Onset In Early Childhood Research Articles

Evolution of treatment for children with esthesioneuroblastoma (1969–2019)

Introduction. Esthesioneuroblastoma is a rare neuroectodermal malignant tumor. The incidence of this tumor in children under 15 years of age is 0.1 per 100,000 pediatric population. The information on incidence, disease course, and treatment of esthesioneuroblastoma in children vary significantly and depend on the follow-up period and statistical methods.Objective – to assess risk factors for esthesioneuroblastoma and evaluate treatment strategies used in children and their prospects.Materials and methods. This study included 29 patients aged 2 to 17 years diagnosed with esthesioneuroblastoma and treated at the Research Institute of Oncology and Hematology, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia between 1969 and 2019. The median age upon diagnosis was 10 years. Six patients (20 %) developed the disease early in their life (being under 3 years of age). Esthesioneuroblastoma was equally common in boys and girls. More than half of the patients (n = 15; 51 %) had stage IV disease. The primary tumor invaded the maxillary sinus (n = 25; 86 %), orbit (n = 10; 34 %), ethmoid sinus (n = 18; 62 %), and cranial cavity (n = 12; 41 %). The majority of children (n = 28; 96 %) received pharmacotherapy and radiotherapy (n = 27; 93 %); the total focal dose was 50 Gy in case of primary tumor. The affected cervical lymph nodes were irradiated in 10 (35 %) patients (total focal dose 40 Gy). Ten (35 %) patients have undergone surgery.Results. The follow-up period varied between 3 months and 50 years. Nine (34 %) patients are still alive. Fourteen patients (48 %) died due to tumor progression; 1 (3 %) patient died due to complications from special treatment. Five (17 %) patients were lost to follow-up at different stages.Conclusion. The following risk factors were associated with poor prognosis in children with esthesioneuroblastoma: disease onset in early childhood, no adequate diagnosis of distant metastases prior to specific treatment initiation, disseminated disease, and high Ki-67 index. In patients with advanced cancer, surgeries were effective only in combination with chemoradiotherapy. Long-term treatment outcomes in children with esthesioneuroblastoma are poor due to high risk of recurrence and tumor dissemination.

Genetic correction strategies for Duchenne muscular dystrophy and their impact on the heart

BackgroundDuchenne muscular dystrophy (DMD) is an X-linked recessive disorder with early childhood onset characterized by profound loss of muscle strength and associated cardiomyopathy. DMD affects is most often caused by deletions involving single or multiple exons that disrupt the open reading frame of the DMD gene. Mutations causing loss or premature truncation of dystrophin result in dystrophin protein deficiency, which renders the plasma membrane of skeletal myofibers and cardiomyocytes weakened. Aim of reviewGenetic correction is in use to treat DMD since several drugs have been already approved which partially restore dystrophin production through the use of antisense oligonucleotides. There are multiple ongoing clinical trials to evaluate the efficacy of treating DMD with micro-dystrophins delivered by adeno-associated viruses. Future approaches entail gene editing to target the single copy of the DMD gene on the X-chromosome. The primary, near-term goal is restoration of skeletal muscle dystrophin, and for some of these treatments, the efficacy in the heart is not fully known. Here, we discuss the anticipated cardiac outcomes of dystrophin-targeted therapies, and how this information informs genomic medicine for cardiomyopathies, especially in childhood. Key scientific concepts of reviewMany genetic treatment strategies are being implemented to treat DMD. Since most preclinical testing has focused on skeletal muscle, there is a gap in knowledge about the expected effects of these approaches on cardiac genetic correction and cardiomyopathy progression in DMD. Additional study is needed.

Cortical Auditory Evoked Potential in Adults With Cochlear Implants: A Comparison With Adults With Normal Hearing.

