Are CUL3 variants an underreported cause of congenital heart disease?

Complex heart defects (CHD) are a common malformation associated with disruption of developmental pathways. The Cullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases in which Cullin 3 (CUL3) serves as a scaffolding subunit. Heterozygous CUL3 variants have been associated with neurodevelopmental disorders and pseudohypoaldosteronism type IIE. We report a fetus with CHD and a de novo CUL3 variant (NM_003590.4:c.[1549_1552del];[=], p.(Ser517Profs*23)) and review CUL3 variants reported with CHD. We postulate that CUL3 variants predispose to CHD and hypothesize mechanisms of pathogenesis.

Lethal respiratory course and additional features expand the phenotypic spectrum of PIEZO2-related distal arthrogryposis type 5.

Distal arthrogryposes (DA) are a group of conditions presenting with multiple congenital contractures in the distal joints. The 10 types of DA are distinguished by different extra-articular manifestations. Heterozygous gain-of-function variants in PIEZO2 are known to cause a spectrum of DA conditions including DA type 3, DA type 5, and possibly Marden Walker syndrome, which are usually distinguished by the presence of cleft palate (DA3), ptosis and restriction in eye movements (DA5), and specific facial abnormalities and central nervous system involvement, respectively. We report on a boy with a recurrent de novo heterozygous PIEZO2 variant in exon 20 (NM_022068.3: c.2994G > A, p.(Met998Ile); NM_001378183.1: c.3069G > A, p.(Met1023Ile)), who presented at birth with DA and later developed respiratory insufficiency. His phenotype broadly fits the PIEZO2 phenotypic spectrum and potentially extends it with novel phenotypic features of pretibial linear vertical crease, immobile skin, immobile tongue, and lipid myopathy.

Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant: A clinical and histopathological distinct entity showing epigenetic similarity with ATRT-MYC.

Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant, is a histopathological distinct low-grade lesion encountered in older children and young adults that shows epigenetic similarity with ATRT-MYC and has the potential for malignant progression.

An infant with congenital respiratory insufficiency and diaphragmatic paralysis: A novel BICD2 phenotype?

Monoallelic pathogenic variants in BICD2 are associated with autosomal dominant Spinal Muscular Atrophy Lower Extremity Predominant 2A and 2B (SMALED2A, SMALED2B). As part of the cellular vesicular transport, complex BICD2 facilitates the flow of constitutive secretory cargoes from the trans-Golgi network, and its dysfunction results in motor neuron loss. The reported phenotypes among patients with SMALED2A and SMALED2B range from a congenital onset disorder of respiratory insufficiency, arthrogryposis, and proximal or distal limb weakness to an adult-onset disorder of limb weakness and contractures. We report an infant with congenital respiratory insufficiency requiring mechanical ventilation, congenital diaphragmatic paralysis, decreased lung volume, and single finger camptodactyly. The infant displayed appropriate antigravity limb movements but had radiological, electrophysiological, and histopathological evidence of myopathy. Exome sequencing and long-read whole-genome sequencing detected a novel de novo BICD2 variant (NM_001003800.1:c.[1543G>A];[=]). This is predicted to encode p.(Glu515Lys); p.Glu515 is located in the coiled-coil 2 mutation hotspot. We hypothesize that this novel phenotype of diaphragmatic paralysis without clear appendicular muscle weakness and contractures of large joints is a presentation of BICD2-related disease.

Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants.

Mosaic KRAS variants and other RASopathy genes cause oculoectodermal, encephalo-cranio-cutaneous lipomatosis, and Schimmelpenning-Feuerstein-Mims syndromes, and a spectrum of vascular malformations, overgrowth and other associated anomalies, the latter of which are only recently being characterized. We describe eight individuals in total (six unreported cases and two previously reported cases) with somatic KRAS variants and variably associated features. Given the findings of somatic overgrowth (in seven individuals) and vascular or lymphatic malformations (in eight individuals), we suggest mosaic RASopathies (mosaic KRAS variants) be considered in the differential diagnosis for individuals presenting with asymmetric overgrowth and lymphatic or vascular anomalies. We expand the association with embryonal tumors, including the third report of embryonal rhabdomyosarcoma, as well as novel findings of Wilms tumor and nephroblastomatosis in two individuals. Rare or novel findings in our series include the presence of epilepsy, polycystic kidneys, and T-cell deficiency in one individual, and multifocal lytic bone lesions in two individuals. Finally, we describe the first use of targeted therapy with a MEK inhibitor for an individual with a mosaic KRAS variant. The purposes of this report are to expand the phenotypic spectrum of mosaic KRAS-related disorders, and to propose possible mechanisms of pathogenesis, and surveillance of its associated findings.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex 1 deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Congenital lactic acidosis, cerebral cysts and pulmonary hypertension in an infant with FOXRED1 related complex I deficiency.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1. Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts. Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Comparative RNA-Sequencing Analysis Benefits a Pediatric Patient With Relapsed Cancer.

