Mapping brain volume change across time in primary-progressive multiple sclerosis.

PURPOSE: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps compare age-related changes in both cortical and sub-cortical regions with those in healthy individuals. METHODS: We conducted retrospective analyses of brain volume using T1-weighted Magnetic Resonance Imaging (MRI) scans of a large cohort of PPMS patients and healthy subjects. The volume of brain parenchyma (BP), cortex, white matter (WM), deep gray matter, thalamus, and cerebellum were measured using the robust SynthSeg segmentation tool. Age- and gender-related regression curves were constructed based on data from healthy subjects, with the 95% prediction interval adopted as the normality threshold for each brain region. RESULTS: We analyzed 495 MRI scans from 169 PPMS patients, aged 20-79 years, alongside 563 exams from healthy subjects aged 20-86. Compared to healthy subjects, a higher proportion of PPMS patients showed lower than expected brain volumes in all regions except the cerebellum. The most affected areas were BP, WM, and thalamus. Lower brain volumes correlated with longer disease duration for BP and WM, and higher disability for BP, WM, cortex, and thalamus. CONCLUSIONS: Constructing age- and gender-related brain volume maps enabled identifying PPMS patients at a higher risk of brain volume loss. Monitoring these high-risk patients may lead to better treatment decisions and improve patient outcomes.

Prenatal imaging of the normal and abnormal spinal cord: recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee.

Spinal dysraphisms are amenable to diagnosis in utero. The prognosis and the neonatal management of these conditions differ significantly depending on their types, mainly on the distinction between open and closed defects. A detailed evaluation not only of the fetal spine, but also of the brain, skull, and lower limbs is essential in allowing for the right diagnosis. In this article, recommendations from the Fetal Task Force of the European Society of Paediatric Radiology (ESPR) and the European Society of Neuroradiology (ESNR) Pediatric Neuroradiology Committee will be presented. The aim of this paper is to review the imaging features of the normal and abnormal fetal spinal cord, to clarify the prenatal classification of congenital spinal cord anomalies and to provide guidance in their reporting.

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

Effect of General Anesthesia on MR Optic Nerve Sheath Diameter in the Pediatric Population.

BACKGROUND: Papilledema is thought to be the hallmark sign of increased intracranial pressure (ICP). Distension of the subarachnoid space within the optic nerve sheath is also commonly reported in MR studies as an indirect sign of increased ICP. HYPOTHESIS: General anesthesia and positive pressure ventilation might result in changes in optic sheath diameter (OSD) observed on clinical brain MRI. STUDY TYPE: Retrospective. POPULATION: One hundred forty-five  patients (154 MRI scans, 7.3 years ± 5.1); 97 studies in the anesthesia group (4.4 years ± 3.4) of which 22 had papilledema, and 57 in the non-anesthesia group (12.3 years ± 3.2), of which 28 had papilledema. FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T volumetric T2 images. T2 images were obtained from different vendors. ASSESSMENT: OSD, optic nerve diameter (OND), and peri-optic cerebrospinal fluid (CSF) were measured manually on T2-weighted MR images for various population subgroups (with and without anesthesia; with or without papilledema). The correlation between these measurements and the clinical diagnosis of papilledema was evaluated via receiver operating characteristic (ROC) analysis. STATISTICAL TESTS: Chi-square test; Mann-Whitney Test; Spearman's test and ROCs; Interclass correlation coefficient, P = 0.05. RESULTS: General anesthesia resulted in significantly larger mean OSD in patients with or without papilledema (7.3 ± 1.0 mm vs. 6.1 ± 1.1 mm and 6.7 ± 1.0 mm vs. 5.4 ± 0.9 mm, respectively). In the non-anesthesia group, the average OSD values (6.1 ± 1.1 mm) were significantly higher in papilledema patients compared to non-papilledema patients (5.4 ± 0.9 mm), with larger peri-optic CSF rim (1.6 ± 0.4 mm vs. 1.3 ± 0.3 mm). In the anesthesia group, OND was significantly larger in papilledema patients (3.4 ± 0.4 mm vs. 3.1 ± 0.5 mm), though the average peri-optic CSF rim did not reach a significance in papilledema compared with non-papilledema patients (2.0 ± 0.3 mm vs. 1.8 ± 0.4 mm, P = 0.06). In patients with general anesthesia, peri-optic CSF rim had a limited correlation with increased ICP. DATA CONCLUSION: In the pediatric population, imaging findings of increased OSD on brain MRI might be related to general anesthesia rather than increased ICP. The interpretation of optic nerve sheath distention should be reported cautiously in conjunction with anesthesia status, especially in the pediatric population. EVIDENCE LEVEL: 4 Technical Efficacy: 5.