Background and ObjectivesTo examine the maturational status of the auditory cortex in adults with cochlear implants (CIs) using the latencies of the P1, N1, and P2 components of cortical auditory-evoked potentials (CAEPs).Subjects and MethodsA total of 25 adults with CIs and 25 age-matched, normal-hearing control subjects participated in this study. Specifically, patients with CIs were divided into three groups depending on their age of deafness onset: Group A comprised patients with prelingual deafness who had received CI during early childhood (n=7), Group B comprised patients with early childhood-onset, progressive deafness who had received CI during childhood (n=6), and Group C comprised patients with adult-onset deafness (n=12). The P1, N1, and P2 latencies of their CAEPs were then compared between CI patients and normal-hearing subjects.ResultsAll participants showed clear CAEP responses. P1 and N1 latencies in Group A and Group C patients were significantly longer than those in the control group. Meanwhile, Group B patients had significantly longer N1 and P2 latencies, as compared with those in the control group.ConclusionsPatients with prelingual deafness and those with early-childhood onset, progressive deafness who received CI developed primary and higher-order auditory areas postoperatively when they became adults. However, their auditory cortex maturational statuses seemed to be worse than that of normal-hearing individuals. Furthermore, adult patients with late-onset deafness might experience degenerative auditory cortex changes during the auditory deprivation period between deafness onset and cochlear implantation.

Protective effects of medium chain triglyceride diet in a mouse model of Dravet syndrome.

Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with early childhood onset. Patients with DS do not respond well to antiepileptic drugs and have only a few treatment options available. Here, we evaluated the effect of medium chain triglyceride (MCT) diet therapy in a mouse model of DS. Scn1aR1407X/+ DS mice were given diets supplemented with MCTs with varying ratios of decanoic (C10) and octanoic (C8) acid or a control diet for 4weeks. Video monitoring was performed to evaluate spontaneous convulsive seizure frequency. Susceptibility to hyperthermia-induced seizures was also examined. Medium chain fatty acids, and mitochondrial and antioxidant markers were assessed in brain homogenate. Dietary intervention with MCTs significantly prolonged survival and reduced convulsive seizure frequency during the critical period of highest seizure occurrence in the Scn1aR1407X/+ DS mice. Moreover, MCT diet therapy showed protective effects against hyperthermia-induced seizures. We demonstrated that coadministration of C10/C8 was effective at reducing both seizures and mortality, whereas C10 alone only reduced mortality, suggesting that the ratio of C10 to C8 in the MCT is an important factor for efficacy. When C10 and C8 are supplemented at an 80:20 ratio in the diet, C10 accumulates in the brain in high enough concentrations to enhance brain energy metabolism by both stimulating mitochondrial enrichment and increasing its antioxidant status. The results from this study indicate that MCT diet therapy may provide therapeutic benefits in DS. Future clinical studies would elucidate whether these positive effects are mirrored in human patients.

Cohort of patients with hypertrophic cardiomyopathy and alpha tropomyosin 1 variants followed up at a national reference center

Abstract Background Hypertrophic cardiomyopathy (HCM), the most common inherited cardiac condition, is mainly caused by pathogenic variants in sarcomeric genes. Alpha tropomyosin gene (TPM1) account for a small percentage (1–5%) of HCM cases with ∼20 relevant variants described so far related to this condition. However, TPM1–hypertrophic cardiomyopathy is thought to be associated with high rates of heart failure and sudden death (SD). Purpose To describe the phenotype and genotype of a cohort of adult and pediatric patients with HCM and variants in TPM1 followed up in an inherited cardiovascular disease program of a national reference center. Methods Patients with HCM and TPM1 variants potentially related to the phenotype were retrospectively identified. Genetic test was performed by next generation sequencing panels or clinical exome. Clinical data, any need of intervention (obstruction relief, device implantation, heart transplant) and major adverse cardiovascular events were collected from medical records. We performed co-segregation studies whenever possible. Predictive models in order to support the possible pathogenicity of the variants were also applied. Results We identified 13 individuals (54% females) from 11 families with HCM and variants in TPM1. 12 patients had phenotype and one was a carrier. 5 out of 12 patients (42%) were diagnosed before the age of 12 years, all with severe phenotype. The most frequent pattern was asymmetric septal hypertrophy, with a mean thickness of the septum of 22 mm (range 14–37). 4 cases were obstructive, of which 3 required surgical myectomy. 4 patients required an implanted cardiac defibrillator (ICD), all in childhood. One was in secondary prevention after an aborted SD in a 12-year-old girl. 3 appropriate therapies were recorded in 2 patients during follow-up. A girl underwent heart transplantation at the age of 12 because of angina at rest. At last evaluation 67% were symptomatic, with 3 patients in functional class II and 5 patients in functional class III-IV/IV. 8 missense variants in TPM1 were identified in the 11 families (table 1). All variants are described in Clinvar as variants of unknown significance (VUS). They appear at a very low frequency (<0.01%) or are absent in general population and predictive models of protein structure and functionality (PreditProtein) indicate an impact on the structure of the protein, supporting their possible pathogenicity. Figure 1 shows a diagram of the variants position within TPM1 gen. Cossegregation data and the presence of the same variant in non_related families allowed us to reclassify 4 variants as “likely pathogenic”. Conclusion This study provides cosegregation data and “in silico” analysis of the potential functional impact of several TPM1 variants, supporting their pathogenicity. In our cohort, HCM related to TMP1 variants is associated with high penetrance (92%), early onset and poor clinical course in childhood and youth. Funding Acknowledgement Type of funding sources: None. Figure 1

