The clinical and imaging features of cerebrotendinous xanthomatosis: A case report and review of the literature.

RATIONALE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid deposition disorder characterized by systemic signs and neurological dysfunction. The radiological features of CTX are infrequently summarized in the literature. PATIENT CONCERNS: We described a 40-year-old male patient who repeatedly engaged in wrestling matches and presented with progressive difficulty in walking and reduced balance with egg-sized, hard, smooth, and painless masses in both ankles. DIAGNOSIS: Neuroimaging examination showed abnormalities both supra- and infratentorially. Bilateral ankle joint magnetic resonance imaging showed bilateral xanthomata of the Achilles tendon. The diagnosis was confirmed by the detection of a sterol 27-hydroxylase gene mutation. INTERVENTIONS: The patient was treated with chenodeoxycholic acid (250 mg 3 times per day). OUTCOMES: To date, the patient's bilateral xanthomas of the Achilles tendon have begun to diminish, and his neurological impairment has not deteriorated further but has not yet improved. LESSONS: We report a rare case of CTX and summarize the clinical and imaging features of this disease. Our findings suggest that the abnormal signals in the dentate nucleus or a long spinal cord lesion involving the central and posterior cord, combined with tendon xanthoma, are important clues for the diagnosis of CTX.

Inverse Bell's phenomenon: a rare complication of levator resection surgery in a case of congenital ptosis.

A 27-year-old woman with moderate congenital ptosis and a positive Marcus-Gunn jaw winking reflex underwent levator resection surgery to correct the ptosis. Preoperatively, a normal Bell's reflex was documented. Postoperatively, she developed an inverse Bell's reflex and increased symptoms of ocular surface exposure. The Bell's reflex normalised in a week, with resolution of the corneal exposure. Reversal of the Bell's reflex can be an unforeseen complication following maximal levator resection. The early postoperative care in such cases is crucial, and the cornea must be protected from exposure changes. Accurate documentation of the Bell's phenomenon preoperatively is vital to recognise this rare event and plan management.

High-risk follow-up: Early intervention and rehabilitation.

Early detection of childhood disability is possible using clinically available tools and procedures. Early detection of disability enables early intervention that maximizes the child's outcome, prevents the onset of complications, and supports parents. In this chapter, first we summarize the best-available tools for accurately predicting major childhood disabilities early, including autism spectrum disorder, cerebral palsy, developmental coordination disorder, fetal alcohol spectrum disorder, intellectual disability, hearing impairment, and visual impairment. Second, we provide an overview of the preclinical and clinical evidence for inducing neuroplasticity following brain injury. Third, we describe and appraise the evidence base for: (a) training-based interventions that induce neuroplasticity, (b) rehabilitation interventions not focused on inducing neuroplasticity, (c) complementary and alternative interventions, (d) environmental enrichment interventions in the neonatal intensive care and community settings, and (e) parent-child interaction interventions in the neonatal intensive care and community settings. Fourth, we explore emergent treatment options at clinical trial, designed to induce brain repair following injury. In conclusion, early diagnosis enables early intervention, which improves child and parent outcomes. We now know which interventions provide the biggest gains and the information can be used to help inform parental decision making when designing treatment plans for their children.

Understanding and addressing barriers to communication in the context of neonatal neurologic injury: Exploring the ouR-HOPE approach.

Predicting neurologic outcomes for neonates with acute brain injury is essential for guiding the development of treatment goals and appropriate care plans in collaboration with parents and families. Prognostication helps parents imagine their child's possible future and helps them make ongoing treatment decisions in an informed way. However, great uncertainty surrounds neurologic prognostication for neonates, as well as biases and implicit attitudes that can impact clinicians' prognoses, all of which pose significant challenges to evidence-based prognostication in this context. In order to facilitate greater attention to these challenges and guide their navigation, this chapter explores the practice principles captured in the ouR-HOPE approach. This approach proposes the principles of Reflection, Humility, Open-mindedness, Partnership, and Engagement and related self-assessment questions to encourage clinicians to reflect on their practices and to engage with others in responding to challenges. We explore the meaning of each principle through five clinical cases involving neonatal neurologic injury, decision making, and parent-clinician communication. The ouR-HOPE approach should bring more cohesion to the sometimes disparate concerns reported in the literature and encourage clinicians and teams to consider its principles along with other guidelines and practices they find to be particularly helpful in guiding communication with parents and families.

