Feasibility of developing a pediatric telehealth network in Honduras with international consultation support.

INTRODUCTION: Honduras is the second poorest country in Central America, and roughly 50% of the population lives in rural areas. A telehealth network linking these areas to larger health centers may improve patient access to care, and physician access to educational opportunities. This pilot study assessed the feasibility of establishing a pediatric telehealth network between underserved clinics in Honduras and the Medical University of South Carolina (MUSC). METHODS: Two underserved Honduran clinics were identified and invited to participate in the telehealth network. Providers from these clinics connected remotely to educational conferences at MUSC, and received teleconsults from MUSC physicians and physicians from the other Honduran site. Honduran providers completed five-point Likert scale satisfaction surveys following participation in the conferences and teleconsults. RESULTS: Survey feedback was positive, with 100% of respondents stating they would utilize telemedicine in the future. Dissatisfaction was expressed subjectively in the survey comments with regards to poor Internet connectivity and unreliable electrical power. CONCLUSIONS: The establishment of a telehealth network between Honduras and MUSC is feasible, and rural providers were receptive to the clinical and educational opportunities this network provides. Future projects will expand telehealth capabilities to other Honduran sites and focus on intra-country collaboration to ensure sustainability.

A novel familial autosomal dominant mutation in ARID1B causing neurodevelopmental delays, short stature, and dysmorphic features.

Recent studies have identified mutations in the ARID1B gene responsible for neurodevelopmental delays, intellectual disability, growth delay, and dysmorphic features. ARID1B encodes a subunit of the BAF chromatin-remodeling complex, and mutations in multiple components of the BAF complex have been implicated as causes of Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, and non-syndromic intellectual disability. The majority of documented pathogenic ARID1B mutations to date have arisen in a sporadic, de novo manner with no reports of inheritance of a pathogenic mutation from an affected parent. We describe here two patients (a 21-year-old female and her 21-month-old son) with a novel frameshift mutation in ARID1B inherited in an autosomal dominant fashion in the affected offspring. Both patients presented with neurodevelopmental delays, growth delay, and dysmorphic features including prominent nose with full nasal tip, long philtrum, and high-arched palate. Exome sequencing analysis in the female patient demonstrated a heterozygous deletion of nucleotide 1259 of the ARID1B gene (c.1259delA) resulting in a frameshift and creation of a premature stop codon. Further family testing by targeted Sanger sequencing confirmed that this arose as a de novo mutation in the mother and was passed on to her affected son. The clinical features of both patients are felt to be consistent with an ARID1B-related disorder. To our knowledge, this is the first report of a pathogenic mutation in ARID1B being passed from an affected parent to their offspring. © 2016 Wiley Periodicals, Inc.

Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome.

Microduplication of chromosome 17p13.1 is a rarely reported chromosome abnormality associated with neurodevelopmental delays. We describe two unrelated patients with overlapping microduplications of chromosome 17p13.1. The first patient is a 2-year-old male who presented with neurodevelopmental delays and macrocephaly. He was found to have a de novo 788 kb copy gain of 17p13.2p13.1 and a de novo 134 kb copy gain of 17p13.1. These duplications include multiple candidate genes, including EFNB3, NLGN2, DLG4, GABARAP, and DULLARD, which may be responsible for neurodevelopmental delays in affected individuals. The second patient is a 29-year-old female with mild intellectual disability and relative macrocephaly. She was found to have a 62.5 kb copy gain of chromosome 17p13.1 that includes the DLG4, GABARAP, and DULLARD genes. The DLG4, GABARAP, and DULLARD genes included in the microduplications of both our patients appear to be candidate genes for neurodevelopmental delays and macrocephaly in individuals with 17p13.1 microduplication syndrome.

ß-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Mutations in the cilia gene ARL13B lead to the classical form of Joubert syndrome.

Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Microdeletion at 4q21.3 is associated with intellectual disability, dysmorphic facies, hypotonia, and short stature.

Chromosomal imbalances are a major cause of intellectual disability (ID) and multiple congenital anomalies. We have clinically and molecularly characterized two patients with chromosome translocations and ID. Using whole genome array CGH analysis, we identified a microdeletion involving 4q21.3, unrelated to the translocations in both patients. We confirmed the 4q21.3 microdeletions using fluorescence in situ hybridization and quantitative genomic PCR. The corresponding deletion boundaries in the patients were further mapped and compared to previously reported 4q21 deletions and the associated clinical features. We determined a common region of deletion overlap that appears unique to ID, short stature, hypotonia, and dysmorphic facial features.

