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Protein translation is an essential cellular process initiated by the association of a methionyl-tRNA with the translation initiation factor eIF2. The Met-tRNA/eIF2 complex then associates with the small ribosomal subunit, other translation factors and mRNA, which together comprise the translational initiation complex. This process is regulated by the phosphorylation status of the α subunit of eIF2 (eIF2α); phosphorylated eIF2α attenuates protein translation. Here, we report a consanguineous family with severe microcephaly, short stature, hypoplastic brainstem and cord, delayed myelination and intellectual disability in two siblings. Whole-exome sequencing identified a homozygous missense mutation, c.1972G>A; p.Arg658Cys, in protein phosphatase 1, regulatory subunit 15b (PPP1R15B), a protein which functions with the PPP1C phosphatase to maintain dephosphorylated eIF2α in unstressed cells. The p.R658C PPP1R15B mutation is located within the PPP1C binding site. We show that patient cells have greatly diminished levels of PPP1R15B-PPP1C interaction, which results in increased eIF2α phosphorylation and resistance to cellular stress. Finally, we find that patient cells have elevated levels of PPP1R15B mRNA and protein, suggesting activation of a compensatory program aimed at restoring cellular homeostasis which is ineffective due to PPP1R15B alteration. PPP1R15B now joins the expanding list of translation-associated proteins which when mutated cause rare genetic diseases.

β-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene.

Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID., Author Summary Intellectual disability (ID) is the most frequent severe handicap of childhood. Several observations indicate that genetic factors explain a large fraction of cases with ID. We and others have recently found that de novo mutations (DNMs; genetic changes not transmitted from the parents) represent a common cause of ID. To further assess the contribution of DNMs to the development of ID, we interrogated virtually all the genes of the genome in 41 affected children with moderate or severe ID and in their healthy parents. In 12 of the cases, we identified disease-causing DNMs in genes known to be associated with ID, resulting in a molecular diagnostic yield of 29%. We also found 12 possibly disease-causing DNMs in genes that were not previously causally linked to ID. Interestingly, many of the genes with deleterious DNMs uncovered by this study encode proteins that interact with each other and affect specific processes in brain cells. In contrast, we did not identify any inherited mutations that could explain our cases. We conclude that DNMs play a predominant role in moderate or severe ID.

Spinal cord infarction is extremely rare in childhood and can result from a wide range of causes. Fibrocartilaginous embolism can give rise to spinal stroke and mimic non-vascular disease such as acute transverse myelitis.We report two children who suffered an asymmetrical spinal cord infarction due to fibrocartilaginous embolism. The clinical presentation, radiological findings, and pathophysiology of fibrocartilaginous embolism are described. Each patient demonstrated marked clinical improvement after receiving extensive physical therapy and rehabilitation. One child demonstrated complete clinical recovery. The other had persistent asymmetrical foot weakness and distal sensory deficits.We outline the key clinical and radiographic features that enable spinal cord infarction to be differentiated from transverse myelitis. Prognosis depends on many factors such as extent and type of injury, level of the cord affected, and age at the time of spinal cord infarction.

Purpose: Computerized artificial neural networks are analogous to biological neuronal systems. Since they may be trained to recognize the relevance of complex patterns in data, neural networks may be useful for decision making in the multifactorial management of ureteropelvic junction obstruction. We determine the ability of a customized neural network to predict sonographic outcome after pyeloplasty in children with ureteropelvic junction obstruction.Materials and Methods: A data set was constructed with 242 demographic, clinical, radiological and surgical elements. We analyzed the available retrospective data in 100 consecutive children who underwent unilateral pyeloplasty for ureteropelvic junction obstruction chosen from all 144 surgically treated for ureteropelvic junction obstruction between 1993 and 1995. One radiologist reviewed all film data and provided a final sonographic outcome designation in each case. We wrote a set of computer programs to construct a neural network. A composite 4-l...

Introduction The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis. Methods A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed. Review Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10 and polyunsaturated fatty acids. Conclusion Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine.

The Canadian Multiple Sclerosis Working Group (CMSWG) developed practical recommendations in 2004 to assist clinicians in optimizing the use of disease-modifying therapies (DMT) in patients with relapsing multiple sclerosis. The CMSWG convened to review how disease activity is assessed, propose a more current approach for assessing suboptimal response, and to suggest a scheme for switching or escalating treatment. Practical criteria for relapses, Expanded Disability Status Scale (EDSS) progression and MRI were developed to classify the clinical level of concern as Low, Medium and High. The group concluded that a change in treatment may be considered in any RRMS patient if there is a high level of concern in any one domain (relapses, progression or MRI), a medium level of concern in any two domains, or a low level of concern in all three domains. These recommendations for assessing treatment response should assist clinicians in making more rational choices in their management of relapsing MS patients.