Majewski dwarfism type II: an atypical neuroradiological presentation with a novel variant in the PCNT gene.

Microcephalic osteodysplastic primordial dwarfism syndrome II (MOPDII) is microcephalic primordial dwarfism and is a very rare form of disproportionate short stature. This disorder shares common features with other forms of microcephalic primordial dwarfism, including severe prenatal and postnatal growth retardation with marked microcephaly. However, it includes characteristic skeletal dysplasia, abnormal dentition and increased risk for cerebrovascular diseases. Recent reports added more features, including café-au-lait lesions, cutis marmorata, astigmatism, Moyamoya disease, insulin resistance, obesity, abnormal skin pigmentation and acanthosis nigricans around the neck. Clearly, the more MOPDII reports that are produced, the more information will be added to the spectrum of MOPDII features that can improve our understanding of this disorder. In this paper, we reported a new case of MOPDII with more severe clinical features, earlier onset of common features, in addition to a homozygous novel variant in the PCNT gene.

Neurological manifestations of congenital Zika virus infection.

INTRODUCTION: In 2015, it was observed a rise in the number of microcephalic newborns associated with a history of non-specific febrile sickness and rash during pregnancy in Brazil. Since then, microcephaly has emerged as a public health concern. A few months after, the causal relation between congenital microcephaly and the Zika virus was discovered. Zika virus, an arbovirus, is a new TORCH member that leads to congenital infection through vertical transmission and harms the developing brain, disrupting synaptogenesis, and causing other central nervous system lesions. OBJECTIVE: The purpose of this article is to report the congenital Zika syndrome (CZS) and to emphasize the need for follow-up of the affected children to better know the evolutionary history of this new agent and to optimize the provision of healthcare and improve the quality of life of these patients. METHODS: We review the most relevant literature about clinical manifestations and neuroimaging findings related to neurotropism of Zika virus to characterize the congenital Zika syndrome and suggest the systematization of some exams and procedures to evaluate children exposed to ZIKV with or without microcephaly, according to the author's own experience. CONCLUSIONS: Vertical ZIKV infection can cause a wide spectrum of neurological manifestations that go beyond microcephaly, and even the non-microcephalic child should be followed during the first years of life, because infection may be asymptomatic or lead to neuropsicomotor delay, epilepsy, and visual abnormalities. The appropriate prospective multidisciplinary follow-up of these patients aims to understand the natural history of this new agent and to provide a better development and quality of life for them and their families.

Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis.

BACKGROUND: Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. OBJECTIVE: The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis. STUDY DESIGN: During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data. RESULTS: Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. CONCLUSION: Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice.

[Correlation between prenatal ultrasound and postnatal diagnosis of birth defects]. / Correlación entre la ecografía prenatal y el diagnóstico postnatal de las malformaciones congénitas.

OBJECTIVES: To assess the accuracy of prenatal ultrasound diagnosis and to analyze the protocol applied for congenital defects (CD) in our environment. METHODS: Descriptive study of prenatally diagnosed CD in our area between 2004-2013. Includes: total births, fetal medicine referrals (number of consultations, ultrasound, invasive techniques) anatomical and chromosomal abnormalities, confirmed diagnoses, necropsies performed, false diagnoses, absence of prenatal diagnoses, and number and reasons for abortions (VIEs). RESULTS: Mean annual births were 3,646 ± 1,299, with a mean prenatal ultrasound of 2,144 ± 307 and 512 ± 74 invasive techniques per year. The annual average of prenatal chromosomopathies diagnosed were 26 ± 8 and 140 ± 14 anatomical abnormalities, which represents a 36.44% from all of the prenatal ultrasound performed. These include: neurological, cardiac and nephron-urological anatomic anomalies. Pre and post-natal correlation was observed in 95.6% of the DCs detected. Most common causes of abortion were chromosomal abnormalities, heart and neurological diseases. CONCLUSIONS: Due to the variety of CD that cause VIEs, a highly specialized multidisciplinary approach is recommended to ensure optimal information for parents.

