger (especially 20-44 years), not enrolled in a primary health organisation before admission and female had lower rate of regular allopurinol after admission.In this nationwide study, rates of admission for gout were highest in Pacific peoples and in Māori. Rates of regular allopurinol dispensing were low even after admission for a primary diagnosis of gout. These findings highlight the need for improvements in gout management in Aotearoa New Zealand, including in post-discharge planning from secondary care inpatient services.

This study investigated a 2-stage arterial switch operation (ASO) to treat transposition of the great arteries (TGA) with intact ventricular septum (TGA-IVS) in late referral patients.We retrospectively analyzed patients with TGA-IVS or TGA with restricted ventricular septal defects who had undergone 2-stage ASO at our institution from February 2007 to August 2018. Included were 41 patients: 21 (51.2%) who had undergone long-term 2-stage ASO and 20 (48.8%) who had undergone rapid 2-stage ASO.The long-term 2-stage group was older at ASO (3.5 vs 25 months; P.001). Results were more satisfactory in the long-term group than in the rapid group for intensive care unit time (P = .004), mechanical ventilation time (P = .004), and length of stay (P = .007). No in-hospital death occurred in the long-term group, and the postoperative course was more manageable in the long-term group than in the rapid group. However, the risk of significant neoaortic regurgitation was lower in the rapid group, which also had a better left ventricular ejection fraction.The long-term group achieved better early-term outcomes than the rapid group. However, a high risk of neoaortic regurgitation and myocardial dysfunction was also noted.

The hypoglossal canal (HC) is an unusual location of the posterior fossa dural arteriovenous fistula (AVF), which usually occurs in the transverse or sigmoid sinus. Herein, we report a case of HC dural AVF successfully treated with transvenous coil embolization using detachable coils in a 68-year-old woman who presented with headache and left pulsatile tinnitus for 2 months. Brain magnetic resonance imaging (MRI) and cerebral angiography revealed left HC dural AVF. The pulsatile bruit disappeared immediately after the procedure. Follow-up MRI showed complete disappearance of the fistula. Precise localization of the fistula through careful consideration of the anatomy and transvenous coil embolization using a detachable coil can facilitate the treatment for HC dural AVF.

Prader-Willi syndrome (PWS) is characterized by hypotonia, distinctive facial features, hyperphagia, obesity, short stature, hypogonadism, intellectual disability, and behavior problems. Uncontrolled hyperphagia can lead to dangerous food-seeking behavior and with life-threatening obesity. Severe obesity is prone to obstructive sleep apnea (OSA) and can lead to cor pulmonale. This study reports on a case involving a 21-year-old man with PWS who developed OSA due to severe obesity, which led to cor pulmonale, a life-threatening complication. Multidisciplinary care provided in the intensive care unit included weight reduction, ventilation support, antipsychotics, sedative drugs, rehabilitation, and meticulous skin care. The patient did recover. To prevent severe obesity in adults with PWS, hyperphagia must be controlled, and the patient must also be managed by an endocrinologist throughout childhood.

Summary Aim Comparison of gender personality traits in CAH-affected 46,XX patients with those in 46,XY patients with complete androgen insensitivity syndrome (AIS) or gonadal dysgenesis (GD). Patients and methods Thirty-six 46,XX CAH, three 46,XY AIS, four 46, XY GD patients. The Bem Sex-Role Inventory (BSRI) was used to measure masculinity, femininity and to research gender roles. Results The lowest femininity values were in the patients with CAH, the highest in patients with AIS. Age at study was not associated with the value of BSRI score. CAH patients with the Prader score 4 had lower median femininity score values than those who had the Prader score 3, however, the difference was statistically insignificant. Conclusion More masculinizied personality behavioral traits in females with CAH most likely result from exposure of the fetal brain to high levels of androgens.

Background Henry Meige (1866-1940), a French neurologist, the pupil of Charcot, is remembered for the eponym, the Meige syndrome, describing the clinical picture of craniocervical dystonia. This historical review highlights the controversies from his essay on “Le Juif Errant” (the Wandering Jew), and the evolution of his understanding of the movement disorders of the face and neck at the time of the encephalitis lethargica. Results His thesis reported 5 patients from Eastern Europe, presenting with functional neurological disorders following traumatic life experiences. He wrote with Feindel the first book on movement disorders “Les tics et leur traitement”. He pioneered the concept of focal dystonia and distinguished the facial median spasm as a dystonic movement disorder of the face. He highlighted the co-existence of psychopathology and the influence of the mental on tics and dystonia. He coined with Brissaud and Feindel the term “geste antagoniste” in cervical dystonia. He emphasized the importance of self-management and psycho-motor retraining for focal dystonia. Conclusion Meige made an invaluable contribution to our understanding of movement disorders, during his long medical career. The eponym Meige syndrome should be retained to describe an individual clinical entity.

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous MFN2 pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.

