Early Onset Of Symptoms Research Articles

ECMO in Single Ventricle Heart Disease

Cardiac extracorporeal membrane oxygenation (ECMO) for single ventricle heart disease is a complex intervention applied to a heterogeneous population of children. In this review, we describe the variable single ventricle populations who may be supported with ECMO and highlight recent literature regarding outcomes, trends, and evolving strategies. In the last decade, there has been a significant increase in the international volume of single ventricle cardiac ECMO, with an overall trend towards improved survival. Single ventricle ECMO has now been accepted as a viable modality in most international centers, with an overall survival approximating 45% in the modern era. Single ventricle cardiac disease, with or without the requirement for ECMO, has an important impact upon long-term health-related quality of life outcomes. While survival is slightly lower for single ventricle ECMO than in children with biventricular physiology, the need for ECMO identifies a subset of single ventricle patients who are at increased risk for interstage mortality, adverse neurodevelopmental outcomes, and the early onset of advanced heart failure symptoms. Care for survivors after ECMO requires increased surveillance and risk assessment prior to future intervention.

Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7.

Spinocerebellar ataxia type 7 (SCA7) is a rare autosomal dominant neurodegenerative disorder characterized by progressive neuronal loss in the cerebellum, brainstem, and retina, leading to cerebellar ataxia and blindness as major symptoms. SCA7 is due to the expansion of a CAG triplet repeat that is translated into a polyglutamine tract in ATXN7. Larger SCA7 expansions are associated with earlier onset of symptoms and more severe and rapid disease progression. Here, we summarize the pathological and genetic aspects of SCA7, compile the current knowledge about ATXN7 functions, and then focus on recent advances in understanding the pathogenesis and in developing biomarkers and therapeutic strategies. ATXN7 is a bona fide subunit of the multiprotein SAGA complex, a transcriptional coactivator harboring chromatin remodeling activities, and plays a role in the differentiation of photoreceptors and Purkinje neurons, two highly vulnerable neuronal cell types in SCA7. Polyglutamine expansion in ATXN7 causes its misfolding and intranuclear accumulation, leading to changes in interactions with native partners and/or partners sequestration in insoluble nuclear inclusions. Studies of cellular and animal models of SCA7 have been crucial to unveil pathomechanistic aspects of the disease, including gene deregulation, mitochondrial and metabolic dysfunctions, cell and non-cell autonomous protein toxicity, loss of neuronal identity, and cell death mechanisms. However, a better understanding of the principal molecular mechanisms by which mutant ATXN7 elicits neurotoxicity, and how interconnected pathogenic cascades lead to neurodegeneration is needed for the development of effective therapies. At present, therapeutic strategies using nucleic acid-based molecules to silence mutant ATXN7 gene expression are under development for SCA7.

Gender-dependent effect of coffee consumption on tremor severity in de novo Parkinson\u2019s disease

BackgroundCoffee consumption represents a negative risk factor for Parkinson’s disease (PD) and seems to affect PD motor symptoms. We aimed to investigate the association between coffee consumption and motor symptoms in de novo PD patients.MethodsIn total, 284 patients with de novo PD were included in the current study. Motor and non-motor symptoms were evaluated using various scales. History of coffee consumption was obtained via a semi-structured interview.ResultsIn total, 204 patients were categorized as coffee drinkers and 80 as non-coffee drinkers. Coffee drinkers were predominantly male and had early symptom onset; in addition, they were younger, reported more years in formal education, and had better motor and non-motor scores than did non-coffee drinkers. After adjustments, coffee drinkers had lower tremor scores than did non-coffee drinkers, and coffee consumption was related to tremors in a dose-dependent manner. These relationships were statistically significant in case of rest tremor but not in case of action tremor. The dose-dependent relationship between coffee consumption and tremor severity was significant only in men. Non-motor symptom scores were not significantly different between coffee drinkers and non-coffee drinkers.ConclusionsCoffee consumption and tremor severity are inversely related in male patients with de novo PD.