OBJETIVOS: Valorar la precisión del diagnóstico ecográfico prenatal y analizar el protocolo de actuación frente a un determinado defecto congénito (DC) en nuestro medio. MATERIAL Y METODOS: Estudio descriptivo de los DC diagnosticados prenatalmente en nuestra área sanitaria entre los años 2004-2013. Como variables del estudio se incluyeron el número de nacimientos totales, derivaciones a medicina fetal (número de consultas, ecografías, técnicas invasivas) anomalías anatómicas por sistemas, cromosomopatías, diagnósticos confirmados, necropsias realizadas, falsos diagnósticos, ausencia de diagnóstico prenatal, número y motivo de interrupciones voluntarias del embarazo (IVEs). RESULTADOS: Durante el período estudiado, la media de nacimientos anuales fue de 3.646 ± 1.299, con una media de 2.144 ± 307 ecografías prenatales y 512 ± 74 técnicas invasivas anuales. La media anual de diagnóstico prenatal fue de 26 ± 8 cromosomopatías y 140 ± 14 anomalías anatómicas que suponen un 36,44% del total de las ecografías prenatales realizadas. Entre estas últimas se observaron malformaciones del sistema urinario, cardíacas y neurológicas, entre otras. Se observó correlación pre y postnatal en el 95,6% de los DC detectados. Las causas de interrupción del embarazo más frecuentes fueron las cromosomopatías, seguidas de las malformaciones congénitas (MC) cardíacas y neurológicas. CONCLUSIONES: Debido a la variedad de DC que originan IVE, es recomendable un abordaje multidisciplinar altamente especializado que garantice una información óptima a los padres.

Maternal Zika Virus Disease Severity, Virus Load, Prior Dengue Antibodies, and Their Relationship to Birth Outcomes.

BACKGROUND: Congenital Zika virus (ZIKV) syndrome is a newly identified condition resulting from infection during pregnancy. We analyzed outcome data from a mother-infant cohort in Rio de Janeiro in order to assess whether clinical severity of maternal ZIKV infection was associated with maternal virus load, prior dengue antibodies, or abnormal pregnancy/infant outcomes. METHODS: A clinical severity assessment tool was developed based on duration of fever, severity of rash, multisystem involvement, and duration of symptoms during ZIKV infection. ZIKV-RNA load was quantified by polymerase chain reaction (PCR) cycles in blood/ urine. Dengue immunoglobulin G (IgG) antibodies were measured at baseline. Adverse outcomes were defined as fetal loss or a live infant with grossly abnormal clinical or brain imaging findings. Regression models were used to study potential associations. RESULTS: 131 ZIKV-PCR positive pregnant women were scored for clinical disease severity, 6 (4.6%) had mild disease, 98 (74.8%) had moderate disease, and 27 (20.6%) severe manifestations of ZIKV infection. There were 58 (46.4%) abnormal outcomes with 9 fetal losses (7.2%) in 125 pregnancies. No associations were found between: disease severity and abnormal outcomes (P = .961; odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.796-1.270); disease severity and viral load (P = .994); viral load and adverse outcomes (P = .667; OR: 1.02; 95% CI: 0.922-1.135); or existence of prior dengue antibodies (88% subjects) with severity score, ZIKV-RNA load or adverse outcomes (P = .667; OR: 0.78; 95% CI: 0.255-2.397). CONCLUSIONS: Congenital ZIKV syndrome does not appear to be associated with maternal disease severity, ZIKV-RNA load at time of infection or existence of prior dengue antibodies.

De Novo Mutations in DENR Disrupt Neuronal Development and Link Congenital Neurological Disorders to Faulty mRNA Translation Re-initiation.

