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Background and Purpose: Neuronal ceroid lipofuscinoses are a group of neurodegenerative disorders. Recently, enzyme replacement therapy (ERT) was approved for neuronal ceroid lipofuscinosis type 2 (CLN2), a subtype of neuronal ceroid lipofuscinoses. The aim of this study was to quantify brain volume loss in CLN2 disease in patients on ERT in comparison with a natural history cohort using MRI., Materials and Methods: Nineteen (14 female, 5 male) patients with CLN2 disease at 1 UK center were studied using serial 3D T1-weighted MRI (follow-up time, 1-9 years). Brain segmentation was performed using FreeSurfer. Volume measurements for supratentorial gray and white matter, deep gray matter (basal ganglia/thalami), the lateral ventricles, and cerebellar gray and white matter were recorded. The volume change with time was analyzed using a linear mixed-effects model excluding scans before treatment onset. Comparison was made with a published natural history cohort of 12 patients (8 female, 4 male), which was re-analyzed using the same method., Results: Brain volume loss of all segmented brain regions was much slower in treated patients compared with the natural history cohort. For example, supratentorial gray matter volume in treated patients decreased by a mean of 3% (SD, 0.74%) ( P < .001) annually compared with an annual volume loss of a mean of 16.8% (SD, 1.5%) ( P < .001) in the natural history cohort., Conclusions: Our treatment cohort showed a significantly slower rate of brain parenchymal volume loss compared with a natural history cohort in several anatomic regions. Our results complement prior clinical data that found a positive response to ERT. We demonstrate that automated MRI volumetry is a sensitive tool to monitor treatment response in children with CLN2 disease., (© 2024 by American Journal of Neuroradiology.)

Background and Objectives: Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD)., Methods: This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ 2 /Fisher exact test for statistical analysis., Results: Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%])., Discussion: Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

Data on fetal MRI in L1 syndrome are scarce with relevant implications for parental counseling and surgical planning. We identified two fetal MR imaging patterns in 10 fetuses harboring L1CAM mutations: the first, observed in 9 fetuses was characterized by callosal anomalies, diencephalosynapsis, and a distinct brainstem malformation with diencephalic-mesencephalic junction dysplasia and brainstem kinking. Cerebellar vermis hypoplasia, aqueductal stenosis, obstructive hydrocephalus, and pontine hypoplasia were variably associated. The second pattern observed in one fetus was characterized by callosal dysgenesis, reduced white matter, and pontine hypoplasia. The identification of these features should alert clinicians to offer a prenatal L1CAM testing., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Galactosemia is a rare genetic condition caused by mutation of enzymes involved in galactose and glucose metabolism. The varying clinical spectrum reflects the genetic complexity of this entity manifesting as acute neonatal toxicity syndrome, requiring prompt diagnosis and treatment, to more insidious clinical scenarios as observed in the subacute and chronic presentations. The current literature predominantly focuses on the long-standing sequelae of this disease. The purpose of this multicenter clinical report comprising 17 patients with galactosemia is to highlight the MR imaging patterns encompassing the whole spectrum of galactosemia, emphasizing the 3 main clinical subtypes: 1) acute neonatal presentation, with predominant white matter edema; 2) subacute clinical onset with a new finding called the "double cap sign"; and 3) a chronic phase of the disease with heterogeneous imaging findings. The knowledge of these different patterns together with MR spectroscopy and the clinical presentation may help in prioritizing galactosemia over other neonatal metabolic diseases and prevent possible complications., (© 2021 by American Journal of Neuroradiology.)

This article is the first of a two-part series on intracranial calcification in childhood. Intracranial calcification can be either physiological or pathological. Physiological intracranial calcification is not an expected neuroimaging finding in the neonatal or infantile period but occurs, as children grow older, in the pineal gland, habenula, choroid plexus and occasionally the dura mater. Pathological intracranial calcification can be broadly divided into infectious, congenital, endocrine/metabolic, vascular and neoplastic. The main goals in Part 1 are to discuss the chief differences between physiological and pathological intracranial calcification, to discuss the histological characteristics of intracranial calcification and how intracranial calcification can be detected across neuroimaging modalities, to emphasize the importance of age at presentation and intracranial calcification location, and to propose a comprehensive neuroimaging approach toward the differential diagnosis of the causes of intracranial calcification. Finally, in Part 1 the authors discuss the most common causes of infectious intracranial calcification, especially in the neonatal period, and congenital causes of intracranial calcification. Various neuroimaging modalities have distinct utilities and sensitivities in the depiction of intracranial calcification. Age at presentation, intracranial calcification location, and associated neuroimaging findings are useful information to help narrow the differential diagnosis of intracranial calcification. Intracranial calcification can occur in isolation or in association with other neuroimaging features. Intracranial calcification in congenital infections has been associated with clastic changes, hydrocephalus, chorioretinitis, white matter abnormalities, skull changes and malformations of cortical development. Infections are common causes of intracranial calcification, especially neonatal TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus and herpes) infections.

Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term 'hypomyelination'., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 European Paediatric Neurology Society. All rights reserved.)

Background: More than half of pediatric tumors of central nervous system (CNS) primarily originate in the posterior fossa and are conventionally treated with radiation therapy (RT)., Objectives: The objective of this study was to establish whether corpus callosum volumes (CCV) and whole brain volumes (WBV) are correlated and to determine the impact of whole-brain lowvs high-dose RT on brain parenchymal volume loss as assessed using each technique., Material and Methods: Of the 30 identified children (6-12 years) with newly diagnosed posterior fossa tumors treated with cranial RT, including focal and whole-brain RT, suitable imaging was obtained for 23. Radiotherapy regimens were the following: no whole-brain RT (Group 1, n = 7), low-dose whole-brain RT (<30 Gy, Group 2, n = 9) and high-dose whole-brain RT (>30 Gy, Group 3, n = 7) in addition to focal boost. Magnetic resonance images (MRIs) were analyzed at baseline and follow-up (median 14 months). The CCVs were manually segmented on midline sagittal slice (n = 23), while WBVs were segmented semi-automatically using Freesurfer (n = 15). This was done twice (6-month interval) for all baseline CCV measurements and 5 randomly selected WBV measurements to establish measurement reproducibility. Correlations between CCV and WBV were investigated and percentage of children demonstrating reduction in CCV or WBV noted., Results: Correlation between baseline CCV and WBV was not significant (p = 0.37). Measurement reproducibility was from 6% to -9% for CCV and from 4.8% to -1.2% for WBV. Among the children studied, 30.4% (7/23) had >9% reduction in CCV at follow-up, while 33.3% (5/15) had >1.2% reduction in WBV. Five of 7 patients with CCV loss were not picked up by WBV measurements. Similarly, 3 of 5 patients with WBV loss were not picked up by CCV measurements., Conclusions: The CCV and the WBV are unrelated and may indicate different brain parenchymal losses following RT. Up to a third of posterior fossa tumors treated with RT have measurable CCV or WBV loss; incidence was equivalent in lowvs high-dose whole-brain RT.

EML1 encodes the protein Echinoderm microtubule-associated protein-like 1 or EMAP-1 that binds to the microtubule complex. Mutations in this gene resulting in complex brain malformations have only recently been published with limited clinical descriptions. We provide further clinical and imaging details on three previously published families, and describe two novel unrelated individuals with a homozygous partial EML1 deletion and a homozygous missense variant c.760G>A, p.(Val254Met), respectively. From review of the clinical and imaging data of eight individuals from five families with biallelic EML1 variants, a very consistent imaging phenotype emerges. The clinical syndrome is characterized by mainly neurological features including severe developmental delay, drug-resistant seizures and visual impairment. On brain imaging there is megalencephaly with a characteristic ribbon-like subcortical heterotopia combined with partial or complete callosal agenesis and an overlying polymicrogyria-like cortical malformation. Several of its features can be recognized on prenatal imaging especially the abnormaly formed lateral ventricles, hydrocephalus (in half of the cases) and suspicion of a neuronal migration disorder. In conclusion, biallelic EML1 disease-causing variants cause a highly specific pattern of congenital brain malformations, severe developmental delay, seizures and visual impairment., (© 2019 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals, Inc.)

Mutations causing dysfunction of the tubulins and microtubule-associated proteins, otherwise known as tubulinopathies, are a group of recently described entities, that lead to complex brain malformations. An understanding of the fundamental principles of operation of the cytoskeleton and compounds in particular microtubules, actin, and microtubule-associated proteins, can assist in the interpretation of the imaging findings of tubulinopathies. Somewhat consistent morphological imaging patterns have been described in tubulinopathies such as dysmorphic basal ganglia-the hallmark (found in 75% of cases), callosal dysgenesis, cerebellar hypoplasia/dysplasia, and cortical malformations, most notably lissencephaly. Recognizing the common imaging phenotypes present in tubulinopathies can prove invaluable in directing the genetic workup for a patient with brain malformations.