Механізми формування гіперреактивності бронхів з урахуванням фенотипової неоднорідності та клінічної девіації бронхіальної астми в підлітковому віці (огляд літератури)

Bronchial asthma is a disease characterized by recurrent episodes of variable bronchial obstruction, chronic bronchial inflammation, bronchial hypersensitivity and remodulation. Modern therapy of the disease was aimed at these links of pathogenesis, and this concept postulated the need for long-term use of anti-inflammatory drugs and, above all, topical inhaled corticosteroids. However, it should be recognized that the coherent inflammatory theory currently requires revision and new understanding, or even replacement with a new theory, which, considering these characteristics of the disease as an epiphenomenon, will serve as a basis for new approaches in treatment and prevention. The aim of our work — to analyze the mechanisms of formation of bronchial hyperreactivity, taking into account the phenotypic heterogeneity and clinical deviation of bronchial asthma in adolescence (based on the analysis of scientific sources). It is extremely important to determine the risk of transition of the adolescents' bronchial asthma into adulthood, when chronic obstructive pulmonary diseases might develop. Among the main predictors of this risk such factors as age, obesity, early puberty, body weight at birth and in the newborn period and sex can be distin guished. Thus, some authors associate the risk of persistence of the disease with its onset in early childhood, and others — at the age of 6 years old. High body mass index and early onset of puberty are considered to be the predictors of persistent bronchial asthma. It is noted that low and extremely low birth weight of premature infants or rapid weight gain in the neonatal period are associated with a decrease in lung ventilation and the risk of persistent asthma in the future. It is believed that bronchial asthma in children is more common in boys than in girls, in contrast, during puberty, allergic diseases and asthma are more common in girls. Conclusions. The above mentioned literature data give reason to believe that, despite advances in the scientific understanding of the pathogenesis of the main characteristics of bronchial asthma, there are great difficulties in using them in practice. Moreover, current inflammatory paradigm of bronchial asthma needs to be revised because it being a dogma becomes unproductive from a clinical point of view. No conflict of interest was declared by the authors. Key words: asthma, adolescents, hyperreactivity, remission.

PIK3CA-Related Overgrowth Spectrum From Diagnosis to Targeted Therapy: A Case of CLOVES Syndrome Treated With Alpelisib.