This chapter articulates the clinical manifestations of multiple sclerosis (MS) in children. Defining the clinical features of MS in children is challenged by the variability of the available literature with respect to consistency in the definition of clinical features and diagnostic criteria for pediatric MS; age of inclusion; duration of clinical observation, a key issue in recognizing features that may not be present at onset or may change during the course of MS in children; and definition of disease onset. Impairment of executive functions, processing speed, working memory, and low functioning in activities related to school performances have been described in children with MS. Kurtzke's Functional System and Expanded Disability Status Scale (EDSS) is the most widely used scale to score neurological impairment in pediatric and adult MS patient. A key facet of care of children with MS involves the use of medications aimed at the reduction of relapse rate.

The objective of this study was to determine the major comorbidities in patients with spastic quadriplegic (SQ) cerebral palsy (CP) and their possible clinical associations. Medical records of patients with SQ CP from a pediatric neurology practice over a 14-year period were retrospectively and systematically reviewed. Variables examined included demographics, prenatal, perinatal, and postnatal risk factors. Comorbidities documented included those involving hearing, vision, feeding status, and epilepsy. Binomial logistic regression analyses were applied to identify clinical associations of the comorbidities. Ninety-two children were included in this study of whom 39 were born preterm. Mean age of presentation was 2 months (SD 3.5) and males comprised 60% of the group. A total of 57% had a Gross Motor Function Classification Score (GMFCS) of Level IV or V. The four documented comorbidities occurred at a high frequency: 66 out of 83 children (80%) had a visual impairment with 13 (21%) having a substantial impairment; 37 out of 86 children (40%) had a hearing deficit; 43 out of 92 children (47%) had epilepsy; and 29 (33%) required assisted feeding. A GMFCS Level of IV or V and documented microcephaly was associated with the need for assisted feeding (odds ratio [OR] 8.1; 95% confidence interval [CI] 2.1-29.8, p=0.002 and OR 4.9, 95% CI 1.7-14.8, p=0.004 respectively). Epilepsy was associated with the occurrence of neonatal encephalopathy (OR 2.3, 95% CI 1.0-55; p=0.05), microcephaly (OR 4.9, 95% CI 1.6-14.8; p=0.004), periventricular leukomalacia (OR 7.4, 95% CI 1.6-35.0; p=0.012), and perinatal asphyxia (OR 3.6, 95% CI 1.5-8.9; p=0.005). There is a high frequency of comorbidity in the setting of SQ CP which can impact on quality of life and burdens of care. Few clinical associations of this burden appear, thus necessitating systematic programmatic follow-up of these children to facilitate early identification and intervention.

The etiologic profile and possible predictors of etiology in children with spastic quadriplegia were assessed in a consecutive cohort of children with this motor impairment. Medical records from a single pediatric neurology practice over a 14-year interval were retrospectively and systematically reviewed. Variables comprised possible demographic, prenatal, perinatal, and postnatal risk factors. Of the 99 patients included in the study, 39 were premature (37 weeks gestation). The overall etiologic yield was 83%. The top three diagnoses were hypoxic-ischemic perinatal asphyxia (33%), periventricular leukomalacia (15%), and central nervous system infections (11%). In premature children, the most common diagnoses were periventricular leukomalacia (33%), perinatal asphyxia (26%), and central nervous system infections (15%). In term-born children, the most frequent diagnoses were perinatal asphyxia (37%), metabolic disease (12%), and structural malformation or infection (9% each). Factors predicting the identification of an etiology included male sex (P = 0.05), low birth weight (P = 0.003), prematurity (P = 0.01), perinatal complications (P = 0.002), and neonatal encephalopathy (P = 0.006). The etiologic yield in patients with spastic quadriplegia was 83%, with differing underlying etiologies depending on gestational age. These results should help guide physicians in investigating possible underlying etiologies in patients with spastic quadriplegia.

Pediatric acquired demyelinating syndromes have overlapping clinical and imaging features, but management and prognosis vary. We describe four children between the ages of 3 and 10 presenting with inflammatory brain disease - one with polyfocal neurological symptoms, one with severe bilateral optic neuritis and two with transverse myelitis, all without encephalopathy. All brain MRIs had extensive involvement of both deep grey and subcortical white matter. Three patients had longitudinally extensive spinal cord lesions. Clinical and radiological findings did not meet criteria for multiple sclerosis, acute disseminated encephalomyelitis, or neuromyelitis optica (NMO). NMO IgG testing was negative. All patients had resolution of clinical and imaging findings after treatment with steroids and IVIg. We found, elevated levels of anti-myelin oligodendrocyte glycoprotein antibodies in all four patients. Three of the children receive monthly IVIg infusions. Two of the patients relapsed once within 18 months of their initial attack and have since remained relapse free for 32 months and 43 months, respectively. The third patient (transverse myelitis) has not had any relapses since her initial attack 15 months ago. It appears that children with this syndrome may have more favourable outcomes when compared to other CNS relapsing inflammatory conditions.