Clinical detection of sequence and structural variants in known cancer genes points to viable treatment options for a minority of children with cancer.1 To increase the number of children who benefit from genomic profiling, gene expression information must be considered alongside mutations.2,3 Although high expression has been used to nominate drug targets for pediatric cancers,4,5 its utility has not been evaluated in a systematic way.6 We describe a child with a rare sarcoma that was profiled with whole-genome and RNA sequencing (RNA-Seq) techniques. Although the tumor did not harbor DNA mutations targetable by available therapies, incorporation of gene expression information derived from RNA-Seq analysis led to a therapy that produced a significant clinical response. We use this case to describe a framework for inclusion of gene expression into the clinical genomic evaluation of pediatric tumors.

Compound heterozygous TRPV4 mutations in two siblings with a complex phenotype including severe intellectual disability and neuropathy.

TRPV4 encodes a polymodal calcium-permeable plasma membrane channel. Dominant pathogenic mutations in TRPV4 lead to a wide spectrum of abnormal phenotypes. This is the first report of biallelic TRPV4 mutations and we describe two compound heterozygous siblings presenting with a complex phenotype including severe neuromuscular involvement. In light of previously well described dominant inheritance for TRPV4-related neuromuscular disease, our study suggests a role for compound heterozygosity and loss-of-function as a potential novel disease mechanism for this group of disorders. Profound intellectual disability was also noted in both affected children, suggesting that TRPV4 may be necessary for normal brain development.

Clinical, imaging, and immunohistochemical characteristics of focal cortical dysplasia Type II extratemporal epilepsies in children: analyses of an institutional case series.

OBJECTIVE Focal cortical dysplasia (FCD) Type II is divided into 2 subgroups based on the absence (IIA) or presence (IIB) of balloon cells. In particular, extratemporal FCD Type IIA and IIB is not completely understood in terms of clinical, imaging, biological, and neuropathological differences. The aim of the authors was to analyze distinctions between these 2 formal entities and address clinical, MRI, and immunohistochemical features of extratemporal epilepsies in children. METHODS Cases formerly classified as Palmini FCD Type II nontemporal epilepsies were identified through the prospectively maintained epilepsy database at the British Columbia Children's Hospital in Vancouver, Canada. Clinical data, including age of seizure onset, age at surgery, seizure type(s) and frequency, affected brain region(s), intraoperative electrocorticographic findings, and outcome defined by Engel's classification were obtained for each patient. Preoperative and postoperative MRI results were reevaluated. H & E-stained tissue sections were reevaluated by using the 2011 International League Against Epilepsy classification system and additional immunostaining for standard cellular markers (neuronal nuclei, neurofilament, glial fibrillary acidic protein, CD68). Two additional established markers of pathology in epilepsy resection, namely, CD34 and α-B crystallin, were applied. RESULTS Seven nontemporal FCD Type IIA and 7 Type B cases were included. Patients with FCD Type IIA presented with an earlier age of epilepsy onset and slightly better Engel outcome. Radiology distinguished FCD Types IIA and IIB, in that Type IIB presented more frequently with characteristic cortical alterations. Nonphosphorylated neurofilament protein staining confirmed dysplastic cells in dyslaminated areas. The white-gray matter junction was focally blurred in patients with FCD Type IIB. α-B crystallin highlighted glial cells in the white matter and subpial layer with either of the 2 FCD Type II subtypes and balloon cells in patients with FCD Type IIB. α-B crystallin positivity proved to be a valuable tool for confirming the histological diagnosis of FCD Type IIB in specimens with rare balloon cells or difficult section orientation. Distinct nonendothelial cellular CD34 staining was found exclusively in tissue from patients with MRI-positive FCD Type IIB. CONCLUSIONS Extratemporal FCD Types IIA and IIB in the pediatric age group exhibited imaging and immunohistochemical characteristics; cellular immunoreactivity to CD34 emerged as an especially potential surrogate marker for lesional FCD Type IIB, providing additional evidence that FCD Types IIA and IIB might differ in their etiology and biology. Although the sample number in this study was small, the results further support the theory that postoperative outcome-defined by Engel's classification-is multifactorial and determined by not only histology but also the extent of the initial lesion, its location in eloquent areas, intraoperative electrocorticographic findings, and achieved resection grade.