The aim of this study was to evaluate the incidence, severity, and treatment modalities of retinopathy of prematurity (ROP) in moderate and late preterm infants with a gestational age (GA)31 + 6 weeks.ROP screening results of preterm infants with GA31 + 6 weeks to 36 + 6 weeks between March 2013 and January 2019 were evaluated retrospectively. Infants were divided into 2 groups according to GA as 32-33 + 6 weeks (moderate preterm) and 34-36 + 6 weeks (late preterm). In these groups, any ROP and severe ROP (requiring treatment) development rates and ROP types and treatment modalities were evaluated.A total of 4156 preterm infants, 1875 (45.1%) female and 2281 (54.9%) male, were included. Overall, 1466 (35.2%) of the infants were moderate preterm and 2690 (64.8%) were late preterm. The incidences of any ROP and severe ROP were 22% and 2.5%, respectively. The rate of severe ROP was 5.3% in moderate preterm infants and 0.9% in late preterm infants. Significant correlations were determined between duration of hospital stay, birth weight (BW), and GA with ROP development (r = +0.415, r = -0.258, r = -0.199, respectively; p0.001 for all). Of 102 patients (2.5%) requiring treatment, 64 (62.7%) had laser, 34 (33.3%) had intravitreal bevacizumab (IVB), 2 (1.9%) had sequential IVB and laser, and 2 (1.9%) had vitreoretinal surgery.ROP seems to still be an important health problem in moderate and late preterm infants in our country according to data from screening high-risk preterm infants with a GA31 + 6 weeks. In this cohort, ROP development correlates with GA, BW, and duration of hospitalization significantly.

Purpose To validate the performance of postnatal growth and retinopathy of prematurity (G-ROP) screening criteria in a Taiwanese cohort. Design Screening evaluation with retrospective data Method Premature infants who underwent retinopathy of prematurity (ROP) screening between January 2015 and April 2019 at a tertiary hospital were examined. Infants with known final ROP results and complete longitudinal weight records were included. G-ROP screening criteria, both original and simplified (G-ROP 180 g), were applied as the prediction model for type 1 ROP; sensitivity and specificity were analyzed. The reduction in the number of infants requiring ROP screening and the number of funduscopic examinations were calculated. Result A total of 303 infants with documented ROP outcomes and complete weight gain records were examined; 103 infants developed ROP, of whom 29 developed type 1 ROP, while the other 200 did not develop ROP. For the detection of type 1 ROP, the sensitivity and specificity of the original G-ROP screening criteria were 96.6% and 42.3%, and 100% and 31% for the simplified G-ROP 180 g model, respectively. The reduction in the number of infants requiring screening and funduscopic examinations was 32.6% and 33.5% for the original G-ROP criteria, and 28.1% and 23.2% for the G-ROP 180 g model, respectively. Conclusion Both the original G-ROP and G-ROP 180 g criteria attained high sensitivities in detecting type 1 ROP in the current Taiwanese cohort, with the G-ROP 180 g model outperforming the original one. Validation and modification may be required before applying G-ROP screening criteria to different populations.

BACKGROUND: There remains controversy regarding the outcomes resulting from treatment versus conservative management of patent ductus arteriosus (PDA) among preterm infants. The effects of extreme prematurity, hemodynamic status of the PDA, and age at treatment remain poorly defined. STUDY DESIGN: This retrospective case-control study including infants

Unifocalization of the major aorto-pulmonary collaterals (MAPCAs) followed by intra-cardiac repair with ventricular septal defect (VSD) closure and restoration of right ventricle to pulmonary artery (RV-PA) continuity is the ultimate treatment goal in a case of VSD with pulmonary atresia (PA) and MAPCAs. It may be achieved in a single stage or may require multiple surgeries. We present a case of a 2 year old boy with VSD/PA who underwent single stage unifocalization of MAPCAs through midline followed by intra-cardiac repair using two polytetrafluoroethylene (PTFE) tube grafts; one for unifocalization and other as a bicuspid valved RV-PA conduit.

The present study included the first case of mucopolysaccharidosis (MPS) type VII in Taiwan. During pregnancy, the patient was diagnosed with hydrops fetalis and had ascites aspiration 4 times. In the following years, she presented gradually with chronic lung disease, developmental delay, short stature, dysmorphic features of coarse face, macroglossia and pigeon chest with scoliosis. Upon referral at age 4 years, she had corneal clouding, mild limitation of range of motion (ROM) and hepatosplenomegaly. X-ray showed paddle ribs and dysplastic vertebral bodies. MPS was suspected and urine glycosaminoglycans (GAGs) elevated were noted. The leukocyte enzymatic analyses for MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI were all normal. Afterward, the molecular analysis showed two heterozygous genetic variants of c.104C > A and c.1454C > T in trans in the GUSB gene ( NM_000181.4 ) which were the causes for MPS VII. Then, we checked the leukocyte β-glucuronidase activity for MPS VII and showed extremely low, therefore confirmed the diagnosis. Clinicians should increase the awareness on the early signs of MPS to have a prompt diagnosis and offer the correct treatment like enzyme replacement therapy (ERT) as early as possible.