Reduction in rate of epilepsy from neurocysticercosis by community interventions: the Salamá, Honduras study.

PURPOSE: Epilepsy is highly prevalent in developing countries like Honduras, with few studies evaluating this finding. This population-based study evaluated the impact of an 8-year public health and educational intervention program in reducing symptomatic epilepsies in rural Salamá, Honduras. METHODS: We used the capture and recapture method including review of charts, previous databases, key informants from the community, and a second house-to-house survey for epilepsy. Epilepsy incidence and prevalence day after the interventions was May 5, 2005. Residents with active epilepsy with onset after May 1997 were offered neurologic evaluation, electroencephalography, and brain tomography. New data over 8 years were compared to preintervention data from the initial baseline 1997 study utilizing prevalence ratios and confidence intervals. Other calculations utilized chi square or Fisher's exact tests. KEY FINDINGS: Thirty-three of 36 patients with onset of active epilepsy after 1997 accepted evaluations to determine etiology. Symptomatic etiology was found in 58.3%. Neurocysticercosis (NCC) was again the most frequent cause (13.9%), followed by perinatal insults (11.1%). Epilepsy secondary to NCC was significantly reduced from 36.9% in 1997 (p = 0.02). The incidence (35.7/100,000) and prevalence (11.8/1,000) of active epilepsy were not significantly reduced when compared to the incidence (92.7/100,000) and prevalence (15.4/1,000) of active epilepsy in 1997. SIGNIFICANCE: Our cohort appears to indicate that health and educational community interventions can reduce preventable epilepsy from NCC in a hyperendemic population in a low-resource, developing country. Plans are underway for the Honduran Government to institute this rural model countrywide.

Autism in two females with duplications involving Xp11.22-p11.23.

We present two phenotypically similar females with Xp duplication who have autism and epilepsy. Case 1 is a 14-year-old Honduran female with autism and medically refractory complex partial, secondarily generalized epilepsy. Case 2 is a 3-year-old Austrian female with autism and medically refractory complex partial epilepsy. Both patients also share features of severe intellectual disability (case 1 has a developmental quotient of 23, case 2 has a developmental quotient of 42) and dysmorphic facial features. Autism was confirmed by thorough clinical evaluations and testing. Case 1 has a karyotype of 46,X,dup(X)(p11.2-p22.33) and a highly skewed X-inactivation pattern (94:6). Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were abnormal. Case 2 has a 5-megabase duplication of Xp11.22-p11.23 on chromosome microarray analysis. The patient has a random X-inactivation pattern (77:23). Brain MRI was normal, but EEG was abnormal. Both patients have duplications involving the Xp11.22-p11.23 region, indicating that this is an area of interest for future translational autism research.

United States head circumference growth reference charts: birth to 21 years.

OBJECTIVE: To produce a more reliable, continuous set of occipitofrontal head circumference (OFC) growth reference charts for males and females from birth to adulthood in the United States. STUDY DESIGN: After investigating the strengths and shortcomings of previous reports, we combined the most recent statistically reliable reports of OFC growth reference data into a locally weighted regression analysis to estimate percentile curves. We used cross-sectional prospective local pediatric data to validate our results. RESULTS: We present new age- and sex-appropriate US OFC growth charts from birth to adulthood that include 3rd and 97th percentile cutoff values. Our local pediatric data validate that our new proposed OFC growth charts' assessment of attained OFC growth is comparable with previous references. CONCLUSIONS: We have eliminated disagreements between multiple current references by unifying previously reported US OFC data into a single set of smoothed male and female growth reference charts from birth to adulthood. This will reduce confusion or errors in interpretation of normal versus abnormal measurements currently encountered by primary care clinicians and subspecialists when using OFC growth charts for the US pediatric population.

Natural history of Christianson syndrome.

Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others. They also noted the clinical similarities to Angelman syndrome and found cerebellar atrophy on MRI and elevated glutamate/glutamine in the basal ganglia on MRS. Here we report on nonsense mutations in two additional families. The natural history is detailed in childhood and adult life, the similarities to Angelman syndrome confirmed, and the MRI/MRS findings documented in three affected boys.

Pediatric convulsive status epilepticus in Honduras, Central America.