Disruptions to neuronal mRNA translation are hypothesized to underlie human neurodevelopmental syndromes. Notably, the mRNA translation re-initiation factor DENR is a regulator of eukaryotic translation and cell growth, but its mammalian functions are unknown. Here, we report that Denr influences the migration of murine cerebral cortical neurons in vivo with its binding partner Mcts1, whereas perturbations to Denr impair the long-term positioning, dendritic arborization, and dendritic spine characteristics of postnatal projection neurons. We characterized de novo missense mutations in DENR (p.C37Y and p.P121L) detected in two unrelated human subjects diagnosed with brain developmental disorder to find that each variant impairs the function of DENR in mRNA translation re-initiation and disrupts the migration and terminal branching of cortical neurons in different ways. Thus, our findings link human brain disorders to impaired mRNA translation re-initiation through perturbations in DENR (OMIM: 604550) function in neurons.

Neuroimaging in neonatal seizures.

Seizures are the most common sign of neurological dysfunction in full-term neonates, with an incidence estimated at 0.15-3.5/1,000 live births. Neonatal seizures often reflect severe underlying brain injury and are associated with high rates of mortality and morbidity. Prognosis is primarily determined by the nature, site and extent of the underlying aetiology, making accurate diagnosis and identification of associated brain lesions essential. Data on neuroimaging in newborns presenting with seizures is limited and most studies report on MRI findings in infants with a specific underlying problem, such as hypoxic-ischaemic encephalopathy, stroke or metabolic disorders. The aim of this review is to discuss the spectrum of neuroimaging findings in full-term newborns presenting with seizures, divided into subgroups with different underlying aetiologies. A standard neonatal MRI protocol is presented.

tRNAs: new tricks from old dogs.

tRNA biology has lately seen a revival with the discovery of tRNA cleavage products as mediators of stress responses. In this issue of The EMBO Journal, Blanco et al now report that tRNA methylation, by protecting from cleavage, is relevant for normal brain development. The versatility of tRNA is further emphasized by a recent study in Cell that uncovered differential expression of tRNAs as a means to accustom codon usage bias to the needs in proliferating versus differentiating cells.

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.

A review of cognitive outcomes in children following perinatal stroke.

Perinatal stroke is a significant cause of congenital neurological disability. Although motor deficits and epilepsy are relatively easy to identify, developmental and behavioral co-morbidities are more complex and challenging to define. We provide an overview of perinatal stroke syndromes and theories relating injury in the developing brain to long-term outcomes. We present a comprehensive overview of the effects on intelligence and other specific cognitive domains, as well as investigations relating clinical features and neuroimaging to deficits. Better understanding of the impact of early stroke has potential to elucidate processes of brain development, in addition to providing guidance for prognosis and rehabilitation.

Intrapartum fetal heart rate monitoring: evaluation of a standardized system of interpretation for prediction of metabolic acidosis at delivery and neonatal neurological morbidity.

OBJECTIVE: To assess the ability of the intrapartum fetal heart rate interpretation system developed in 2008 by the National Institute of Child Health and Human Development (NICHD) to predict fetal metabolic acidosis at delivery and neonatal neurological morbidity. METHODS: We analyzed the intrapartum fetal heart rate tracings of 314 singleton fetuses at ≥ 37 weeks using the NICHD three-tier system of interpretation: Category I (normal), Category II (indeterminate) and Category III (abnormal). Category II was further divided into Category IIA, with moderate fetal heart rate variability or accelerations, and Category IIB, with minimal/absent fetal heart rate variability and no accelerations. The presence and duration of the different patterns were compared with several clinical neonatal outcomes and with umbilical artery acid-base balance at birth. RESULTS: The mean values of pH and base excess decreased proportionally as tracings worsened (p < 0.001). The duration of at least 30 min for Category III tracings was highly predictive of a pH <7.00 and a base excess ≤-12 mmol/L. The same was true for the duration of Category IIB tracings that lasted for at least 50 min. CONCLUSIONS: Our study demonstrates that the interpretation of fetal heart rate tracings based on a strictly standardized system is closely associated with umbilical artery acid-base status at delivery.

Ethical issues in the care of the neurologically devastated infant.