Phenotypic expression and species-specific reaction of Lactuca sativa ‘PI 342444’ to groundnut ringspot virus (GRSV) and tomato spotted wilt virus (TSWV) isolates

Currently, diseases caused by tospovirus species are among the most limiting factors for lettuce (Lactuca sativa L.) production in Brazil, where losses can reach up to 100%. In cultivated lettuce germplasm, the highest levels of resistance to tospoviruses were identified in the accession ‘PI 342444’ (= cultivar ‘Tinto’). We carried out controlled inoculation assays aiming to characterize the phenotypic expression and verify the spectrum of ‘PI 342444’-mediated resistance against a panel of isolates of two tospovirus species: Tomato spotted wilt virus (TSWV) and Groundnut ringspot virus (GRSV). Lettuce seedlings were mechanically inoculated with seven isolates (three TSWV and four GRSV). Plants of ‘PI 342444’ did not exhibit symptoms after inoculation with TSWV isolates, whereas severe symptoms were observed on the susceptible lettuce control (cultivar ‘Vanda’). The absence of TSWV infection in the majority of ‘PI 342444’ plants was also confirmed by serological testing. In contrast, all ‘PI 342444’ plants inoculated with GRSV isolates displayed early onset of severe symptoms, indicating that this resistance is not effective against this viral species. Further studies shall be conducted to characterize the genetic factors associated with a putative TSWV-specific resistance observed in ‘PI 342444’. On the other hand, our assays indicated that additional lettuce germplasm screenings searching for sources of resistance effective against GRSV isolates are among the major breeding priorities under Brazilian conditions, since this ‘PI 342444’ resistance-breaking virus is currently the predominant lettuce-infecting tospovirus species in the country.

Early Blood Biomarkers to Improve Sepsis/Bacteremia Diagnostics in Pediatric Emergency Settings.

Background: Sepsis is the leading cause of death in children worldwide. Early recognition and treatment are essential for preventing progression to lethal outcomes. CRP and Complete Blood Count (CBC) are the initial preferred tests to distinguish between bacterial and viral infections. Specific early diagnostic markers are still missing. Aim: To investigate diagnostic value of Neutrophil–Lymphocyte Ratio (NLR), Mean Platelet Volume (MPV) and Platelet–MPV ratio (PLT/MPV) to distinguish sepsis/bacteremia and viral infection. Methods: We conducted a retrospective data analysis of case records of 115 children from 1 month to 5 years of age. All cases were divided into two groups—sepsis/bacteremia (n = 68) and viral (n = 47) patients, and further subdivided according to the time of arrival into early or late (≤12 or 12–48 h post the onset of fever, respectively). Analysis of CBC and CRP results was performed. NLR and PLT/MPV were calculated. Results: Sepsis/bacteremia group demonstrated higher absolute platelets count (370.15 ± 134.65 × 109/L versus 288.91 ± 107.14 × 109/L; p = 0.001), NLR (2.69 ± 2.03 versus 1.83 ± 1.70; p = 0.006), and PLT/MPV (41.42 ± 15.86 versus 33.45 ± 17.97; p = 0.001). PLT/MPV was increased in early arrival sepsis/bacteremia infants (42.70 ± 8.57 versus 31.01 ± 8.21; p = 0.008). NLR and MPV were significantly lower in infants (≤12 months) with viral infection on late arrival (1.16 ± 1.06 versus 1.90 ± 1.25, p = 0.025 for NLR and 8.94 ± 0.95fl versus 9.44 ± 0.85fl, p = 0.046 for MPV). Conclusion: Together with standard blood biomarkers, such as CRP, neutrophils, or platelets count, PLT/MPV is a promising biomarker for clinical practice to help discriminate between viral disease or sepsis/bacteremia in all children, especially in early onset of symptoms. NLR and MPV could support exclusion of sepsis/bacteremia in late arrival cases.