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila. RESULTS: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated ß-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways. CONCLUSIONS: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.

Histopathology of the filum terminale in children with and without tethered cord syndrome with attention to the elastic tissue within the filum.

PURPOSE: To compare histologically transected fila from pediatric patients with tethered cord syndrome (TCS), with and without a low conus, with controls, focusing on collagenous and elastic tissue. METHODS: Thirty fila from patients with TCS, including 5 where minimal cautery was used prior to filum section, were compared with fila from 27 pediatric cadavers without TCS (controls). Sections of fila were stained with H&E, Masson trichrome and Verhoeff von Gieson elastic stains, and 7 with Gordon and Sweet's reticulin stain. RESULTS: Fila from controls showed loose fibrous connective tissue (FCT) with thin and evenly dispersed elastic fibers (EFs). Reticulin fibers (RFs) were seen in blood vessel walls and nerve twigs. Fat was identified microscopically in 2 fila. All fila from patients with TCS had dense FCT. The EFs were in normal numbers in 17, and focally or diffusely decreased in 13. All 25 patients where the fila were cauterized during resection had thick and coiled EFs. Coiling was not seen when minimal cautery was applied. RFs were seen in blood vessel walls and nerve twigs. Fat was identified in 19 patients. Findings were similar, whether the conus termination was normal or low. CONCLUSION: The fila of all patients with TCS, whether or not the conus was low, showed abnormal FCT. EFs were decreased in 48 % of patients; however, there were thick and coiled EFs in all patients. Coiling of EFs, initially thought to be an abnormality in patients, is considered most likely to be a result of cautery (i.e., artifactual/iatrogenic coiling).

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy.

Congenital myopathies are a clinically and genetically heterogeneous group of muscle disorders characterized by congenital or early-onset hypotonia and muscle weakness, and specific pathological features on muscle biopsy. The phenotype ranges from foetal akinesia resulting in in utero or neonatal mortality, to milder disorders that are not life-limiting. Over the past decade, more than 20 new congenital myopathy genes have been identified. Most encode proteins involved in muscle contraction; however, mutations in ion channel-encoding genes are increasingly being recognized as a cause of this group of disorders. SCN4A encodes the α-subunit of the skeletal muscle voltage-gated sodium channel (Nav1.4). This channel is essential for the generation and propagation of the muscle action potential crucial to muscle contraction. Dominant SCN4A gain-of-function mutations are a well-established cause of myotonia and periodic paralysis. Using whole exome sequencing, we identified homozygous or compound heterozygous SCN4A mutations in a cohort of 11 individuals from six unrelated kindreds with congenital myopathy. Affected members developed in utero- or neonatal-onset muscle weakness of variable severity. In seven cases, severe muscle weakness resulted in death during the third trimester or shortly after birth. The remaining four cases had marked congenital or neonatal-onset hypotonia and weakness associated with mild-to-moderate facial and neck weakness, significant neonatal-onset respiratory and swallowing difficulties and childhood-onset spinal deformities. All four surviving cohort members experienced clinical improvement in the first decade of life. Muscle biopsies showed myopathic features including fibre size variability, presence of fibrofatty tissue of varying severity, without specific structural abnormalities. Electrophysiology suggested a myopathic process, without myotonia. In vitro functional assessment in HEK293 cells of the impact of the identified SCN4A mutations showed loss-of-function of the mutant Nav1.4 channels. All, apart from one, of the mutations either caused fully non-functional channels, or resulted in a reduced channel activity. Each of the affected cases carried at least one full loss-of-function mutation. In five out of six families, a second loss-of-function mutation was present on the trans allele. These functional results provide convincing evidence for the pathogenicity of the identified mutations and suggest that different degrees of loss-of-function in mutant Nav1.4 channels are associated with attenuation of the skeletal muscle action potential amplitude to a level insufficient to support normal muscle function. The results demonstrate that recessive loss-of-function SCN4A mutations should be considered in patients with a congenital myopathy.