PIK3CA-related overgrowth spectrum (PROS) is an umbrella term referring to various clinical entities, which share the same pathogenetic mechanism. These conditions are caused by somatic gain-of-function mutations in PIK3CA, which encodes the 110-kD catalytic α subunit of PI3K (p110α). These PIK3CA mutations occur as post-zygotic events and lead to a gain of function of PI3K, with consequent constitutional activation of the downstream cascades (e.g., AKT/mTOR pathway), involved in cellular proliferation, survival and growth, as well as in vascular development in the embryonic stage. PIK3CA-related cancers and PROS share almost the same PIK3CA mutational profile, with about 80% of mutations occurring at three hotspots, E542, E545, and H1047. These hotspot mutations show the most potent effect on enzymatic activation of PI3K and consequent downstream biological responses. If present at the germinal level, these gain-of-function mutations would be lethal to the embryo, therefore we only see them in the mosaic state. The common clinical denominator of PROS disorders is that they are sporadic conditions, presenting with congenital or early childhood onset overgrowth with a typical mosaic distribution. However, the severity of PROS is highly variable, ranging from localized and apparently isolate overgrowth to progressive and extensive lipomatous overgrowth associated with life-threatening vascular malformations, as seen in CLOVES syndrome. Traditional therapeutic approaches, such as sclerotherapy and surgical debulking, are often not curative in PROS patients, leading to a recrudescence of the overgrowth in the treated area. Specific attention has been recently paid to molecules that are used and studied in the oncogenic setting and that are targeted on specific alterations of the pathway PI3K/AKT/mTOR. In June 2018, Venot et al. showed the effect of Alpelisib (BYL719), a specific inhibitor for the p110α subunit of PI3K, in patients with PROS disorders who had severe or life-threatening complications and were not sensitive to any other treatment. In these cases, dramatic anatomical and functional improvements occurred in all patients across many types of affected organ. Molecular testing in PROS patients is a crucial step in providing the conclusive diagnosis and then the opportunity for tailored therapy. The somatic nature of this group of diseases makes challenging to reach a molecular diagnosis, requiring deep sequencing methods that have to be performed on DNA extracted from affected tissue. Moreover, even analyzing the DNA extracted from affected tissue there is no guarantee to succeed in detection of the casual somatic mutation, since the affected tissue itself is highly heterogeneous and biopsy approaches can be burdened by incorrect sampling or inadequate tissue sample. We present an 8-year-old girl with CLOVES syndrome, born with a large cystic lymphangioma involving the left hemithorax and flank, multiple lipomas, and hypertrophy of the left foot and leg. She developed severe scoliosis. Many therapeutic approaches have been attempted, including Sildenafil treatment, scleroembolization, laser therapy, and multiple debulking surgeries, but none of these were of benefit to our patient's clinical status. She then started treatment with Rapamycin from May 2019, without significant improvement in both vascular malformation and leg hypertrophy. A high-coverage Whole Exome Sequencing analysis performed on DNA extracted from a skin sample showed a mosaic gain-of-function variant in the PIK3CA gene (p.H1047R, 11% of variant allele frequency). Once molecular confirmation of our clinical suspicion was obtained, after a multidisciplinary evaluation, we decided to discontinue Sirolimus and start targeted therapy with Alpelisib (50 mg/day). We noticed a decrease in fibroadipose overgrowth at the dorsal level, an improvement in in posture and excellent tolerability. The treatment is still ongoing.

CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%–70% of genetically confirmed DOA cases are associated with variants in OPA1, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of OPA1 pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived OPA1 c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of OPA1 through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of OPA1 correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of OPA1 correction, with successful gene correction in 57% of isolated iPSCs. Correction of OPA1 restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of OPA1 re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an OPA1 variant.

Sensorimotor Integration in Childhood Dystonia and Dystonic Cerebral Palsy—A Developmental Perspective

Dystonia is a disorder of sensorimotor integration, involving dysfunction within the basal ganglia, cortex, cerebellum, or their inter-connections as part of the sensorimotor network. Some forms of dystonia are also characterized by maladaptive or exaggerated plasticity. Development of the neuronal processes underlying sensorimotor integration is incompletely understood but involves activity-dependent modeling and refining of sensorimotor circuits through processes that are already taking place in utero and which continue through infancy, childhood, and into adolescence. Several genetic dystonias have clinical onset in early childhood, but there is evidence that sensorimotor circuit development may already be disrupted prenatally in these conditions. Dystonic cerebral palsy (DCP) is a form of acquired dystonia with perinatal onset during a period of rapid neurodevelopment and activity-dependent refinement of sensorimotor networks. However, physiological studies of children with dystonia are sparse. This discussion paper addresses the role of neuroplasticity in the development of sensorimotor integration with particular focus on the relevance of these mechanisms for understanding childhood dystonia, DCP, and implications for therapy selection, including neuromodulation and timing of intervention.

CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants

BackgroundPathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published.Case presentationWe identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2.Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions.ConclusionsThis expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

Marked Facial Weakness, Ptosis, and Hanging Jaw: A Case with RYR1 -Related Congenital Centronuclear Myopathy.

Congenital myopathies are an expanding spectrum of neuromuscular disorders with early infantile or childhood onset hypotonia and slowly or nonprogressive skeletal muscle weakness. RYR1 -related myopathies are the most common and frequently diagnosed class of congenital myopathies. Malignant hyperthermia susceptibility and central core disease are autosomal dominant or de novo RYR1 disorder, whereas multiminicore, congenital fiber type disproportion and centronuclear myopathy are autosomal recessive RYR1 disorders. The presence of ptosis, ophthalmoparesis, facial, and proximal muscles weakness, with the presence of dusty cores and multiple internal nuclei on muscle biopsy are clues to the diagnosis. We describe an 18-year-old male, who presented with early infantile onset ptosis, ophthalmoplegia, myopathic facies, hanging lower jaw, and proximal muscle weakness confirmed as an RYR1 -related congenital centronuclear myopathy on genetic analysis and muscle biopsy.

Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Here, we report on cross-sectional data from the first study visit of a prospectively collected natural history study of 45 individuals, age range 3-21 years with genetically confirmed GAN to describe and cross-correlate baseline clinical and functional cohort characteristics. We review causative variants distributed throughout the GAN gene in this cohort and identify a recurrent founder mutation in individuals with GAN of Mexican descent as well as cases of recurrent uniparental isodisomy. Through cross-correlational analysis of measures of strength, motor function and electrophysiological markers of disease severity, we identified the Motor Function Measure 32 to have the strongest correlation across measures and age in individuals with GAN. We analysed the Motor Function Measure 32 scores as they correspond to age and ambulatory status. Importantly, we identified and characterized a subcohort of individuals with a milder form of GAN and with a presentation similar to Charcot-Marie-Tooth disease. Such a clinical presentation is distinct from the classic presentation of GAN, and we demonstrate how the two groups diverge in performance on the Motor Function Measure 32 and other functional motor scales. We further present data on the first systematic clinical analysis of autonomic impairment in GAN as performed on a subset of the natural history cohort. Our cohort of individuals with genetically confirmed GAN is the largest reported to date and highlights the clinical heterogeneity and the unique phenotypic and functional characteristics of GAN in relation to disease state. The present work is designed to serve as a foundation for a prospective natural history study and functions in concert with the ongoing gene therapy trial for children with GAN.

Differential diagnosis of POLG related disorders: What to keep in mind when multiorgan system is involved?

Mitochondrial and lysosomal dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) leading to deficient energy production and defects in phagocytosis in endosomal-lysosomal pathway respectively. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of inheritance that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. In this review article, we summarized the spectrum of mtDNA depletion disorders along with minor learning of lysosomal storage diseases. This current article offers a perspective on the role of genetics in medical practice and how this role may evolve over the next several years.

Childhood sarcoidosis: A case report

Childhood sarcoidosis is a rare multisystemic granulomatous disorder of unknown etiology. The diagnosis is often delayed due to lacking of recognition of clinical features. We report a 23 month-old boy who presented with multiple pinkish papules and painless cystic swellings in his ankles and wrists. A skin biopsy showed multiple sarcoidal granulomatous lesions. He was treated with steroids and had a good response. Childhood sarcoidosis is characterized by arthritis, uveitis, and cutaneous involvement. Glucocorticoids remain the first choice therapy for children with multisystem involvement. The prognosis of early-onset childhood sarcoidosis varies in different studies due to the rarity of the disease.