A novel PHKA2 mutation in a Chinese child with glycogen storage disease type IXa: a case report and literature review

BackgroundPHKA2 gene mutations can cause liver phosphorylase kinase (PhK) deficiency, resulting in glycogen storage disease type IXa (GSD IXa). Elevated liver transaminase levels and liver enlargement are the most frequent phenotypes of GSD IXa. However, whether the phenotypes are applicable to Chinese patients remains unclear.Case reportA boy aged 2 years and 8 months with a history of episodic fatigue and weakness since he was 2 years old was referred to our endocrinology clinic. Apart from symptomatic ketotic hypoglycemic episodes (palpitation, hand shaking, sweating, etc.), no abnormalities of liver transaminase levels or liver size were found. To identify the aetiology of his clinically diagnosed hypoglycaemia, the proband and his parents were screened for PHKA2 gene mutations by next-generation sequencing. A heterozygous mutation (c.2972C > G, p.G991A) in PHKA2 was found in the proband and his mother. Twenty-one Chinese cases with GSD IXa have been reported in the literature to date, and elevated liver transaminase levels (95%) and liver enlargement (91%) are the most frequent phenotypes of GSD IXa in Chinese patients. Hypoglycaemia may be one of the early onset symptoms in infants with GSD IXa.ConclusionsThis study enriches our knowledge of the PHKA2 gene mutation spectrum and provides further information about the phenotypic characteristics of Chinese GSD IXa patients.

Neurophysiology of the brain stem in Parkinson's disease.

Parkinson's disease (PD) is predominantly idiopathic in origin, and a large body of evidence indicates that gastrointestinal (GI) dysfunctions are a significant comorbid clinical feature; these dysfunctions include dysphagia, nausea, delayed gastric emptying, and severe constipation, all of which occur commonly before the onset of the well-known motor symptoms of PD. Based on a distinct distribution pattern of Lewy bodies (LB) in the enteric nervous system (ENS) and in the preganglionic neurons of the dorsal motor nucleus of the vagus (DMV), and together with the early onset of GI symptoms, it was suggested that idiopathic PD begins in the ENS and spreads to the central nervous system (CNS), reaching the DMV and the substantia nigra pars compacta (SNpc). These two areas are connected by a recently discovered monosynaptic nigro-vagal pathway, which is dysfunctional in rodent models of PD. An alternative hypothesis downplays the role of LB transport through the vagus nerve and proposes that PD pathology is governed by regional or cell-restricted factors as the leading cause of nigral neuronal degeneration. The purpose of this brief review is to summarize the neuronal electrophysiological findings in the SNpc and DMV in PD.

Myelopathy due to bilateral symmetrical dumbbell cervical ganglioneuroma in a pediatric neurofibromatosis type 1 patient and rigid posterior instrumentation\u2014a case report

BackgroundAlthough neurofibromatosis type 1 (NF1) is a common genetical disorder, symptoms due to neural involvement are rare among infants and children. Ganglioneuromas are slow-growing tumors and can be seen in patients with NF1. However, bilateral symmetrical involvement is very rarely reported in the literature. We present a rare pediatric case with NF1 who presented with upper cervical bilateral symmetrical ganglioneuroma.Case presentationA 7-year-old male presented with progressive gait disturbance, falls, and bilateral limb and trunk numbness that started several weeks ago. Physical examination revealed generalized café au lait spots, neurofibromas, and axillary and inguinal freckling. Family history for NF1 was positive. Neurological examination showed slight paraparesis and hypoesthesia of the upper extremities with C4–C5 dermatomas being more distinct. Cervical magnetic resonance imaging (MRI) revealed contrast enhancing dumbbell-shaped symmetrical lesions originating from both C3 nerve roots extending to C2–C5 vertebral body levels. There was a significant spinal cord compression causing myelopathy as well as dystrophic changes and kyphotic deformity at those levels. The patient was operated and the lesions were totally excised via C2–3–4 laminoplasty. Histopathological evaluation reported the lesion as ganglioneuroma. Following the surgery for excision of the lesions, the patient presented with rapidly progressing kyphotic deformity and underwent rigid craniocervical fusion.ConclusionGanglioneuromas are seen among children, tend to occur in the mediastinum, abdomen, and retroperitoneal area, and may accompany NF1. Cervical spinal ganglioneuroma, however, is a very rare entity. Co-existence of NF1 and bilateral symmetrical cervical ganglioneuroma is highly unusual. Like neurofibromas, ganglioneuromas are slow-growing tumors and therefore they are not expected to cause myelopathy and related symptoms during childhood. Symmetrical nature of the lesions results in myelopathy and early onset of symptoms. Due to the risk of postoperative increase of kyphotic angulation, laminoplasty should be considered. Although laminoplasty alone does not prevent the progression of kyphotic changes, the procedure may allow the use of sublaminar wires and laminar hooks for future surgeries to correct the deformity.