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

Background Repair of complete atrioventricular septal defect with absent or diminutive primum defect is challenging because of atrial septal malposition and abnormal anatomy of the left atrioventricular valve. We sought to define the incidence, anatomy, and surgical outcomes of this entity. Methods We identified all patients in our institutional database presenting for complete atrioventricular septal defect repair from 2006 to 2018. Operative reports and echocardiograms were reviewed to determine the presence and size of the primum defect, atrioventricular valve anatomy, degree of atrioventricular valve regurgitation, repair method, and complications, including reoperation for atrioventricular valve regurgitation. Functionally univentricular patients and those receiving repair at an outside institution were excluded. Results Of 183 patients with complete atrioventricular septal defect, absent/diminutive primum defect occurred in 16 patients (8.7%; 10 absent, 6 diminutive). Six patients (38%) had leftward malposition of the atrium septum on the common atrioventricular valve. The rate of reoperation for left atrioventricular valve regurgitation was 31% (3 early, 2 late), for which preoperative predictors included leftward malposition of the atrial septum onto the common atrioventricular valve (4/6 patients with malposition required reoperation, P = .036, Fisher exact test). One patient exhibiting this risk factor died. The overall rate of moderate or greater left atrioventricular valve regurgitation on the most recent postoperative echocardiogram was 13% (2/16 patients; median follow-up, 141 days; range, 3-2236 days). Conclusions Complete atrioventricular septal defect with absent or diminutive primum defect is a unique variant of complete atrioventricular septal defect for which the risk of reoperation for left atrioventricular valve regurgitation after complete repair is high and risk factors include leftward malposition of the atrial septum on the common atrioventricular valve.

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes. Previous studies suggested dysregulated molecular networks in a CAG length genotype- and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats. Furthermore, a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats. However, an integrated analysis correlating phenotype features with genotypes (CAG repeat expansions) was not conducted previously. In this study, we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples, together with behavioral features (396 PhenoCube behaviors and 111 NeuroCube behaviors) in Htt CAG-knock-in mice. We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration. The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions, which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain. We also identified 15 chemicals with significant responses for genes with enriched behavioral features, most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry. Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.

The primary aim of this study is to compare the preoperative risk factors and postoperative outcomes between Charcot neuroarthropathy patients with dislocation versus purely fracture pattern breakdown. The secondary aim is to compare the same factors between Charcot neuroarthropathy patients with dislocation versus fracture-dislocation pattern breakdown. A total of 55 patients with forefoot, midfoot, or hindfoot Charcot Neuroarthopathy were assessed at a mean follow up of 2.99 years. Bivariate analysis compared preoperative risk factors and postoperative outcomes, and segmented multivariable regression analysis was performed. Dislocation pattern Charcot had statistically significant higher rates of broken hardware (p = .05), mean age (p = .01), and revisional exostectomy (p = .01) compared to pure fracture pattern Charcot. Dislocation pattern Charcot was 12 times more likely to have revisions exostectomy (odds ratio [OR] 12.0, 95% confidence interval [CI] 1.84-78.37), and was 8 times more likely to have osteomyelitis (OR 7.8, 95% CI 1.4-42.7, p = .02) compared to the fracture-dislocation pattern Charcot. The patients with pure fracture pattern Charcot were 58.8 times more likely to have Charcot breakdown involvement of the talonavicular joint compared to the dislocation pattern cohort (OR 58.83, 95% CI 1.1-3220.3). Involvement of the talonavicular joint, in the fracture pattern Charcot associate with medial column collapse occurring at the onset of Charcot breakdown. The dislocation pattern in Charcot Neuroarthropathy demonstrated a higher propensity for residual collapse as demonstrated by the higher rates of broken hardware, osteomyelitis, and need for revisional exostectomy.

Sickle cell disease (SCD) is the most common hereditary blood disorder in the United States. SCD is frequently associated with osteonecrosis, osteoporosis, osteopenia, and other bone-related complications such as vaso-occlusive pain, ischemic damage, osteomyelitis, and bone marrow hyperplasia known as sickle bone disease (SBD). Previous SBD models have failed to distinguish the age- and sex-specific characteristics of bone morphometry. In this study, we use the Townes mouse model of SCD to assess the pathophysiological complications of SBD in both SCD and sickle cell trait. Changes in bone microarchitecture and bone development were assessed by using high-resolution quantitative micro–computed tomography and the three-dimensional reconstruction of femurs from male and female mice. Our results indicate that SCD causes bone loss and sex-dependent anatomical changes in bone. SCD female mice in particular are prone to trabecular bone loss, whereas cortical bone degradation occurs in both sexes. We also describe the impact of genetic knockdown of cathepsin K– and E-64–mediated cathepsin inhibition on SBD.