Genetic and immunologic findings in children with recurrent aphthous stomatitis with systemic inflammation

BackgroundRecurrent aphthous stomatitis with systemic signs of inflammation can be encountered in inflammatory bowel disease, Behçet’s disease (BD), Systemic Lupus Erythematosus (SLE). In addition, it has been proposed that cases with very early onset in childhood can be underpinned by rare monogenic defects of immunity, which may require targeted treatments. Thus, subjects with early onset recurrent aphthous stomatitis receiving a clinical diagnosis of BD-like or SLE-like disease may deserve a further diagnostic workout, including immunologic and genetic investigations.ObjectiveTo investigate how an immunologic, genetic and transcriptomics assessment of interferon inflammation may improve diagnosis and care in children with recurrent aphthous stomatitis with systemic inflammation.MethodsSubjects referred to the pediatric rheumatologist for recurrent aphthous stomatitis associated with signs of systemic inflammation from January 2015 to January 2020 were enrolled in the study and underwent analysis of peripheral lymphocyte subsets, sequencing of a 17-genes panel and measure of interferon score.ResultsWe enrolled 15 subjects (12 females, median age at disease onset 4 years). The clinical diagnosis was BD in 8, incomplete BD in 5, BD/SLE overlap in 1, SLE in 1. Pathogenic genetic variants were detected in 3 patients, respectively 2 STAT1 gain of function variants in two patients classified as BD/SLE overlap and SLE, and 1 TNFAIP3 mutation (A20 haploinsufficiency) in patients with BD. Moreover 2 likely pathogenic variants were identified in DNASE1L3 and PTPN22, both in patients with incomplete BD. Interferon score was high in the two patients with STAT1 GOF mutations, in the patient with TNFAIP3 mutation, and in 3 genetic-negative subjects. In two patients, the treatment was modified based on genetic results.ConclusionsAlthough recurrent aphthous stomatitis associated with systemic inflammation may lead to a clinical diagnosis of BD or SLE, subjects with early disease onset in childhood deserve genetic investigation for rare monogenic disorders. A wider genetic panel may help disclosing the genetic background in the subset of children with increased interferon score, who tested negative in this study.

837 Narcolepsy in a toddler

Abstract Introduction Narcolepsy is a central disorder of hypersomnia with a bimodal peak incidence at ages 15 and 35. Onset in early childhood has been reported, but rarely under the age of 5. We present a case of Narcolepsy Type 1 in a 2.5-year-old with dropping spells. Report of case(s) A 2.5-year-old African American healthy male presented with acute onset sudden drops, unsteady gait, and staring spells. These episodes lasted a few seconds, occurred multiple times a day, and were associated with eye fluttering and dysarthric speech. History was notable for increased daytime sleep/sleep attacks, disrupted nocturnal sleep with confusional arousals, nightmares and sleepwalking, weight gain and mood instability with aggressive behavior. No preceding head injury or illness. Physical examination demonstrated frequent atonic episodes with loss of deep tendon reflexes. A clinical suspicion of myoclonic/atonic epilepsy prompted video- electroencephalogram (EEG) which showed frequent bursts of generalized intermittent slowing representative of NREM 1 sleep lasting several seconds. Magnetic resonance imaging of the brain and infectious workup was unremarkable. Cerebrospinal fluid (CSF) Orexin was <50 pg/mL. While 76–98% of patients with narcolepsy type-1 have HLADQB1*06:02, our patient tested negative. Due to lack of MSLT validity at this age, only diagnostic PSG was performed which showed REM without atonia and sleep fragmentation. Prior to sleep onset, cataplexy was observed in the patient while laughing, though EMG tone was relatively preserved during this episode. We had limited treatment options considering lack of FDA approved medications for ages less than 7. A helmet was prescribed to prevent head injury. Methylphenidate 5mg/day improved sleepiness and slightly stabilized mood. For cataplexy, neither Fluoxetine nor Imipramine helped. His mother disapproved further medication trials. Continuing methylphenidate, the family was referred to behavior psychology for support, coping with the diagnosis and behavioral changes. Conclusion This case demonstrates an unusual presentation of Narcolepsy Type 1 in a toddler initially thought to have epilepsy. Video-EEG and low CSF orexin led to the diagnosis. His age, severity of cataplexy, mood changes, and parental concerns made treatment challenging. Furthermore, this case highlights the importance of early recognition of Narcolepsy in young children to provide appropriate treatment during critical developmental stages. Support (if any):