A nationwide survey of norovirus-associated encephalitis/encephalopathy in Japan

BackgroundNorovirus is a major pathogen of gastroenteritis and is known to cause encephalitis/encephalopathy. The aim of this national survey was to clarify the clinical features of norovirus-associated encephalitis/encephalopathy (NoVE) among children in Japan. MethodsA nationwide survey of children with NoVE was conducted using a structured research form. The initial survey asked pediatricians about children with NoVE treated between January 2011 and March 2016. The second survey obtained patient information from two sources: hospitals that responded to the initial survey and those identified as having treated cases from a literature search. ResultsClinical information was available for 29 children. Their median age was 2 y 8 m. The outcome was good in 13 patients and poor in 15. The interval between the onset of gastrointestinal symptoms and that of encephalitis/encephalopathy was significantly shorter in those with a poor outcome. At the onset of an elevated serum creatinine level and an abnormal blood glucose level were correlated with a poor outcome. Regarding the subtypes of encephalitis/encephalopathy, acute encephalopathy with biphasic seizures and late reduced diffusion and hemorrhagic shock and encephalopathy syndrome were frequent. ConclusionThe outcome of children with NoVE was poor. Early onset of neurological symptoms, an elevated serum creatinine level, and an abnormal blood glucose level were associated with a poor outcome. No effective treatment was identified and this should be the subject of future studies.

Be a Mom, a Web-Based Intervention to Prevent Postpartum Depression: The Enhancement of Self-Regulatory Skills and Its Association With Postpartum Depressive Symptoms.

Aim: Be a Mom is a self-guided, web-based intervention to prevent persistent postpartum depression symptoms [PPD], targeting both at-risk postpartum women and/or women presenting early-onset postpartum depressive symptoms (selective/indicated preventive intervention). Be a Mom is grounded on the principles of Cognitive-Behavior Therapy and incorporates the recent contributions of acceptance and compassion-based approaches (third-wave approaches) applied to the perinatal context. This study aimed to explore the processes underlying therapeutic change in the Be a Mom intervention, by: (1) exploring whether participation in the Be a Mom promotes the enhancement of self-regulatory skills (emotion regulation abilities, psychological flexibility and self-compassion) in comparison with women who did not participate in the program; and (2) exploring whether changes in self-regulatory skills are associated with changes in depressive symptoms, among women who participated in the Be a Mom program.Methods: A pilot randomized, two-arm controlled trial was conducted. Eligible women (presenting PPD risk-factors and/or early-onset PPD symptoms) were enrolled in the study and were randomly assigned to the intervention group (Be a Mom, n = 98) or to the waiting-list control group (n = 96). Participants in both groups completed baseline (T1) and post-intervention assessments (T2), including measures of depressive symptoms, emotion regulation abilities, psychological flexibility and self-compassion.Results: From baseline to post-intervention assessment, women in the intervention group showed a significantly greater decrease in the levels of emotion regulation difficulties (p < 0.001) and a significant greater increase in the levels of self-compassion (p < 0.001) compared to the control group. No significant differences were found concerning psychological flexibility. Moreover, a greater decrease in difficulties in emotion regulation and greater increase in self-compassion levels were significantly associated with a greater decrease in depressive symptoms, among women in the intervention group.Discussion: Be a Mom promotes the enhancement of women’s emotion regulation abilities and self-compassion, and this seems to exert a protective effect in the presence of PPD risk factors (or early-onset symptoms) because it led to a reduction of depressive symptoms. By providing some insights into the processes that underlie treatment response to Be a Mom, this study highlights the important role of the targeted third-wave processes applied to the perinatal context.