Convulsive status epilepticus (SE) in children is an important public health problem, particularly in low-resource countries. A surveillance study was performed with consecutive enrollment of all children presenting with convulsive SE to Hospital Escuela Materno-Infantil Emergency Department in Tegucigalpa, Honduras over a 13-week period in 2003. In the 47 children with SE, the mean age was 4.5 years and the median seizure duration was 95 min. Mortality and morbidity were higher in children from rural locations, with all six deaths and three cases of new neurologic abnormalities occurring in rural children who had acute symptomatic SE. We conclude that childhood SE is common in the low-resource developing country of Honduras. Given the long delays in obtaining initial treatment in pediatric emergency facilities, availability of prehospital treatment may be of particular importance in this setting.

Adherence and complementary and alternative medicine use among Honduran people with epilepsy.

Adherence to antiepileptic drugs (AEDs) and use of complementary and alternative medicine (CAM) among Hondurans with epilepsy were evaluated. Our epilepsy cohort of 274 outpatients was surveyed to determine demographics, epilepsy treatment history, adherence, and use of CAM. Nonadherence to epilepsy therapy was reported by 121, with unavailability of AEDs (48%) the most common reason. CAM was reportedly used by 141, with prayer, herbs, and potions being common. Forty-nine rural Miskito Hondurans without epilepsy were also interviewed to gain an understanding of their beliefs and longstanding practices regarding epilepsy. Seventeen (34.7%) attributed epilepsy to the supernatural; only three knew of an AED. Widespread nonadherence to evidence-based epilepsy treatments in Honduras can be attributed to inadequate education, AED unavailability, insufficient resources, cultural beliefs, and wide use of CAM. A comprehensive epilepsy education program and improved access to evidence-based AEDs represent initial priorities to improve the Honduran epilepsy treatment gap.

ATP6AP2 variant impairs CNS development and neuronal survival to cause fulminant neurodegeneration.

Vacuolar H+-ATPase-dependent (V-ATPase-dependent) functions are critical for neural proteostasis and are involved in neurodegeneration and brain tumorigenesis. We identified a patient with fulminant neurodegeneration of the developing brain carrying a de novo splice site variant in ATP6AP2 encoding an accessory protein of the V-ATPase. Functional studies of induced pluripotent stem cell-derived (iPSC-derived) neurons from this patient revealed reduced spontaneous activity and severe deficiency in lysosomal acidification and protein degradation leading to neuronal cell death. These deficiencies could be rescued by expression of full-length ATP6AP2. Conditional deletion of Atp6ap2 in developing mouse brain impaired V-ATPase-dependent functions, causing impaired neural stem cell self-renewal, premature neuronal differentiation, and apoptosis resulting in degeneration of nearly the entire cortex. In vitro studies revealed that ATP6AP2 deficiency decreases V-ATPase membrane assembly and increases endosomal-lysosomal fusion. We conclude that ATP6AP2 is a key mediator of V-ATPase-dependent signaling and protein degradation in the developing human central nervous system.

Persistent growth failure in Prader-Willi syndrome associated with short-chain acyl-CoA dehydrogenase gene variant.

The authors report the rare association of Prader-Willi syndrome and short-chain acyl-CoA dehydrogenase gene variant. Prader-Willi syndrome, associated with paternal chromosome 15q11-q13 silencing, is characterized by neonatal/infantile hypotonia, growth failure, and neurodevelopmental delays in the first 1 to 2 years of life, typically followed by hyperphagia and obesity. Short-chain acyl-CoA dehydrogenase gene variant, with 625 G-to-A and 511 C-to-T changes, impairs C4-C6 fatty acid metabolism and variably causes neonatal/infantile hypotonia with developmental delays. The authors' patient continues to exhibit the classic severe growth failure of early infancy Prader-Willi syndrome at 40 months. Extensive laboratory investigations indicate that the short-chain acyl-CoA dehydrogenase gene variant is likely preventing or delaying the normal expression of the Prader-Willi syndrome phenotype.

Developing a neurology training program in Honduras: a joint project of neurologists in Honduras and the World Federation of Neurology.

One of the major barriers to the provision of quality care for patients with neurological disorders in developing countries is a low ratio of neurologists per inhabitants, the World Health Organization recommends one neurologist per 100,000. In 1998 Honduras had one neurologist per 325,000 inhabitants and all the neurologists were trained outside the country. The Education Committee of the World Federation of Neurology (WFN), in collaboration with the Postgraduate Direction of the National Autonomous University of Honduras, the Honduran Neurological Association, and the Honduran Secretary of Health helped establish the country's first Neurology Training Program in 1998. This program was established using a problem- and epidemiological-oriented methodology with oversight by an external WFN review board. By 2006 the program has resulted in a 31% increase in the national neurologist ratio per inhabitant, significantly improved the quality of patient care and promoted research in the neurosciences. The Honduras Neurology Training Program has provided a valuable model for other developing countries with similar needs for neurological care. Based on this Honduras experience, members of the Education Committee of the WFN have established guidelines for neurology training programs in developing countries.