Assessing the accuracy of death records and pre-mortem clinical diagnoses in children diagnosed with brain tumors: A retrospective chart review of children in British Columbia, Canada.

The advantages of autopsy have been demonstrated in pediatric oncology; however, it is unknown to what extent the utility of autopsy is in deceased children diagnosed with a pediatric brain tumor (PBT). The purpose of this study was to describe the frequency of autopsy, prevalence of clinical discrepancies, and accuracy of cancer registry death records for deceased children diagnosed with a PBT in British Columbia, Canada. A retrospective chart review was performed of medical records and autopsy reports of pediatric patients diagnosed with a PBT that died between 1982 and 2012 in British Columbia. Clinical discrepancies between pre- and post-mortem findings were classified based on a modified classification system of the Goldman Criteria. The overall autopsy rate was 15.5% (32 of 206) during 1982-2012, with a significant (P=0.001) decrease of 22.4% observed between decade 1 (32.8%) and decade 2 (10.4%) and a further slight decrease (4.5%) between decade 2 (10.4%) and decade 3 (5.9%) (P=0.379). A third of patients had discrepancies between pre-mortem and post-mortem clinical diagnoses, with slightly over 10% of these cases revealing information that would have altered the probability of survival had it been known prior to death. More than half (59.3%) of cases had discordant cause of death as recorded in the cancer registry when compared to autopsy findings. Autopsy for children diagnosed with a PBT can provide health care professionals with important information about the accuracy of their diagnoses and evaluate the efficacy of therapy.

Transcriptional and posttranscriptional mechanisms contribute to the dysregulation of elastogenesis in Schimke immuno-osseous dysplasia.

BACKGROUND: Schimke immuno-osseous dysplasia (SIOD) is an autosomal recessive disorder caused by mutations in SMARCAL1. A frequent complication is arteriosclerosis associated with reduced elastin expression; however, the mechanism underlying the reduced elastin expression remains unknown. METHODS: Expression of transcriptional regulators of elastin (ELN) and microRNA (miRNA) regulators of ELN messenger RNA (mRNA), ELN promoter methylation, and ELN mRNA poly(A) tail length were assessed by quantitative RT-PCR, bisulfite Sanger sequencing, and the Poly(A) Tail Length Assay Kit, respectively, in unaffected developing human aortae and in an SIOD aorta. RESULTS: Comparing unaffected fetal and adult aortae, ELN precursor mRNA (pre-mRNA) levels remained nearly constant, whereas mRNA levels declined by ~10(2)-fold. This corresponded with a reduction in poly(A) tail length but not with changes in the other parameters. In contrast, compared to the unaffected fetal aortae, the SIOD aorta had 18-fold less ELN pre-mRNA and 10(4)-fold less mRNA. This corresponded with increased expression of miRNA regulators and shorter ELN mRNA poly(A) tail lengths but not with altered expression of ELN transcriptional regulators or ELN promoter methylation. CONCLUSION: Posttranscriptional mechanisms account for the reduction in ELN mRNA levels in unaffected aortae, whereas transcriptional and posttranscriptional mechanisms reduce elastin expression in SIOD aorta and predispose to arteriosclerosis.

EZH2 expression is a prognostic factor in childhood intracranial ependymoma: a Canadian Pediatric Brain Tumor Consortium study.