Abstract TP310: Barriers Experienced by Emergency Medical Service Providers When Responding, Assessing, and Transporting Stroke Patients in a Rural State: Findings from Mission: Lifeline North Dakota

Introduction: In predominantly rural states, effective and efficient response of Emergency Medical Services (EMS) to stroke cases is often delayed by geographically large, sparsely populated service areas and limited access to healthcare professionals and services. North Dakota is a rural state with 36 of 53 counties designated as Frontier (less than six persons per square mile) and a total population estimated at 755,393. Purpose: To identify barriers experienced by EMS professionals in North Dakota when responding to, assessing, providing care, and transporting potential stroke patients. Methods: EMS providers were recruited to participate in in-person focus groups. Four focus groups were performed (n=24) using a semi-structured interview guide. Sessions were digitally recorded and field notes with abridged transcripts were analyzed for recurrent themes using content analysis. Results: Participants were 37.5% male, 91.7% non-Hispanic White and included unpaid EMS volunteers (29.0%). Several common themes were identified, including: 1) importance of public awareness for timely recognition of stroke symptoms and the importance of calling 9-1-1 at early onset of symptoms; 2) frequent receipt of inaccurate/insufficient information from Dispatch; 3) difficulties notifying accepting hospitals due to loss of cell service in rural areas; 4) perceptions that accepting hospital staff due not trust EMS clinical assessments; 5) technical barriers and time restraints experienced when providing written and verbal patient reports to hospitals; and 6) lack of formal feedback from hospitals to EMS agencies regarding stroke patients transported by EMS agencies. Conclusions: EMS providers in North Dakota experience several challenges inhibiting their ability to provide timely pre-hospital care to stroke patients. Although several barriers were identified, most are modifiable and can be remedied with enhanced education and training focused on improving effectiveness and efficiency of EMS communications with dispatch and hospitals.

Whole-exome sequencing identifies rare compound heterozygous mutations in the MSTO1 gene associated with cerebellar ataxia and myopathy

Human MSTO1 is involved in the regulation of mitochondrial distribution and morphology and its unregulated expression leads to mitochondrial disorder. Despite its significance for mitochondrial functions, human MSTO1 gene is rarely studied before 2017. As of late, MSTO1 mutations have been reported to cause clinical manifestations such as myopathy, cerebellar atrophy and ataxia, motor developmental delay, and pigmentary retinopathy. Here we have performed a whole-exome sequencing in a family which includes two brothers showing cerebellar atrophy and ataxia, intellectual disability, and myopathy. As a result, two mutations were identified. One of these mutations has been identified as a missense mutation, c.836G > A; p. (Arg279His) and a novel frameshift variant, c.1259delG; p. (Gly420ValfsTer2). So, the two brothers both had compound heterozygous mutations with a combination of protein-truncation mutation and missense mutation. These findings suggested an association of MSTO1 mutations with the early onset of symptoms and revealed the genotype-phenotype correlation between different mutation cases. In this case, the two brothers both have pes planus which is not reported in other cases. This might suggest that the novel mutation is responsible for dysmorphia. Thus, the recessive and novel MSTO1 mutations enriches genetic information on the pathogenicity of MSTO1 in humans.

Exome diagnostics in neurology

After an impressively successful application as a research instrument, whole-exome sequencing (WES) now enters the clinical practice due to its high diagnostic, time, and economic efficiency. WES is the diagnostic method of choice for symptoms that may be due to many different monogenic causes. Neurological indications include movement disorders, especially in cases of early symptom onset, familial clustering and complex manifestation. Starting from ablood sample, enrichment and sequencing of the exome enable the examination of all coding DNA regions for point mutations and small insertions/deletions. The identification of variants as the cause of adisease requires aprofessional evaluation pipeline, variant prioritization schemes and variant classification databases. Whereas many variants can be reliably classified as pathogenic or benign, variants of unclear significance (VUS) remain achallenge for the clinical evaluation and necessitate aperiodic reanalysis of WES data. As agenetic examination WES requires adequate patient informed consent which in particular should address possible secondary findings as well as data security. Apositive molecular result ends diagnostic odysseys, enables accurate genetic counseling and can point to targeted preventive measures and treatment. A WES significantly contributes to the understanding of the genetic architecture and pathophysiology of neurological diseases, enriching and enabling precision medicine.