Expansion of the deletion 13q syndrome phenotype: a case report.

The phenotypic description of deletion 13q syndrome is dependent on the location and size of the deleted segment. At present, the syndrome is divided into 3 groups based on the deletion's location relative to chromosomal band 13q32. Groups 1 (proximal to q32) and 2 (including q32) have shown distinctive phenotypes including mental retardation and growth deficiency, whereas group 3 (q33-34 deletion) is defined by the presence of mental retardation but usually the absence of major malformations. The authors report an 8-year-old Hispanic female with dysmorphic facial features, microcephaly, moderate to severe mental retardation, and uncontrolled epilepsy associated with a terminal 13q33.3 deletion. These features expand the characterization of the phenotype associated with group 3 of the 13q deletion syndrome to include major clinical manifestations. This case report will contribute to more accurate genetic counseling as well as may help identify more individuals with this syndrome.

Clinical Features and Neurologic Complications of Children Hospitalized With Chikungunya Virus in Honduras.

The first case of Chikungunya virus in Honduras was identified in 2014. The virus has spread widely across Honduras via the Aedes aegypti mosquito, leading to an outbreak of Chikungunya virus (CHIKV) in 2015 that significantly impacted children. A retrospective chart review of 235 children diagnosed with CHIKV and admitted to the National Autonomous University of Honduras Hospital Escuela (Hospital Escuela) in Tegucigalpa, Honduras, was accomplished with patients who were assessed for clinical features and neurologic complications. Of 235 children admitted to Hospital Escuela with CHIKV, the majority had symptoms of fever, generalized erythematous rash, and irritability. Fourteen percent had clinical arthritis. Ten percent of patients had seizures. Six percent had meningoencephalitis. There were 2 childhood deaths during the course of this study, one from meningoencephalitis and another from myocarditis. Chikungunya virus can cause severe complications in children, the majority of which impact the central nervous system.

Transgenerational Inheritance of Familial Lipomyelomeningocele.

Lipomyelomeningocele is a type of neural tube defect characterized by lipomatous tissue causing a defect in the vertebrae, infiltrating the dura, and tethering the spinal cord. Despite significant neurologic consequences, the underlying etiology remains poorly understood. We present a father and son with remarkably similar presentations of lipomyelomeningocele. Genetic testing did not reveal an underlying cause but whole exome sequencing identified variants in the ARHGAP29 and RADIL genes in the proband and his affected father. Genetic analyses of asymptomatic family members revealed several carriers of the ARHGAP29 or RADIL variants, but only the proband and his father carried both variants, suggesting a possible shared genetic mechanism. Rare cases of siblings affected with lipomyelomeningocele have suggested the possibility of autosomal recessive or germline mosaicism. We present the first documented cases of transgenerational lipomyelomeningocele with important implications for family counseling about the recurrence of lipomyelomeningocele.

Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts.

We report a new fibroblast and lymphoblast based protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzymatic assay, which allows rapid and accurate diagnosis of carriers and patients with muscle-eye-brain type of congenital muscular dystrophy. Seven patients with genetically confirmed muscle-eye-brain disease were assayed for protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 enzyme activity. In three patients and their heterozygous parents, the assays were done on EBV-transformed lymphoblasts, in another three patients they were done on cultured fibroblasts and in the last patient on both fibroblasts and lymphoblasts. Cultured fibroblasts and lymphoblasts from the muscle-eye-brain patients showed a highly significant decrease in protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity relative to controls. The residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in fibroblasts (average 0.11 nmoles/h per mg) was about 13% of normal controls. The ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity to the activity of a glycosyltransferase control (N-acetylglucosaminyltransferase 1; GnT1) in fibroblasts was on average 0.006 in muscle-eye-brain patients and 0.045 in controls. The average residual protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 level in lymphoblasts was 15% of normal controls. The average ratio of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1/GnT1 activity was 0.007 in muscle-eye-brain patients, 0.026 in heterozygous carriers and 0.046 in normal controls. Assay of protein O-mannosyl beta-1,2-N-acetylglucosaminyltransferase 1 activity in fibroblasts and lymphoblasts from muscle-eye-brain carriers and patients provides a rapid and relatively simple diagnostic test for this disease and could be used as a screening test in carriers and patients with complex congenital muscular dystrophy.