Psychophysical Evaluation of Visual vs. Computer-Aided Detection of Brain Lesions on Magnetic Resonance Images.

BACKGROUND: Magnetic resonance imaging (MRI) diagnosis is usually performed by analyzing contrast-weighted images, where pathology is detected once it reached a certain visual threshold. Computer-aided diagnosis (CAD) has been proposed as a way for achieving higher sensitivity to early pathology. PURPOSE: To compare conventional (i.e., visual) MRI assessment of artificially generated multiple sclerosis (MS) lesions in the brain's white matter to CAD based on a deep neural network. STUDY TYPE: Prospective. POPULATION: A total of 25 neuroradiologists (15 males, age 39 ± 9, 9 ± 9.8 years of experience) independently assessed all synthetic lesions. FIELD STRENGTH/SEQUENCE: A 3.0 T, T2 -weighted multi-echo spin-echo (MESE) sequence. ASSESSMENT: MS lesions of varying severity levels were artificially generated in healthy volunteer MRI scans by manipulating T2 values. Radiologists and a neural network were tasked with detecting these lesions in a series of 48 MR images. Sixteen images presented healthy anatomy and the rest contained a single lesion at eight increasing severity levels (6%, 9%, 12%, 15%, 18%, 21%, 25%, and 30% elevation in T2 ). True positive (TP) rates, false positive (FP) rates, and odds ratios (ORs) were compared between radiological diagnosis and CAD across the range lesion severity levels. STATISTICAL TESTS: Diagnostic performance of the two approaches was compared using z-tests on TP rates, FP rates, and the logarithm of ORs across severity levels. A P-value <0.05 was considered statistically significant. RESULTS: ORs of identifying pathology were significantly higher for CAD vis-à-vis visual inspection for all lesions' severity levels. For a 6% change in T2 value (lowest severity), radiologists' TP and FP rates were not significantly different (P = 0.12), while the corresponding CAD results remained statistically significant. DATA CONCLUSION: CAD is capable of detecting the presence or absence of more subtle lesions with greater precision than the representative group of 25 radiologists chosen in this study. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Effect of magnet strength on fetal brain biometry - a single-center retrospective MRI-based cohort study.

PURPOSE: Abnormal fetal brain measurements might affect clinical management and parental counseling. The effect of between-field-strength differences was not evaluated in quantitative fetal brain imaging until now. Our study aimed to compare fetal brain biometry measurements in 3.0 T with 1.5 T scanners. METHODS: A retrospective cohort of 1150 low-risk fetuses scanned between 2012 and 2021, with apparently normal brain anatomy, were retrospectively evaluated for biometric measurements. The cohort included 1.5 T (442 fetuses) and 3.0 T scans (708 fetuses) of populations with comparable characteristics in the same tertiary medical center. Manually measured biometry included bi-parietal, fronto-occipital and trans-cerebellar diameters, length of the corpus-callosum, vermis height, and width. Measurements were then converted to centiles based on previously reported biometric reference charts. The 1.5 T centiles were compared with the 3.0 T centiles. RESULTS: No significant differences between centiles of bi-parietal diameter, trans-cerebellar diameter, or length of the corpus callosum between 1.5 T and 3.0 T scanners were found. Small absolute differences were found in the vermis height, with higher centiles in the 3.0 T, compared to the 1.5 T scanner (54.6th-centile, vs. 39.0th-centile, p < 0.001); less significant differences were found in vermis width centiles (46.9th-centile vs. 37.5th-centile, p = 0.03). Fronto-occipital diameter was higher in 1.5 T than in the 3.0 T scanner (66.0th-centile vs. 61.8th-centile, p = 0.02). CONCLUSIONS: The increasing use of 3.0 T MRI for fetal imaging poses a potential bias when using 1.5 T-based charts. We elucidate those biometric measurements are comparable, with relatively small between-field-strength differences, when using manual biometric measurements. Small inter-magnet differences can be related to higher spatial resolution with 3 T scanners and may be substantial when evaluating small brain structures, such as the vermis.