SA105 - IDENTIFICATION OF PHENOTYPIC PREDICTORS OF PATHOGENIC COPY NUMBER VARIANTS IN A PSYCHOSIS POPULATION

Background Copy Number Variants (CNVs) significantly impact one's risk of developing a Neurodevelopmental Disorder (NDD). Eleven CNVs are robustly implicated in Schizophrenia (SCZ), increasing risk by 2 to 60-fold. Carriers are also at substantially higher risk of developing other NDDs (penetrance for autism/developmental delay/congenital malformations= 8–88%). Genetic testing is a standard of care for people with Autism Spectrum Disorder (ASD); 10–20% carry CNVs that may have implications for clinical management and genetic counselling. As The aim of this study was 1) to investigate clinically identifiable phenotypic features for association with putatively pathogenic CNVs, in a psychosis population, and 2) to investigate whether associated phenotypic features were predictive of CNV carrier status in patients with psychosis. Putatively predictive phenotypic characteristics may aid the identification of patients who would benefit from clinical genetic testing. Methods The primary analysis was carried out on a data set derived from an Irish SCZ research cohort with extensive clinical phenotype information and Genome-Wide Association Study (GWAS) data. Literature review identified neurodevelopmentally related phenotype variables for correlation analyses in a group of carriers of CNVs at 15 SCZ-associated loci, compared to a group without the CNVs. Phenotype variables identified included: early onset of symptoms, history of learning difficulties, specific learning disorder, remedial school support, low educational attainment, history of developmental delay, comorbid neurodevelopmental diagnosis (ASD, intellectual disability, epilepsy, ADHD), family history of NDD. The probability of pathogenic CNV carrier-status was analysed using logistic regression. A subsequent analysis was undertaken in a second psychosis data set (Cardiff) with similar neurodevelopmental phenotype and genetic data. Results In the Irish data set, nineteen individuals (1.6%) carried risk CNVs from a total sample of 1,215 cases. ‘Specific learning disorder’ (OR=9.0 (95% CI 1.38–39.98, p=0.03)); ‘History of learning difficulties’ (OR=4.0 (95% CI 1.55- 10.30, p=0.005)); ‘History of developmental delay’ (OR=5.8 (95% CI 1.91 - 16.44, p=0.005)) and ‘co-morbid NDD’ (OR=4.9 (95% CI 1.18 - 16.73, p=0.034)) were significantly associated with carrier status. ‘History of learning difficulties’ was significantly correlated with the other three variables. Logistic regression odds ratios for probability of a pathogenic CNV were 9.2, 5.3, 6.4 respectively in the presence of positive history of specific LD, history of developmental delay or co-morbid NDD. Analyses in the Cardiff data set (n=479) were supportive of a significant correlation between the CNV carrier group and presence of co-morbid NDD (p=0.0012). Correlation with history of developmental delay did not reach significance (p=0.13). Broad confidence intervals were observed in analyses in both data sets, indicating need for replication in larger datasets. Discussion These preliminary analyses indicate that symptoms of early developmental compromise, similar to symptoms observed in ASD and developmental delay may have clinical utility in screening for SCZ patients at increased risk of carrying pathogenic CNVs. The finding requires replication in larger datasets which is currently being pursued.

Laboratory diagnostic approaches in metabolic disorders.

The diagnosis of inborn errors of metabolism (IEM) takes many forms. Due to the implementation and advances in newborn screening (NBS), the diagnosis of many IEM has become relatively easy utilizing laboratory biomarkers. For the majority of IEM, early diagnosis prevents the onset of severe clinical symptoms, thus reducing morbidity and mortality. However, due to molecular, biochemical, and clinical variability of IEM, not all disorders included in NBS programs will be detected and diagnosed by screening alone. This article provides a general overview and simplified guidelines for the diagnosis of IEM in patients with and without an acute metabolic decompensation, with early or late onset of clinical symptoms. The proper use of routine laboratory results in the initial patient assessment is also discussed, which can help guide efficient ordering of specialized laboratory tests to confirm a potential diagnosis and initiate treatment as soon as possible.