Background and Purpose: It has been hypothesized that skull marrow signal alteration may represent an early disease manifestation of Sturge-Weber syndrome before development of its intracranial manifestations. We alternatively hypothesized that intraosseous changes are associated with the overlying port-wine stain rather than the intracranial stigmata of Sturge-Weber syndrome and hence are not a predictor of brain involvement., Materials and Methods: MR imaging of children presenting with port-wine stain and/or Sturge-Weber syndrome between 1998 and 2017 was evaluated by 2 pediatric neuroradiologists for marrow signal abnormality and pial angioma and other Sturge-Weber syndrome features: ocular hemangioma, atrophy, and white matter changes (advanced myelination). Groups were divided into port-wine stain-only (without intracranial Sturge-Weber syndrome features) and Sturge-Weber syndrome (the presence of cerebral pial angioma). The χ 2 test was performed to evaluate the association between port-wine stain and bone marrow changes and between osseous change and pial angioma., Results: We reviewed 139 cases: 40 with port-wine stain-only and 99 with Sturge-Weber syndrome with pial angioma. Fifteen of 99 cases of Sturge-Weber syndrome had no port-wine stain. In the port-wine stain-only cohort, 78% had ipsilateral bony changes and 17% had no intraosseous changes. In the Sturge-Weber syndrome cohort, 84/99 had associated port-wine stain, 91% ( P < .01) had bony changes ipsilateral to the port-wine stain or had no bone changes in the absence of port-wine stain, and 77% ( P = .27) had bony changes ipsilateral to a cerebral pial angioma. Eighty percent of patients with Sturge-Weber syndrome who lacked a port-wine stain also lacked marrow changes. Five patients with bilateral port-wine stain and bilateral marrow changes had only a unilateral pial angioma., Conclusions: Intraosseous marrow changes are strongly associated with facial port-wine stain; no significant association was found between pial angioma and bone marrow changes., (© 2018 by American Journal of Neuroradiology.)

Macrocephaly is a relatively common clinical condition affecting up to 5% of the pediatric population. It is defined as an abnormally large head with an occipitofrontal circumference greater than 2 standard deviations above the mean for a given age and sex. Megalencephaly refers exclusively to brain overgrowth exceeding twice the standard deviation. Macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, whereas megalencephaly is more often syndromic. Megalencephaly can be divided into 2 subtypes: metabolic and developmental, caused by genetic defects in cellular metabolism and alterations in signaling pathways, respectively. Neuroimaging plays an important role in the evaluation of macrocephaly, especially in the metabolic subtype which may not be overtly apparent clinically. This article outlines the diverse etiologies of macrocephaly, delineates their clinical and radiographic features, and suggests a clinicoradiological algorithm for evaluation.

There is an extensive and diverse set of medical conditions affecting the neonatal brain within the spectrum of neurometabolic disorders. As such, their clinical presentations can be rather nonspecific, and can often mimic acquired entities such as hypoxic-ischemic encephalopathy and sepsis. Similarly, the radiological findings in these entities can also be frequently nonspecific, but a more detailed analysis of imaging findings (especially magnetic resonance imaging) alongside the relevant clinical details can be a rewarding experience, thus enabling a timely and targeted diagnosis. Early diagnosis of an underlying neurometabolic disorder is vital, as some of these entities are potentially treatable, and laboratory and genetic testing can be precisely targeted. Further, their detection helps with counselling families for future pregnancies. We present a review of neurometabolic disorders specific to the newborns with a focus on how neuroimaging findings match their clinical presentation patterns.

PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Familial spinal neurofibromatosis is a form of neurofibromatosis 1 (NF1), consisting of extensive, symmetrical, histologically proven, multiple neurofibromas of the spinal roots at every level and of all major peripheral nerves sometimes associated with typical NF1 stigmata; most cases underlie NF1 gene mutations., Objectives: The objectives of this study are (1) to report the findings in a set of 16-year-old monozygotic twin girls and a 14-year-old boy and (2) to review the existing literature., Methods and Results: In this article, we report the cases of three children who (1) had manifested mildly different symptomatic neuropathy (twins, aged 4 years; and a boy, aged 9 years) associated with massive, symmetrical neurofibromas; (2) had few café-au-lait spots with irregular margins and pale brown pigmentation; (3) were presented with, at brain magnetic resonance imaging (MRI), bilateral, NF1-like high-signal abnormalities in the basal ganglia; (4) yielded missense NF1 gene mutations in exon 39; and (5) had unaffected parents with negative NF1 genetic testing as well as discuss 12 families and 20 sporadic and 5 additional cases that presented spinal neurofibromatosis within classical NF1 families (53 cases) that were reported in the literature., Conclusions: This article presents the first report on (1) spinal neurofibromatosis in a set of affected monozygotic twins; (2) the earliest onset of the disease; and (3) the occurrence of high signal lesions in the brain at MRI., (Georg Thieme Verlag KG Stuttgart · New York.)