The interplay of protective and risk factors linked to autism

Over the last century, Autism has undergone considerable diagnostic evolution. It is only in the past eight years that autism has been identified not as a single disorder but as a “Spectrum” of developmental disabilities inclusive of “Autistic Disorder, Pervasive Developmental Disorder not Otherwise Specified (PDD-NOS), and Asperger’s Disorder”. Autism Spectrum Disorder (ASD) is a complex disorder with early childhood onset, characterized by impairments in reciprocal social interactions and stereotypic behaviors. The limited scientific knowledge about the pathogenesis of ASD has an undesirable impact on the personal, professional, and social life of ASD patients and their families. The interplay of risk factors such as peculiar genetic make-up, adverse environment, etc., and protective factors like proper maternal care and diet appears to be responsible for the development of ASD. Although there is no US-FDA- certified medication for curing autism, an integrated strategy comprising of psychotropic medications and complementary therapies appears to be quite effective. The authors recommend that focusing on the protective factors antepartum and post-partum might prove to be an effective method for the prevention of ASD.

Leber Congenital Amaurosis

Leber Congenital Amaurosis (LCA) is one of the most severe forms of hereditary retinal dystrophies described approximately 150 years ago and is a cause of vision loss early in childhood. Although LCA is characterized by wandering nystagmus, poor pupillary reflex (amaurotic pupils), and undetectable or severely abnormal ERG responses in infancy, there is a milder form called Severe Early Childhood Onset Retinal Dystrophy (SECORD) presenting after infancy usually before the age of five. LCA and SECORD describe a clinically and genetically diverse group of diseases. To date, there are 30 different genes determined to cause LCA/SECORD, and these genes are thought to account for approximately 70-80% of the disease spectrum. In recent years, with the initial successful results reported in treatment with gene therapy, LCA/SECORD has become the focus of new researches. This review summarizes the genetic and pathophysiological basis, different genetic types, and their clinical findings, diagnosis, differential diagnosis, and current developments in the treatment of LCA/SECORD.

The Potential Role of miRNAs as Predictive Biomarkers in Neurodevelopmental Disorders.

Neurodevelopmental disorders are defined as a set of abnormal brain developmental conditions marked by the early childhood onset of cognitive, behavioral, and functional deficits leading to memory and learning problems, emotional instability, and impulsivity. Autism spectrum disorder, attention-deficit/hyperactivity disorder, Tourette syndrome, fragile X syndrome, and Down's syndrome are a few known examples of neurodevelopmental disorders. Although they are relatively common in both developed and developing countries, very little is currently known about their underlying molecular mechanisms. Both genetic and environmental factors are known to increase the risk of neurodevelopmental disorders. Current diagnostic and screening tests for neurodevelopmental disorders are not reliable; hence, individuals with neurodevelopmental disorders are often diagnosed in the later stages. This negatively affects their prognosis and quality of life, prompting the need for a better diagnostic biomarker. Recent studies on microRNAs and their altered regulation in diseases have shed some light on the possible role they could play in the development of the central nervous system. This review attempts to elucidate our current understanding of the role that microRNAs play in neurodevelopmental disorders with the hope of utilizing them as potential biomarkers in the future.

Rehabilitation Challenges in Limb-Girdle Muscular Dystrophies

Limb-girdle muscular dystrophy (LGMD) is a burdensome progressive neuromuscular disease, with a great impact upon quality of life. Unlike other types of neuromuscular dystrophies, which have onset in early childhood and severely limit the life expectancy, LGMD is usually diagnosed at young adulthood age. Since no etiological treatment is currently available, physiotherapy and generally, rehabilitation therapy, are mandatory for preserving the functional capabilities of the muscles for as long as possible. Exercise therapy, electrical stimulation or novel therapies such as exoskeleton devices aim towards alleviating the impact of disability. It is ideal that muscular dystrophy should be assessed in interdisciplinary clinics (physical therapy, neurology, cardiology, pneumology, surgery and orthopedics) for proper long-term care. Keywords: LGMD, muscle strength, rehabilitation, quality of life,