Impact of Inotersen on Subgroups of Patients with Hereditary TTR Amyloidosis: Results from a Double-Blind Placebo-Controlled Trial

Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. Primary results from the NEUTO-TTR trial indicated that patients with hATTR amyloidosis who received 65 weeks of treatment with inotersen had better preservation of quality of life (QOL), as measured by the Norfolk QOL-Diabetic Neuropathy (DN) Questionnaire total score and the physical component summary score of the SF-36v2® Health Survey (SF-36v2), than did patients who received placebo. Whether the benefits of inotersen on domains of QOL differ across subgroups of patients has not been previously addressed.Objective: To examine the efficacy of inotersen for preserving QOL in subgroups of patients with hATTR amyloidosis, defined by time of disease onset (early or late) and ambulatory stage (Stage 1 or Stage 2).Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of treatment with either the investigational drug inotersen, which is an antisense oligonucleotide, or matching placebo. The Norfolk QOL-DN and SF-36v2 were administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL, representing five domains: activities of daily living, autonomic neuropathy, large fiber neuropathy/physical functioning, small fiber neuropathy, and neuropathic symptoms. The SF-36v2 is a 36-item measure which captures generic health-related QOL, representing eight domains: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional health (role-emotional), and mental health. Patient subgroups were defined by: (1) patients' time of symptom onset: whether symptoms first occurred early (at or before age 50) or late (after age 50) in life; and (2) patients' disease severity, as defined by ambulatory disability - Stage 1 (walking without assistance) or Stage 2 (walking with assistance, such as a cane or walker). Mixed-effects repeated-measures models tested treatment differences (inotersen vs. placebo) in changes of mean Norfolk QOL-DN and SF-36v2 domain scores from baseline to week 66 for each patient subgroup.Results: Inotersen was more effective than placebo for preserving QOL in patients with early onset of symptoms: treatment differences in scores were statistically significant (p<0.05) for four of the five Norfolk QOL-DN domains (all except small fiber neuropathy) and for all eight SF-36v2 domains. In patients with late onset of symptoms: statistically significant treatment differences in scores were observed for no Norfolk QOL-DN domains and only one of eight SF-36v2 domains (physical functioning). Inotersen was more effective than placebo for preserving QOL in patients with Stage 1 severity, treatment differences were statistically significant for three of the five Norfolk QOL-DN domains (all except autonomic neuropathy and small fiber neuropathy) and for five of eight SF-36v2 domains (all except general health, vitality, and mental health). In patients with Stage 2 severity, significant treatment differences in scores were observed for only one Norfolk QOL-DN domain (activities of daily living) and no SF-36v2 domains.Conclusion: Following 66 weeks of treatment, inotersen was more effective than placebo for preserving QOL in patients with hATTR amyloidosis who had early onset of symptoms or who were in Stage 1 of disease severity. Preserving QOL in patients with early onset is critical, as many of these patients are likely to be in the work force, raising children, and leading active lives. The benefits seen for patients in Stage 1 disease severity point to the crucial importance of early diagnosis and treatment, as there may be a window in which treatment can preserve QOL in patients with hATTR amyloidosis prior to the late progressive stages. DisclosuresYarlas:Optum: Employment; Akcea: Research Funding. Merlini:Pfizer: Consultancy; Millenium: Consultancy; Akcea: Consultancy; Prothena: Consultancy; Janssen: Consultancy; Ionis: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; celgene: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; annexon: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Prothena: Honoraria; janssen: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria.

Perceived burden among caregivers of patients with frontotemporal degeneration in the United States.