BACKGROUND: Sickle cell disease (SCD) is a rare hemoglobinopathy which can result in chronic liver disease and cirrhosis. Patients with SCD have an increased risk of hematologic malignancy, but the prevalence of hepatocellular carcinoma (HCC) in this population is unknown. Herein, the association of SCD with HCC was examined using registry data. METHODS: The SEER-Medicare database was queried to identify patients diagnosed with HCC between 2000 and 2015, and further stratified by SCD status. Propensity matching was performed to examine cancer-related survival and treatment outcomes. RESULTS: Overall 56,934 patients with HCC were identified, including 81 patients with SCD. Patients with SCD more frequently had cirrhosis [48.1% (39/81) vs 23.5% (13,377/56,853), p

Mismatch repair-deficient (MMRD) brain tumors are rare among primary brain tumors and can be induced by germline or sporadic mutations. Here, we report 13 MMRD-associated (9 sporadic and 4 Lynch syndrome) primary brain tumors to determine clinicopathological and molecular characteristics and biological behavior. Our 13 MMRD brain tumors included glioblastoma (GBM) IDH-wildtype (n = 9) including 1 gliosarcoma, astrocytoma IDH-mutant WHO grade 4 (n = 2), diffuse midline glioma (DMG) H3 K27M-mutant (n = 1), and pleomorphic xanthoastrocytoma (PXA) (n = 1). Next-generation sequencing using a brain tumor-targeted gene panel, microsatellite instability (MSI) testing, Sanger sequencing for germline MMR gene mutation, immunohistochemistry of MMR proteins, and clinicopathological and survival analysis were performed. There were many accompanying mutations, suggesting a high tumor mutational burden (TMB) in 77%, but TMB was absent in one case of GBM, IDH-wildtype, DMG, and PXA, respectively. MSH2, MLH1, MSH6, and PMS2 mutations were found in 31%, 31%, 31% and 7% of patients, respectively. MSI-high and MSI-low were found in 50% and 8% of these gliomas, respectively and 34% was MSI-stable. All Lynch syndrome-associated GBMs had MSI-high. In addition, 77% (10/13) had histopathologically multinucleated giant cells. The progression-free survival tended to be poorer than the patients with no MMRD gliomas, but the number and follow-up duration of our patients were insufficient to get statistical significance. In the present study, we found that the most common MMRD primary brain tumor was GBM IDH-wildtype. The genetic profile of MMRD GBM was different from that of conventional GBM. MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide. Our findings can help develop better treatment options., The authors examined 13 mismatch repair-deficient (MMRD)-associated primary brain tumors to determine molecular characteristics and biological behavior. MMRD occurred after chemotherapy and radiotherapy in two cases. The genetic profile of MMRD glioblastoma was different from that of conventional glioblastoma. Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

While cystic hepatic lesions are frequently encountered in clinical practice, differentiation amongst the various entities can prove difficult if the histologic pitfalls and diagnostic caveats are unknown. Many patients present with vague clinical symptoms and overlapping imaging findings. Herein we discuss the most commonly encountered cystic hepatic lesions including abscesses (pyogenic and amebic), echinococcal cyst, simple hepatic cyst, ciliated hepatic foregut cyst, intrahepatic pseudocyst, mucinous cystic neoplasm, hemangioma, angiosarcoma, multilocular cystic hepatocellular carcinoma, cystic metastatic lesions, hematoma, and biloma.

Prader–Willi syndrome (PWS) is a rare genetic syndrome, caused by the loss of expression of the paternal chromosome 15q11-q13 region. Over the past years, many cases of patients with characteristics similar to PWS, but without a typical genetic aberration of the 15q11-q13 region, have been described. These patients are often labelled as Prader–Willi-like (PWL). PWL is an as-yet poorly defined syndrome, potentially affecting a significant number of children and adults. In the current clinical practice, patients labelled as PWL are mostly left without treatment options. Considering the similarities with PWS, children with PWL might benefit from the same care and treatment as children with PWS. This review gives more insight into the pheno- and genotype of PWL and includes 86 papers, containing 368 cases of patients with a PWL phenotype. We describe mutations and aberrations for consideration when suspicion of PWS remains after negative testing. The most common genetic diagnoses were Temple syndrome (formerly known as maternal uniparental disomy 14), Schaaf–Yang syndrome (truncating mutation in the MAGEL2 gene), 1p36 deletion, 2p deletion, 6q deletion, 6q duplication, 15q deletion, 15q duplication, 19p deletion, fragile X syndrome, and Xq duplication. We found that the most prevalent symptoms in the entire group were developmental delay/intellectual disability (76%), speech problems (64%), overweight/obesity (57%), hypotonia (56%), and psychobehavioral problems (53%). In addition, we propose a diagnostic approach to patients with a PWL phenotype for (pediatric) endocrinologists. PWL comprises a complex and diverse group of patients, which calls for multidisciplinary care with an individualized approach.