BACKGROUND: The cure rate for childhood intracranial ependymoma is approximately 70% in the setting of a gross total resection followed by radiation, but management remains challenging in patients with residual disease. Therefore, robust biomarkers are needed to guide the development of new targeted therapy. The authors evaluated the expression of several biomarkers in pediatric intracranial ependymoma and observed that the expression of enhancer of zeste homolog 2 (EZH2), a polycomb complex protein involved in epigenetic regulation of gene expression, was independently associated with poor survival. METHODS: Tissue microarray immunostaining was performed on 180 ependymoma samples from 12 of 16 Canadian pediatric centers. Expression levels of EZH2, Ki-67, B lymphoma Moloney-murine leukemia virus insertion region 1 homolog, tumor protein 16 (P16), Y-box binding protein 1, phosphorylated protein kinase B (pAKT), and epidermal growth factor receptor were evaluated. Cox regression analyses were performed, and the Kaplan-Meier method was used to construct survival curves. RESULTS: EZH2 expressed in 16% of tumors was associated with inferior 5-year overall survival. Ki-67 and pAKT levels were associated with a poor outcome in patients with posterior fossa ependymoma, and the absence of P16 was associated with a poor outcome in patients with supratentorial ependymoma. Multivariate analysis revealed that younger age and EZH2 expression (95% confidence interval, 1.1-36.0) were independent markers of a poor prognosis. CONCLUSIONS: EZH2 is a novel, independent marker of a poor prognosis in patients with ependymoma, especially in those who have tumors located in the posterior fossa. EZH2, pAKT, and P16 are potential therapeutic targets, particularly for patients who have tumors in which standard gross total resection plus fractionated radiotherapy is not feasible.

The role of resection alone in select children with intracranial ependymoma: the Canadian Pediatric Brain Tumour Consortium experience.

PURPOSE: Gross total resection (GTR) of intracranial ependymoma is an accepted goal. More controversial is radiotherapy deferral. This study reports on children treated with gross total resection who did not receive upfront adjuvant radiotherapy. METHODS: We conducted a retrospective review of children with intracranial ependymoma in 12 Canadian centers. Patients who had GTR of their tumor and no upfront radiotherapy were identified. Immunostaining was performed for Ki-67, epidermal growth factor receptor (EGFR), and EZH2 on archived tissue. The Kaplan-Meier survival analysis was performed and compared with those who had GTR followed by radiation. RESULTS: Twenty-six children were identified treated with GTR alone at diagnosis; 12 posterior fossa ependymoma (PFE) WHO grade II, and 14 supratentorial ependymoma (STE). Progression-free survival (PFS) in ependymoma treated with GTR alone at diagnosis was inferior in those with high Ki-67 or positive EZH2 immunostaining. Survival was inferior for patients less than 2 years old at diagnosis (p = 0.002). Survival was comparable to PFE WHO grade II and STE who had GTR followed by radiation (p = 0.62). Five-year PFS and overall survival (OS) of those treated with GTR alone were 60 and 70% respectively for PFE and 45 and 70% respectively for STE (p = 0.2; 0.55). CONCLUSIONS: This study suggests that there is a subset of children with certain biologic features who, in the setting of a prospective clinical trial, might be candidates for observation following GTR. Good risk factors for this approach include age of 2 years or older, low Ki-67, and negative EZH2. If relapse occurs, it may be confined to the primary site, allowing for possible salvage with GTR followed by XRT.

Magnetic resonance imaging in the encephalopathic term newborn.

Neonatal encephalopathy is a neurological emergency with heterogeneous etiologies and several management challenges. Neonatal encephalopathy of hypoxic-ischemic origin is associated with high rate of neonatal morbidity and mortality, and the long-term neurodevelopmental outcome of survivors with moderate to severe encephalopathy is poor. Magnetic resonance imaging now provides new insights on the diagnosis and prognosis of this condition. Typical patterns of brain injury have been recognized and in contemporary cohorts of newborns these patterns reflect different risk factors and clinical presentation, as well as specific patterns of neurodevelopmental outcome. Magnetic resonance spectroscopy, diffusion-weighted imaging, and diffusion tensor imaging are advanced MR techniques that are increasingly used in the assessment of encephalopathic newborns, providing innovative perspectives on neonatal brain metabolism, microstructure, and connectivity. These techniques have been particularly helpful in elucidating the unique time course of neonatal brain injury and in providing quantitative biomarkers for prognostication. To better refine the prognostic value of these new imaging tools, standardization of protocols, imaging modalities and scan timing are needed across centers. It is hoped that these techniques will permit earlier identification of newborns at risk of neurodevelopmental impairment and complement ongoing trials of emerging therapies such as hypothermia and novel pharmacological agents with neuroprotective properties.