Radiological Disease Activity in Secondary Progressive Multiple Sclerosis.

INTRODUCTION: MRI activity is less frequent among secondary progressive multiple sclerosis (SPMS) patients. In the current study, we aimed to identify SPMS patients with higher radiological disease activity (RDA) and determine their clinical characteristics. METHODS: We evaluated the occurrence of RDA in SPMS patients followed at the Sheba Multiple Sclerosis Center between January 1, 2015, and December 31, 2020. All patients underwent brain and spinal cord MRI examinations as a routine follow-up unrelated to clinical disease activity. Patients were subdivided into RDA and non-RDA MRI groups based on the presence of active gadolinium-enhancing T1 lesions and/or new/enlarging T2 lesions. Demographic variables and disease-related data were compared. RESULTS: One hundred consecutive SPMS patients, 74 females, median age of 50 years, disease duration of 19.5 years, and neurological disability by the Expanded Disability Status Scale (EDSS) score of 6.0, were included in the study. The RDA group comprised 35 patients (35%), of them 65.7% (n = 23) exhibited only brain MRI activity, 22.8% (n = 8) only spinal cord MRI activity, and 11.4% (n = 4) had both. Patients in the RDA group were diagnosed at a younger mean (SD) age of 28.2 (8.9) versus 33.7 (10.1) years and were younger with a mean (SD) age of 47.8 (9.9) versus 53.4 (10.1) years, as compared with the non-RDA group. No significant differences were found in relation to disease duration, EDSS, exposure to immunomodulatory treatments, and duration of immunomodulatory treatments. CONCLUSIONS: RDA unrelated to clinical symptomatology was more frequent in a subgroup of young SPMS patients.

European recommendations on practices in pediatric neuroradiology: consensus document from the European Society of Neuroradiology (ESNR), European Society of Paediatric Radiology (ESPR) and European Union of Medical Specialists Division of Neuroradiology (UEMS).

Pediatric neuroradiology is a subspecialty within radiology, with possible pathways to train within the discipline from neuroradiology or pediatric radiology. Formalized pediatric neuroradiology training programs are not available in most European countries. We aimed to construct a European consensus document providing recommendations for the safe practice of pediatric neuroradiology. We particularly emphasize imaging techniques that should be available, optimal site conditions and facilities, recommended team requirements and specific indications and protocol modifications for each imaging modality employed for pediatric neuroradiology studies. The present document serves as guidance to the optimal setup and organization for carrying out pediatric neuroradiology diagnostic and interventional procedures. Clinical activities should always be carried out in full agreement with national provisions and regulations. Continued education of all parties involved is a requisite for preserving pediatric neuroradiology practice at a high level.

3.0 Tesla normative diffusivity in 3rd trimester fetal brain.

PURPOSE: Apparent diffusion coefficient (ADC) values in the developing fetus provide valuable information on the diagnosis and prognosis of prenatal brain pathologies. Normative ADC data has been previously established in 1.5 T MR scanners but lacking in 3.0 T scanners. Our objective was to measure ADC values in various brain areas in a cohort of normal singleton fetuses scanned in a 3.0 T MR scanner. METHODS: DWI (diffusion-weighted imaging) was performed in 47 singleton fetuses with normal or questionably abnormal results on sonography followed by normal structural MR imaging. ADC values were measured in cerebral lobes (frontal, parietal, temporal lobes), basal ganglia, and pons. Regression analysis was used to examine gestational age-related changes in regional ADC. RESULTS: Median gestational age was 30.1 weeks (range, 26-34 weeks). There was a significant effect of region on ADC values, whereby ADC values were highest in cerebral lobes (parietal > frontal > temporal lobes), compared with basal ganglia. The lowest values were found in the pons. On regression analysis, there was a decrease in ADC values in basal ganglia and pons with increasing gestational age. ADC values in frontal, parietal, and temporal lobes were stable in our cohort. CONCLUSION: Regional brain ADC values in 3.0 T scanners are comparable with previously reported values in 1.5 T scanners, with similar changes over gestational age. Using 3.0 T scanners is increasing worldwide. For fetal imaging, establishing normal ADC values is critical as DWI enables a sensitive and quantitative technique to evaluate normal and abnormal brain development.