Mismatch repair deficiency (dMMR) predicts response to immune checkpoint inhibitor therapy in solid tumors. Long mononucleotide repeat (LMR) markers may improve the interpretation of microsatellite instability (MSI) assays. Our cohorts included mismatch repair (MMR) proficient and dMMR colorectal cancer (CRC) samples, MMR proficient and dMMR endometrial cancer (EC) samples, dMMR prostate cancer samples, MSI-high (MSI-H) samples of other cancer types, and MSI-low (MSI-L) samples of various cancer types. MMR status was determined by immunohistochemical staining and/or MSI Analysis System Version 1.2 (V1.2). The sensitivity and specificity of the LMR MSI panel for dMMR detection were both 100% in CRC. The sensitivity values of the MSI V1.2 and LMR MSI panels in EC were 88% and 98%, respectively, and the specificity values were both 100%. The sensitivity of the LMR panel was 75% in dMMR prostate cancer detected by immunohistochemistry. The 22 samples of other cancer types that were previously classified as MSI-H were also classified as MSI-H using the LMR MSI panel. For the 12 samples that were previously classified as MSI-L, 1 sample was classified as microsatellite stable using the LMR MSI panel, 8 as MSI-L, and 3 as MSI-H. The LMR MSI panel showed high concordance to the MSI V1.2 panel in CRC and greater sensitivity in EC. The LMR MSI panel improves dMMR detection in noncolorectal cancers.

Purpose: Cerebellar tonsillar herniation (TH) occurs frequently in syndromic craniosynostosis; however, the exact pathogenesis is unknown. This study evaluates the association between skull base deformities and TH in syndromic craniosynostosis. Methods: Retrospective study MRI study comparing syndromic craniosynostosis to controls. Measured parameters included clivus length, skull base angle, Boogard's angle, foramen magnum area, and cerebellar tonsillar position (TP). The association between skull base parameters and TP was evaluated with linear mixed models, correcting for age and risk factors for TH in craniosynostosis (hydrocephalus, intracranial hypertension, craniocerebral disproportion, and lambdoid synostosis). Results: Two hundred and eighty-two scans in 145 patients were included, and 146 scans in 146 controls. The clivus was smaller at birth, and its growth was retarded in all syndromes. The skull base angle was smaller at birth in Apert and Crouzon syndromes, and the evolution through time was normal. Boogard's angle was smaller at birth in Apert syndrome, and its evolution was disturbed in Apert and Saethre-Chotzen syndromes. The foramen magnum was smaller at birth in Crouzon and Saethre-Chotzen syndromes, and its growth was disturbed in Apert, Crouzon, and Saethre-Chotzen syndromes. TP was higher at birth in Apert syndrome, but lowered faster. In Crouzon syndrome, TP was lower at birth and throughout life. A smaller clivus and larger foramen magnum were associated with a lower TP in controls (p

BackgroundAtaxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity. A-T may present in complicated variable forms, including classic A-T and milder form of AT. Contrary to the classic A-T, the milder form does not present the cardinal features of A-T such as ataxia and telangiectasia. A few ATM mutations have been reported in variant A-T cases manifesting isolated generalized or segmental dystonia without any signs of classical A-T.MethodsAn A-T pedigree with predominant dystonia was collected. Genetic testing was performed by targeted panel of genes involved in movement disorders. The candidate variants were further confirmed by Sanger sequencing. We then reviewed previously published literatures of genetically confirmed A-T cases with predominant dystonia and summarized the clinical characteristics of dystonia-dominant A-T.ResultsTwo novel ATM mutations, p.I2683T and p.S2860P, were identified in the family. The proband presented isolated segmental dystonia without any signs of ataxia and telangiectasias. We reviewed the literatures and found that the patients with dystonia-dominant A-T tend to have a later-onset and slower progression of the disease.ConclusionTo our knowledge, this is the first report of A-T patient with predominant dystonia in China. Dystonia may appear as one of the predominant manifestations or initial symptom of A-T. Early ATM genetic testing should be considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia.

Gorham-Stout disease (GSD) is a rare disorder characterised by massive painless osteolysis due to lymphangiomatous tissue progression. GSD’s pathogenesis is still unclear, but osteoclasts' activation may play a role in its pathogenesis. There are multiple complications associated with GSD. One of the most severe and life-threatening complications is a chylothorax. Herein we discuss a case of a patient with a history of GSD who presented to the hospital with progressive dyspnoea secondary to a large left-sided pleural effusion, which was later confirmed to be a chylothorax. We will further discuss the current literature and treatment of chylothorax associated with GSD.

We present a case of an extreme preterm infant (Baby X) born at 24-week gestation. The echocardiogram showed evidence of hypertrophic cardiomyopathy (HCM) and a patent ductus arteriosus (PDA). There are a number of well-known causes of neonatal HCM including genetic, metabolic and endocrine. PDA is commonly present in preterm infants, and this can contribute to cardiac remodelling and result in cardiac changes mimicking HCM. Furthermore, medications such as steroids can also cause HCM through various mechanisms. A careful consideration of all the different aetiologies for HCM is important for appropriate management of such cases. This report examines the evidence in the literature for the above differential diagnoses and highlights the challenges in diagnosing the underlying cause of HCM in a preterm infant.

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.