Frontotemporal degeneration (FTD) dementia often begins before age 60 and predominantly presents as four subtypes with prominent features of language, behavior, cognition, and motor symptoms. The early onset and unique symptoms place a distinct burden on caregivers of individuals with FTD versus other dementia types, such as Alzheimer's disease. This is the first known study to examine the domains of the FTD caregiver burden and the caregiver and patient characteristics associated with these domains. In 2017, 674 FTD caregivers in the United States (US) completed a web-based survey of caregiver and patient demographics, disease severity/symptoms, caregiver burden, and financial costs of caregiving. The major factors of caregiver burden (Zarit Burden Inventory) were determined using a principal axis factor analysis with varimax rotation. Multiple linear regression analyses examined caregiver and patient characteristics associated with overall burden and three major factors of burden: role strain, personal strain, and performance strain. Increased neuropsychiatric symptoms was associated with overall caregiver burden and greater role, personal, and performance strain. Younger caregivers experienced greater overall burden and performance strain, female caregivers experienced increased role strain, and male caregivers experienced greater performance strain. Financial costs of caregiving and experiencing a caregiving crisis in the past year were associated with higher overall burden and role strain. This study suggests that the severity and sources of burden differ for caregivers of FTD patients versus patients with other dementia types. Differing predictors for each burden domain suggest targeted interventions to address the unique FTD caregiving challenges.

GENETIC TESTING IDENTIFIES CAUSE OF ENTEROPATHY AND GROWTH FAILURE IN A 10 YEAR OLD MALE

Introduction Enteropathies with features of celiac disease or inflammatory bowel disease (IBD) should spark consideration of an immunodeficiency when presenting at an early age. Case Description We present a 10-year old male with chronic diarrhea starting at 6 weeks of life, initially improved with TPN, steroids, and cow's milk free diet. By 2 years of age, diarrhea returned, and he required frequent courses of steroids to manage his symptoms. The patient had mild dermatitis and poor growth, with otherwise negative review of systems. Endoscopies found duodenitis with severe villous blunting and pancolitis. Laboratory evaluations were notable for negative anti-enterocyte antibodies, elevated antigliadin and tissue transglutaminase IgA levels, and normal T regulatory (Treg) cells and forkhead box P3 (FOXP3) expression. He was diagnosed with Celiac Disease and years later, Crohn's Disease. His clinical course did not improve with gluten avoidance or various immunomodulators. Eventually, sequencing of the FOXP3 gene was performed, revealing a missense mutation consistent with Immune dysregulation Polyendocrinopathy Enteropathy X-linked (IPEX) syndrome. Discussion IPEX is a rare syndrome caused by a mutation in the FOXP3 transcription factor of CD4+ Treg cells. The classic IPEX syndrome includes protracted diarrhea, dermatitis, and endocrinopathies, but phenotypes vary. Endoscopic findings of the IPEX enteropathy can mimic those seen in Celiac Disease and IBD, thus a high index of suspicion should be maintained in select patients with early onset of symptoms. Finally, this case highlights the importance of genetic analysis of the FOXP3 gene itself, as IPEX patients can have normal FOXP3 protein expression and Treg numbers.

Impact of allergy on children with attention deficit hyperactivity disorder.

Background. Attention deficit hyperactivity disorder (ADHD) is commonly present worldwide, causing serious problems to those affected. ADHD was suggested to be secondary to allergic disorder or its medication. Both ADHD and allergy depend on complex environmental and genetic interaction, and they meet the hypersensitivity criteria. Objective. Detect the percentage of allergy in ADHD children, the common allergic disorders and allergens, and the effect of allergy on symptom and severity of ADHD. Material and methods. 100 children with ADHD were subjected to psychiatric assessment for ADHD type and severity, history of allergy, skin prick test to common environmental allergens, serum total IgE levels and open food challenge. Co-morbid neuropsychiatric disorders, below average intelligence quotient (IQ), and chronic illnesses were excluded. A control of 60 healthy children was chosen to compare the results of skin prick test and serum total IgE levels. Results. 35 ADHD children (35%) were allergic. Most cases had combined allergic rhinitis and bronchial asthma (25%). Common allergens were hay dust (43%) followed by different pollens (37.5%). There were statistical significant differences between coexistence of allergy, type of ADHD, early onset and severity of symptoms. Conclusion. Children with ADHD had an increased prevalence of allergic diseases. Evaluation of allergy in ADHD is mandatory, to decrease the burden of the condition.

Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p < 0.01). Among the 6 patients who were still alive, all were tracheostomized. Only one case survived beyond 2 years without artificial ventilation. The remaining patients died at a median age of 7 months. Our results may help pediatricians to provide medical information to parents and improve the decision-making process of setting up life support.