Prediction of tuberous sclerosis-associated neurocognitive disorders and seizures via machine learning of structural magnetic resonance imaging.

PURPOSE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by multiorgan hamartomas, including cerebral lesions, with seizures as a common presentation. Most TSC patients will also experience neurocognitive comorbidities. Our objective was to use machine learning techniques incorporating clinical and imaging data to predict the occurrence of major neurocognitive disorders and seizures in TSC patients. METHODS: A cohort of TSC patients were enrolled in this retrospective study. Clinical data included genetic, demographic, and seizure characteristics. Imaging parameters included the number, characteristics, and location of cortical tubers and the presence of subependymal nodules, SEGAs, and cerebellar tubers. A random forest machine learning scheme was used to predict seizures and neurodevelopmental delay or intellectual developmental disability. Prediction ability was assessed by the area-under-the-curve of receiver-operating-characteristics (AUC-ROC) of ten-fold cross-validation training set and an independent validation set. RESULTS: The study population included 77 patients, 55% male (17.1 ± 11.7 years old). The model achieved AUC-ROC of 0.72 ± 0.1 and 0.68 in the training and internal validation datasets, respectively, for predicting neurocognitive comorbidity. Performance was limited in predicting seizures (AUC-ROC of 0.54 ± 0.19 and 0.71 in the training and internal validation datasets, respectively). The integration of seizure characteristics into the model improved the prediction of neurocognitive comorbidity with AUC-ROC of 0.84 ± 0.07 and 0.75 in the training and internal validation datasets, respectively. CONCLUSIONS: This proof of concept study shows that it is possible to achieve a reasonable prediction of major neurocognitive morbidity in TSC patients using structural brain imaging and machine learning techniques. These tools can help clinicians identify subgroups of TSC patients with an increased risk of developing neurocognitive comorbidities.

Fetal and neonatal brain injury in twins complicated by twin anemia polycythemia sequence.

OBJECTIVES: To determine the rate of fetal and neonatal brain lesions and define risk factors for such lesions in pregnancies complicated by Twin Anemia Polycythemia Sequence (TAPS). METHODS: A retrospective cohort study of monochorionic twin pregnancies which were diagnosed with TAPS in a single tertiary medical center between 2013 and 2021. Pregnancies were followed with fetal brain neurosonogram every 2 weeks and fetal brain MRI (magnetic resonance imaging) was performed when indicated at 28-32 weeks of gestation; post-natal brain imaging included neonatal brain ultrasound. Pregnancies with pre- and post-natal brain lesions were compared to those without such findings. RESULTS: Overall, 23 monochorionic diamniotic pregnancies were diagnosed with TAPS over the study period resulting in perinatal survival of 91.3% (42/46). In 6/23 (26%) pregnancies and 7/46 (15.2%) fetuses pre- or post-natal brain lesions were detected, of whom five were the polycythemic twins and two were the anemic twins. Brain findings included intra-cerebral hemorrhage and ischemic lesions and were diagnosed prenatally in 6/7 (85.7%) cases. No risk factors for severe brain lesions were identified. CONCLUSIONS: TAPS may place the fetuses and neonates at increased risk for cerebral injuries. Incorporation of fetal brain imaging protocols may enhance precise prenatal diagnosis and allow for accurate parental counseling and post-natal care.

Neuro-Ophthalmic Phenotype of OPA3.

BACKGROUND: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. METHODS: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. RESULTS: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. CONCLUSIONS: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.

Widespread cortical dyslamination in epilepsy patients with malformations of cortical development.