The debate surrounding neurologically devastated newborns, whether due to severe prematurity or genetic malformations, has continued for over 40 years. Duff and Campbell (1973) first discussed allowing these children to die in the 1970s. In the 1980s, others fought to make sure these children with disabilities were afforded all the rights of other children. Recently, some commentators have advocated for withdrawal of therapies and even euthanasia in the Netherlands. Who is right? What are the ethical principles that should be followed? What decisions are appropriate for distraught parents to make? This chapter reviews international views, laws, and guidelines surrounding the therapies and limitations of care for these imperiled newborns. An ethical argument is presented for how to determine best interests for these special children utilizing the best interest standard. Parents and physicians need to use their individual expertise and values to work together to determine each individual child's best interests. Physicians may have to carry the burden for making final determinations to alleviate the guilt families may have in deciding to limit therapies.

Cytomegalovirus in pregnancy: to screen or not to screen.

BACKGROUND: Cytomegalovirus (CMV) infection is now the commonest congenital form of infective neurological handicap, recognized by the Institute of Medicine as the leading priority for the developed world in congenital infection. In the absence of an effective vaccine, universal screening for CMV in pregnancy has been proposed, in order that primary infection could be diagnosed and- potentially- the burden of disability due to congenital CMV prevented. DISCUSSION: Universal screening for CMV to identify seronegative women at the beginning of pregnancy could potentially reduce the burden of congenital CMV in one of three ways. The risk of acquiring the infection during pregnancy has been shown to be reduced by institution of simple hygiene measures (primary prevention). Among women who seroconvert during pregnancy, CMV hyperimmune globulin (CMV HIG) shows promise in reducing the risk of perinatal transmission (secondary prevention), and CMV HIG and/ or antivirals may be effective in reducing the risk of clinical sequelae among those known to be infected (tertiary prevention). The reports from these studies have re-ignited interest in universal screening for CMV, but against the potential benefit of these exciting therapies needs to be weighed the challenges associated with the implementation of any universal screening in pregnancy. These include; the optimal test, and timing of screening, to maximize detection; an approach to the management of equivocal results, and the cost effectiveness of the proposed screening program. In this article, we provide an overview of current knowledge and ongoing trials in the prevention, diagnosis and management of congenital CMV. Recognising that CMV screening is already being offered to many patients on an ad hoc basis, we also provide a management algorithm to guide clinicians and assist in counseling patients. SUMMARY: We suggest that- on the basis of current data- the criteria necessary to recommend universal screening for CMV are not yet met, but this position is likely to change if trials currently underway confirm that CMV HIG and/ or antivirals are effective in reducing the burden of congenital CMV disease.

Marcus Gunn jaw winking synkinesis: report of two cases.

Marcus Gunn jaw winking synkinesis (MGJWS) is caused by congenital miswiring of a branch of the fifth cranial nerve into the branch of the third cranial nerve supplying the levator muscle. It has been observed in 2-13% of patients with congenital ptosis. Although bilateral cases were reported, most were unilateral and occurred more frequently on the left side than the right. We report two cases of children who presented with ptosis and were diagnosed with MGJWS.

Home enteral nutrition in children: a 14-year multicenter survey.

BACKGROUND/OBJECTIVES: The practice of home enteral nutrition (HEN) represents a relevant aspect of the clinical management of both malnourished children and well-nourished children unable to be fed using an oral diet. The aim of this study was to estimate in an Italian paediatric population over a 14-year period (1996-2009), the clinical relevance and results over time of HEN activity. SUBJECTS/METHODS: HEN-computerized database and medical/dietetic charts were evaluated for patients aged at start of HEN <18 years and HEN duration >1 month. RESULTS: During the study period, we recorded 757 HEN programs. HEN began at a median age of 2 years for a median duration of 8.1 months. The complication rate was 14.8%. In the second period of the survey (2003-2009), the main changes concerned the underlying diseases requiring HEN, choice of formula feeding and access route. In 2009, the estimated overall prevalence of HEN was 3.47 and the incidence 2.45 per 100 000 inhabitants from 0 to 18 years of age. CONCLUSIONS: The epidemiological data of this study demonstrate that HEN concerns a growing number of Italian children and families. Some aspects of HEN clinical management should be modified to reach the recommended standards.