BACKGROUND AND PURPOSE Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are small molecules developed to treat the genetic disease cystic fibrosis (CF). They interact directly with CFTR Cl- channels at the plasma membrane to enhance channel gating. Here, we investigate the action of a new CFTR potentiator, CP-628006 with a distinct chemical structure. EXPERIMENTAL APPROACH Using electrophysiological assays with CFTR-expressing heterologous cells and CF patient-derived human bronchial epithelial (hBE) cells, we compared the effects of CP-628006 with the marketed CFTR potentiator ivacaftor. KEY RESULTS CP-628006 efficaciously potentiated CFTR function in epithelia from cultured hBE cells. Its effects on the predominant CFTR variant F508del-CFTR were larger than those with the gating variant G551D-CFTR. In excised inside-out membrane patches, CP-628006 potentiated wild-type, F508del- and G551D-CFTR by increasing the frequency and duration of channel openings. CP-628006 increased the affinity and efficacy of F508del-CFTR gating by ATP. In these respects, CP-628006 behaved like ivacaftor. CP-628006 also demonstrated notable differences with ivacaftor. Its potency and efficacy were lower than those of ivacaftor. CP-628006 conferred ATP-dependent gating on G551D-CFTR, whereas the action of ivacaftor was ATP-independent. For G551D-CFTR, but not F508del-CFTR, the action of CP-628006 plus ivacaftor was greater than ivacaftor alone. CP-628006 delayed, but did not prevent, the deactivation of F508del-CFTR at the plasma membrane, whereas ivacaftor accentuated F508del-CFTR deactivation. CONCLUSIONS AND IMPLICATIONS CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.

The article presents the main clinical manifestations of Angelman syndrome. The article contains current data about the features of the physical, intellectual, verbal and sexual development of patients with Angelman syndrome. There are shown the data of the relationship of clinical features of Angelman syndrome with the nature of genetic disorders. The article presents the clinical criteria for diagnosis of Angelman syndrome in view of the incidence of key clinical signs. The authors reviewed the intended use of the molecular genetic analysis to verify the diagnosis and determine the genetic mechanism of Angelman syndrome. This article contains the algorithm of laboratory and diagnostic methods for molecular genetic exa-mination of patients with Angelman syndrome., В статье представлены основные клинические проявления синдрома Ангельмана (AS). Статья содержит современные данные об особенностях физического, интеллектуального, речевого и полового развития больных с AS. Представлены данные о взаимосвязи клинических особенностей AS с характером генетических нарушений. В статье приведены клинические критерии диагностики синдрома Ангельмана с учетом частоты встречаемости основных клинических признаков. Авторами рассмотрено целевое назначение молекулярно-генетических анализов, используемых для верификации диагноза и определения генетического механизма AS. Статья содержит алгоритм лабораторно-диагностических действий проведения молекулярно-генетического обследования пациентов с AS., У статті представлені основні клінічні прояви синдрому Ангельмана (AS). Стаття містить сучасні дані про особливості фізичного, інтелектуального, мовного та статевого розвитку хворих з AS. Представлені дані про взаємозв’язок клінічних особливостей AS із характером генетичних порушень. У статті надані клінічні критерії діагностики синдрому Ангельмана з урахуванням частоти зустрічаємості основних клінічних ознак. Авторами розглянуто цільове призначення молекулярно-генетичних аналізів, використовуваних для верифікації діагнозу та визначення генетичного механізму AS. Стаття містить алгоритм лабораторно-діагностичних дій проведення молекулярно-генетичного обстеження пацієнтів з AS.

Purpose: Lynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals. Experimental Design: A retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA. Results: A total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor–positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response. Conclusions: A subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.

Objective: To assess whether procalcitonin (PCT) levels can be a reliable indicator of when it is unnecessary to step up antibiotics in children with cancer and fever without source (FWS). Material and Methods: The medical records of children with hematologic-oncologic malignancies aged 3 months-15 years who had FWS ≥4 days and were admitted to Songklanagarind Hospital from December 2016 to February 2019 were reviewed. Results: FWS was identified in 89 patients. PCT levels were tested in 43 patients; 21 and 22 patients had low PCT (PCT

Machado-Joseph disease (MJD) is a fatal neurodegenerative disorder clinically characterized by prominent ataxia. It is caused by an expansion of a CAG trinucleotide in ATXN3, translating into an expanded polyglutamine (polyQ) tract in the ATXN3 protein, that becomes prone to misfolding and aggregation. The pathogenesis of the disease has been associated with the dysfunction of several cellular mechanisms, including autophagy and transcription regulation. In this study, we investigated the transcriptional modifications of the autophagy pathway in models of MJD and assessed whether modulating the levels of the affected autophagy-associated transcripts (AATs) would alleviate MJD-associated pathology. Our results show that autophagy is impaired at the transcriptional level in phagy activating kinase 1 and 2 (ULK1 and ULK2), two homologs involved in autophagy induction. Reinstating ULK1/2 levels by adeno-associated virus (AAV)-mediated gene transfer significantly improved motor performance while preventing in vitro studies showed that the observed positive effects may be mainly attributed to ULK1 activity. This study provides strong evidence of the beneficial effect of overexpression of ders. national funds through FCT (Foundation for Science and Technology) -Brain Health2020 projects CENTRO-01-0145-FEDER-000008, UID/NEU/04539/2020, CENTRO-01-0145-FEDER-022095, PTDC/NEU-NMC/0084/2014|POCI-01-0145-FEDER-016719, POCI-01-0145-FEDER-029716, POCI-01-0145-FEDER-016807, POCI-01-0145-FEDER-016390, POCI-01-0145-FEDER-032309, info:eu-repo/semantics/publishedVersion

Introdução: A hemorragia peri-intraventricular grave tem sido associada a maior mortalidade e sequelas do neurodesenvolvimento.Mantém-se controverso o impacto da hemorragia peri-intraventricular isolada, sem lesão da substância branca. O objetivo deste trabalho foi avaliar a influência da hemorragia peri-intraventricular grave, associada ou não a leucomalácia peri-ventricular quística, na mortalidade e no neurodesenvolvimento aos 24 meses.Material e Métodos: Estudo de coorte retrospetiva que incluiu os recém-nascidos com hemorragia peri-intraventricular grave, internados numa maternidade de apoio perinatal diferenciado, entre 2006 e 2015, e dois controlos com a mesma idade gestacional, internados logo a seguir ao caso, sem hemorragia peri-intraventricular. A avaliação do neurodesenvolvimento, aos 24 meses, foi realizada em 99 crianças, com recurso à escala The Schedule of Growing Skills Scale II em 52 e à escala de desenvolvimento mental de Ruth Griffiths em 47 crianças. Considerou-se défice grave do neurodesenvolvimento: paralisia cerebral, atraso do desenvolvimento psicomotor, surdez com necessidade de prótese auditiva ou cegueira.Resultados: Foram incluídos 41 recém-nascidos com hemorragia peri-intraventricular grave e 82 controlos. Ocorreram 23 óbitos, 16 (39,0%) nas hemorragias peri-intraventricular graves e sete (8,5%) nos controlos (OR 7,6; IC 95% 2,6 - 20,4; p < 0,001). Verificou-se défice grave do neurodesenvolvimento em sete (30,4%) no grupo de hemorragia peri-intraventricular graves e um (1,3%) no grupo de controlos (OR 32; IC 95% 3,7 - 281; p < 0,001). Na análise individualizada, a mortalidade foi superior quer nas hemorragia peri-intraventricular grau III com leucomalácia peri-ventricular quística associada (OR 4,4 IC 95% 1,3 - 14,2; p = 0,015), quer na hemorragia peri-intraventricular grau IV (OR 12; IC 95% 3,5 - 41,2; p < 0,001), em relação aos controlos. Verificaram-se também diferenças no défice grave do neurodesenvolvimento em relação aos controlos (1,3%) na hemorragia peri-intraventricular grau III com leucomalácia peri-ventricular quística associada (75,0%, p < 0,001) e na hemorragia peri-intraventricular grau IV (50,0%, p < 0,001).Discussão: Este estudo evidenciou maior taxa de mortalidade e de alterações graves do neurodesenvolvimento nos prematuros com hemorragia peri-intraventricular grave. A análise dos grupos estratificados por idade gestacional e a abordagem separada dos vários tipos de hemorragia peri-intraventricular, permitiu evidenciar as complicações associadas à hemorragia peri-intraventriculargrau IV e grau III, associada ou não a leucomalácia peri-ventricular quística.Conclusão: Os recém-nascidos com hemorragia peri-intraventricular de grau IV ou grau III com leucomalácia peri-ventricular quística associaram-se a maior mortalidade e sequelas graves do neurodesenvolvimento.

Background/purpose A heterozygous three-nucleotide (GAG) in-frame deletion in the TOR1A gene causes the rare disease, dystonia (DYT1), which typically presents as focal limb dystonia during adolescence, then spreads to other limbs. This study investigated the frequency and clinical features of DYT1 in a Taiwanese dystonia cohort. Methods We performed targeted next generation sequencing in 318 patients with primary dystonia. We identified one DYT1 family with various types of dystonia, and we described the clinical presentations observed in this family during a 30-year follow-up. We compared the clinical characteristics to those reported in previous studies on DYT1 from 2000 to 2020. Results Among 318 patients, we identified only one DYT1 patient (0.3%) with an autosomal dominant family history of dystonia. The proband was a 43-year-old man that experienced progressive onset of focal lower limb dystonia from age 11 years. The disease spread caudal-rostrally to the upper limbs and cervical muscles. Prominent cervical dystonia was noted during follow-up, which was an atypical presentation of DYT1. Clinical assessments of other family members showed intrafamily variability. The proband's father and an affected sibling demonstrated only mild right-hand writer's cramp. A systematic review of previously reported DTY1 cases showed that Asian patients had a higher frequency of cervical dystonia (44.8%) than groups of Ashkenazi Jews (35%) and Non-Jewish Caucasians (30.5%) (P = 0.04). Conclusion Our findings revealed that DYT1 is rare in a Taiwanese dystonia cohort. The presentation of marked cervical dystonia could be the main feature of Asian patients with DYT1.

Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations on the TSC1/TSC2 genes, which result in alterations in molecular signalling pathways involved in neurogenesis and hamartomas in the brain and other organs. TSC carries a high risk for autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), although the reasons for this are unclear. One proposal is that TSC-related alterations in molecular signalling during neurogenesis lead to atypical development of neural networks, which are involved in the occurrence of ASD and ADHD in TSC. We investigated this proposal in young people with TSC who have been studied longitudinally since their diagnosis in childhood. Electroencephalography (EEG) was used to examine oscillatory connectivity in functional neural networks and local and global network organisation during three tasks (resting-state, attentional and inhibitory control Go/Nogo task, upright and inverted face processing task) in participants with TSC (n = 48) compared to an age- and sex-matched group of typically developing Controls (n = 20). Compared to Controls, the TSC group showed hypoconnected neural networks in the alpha frequency during the resting-state and in the theta and alpha frequencies during the Go/Nogo task (P ≤ .008), as well as reduced local network organisation in the theta and alpha frequencies during the Go/Nogo task (F = 3.95, P = .010). There were no significant group differences in network metrics during the face processing task. Increased connectivity in the hypoconnected alpha-range resting-state network was associated with greater ASD and inattentive ADHD symptoms (rho≥.40, P ≤ .036). Reduced local network organisation in the theta-range during the Go/Nogo task was significantly associated with higher hyperactive/impulsive ADHD symptoms (rho = −.43, P = .041). These findings suggest that TSC is associated with widespread hypoconnectivity in neural networks and support the proposal that altered network function may be involved in the co-occurrence of ASD and ADHD in TSC.

Basaloid follicular hamartoma is a benign, superficial malformation of hair follicles that can be mistaken both clinical and histopathologically for basal cell carcinoma. Basaloid follicular hamartoma has been linked to a mutation in the PTCH-1 gene, which is part of the same pathway involved in Gorlin-Goltz syndrome. Here we present a 9-year-old patient with an asymptomatic congenital lesion on the forehead, which increased in size over the years. Histopathology showed a basaloid follicular hamartoma associated with follicular mucinosis and inflammation. Gorlin-Goltz syndrome was ruled out by clinical examination.

Contains fulltext : 234931.pdf (Publisher’s version ) (Closed access) Spinocerebellar ataxia type 3 (SCA3), the commonest dominantly inherited ataxia worldwide, is characterized by disruption in the cerebellar-cerebral and striatal-cortical networks. Findings on SCA3-associated cognitive impairments are mixed. The classification models, tests and scoring systems used, language, culture, ataxia severity, and depressive symptoms are all potential confounders in neuropsychological assessments and may have contributed to the heterogeneity of the neurocognitive profile of SCA3. We conducted a systematic review of studies evaluating neurocognitive function in SCA3 patients. Of 1304 articles identified, 15 articles met the eligibility criteria. All articles were of excellent quality according to the National Institutes of Health quality assessment tool for case–control studies. In line with the disrupted cerebellar-cerebral and striatal-cortical networks in SCA3, this systematic review found that the neurocognitive profile of SCA3 is characterized by a core impairment of executive function that affects processes such as nonverbal reasoning, executive aspects of language, and recall. Conversely, neurocognitive domains such as general intelligence, verbal reasoning, semantic aspect of language, attention/processing speed, recognition, and visuospatial perception and construction are relatively preserved. This review highlights the importance of evaluating neurocognitive function in SCA3 patients. Considering the negative impact of cognitive and affective impairment on quality of life, this review points to the profound impairments that existing or future treatments should prioritize. 14 p.

Background Mucopolysaccharidosis (MPS) refers to a group of lysosomal storage disorders for which seven types and 11 subtypes are currently recognized. Targeted next-generation sequencing (NGS) offers an important method of disease typing, diagnosis, prenatal diagnosis, and treatment. Methods Gene variations in 48 Chinese MPS patients were evaluated using NGS, and the pathogenicity of the DNA alterations was evaluated using PolyPhen2, SIFT, and Mutation Taster. The effect of amino acid substitution on protein structure was also assessed. Results Four pedigrees with MPS I (8.3%), 28 with MPS II (58.3%), two with MPS IIIA (4.2%), two with MPS IIIB (4.2%), six with MPS IVA (12.5%), one with MPS IVB (2.1%), and five with MPS VI (10.4%) were identified. Of the 69 variations identified, 11 were novel variants (three in IDUA, five in IDS, and three in GALNS), all of which were predicted to be disease-causing except for one, and were associated with impaired protein structure and function. Conclusions Targeted NGS technology is effective for the gene-based testing of MPS disorders, which show high allelic heterogeneity. MPS II was the predominant form in Chinese. Our study expands the existing variation spectrum of MPS, which is important for disease management and genetic counseling.