PURPOSE: Recent research in epilepsy patients confirms our understanding of epilepsy as a network disorder with widespread cortical compromise. Here, we aimed to investigate the neocortical laminar architecture in patients with focal cortical dysplasia (FCD) and periventricular nodular heterotopia (PNH) using clinically feasible 3 T MRI. METHODS: Eighteen epilepsy patients (FCD and PNH groups; n = 9 each) and age-matched healthy controls (n = 9) underwent T1 relaxation 3 T MRI, from which component probability T1 maps were utilized to extract sub-voxel composition of 6 T1 cortical layers. Seventy-eight cortical areas of the automated anatomical labeling atlas were divided into 1000 equal-volume sub-areas for better detection of cortical abnormalities, and logistic regressions were performed to compare FCD/PNH patients with healthy controls with the T1 layers composing each sub-area as regressors. Statistical significance (p < 0.05) was determined by a likelihood-ratio test with correction for false discovery rate using Benjamini-Hochberg method. RESULTS: Widespread cortical abnormalities were observed in the patient groups. Out of 1000 sub-areas, 291 and 256 bilateral hemispheric cortical sub-areas were found to predict FCD and PNH, respectively. For each of these sub-areas, we were able to identify the T1 layer, which contributed the most to the prediction. CONCLUSION: Our results reveal widespread cortical abnormalities in epilepsy patients with FCD and PNH, which may have a role in epileptogenesis, and likely related to recent studies showing widespread structural (e.g., cortical thinning) and diffusion abnormalities in various human epilepsy populations. Our study provides quantitative information of cortical laminar architecture in epilepsy patients that can be further targeted for study in functional and neuropathological studies.

Fetal and neonatal brain lesions following laser ablation for twin-to-twin-transfusion-syndrome as detected by pre- and post-natal brain imaging.

OBJECTIVE: To determine the rate of and risk factors for fetal and neonatal brain lesions following laser ablation for twin-to-twin transfusion syndrome (TTTS). METHODS: A retrospective cohort study of 83 women with monochorionic twin pregnancies who underwent ablation for TTTS at a single tertiary hospital. Post-laser survivors were followed-up with fetal neurosonogram every 2 weeks and fetal brain MRI at 28-32 weeks of gestation; post-natal brain imaging included neurosonogram. Cases with pre- and post-natal brain lesions were compared to those without. RESULTS: 153 fetuses survived the immediate post-laser period and underwent brain imaging. Of these, 17 (11.11%) exhibited brain lesions on prenatal imaging studies, and 36 (32.4%) on post-natal ultrasound. Later gestational age (GA) at the time of ablation (23.0 vs. 21.4 weeks, p = 0.0244), post-laser twin-anemia-polycythemia-sequence (TAPS) (29.41% vs. 9.56%, p = 0.035) and birthweight discordancy (30% vs. 9%, p = 0.0025) were associated with prenatal brain lesions. Earlier GA at delivery (31.0 weeks vs. 32.2, p = 0.0002) and post-laser TAPS (25% vs. 9.33%, p = 0.038) were associated with post-natal brain lesions. CONCLUSIONS: Survivors of ablation for TTTS are at risk for brain lesions, which can be detected prenatally. Incorporation of neurosonogram and fetal brain MRI into the routine surveillance of such pregnancies should be considered.

Prenatal Diagnosis of Snijders Blok-Campeau Syndrome in a Fetus with Macrocephaly.

We present the prenatal imaging and whole exomics sequencing with the newly described Snijders Blok-Campeau macrocephaly syndrome.

Brain Motor Region Diffusion Tensor Imaging in Patients with Catatonic Schizophrenia: A Case-Control Study.

BACKGROUND: Only a small proportion of schizophrenia patients present with catatonic symptoms. Imaging studies suggest that brain motor circuits are involved in the underlying pathology of catatonia. However, data about diffusivity dysregulation of these circuits in catatonic schizophrenia are scarce. OBJECTIVES: To assess the involvement of brain motor circuits in schizophrenia patients with catatonia. METHODS: Diffusion tensor imaging (DTI) was used to measure white matter signals in selected brain regions linked to motor circuits. Relevant DTI data of seven catatonic schizophrenia patients were compared to those of seven non-catatonic schizophrenia patients, matched for sex, age, and education level. RESULTS: Significantly elevated fractional anisotropy values were found in the splenium of the corpus callosum, the right peduncle of the cerebellum, and the right internal capsule of the schizophrenia patients with catatonia compared to those without catatonia. This finding showed altered diffusivity in selected motor-related brain areas. CONCLUSIONS: Catatonic schizophrenia is associated with dysregulation of the connectivity in specific motoric brain regions and corresponding circuits. Future DTI studies are needed to address the neural correlates of motor abnormalities in schizophrenia-related catatonia during the acute and remitted state of the illness to identify the specific pathophysiology of this disorder.

Prenatal diagnosis of congenital head, face, and neck malformations-Is complementary fetal MRI of value?

OBJECTIVES: The aim of this study was to evaluate the role of fetal magnetic resonance imaging (MRI) as a complement to ultrasound (US) in the prenatal diagnosis of craniofacial anomalies. METHODS: A historical cohort study including all pregnant women who were referred for fetal MRI because of antenatal diagnosis of craniofacial anomalies on screening US. Prenatal diagnostic US, MRI, and postnatal diagnosis were compared for consistencies and discrepancies. RESULTS: Forty-five pregnant women with 73 suspected fetal craniofacial anomalies diagnosed by US underwent MRI. In 40 out of 73 anomalies (54.8%), US and MRI findings were in complete agreement with postnatal diagnoses. MRI correctly ruled out the diagnosis of 24 anomalies suspected on US and diagnosed four additional pathologies that were not demonstrated by US. Out of the 85 anomalies (suspected by imaging or confirmed postnatally), confident diagnosis could be made by MRI in 68 anomalies (80%), not diagnosed in 10 (11.8%), and over-diagnosed in seven (8.2%). By US, confident diagnosis could be made in 44 anomalies (51.8%), not diagnosed in 11 (12.9%), and over-diagnosed in 30 (35.3%). CONCLUSION: MRI is valuable in the antenatal evaluation of fetal craniofacial anomalies and may be useful as an adjunct to US in the prenatal work-up of craniofacial anomalies.

MECR Mutations Cause Childhood-Onset Dystonia and Optic Atrophy, a Mitochondrial Fatty Acid Synthesis Disorder.

Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS. All six mutations are extremely rare in the general population, segregate with the disease in the families, and are predicted to be deleterious. The nonsense c.855T>G (p.Tyr285∗), c.247_250del (p.Asn83Hisfs∗4), and splice site c.830+2_830+3insT mutations lead to C-terminal truncation variants of MECR. The missense c.695G>A (p.Gly232Glu), c.854A>G (p.Tyr285Cys), and c.772C>T (p.Arg258Trp) mutations involve conserved amino acid residues, are located within the cofactor binding domain, and are predicted by structural analysis to have a destabilizing effect. Yeast modeling and complementation studies validated the pathogenicity of the MECR mutations. Fibroblast cell lines from affected individuals displayed reduced levels of both MECR and lipoylated proteins as well as defective respiration. These results suggest that mutations in MECR cause a distinct human disorder of the mtFAS pathway. The observation of decreased lipoylation raises the possibility of a potential therapeutic strategy.

Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation.

Defects of the glycosylphosphatidylinositol (GPI) biosynthesis pathway constitute an emerging subgroup of congenital disorders of glycosylation with heterogeneous phenotypes. A mutation in the promoter of PIGM, resulting in a syndrome with portal vein thrombosis and persistent absence seizures, was previously described in three patients. We now report four additional patients in two unrelated families, with further clinical, biochemical and molecular delineation of this unique entity. We also describe the first prenatal diagnosis of PIGM deficiency, allowing characterization of the natural history of the disease from birth. The patients described herein expand the phenotypic spectrum of PIGM deficiency to include macrocephaly and infantile-onset cerebrovascular thrombotic events. Finally, we offer insights regarding targeted treatment of this rare disorder with sodium phenylbutyrate.

Disease duration in E200K familial Creutzfeldt-Jakob disease is correlated with clinical, radiological, and laboratory variables.

Previous studies have suggested that disease duration in Creutzfeldt-Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44-79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2-20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis.