Rapid Progression and Early Mortality in Neonatal-Onset Alexander Disease: Association between Clinical Deterioration, Cranial Ultrasound and Magnetic Resonance Imaging

Rapid Progression and Early Mortality in Neonatal-Onset Alexander Disease: Association between Clinical Deterioration, Cranial Ultrasound and Magnetic Resonance Imaging | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Rapid Progression and Early Mortality in Neonatal-Onset Alexander Disease: Association between Clinical Deterioration, Cranial Ultrasound and Magnetic Resonance Imaging Simone Schwarz, Sylke J. Steggerda, Linda Simone Vries, Katharina Schulz, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6572580/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Alexander disease represents a rare genetic leukodystrophy caused by abnormal astrocytic accumulations of intracytoplasmic proteinaceous inclusions with astrocyte dysfunction. With neonatal onset, survival ranges from 1.5 months to more than 7.5 years, with a possible association between the underlying point mutation, the level of protein accumulation in the cerebral white matter, disease progression, and survival time. Results We describe the clinical and cerebral imaging features of a female newborn with neonatal-onset Alexander disease caused by a heterozygous de novo point mutation c.1106T>C; p.(Leu369Pro) located in the coil 2B area of the glial fibrillary acidic protein (GFAP). Early-onset seizures, lethargy, and rapid loss of spontaneous movements were accompanied by rapidly evolving brain morphologic abnormalities and early death. The progression of cerebral abnormalities was monitored by MR imaging and serial cranial ultrasound exams. Conclusions As shown in this case study and accompanied literature review, rapid accumulation of GFAP, as indicated by volume expansion of affected structures on brain imaging, combined with early onset of seizures, and rapid clinical deterioration seems to be associated with poor prognosis. In this case high-resolution ultrasound offered an easy accessible, serial bedside imaging tool for the detection and follow-up of pathognomonic features of Alexander disease. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Health sciences/Signs and symptoms Neonatal leukodystrophy Neonatal onset Alexander disease Cranial ultrasound White matter disease Neonatal seizures Figures Figure 1 Figure 2 Figure 3 Background Alexander Disease (AxD) is a very rare genetic leukodystrophy caused by dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) gene on chromosome 17q21 [1]. GFAP as the major intermediate filament of astrocytes is involved in the morphology and motility of astrocytes and in the interaction between astrocytes and oligodendrocytes [2]. Overexpression and reduced degeneration of GFAP along with upregulation of heat shock proteins cause accumulation of filaments in the cytoplasm of astrocytes, called "Rosenthal fibers", leading to astrocyte dysfunction [3, 4]. The spectrum of clinical manifestations of AxD and the severity of the disease are closely related to the age of onset [5]. Cases with neonatal manifestation are characterized by rapid onset and progression within the first month of life, leading to severe disability and death mostly within two years [6]. Frequent and intractable seizures occur as an early and obligatory symptom in combination with severe motor and cognitive impairment. Obstructive hydrocephalus due to aqueductal stenosis is caused by typical progressive volume increase of periaqueductal white matter accompanied by increased cerebrospinal fluid protein content [6]. In the neonatal period, disease progression manifests as progressive muscle hypotonia and loss of the ability to suck [7]. Cranial magnetic resonance (MR) imaging shows typical white matter abnormalities with frontal predominance, extensive periventricular enhancement, and involvement of the basal ganglia and cerebellum. To date, 21 cases of neonatal-onset AxD have been described, with survival ranging from 1.5 months to more than 7.5 years, making parental counseling complex [2, 3, 8, 9]. Some studies have suggested an association between genotype and disease severity, which may partially explain the variation of survival times [5, 9]. AxD, like other genetic white matter disorders, has pathognomonic MR imaging features that allow non-invasive diagnosis based on pattern recognition [10-12]. Even in the era of readily available genetic testing such as whole-exome sequencing, pattern recognition continues to play an important role in narrowing down possible diagnoses. The relevance of neuroimaging and the potential role of bedside ultrasound for diagnosis and prognostic prediction in neonatal onset AxD are evaluated in the present case study. Results Clinical report The girl was born at 39+1 weeks' gestation by uncomplicated vaginal delivery as the third child of non-consanguineous parents (weight 3.59 kg (50.-75. percentile), height 53 cm (75.-90. percentile), head circumference 35 cm (25.-50. percentile)). Pregnancy and family history were unremarkable. On her first day of life, she presented with muscular hypotonia and respiratory failure requiring admission to the local neonatal intensive care unit (NICU). Seizures began on DOL 2, on DOL 8 the girl was transferred to our NICU with suspected congenital infection. Symptoms progressed rapidly with loss of spontaneous movements and inability to suck. She became lethargic, hypothermic and bradypnoeic until she died at 8 weeks of age. During these 8 weeks, a continuous increase of the head circumference caused by an obstructive hydrocephalus was observed. Cerebrospinal fluid protein was elevated, but in-depth laboratory tests were unremarkable. The rapid clinical deterioration and morphologic imaging findings mimicked an inflammatory process, suggesting congenital infection as a potential and common cause. Metabolic and genetic diseases with leukoencephalopathy, especially mitochondrial diseases such as Leigh syndrome, were also considered. Cranial ultrasound The first abnormality on CUS was symmetrical increase of white matter echogenicity with frontal predominance and transition to the anterior corpus callosum and septum pellucidum/septal nuclei extending to basal forebrain structures and striatum (Figure 1a-e). More detailed examinations revealed midbrain involvement (Figure 1f). Rapid progression of imaging abnormalities was observed on serial CUS with increasing echogenicity and volume increase/swelling of the aforementioned structures, including the midbrain with occlusion of the aqueduct and development of internal hydrocephalus (Figure 2). MR imaging MR imaging showed typical signs of AxD with 5/5 criteria fulfilled + 1/10 additional criterion for the diagnosis of AxD on DOL 4 with rapid progression to 5/5 criteria + 4/10 additional criteria on DOL 12 (Figure 3, Table 1). Retrospective comparison of cranial ultrasound and MR imaging Evaluation of CUS imaging revealed typical signs of AxD with 4/5 criteria and 3/10 additional criteria for the diagnosis of AxD fulfilled on DOL 11 and 3/5 criteria and 5/10 additional criteria on DOL 32 with rapid progression of the extant of most abnormalities (Table 1). The agreement between MRI and ultrasound was almost perfect with Cohen's Kappa = 0.93 between the examinations on DOL 11/12 with less than 24 hours’ time difference between the two examinations. CUS was inferior to MR imaging for detailed assessment of brainstem and posterior fossa structures, resulting in inapplicable criteria for some imaging features (Table 1). In addition, no comparison could be made with MRI findings using gadolinium as a contrast agent because there is currently no comparable application for ultrasound. However, ultrasound revealed additional abnormalities in follow-up examinations that may also be helpful to characterize the pattern of affected cerebral structures (Figure 1+2, Table 2). Genetic testing A heterozygous, pathogenic de novo point mutation c.1106T>C; p.(Leu369Pro) located in the coil 2B area of GFAP was identified via trio whole exome sequencing from peripheral blood samples of the infant and her parents. This variant has been previously described in one patient with neonatal-onset AxD and early death (Table 3) [9]. No other clinically relevant variant could be identified, including analysis of mitochondrial DNA. Discussion This case study highlights the interplay between clinical presentation, imaging features and genetic testing for diagnosis and prognostication in rare neonatal diseases like genetic leukodystrophies. We present the first direct comparison between high-resolution CUS, the first-line imaging modality in neonates, and MR imaging, the established imaging method for diagnosing AxD, in neonatal onset AxD. Showing an almost perfect agreement between pattern recognition in MR imaging and ultrasound using the AxD criteria described by van der Knaap et al. [12] this case may help in pattern recognition using bedside CUS. Diagnosis of neonatal AxD can be made based on clinical symptoms and typical brain imaging findings and subsequently confirmed by genetics [12]. Prior to the availability of genetic diagnosis, MRI criteria established by von der Knaap et al. allowed the diagnosis of AxD without cranial biopsy [12]. The diagnosis is confirmed when 4 out of 5 main criteria are present with very limited data in neonatal onset AxD. In this case, a pediatric neuroradiologist aware of these criteria suggested the diagnosis, which was confirmed by whole exome sequencing. Cerebral pathologies in AxD are mainly caused by the accumulation of intracytoplasmic proteinaceous inclusions in astrocytes with varying degrees in different brain regions, causing pathologies first in areas with high GFAP content [13]. Like in the presented case neonatal onset AxD is characterized by expansion of the periaqueductal white matter leading to aqueductal stenosis and obstructive hydrocephalus, presumably caused by protein accumulation especially in these areas of the midbrain [3]. The increase in periaqueductal white matter volume detected on DOL 32 was associated with increased echogenicity on CUS with a very fine, homogeneous echo texture, similar to the previously observed frontal pathologies. Other affected structures exhibited progressive volume expansion with increasingly irregular morphology of the lateral and third ventricles, suggesting rapid accumulation of pathological intracytoplasmic proteins that correlated with rapid clinical deterioration. Several studies have reported a strong genotype-phenotype association in AxD [5, 9]. Especially in neonatal onset AxD mutations in the coil 2B domain seem to be linked to early death [9]. To date, only one other case with the same point mutation c.1106T>C; p.(Leu369Pro) in coil2B of the GFAP gene has been described [9]. The clinical course was identical, with progressive white matter lesions on cranial imaging, occlusive hydrocephalus due to aqueductal stenosis, rapid clinical deterioration and death at 6 weeks of age. Presumably, certain mutations like the point mutation c.1106T>C;p.(Leu369Pro) lead to particularly rapid accumulation of GFAP in astrocytes and thus to neonatal presentation. This is consistent with animal studies where mice with the highest GFAP expression died at 3-5 weeks due to early seizures characteristic for neonatal onset AxD [13]. Increasing echogenicity and volume expansion of the affected areas on CUS accompanied by clinical deterioration suggests that GFAP accumulation could possibly be monitored using high-resolution ultrasound. Modern high-resolution, high-end ultrasound equipment allows improved visualization of intracranial structures with high spatial and temporal resolution. In this study, the progression of morphological changes associated with protein deposition was monitored via point-of-care ultrasound and showed excellent intermodal agreement with MR imaging. Point-of-care CUS can be performed serially, is broadly available around the clock and does not require transport and/or sedation. As a relevant limitation, the brain stem and the posterior fossa can only be partially visualized and there is no equivalent to gadolinium contrast agent. Nonetheless, high-resolution ultrasound may be a cost-effective non-invasive bedside alternative to MRI for diagnosis and serial monitoring of white matter abnormalities. In low-income countries, imaging may be a target for even lower-cost genetic testing. In neonatal-onset AxD, integrating multimodal data from clinical assessments, imaging studies, and genetic analyses enables monitoring of disease progression, facilitating prognostication of life expectancy, which in turn informs treatment planning and parental counseling. Early prognostication could enable timely palliative care discussions with parents, avoid unnecessary invasive diagnostics and interventions and facilitate home discharge, allowing the family quality time together. Methods Design and study setting This retrospective case study conducted at Sana Hospital Duisburg aims to elaborate on the prognostic interplay of clinical parameters, cerebral imaging progression and the underlying mutation for outcome prediction in neonatal onset AxD. We collected clinical, genetic and longitudinal imaging findings, compared these data with other published cases and drew conclusions for outcome prediction. Cerebral imaging Cranial ultrasound (CUS) was performed serially using a high-end ultrasound device (GE Logiq E10s R3, GE Healthcare, Boston MA, USA) equipped with high-resolution mini-curved and linear transducers (GE C3-10-D, GE ML4-20-D), according to recommended standards , with the highest quality of the examination being obtained on day of life (DOL) 11 and 32. These images were retrospectively analyzed by two independent experts (LSDV, SJS) using the AxD MRI diagnostic criteria according to van der Knaap et al [11, 12]. MRI was performed on DOL 4 and 12, including T1- and T2-weighted images with and without gadolinium contrast, diffusion-weighted images, and susceptibility-weighted images. These images were also retrospectively analyzed by experienced neuroradiologists (KS, NRD) blinded to the CUS studies using the same AxD MRI diagnostic criteria by van der Knaap. Because the comparison of CUS on DOL 11 and MRI on DOL 12 yielded consistent results, further imaging progression was monitored with CUS. Statistical analysis Cohen's Kappa [15] was calculated to determine the agreement between MRI and CUS findings using Python 3.13 (Python Software Foundation, Beaverton, USA) in a Jupyter Lab environment (Version 4.3.4; Project Jupyter) [16]. Ratings categorized as "not applicable" were excluded from the analyses. This was determined when the corresponding structures could not be evaluated due to image quality or were not visible in the stored images. Ethics The infant's parents provided written informed consent for publication. Declarations Acknowledgments We would like to thank the parents for their permission to publish this case. Authors' contributions SS designed the study, carried out data retrieval, extracted literature, interpreted the results, wrote the initial draft, and created figures. LSDV and SJS scored the CUS images. KS and NRD scored the MR images. NB carried out statistical analyses, interpreted the results, and revised the initial draft. LSDV, MHL, FB, TR interpreted the patient imaging data regarding the initial diagnosis. JL carried out genetic analysis. All authors revised the initial draft, and read/approved the final manuscript. Availability of data and materials The datasets supporting the conclusions of this article are included within the article. Competing interests The authors declare that they have no competing interests related to this paper. Funding No funding was received for the study. References Vazquez E, Macaya A, Mayolas N et al. Neonatal Alexander disease: MR imaging prenatal diagnosis. AJNR Am J Neuroradiol 2008; 29: 1973-1975. DOI: 10.3174/ajnr.A1215 Paprocka J, Nowak M, Machnikowska-Sokolowska M et al. Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia-The Neonatal Type of Alexander Disease. Genes (Basel) 2024; 15. DOI: 10.3390/genes15030350 Takeuchi H, Higurashi N, Kawame H et al. GFAP variant p. Tyr366Cys demonstrated widespread brain cavitation in neonatal Alexander disease. Radiol Case Rep 2022; 17: 771-774. DOI: 10.1016/j.radcr.2021.11.066 Li R, Johnson AB, Salomons G et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 2005; 57: 310-326. DOI: 10.1002/ana.20406 Prust M, Wang J, Morizono H et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011; 77: 1287-1294. DOI: 10.1212/WNL.0b013e3182309f72 Springer S, Erlewein R, Naegele T et al. Alexander disease--classification revisited and isolation of a neonatal form. Neuropediatrics 2000; 31: 86-92. DOI: 10.1055/s-2000-7479 Singh N, Bixby C, Etienne D et al. Alexander's disease: reassessment of a neonatal form. Childs Nerv Syst 2012; 28: 2029-2031. DOI: 10.1007/s00381-012-1868-8 Mura E, Nicita F, Masnada S et al. Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients. Mol Genet Metab 2021; 134: 353-358. DOI: 10.1016/j.ymgme.2021.11.009 Knuutinen O, Kousi M, Suo-Palosaari M et al. Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases. Neuropediatrics 2018; 49: 256-261. DOI: 10.1055/s-0038-1649500 Oikarainen JH, Knuutinen OA, Kangas SM et al. Brain MRI findings in paediatric genetic disorders associated with white matter abnormalities. Dev Med Child Neurol 2024. DOI: 10.1111/dmcn.16036 van der Knaap MS, Salomons GS, Li R et al. Unusual variants of Alexander's disease. Ann Neurol 2005; 57: 327-338. DOI: 10.1002/ana.20381 van der Knaap MS, Naidu S, Breiter SN et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22: 541-552. Messing A, Brenner M, Feany MB et al. Alexander disease. J Neurosci 2012; 32: 5017-5023. DOI: 10.1523/JNEUROSCI.5384-11.2012 Tables Table 1: Criteria for AxD in MRI and CUS Criterion MRI DOL 4 MRI DOL 12 CUS DOL 11 CUS DOL 32 Citerion 1: WM abnormalities and frontal preponderance + ++ ++ +++ WM abnormalities + ++ ++ +++ Frontal predominance + ++ ++ ++ Involvement of periventr. WM + ++ ++ ++ Involvement of deep WM + ++ ++ +++ Involvement of subcortical WM - - - + Swelling of the abnormal WM - + + ++ Atrophy of the abnormal WM - - - - Cystic degeneration of the abnormal WM + + + - Citerion 2: Periventricular rim + ++ (+) - periventricular rim of low signal on T2 and high signal T1 + ++ (+) - rim of low echogenicity Criterion 3: basal ganglia and thalami + ++ ++ ++ Involvement of central nuclei + ++ ++ ++ Head of caudate nucleus + ++ ++ ++ Putamen + + + + Globus pallidus + + + + Thalamus - - + + Aspect of central nuclei abnormal abnormal abnormal abnormal Elevated signal on T2W images - - na na Elevated signal on T1W images + + na na Swelling + ++ ++ ++ Atrophy - - - + Criterion 4: brainstem lesions + ++ ++ +++ Brainstem lesions + ++ ++ +++ Midbrain + ++ ++ +++ Pons - - - + Medulla - + - - Nodular lesions with mass effect - - - - Brainstem atrophy - - - - Criterion 5: contrast enhancement + ++ na na Contrast enhancement + ++ na na Cerebral WM spots + ++ na na Ependymal lining + + na na Brainstem lesions + ++ na na Lesions middle cerebellar peduncles + - na na Dentate nucleus na - na na Chiasm + ++ na na Fornix + ++ na na Extra features Enlargement of lateral ventricles - + + ++ Involvment of cerebellar structures - - - (+) Flattened hemispheres Cerebellar hemispheric WM abnormalities - - na na Hilus of the dentate nucleus abnormalities + + na na Dentate nucleus - - na na Middle cerebellar peduncles - - na na Cerebellar swelling - - - - Cerebellar atrophy - - - + Thickened fornix na + (+) (++) Thickened septal grey nuclei/Septum pellucidum/fornix area Thickened chiasm na + (+) (++) Space-occupying lesion in the area of the optic chiasma between optic recess and infundubulum of the third ventricle CUS = cranial ultrasound, DOL = day of life, MRI = magnetic resonance imaging, na = not applicable, WM = white matter Table 2: Additional findings on cerebral ultrasound compared to MRI CUS findings CUS DOL 11 CUS DOL 32 Very fine, homogeneous echo texture of affected structures with increased echogenicity + ++ Volume expansion of affected structures including midbrain with compression of the aqueduct + ++ CUS = cranial ultrasound, DOL = day of life Table 3: Neonatal-onset AxD caused by mutation in the coil 2B area of GFAP Case study Knuutinen et al (9) Paprocka et al (2) Mura et al (8) Takeuchi et al (3) Li et al (4) Pat. 32 Pat. 33 Pat. 35 Pat. 36 cDNA mutation c.1106T>C c.1106T>C c.1187C>T c.1187C>T c.1097A>G c.1049_1050insCTTGCA c.1055T>C c.1090G>C c.1096T>C Protein mutation p.(Leu369Pro) p.(Leu369Pro) p.(Thr396Ile) p.(Thr396Ile) p.(Tyr366Cys) p.(Tyr349_Gln350insHisLeu) p.(Leu352Pro) p.(Ala364Pro) p.(Tyr366His) Protein structure Coil2B Coil2B Coil2B Coil2B Coil2B Coil2B Coil2B Coil2B Coil2B Age of onset 1. DOL 4. DOL 1. week 1. month ventriculomegaly at 36 weeks of gestation onset at 1 month of age 1. DOL 1. month 1. month First signs muscular hypotonia, respiratory failure drug-resistant seizures increasing apathy, severely limited spontaneous activity, lack of eye tracking na Hydrocephalus severe vomiting, intractable seizures feeding problems na na Seizures 2. DOL, drug resistent 4. DOL, drug resistent drug resistant seizures na 6 months drug resistent yes yes yes Progression rapid progression with seizures, adynamie, loss of spontaneous movements and inability to suck, makrocrania with hydrocephalus rapid progression with lethargy and prolonged seizures, makrocrania with hydrocephalus rapid progression, drug resistant seizures, makrocrania with hydrocephalus very severe rapidly evolving course with absence of postural acquisition, hydrocephalus psychomotor development significantly impaired, no neck control, no vocalization, lack of eye tracking, makrocrania with hydrocephalus devastating course, macrocephaly rapid progression macrocephaly na First MRI findings See table 1 WM loss and hydrocephalus, caused by aqueductal stenosis due to enlargement of the tectum, extensive signal abnormalities decreased T1 and increased T2 WM signals in both hemispheres with frontal domination, midbrain, cortico-spinal tracts, and enlarged basal ganglia with heterogeneous signals and enhancement, DWI with generalized abnormality and signal with increased diffusivity in the frontal white matter typical MRI features with prominent cerebral WM abnormalities with antero-posterior gradient and basal ganglia involvement narrow aqueductus cerebri, ventriculomegaly, abnormal WM signal intensity typical typical na typical Follow-up MRI See table 1 na 1-week follow-up generalized WM T2 hyperintensity with a low signal rim around ventricles, marked symmetrical perivascular spaces in internal capsules 4-month follow-up progression of abnormal, diffused, increased signal of WM with frontal domination, periventricular narrow bands of high T1 and low T2 signals, inhomogeneous signals from the basal nuclei with the most intense changes in the heads of the caudate nuclei, lenticular nuclei, and anteromedial parts of the thalamus, post-contrast enhancement of subcortical nuclei and along the cortico-spinal tracts hydrocephalus, early and rapid cystic degeneration 5-month follow-up hypomyelination and periventricular cavitation localized to the frontal area na na na na CUS findings See table 1 Hydrocephalus, increasing WM abnormalities enlarged supratentorial ventricular system na na na na na na Time point of death 8 weeks 6 weeks 4 month within second year Alive with 1 year of life 3.5 months 38 days 4 month with 1.5 years CUS = cranial ultrasound, DOL = day of life, MRI = magnetic resonance imaging, na = not applicable, WM = white matter Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6572580","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":452668727,"identity":"9b7c8460-55bf-4da9-bfdd-8d974098027a","order_by":0,"name":"Simone Schwarz","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYDACZhhDAkzaQDg8JGhJI0ILHEC0HCasRb6dO/FxQQWDPf/sHsPPFX/OAxnNDxjeVODWYnCYd7PxjDMMiTPunDGWPMNzG8g4ZsA45wweLcy826R52xgSDCRyN0g2SNxOYLiRABRsw+OwZpCWfwz2QC2bfzYYnLOXv5H+gRkoghscBmlpYGDcIJG7TbIh4QDjhhs5QFsaCPiF55hE4owb+d8sGw4kJ268kVNwcM4xPA7rP7vxMU+NjT3/jLTkmw1/7OzlbqRvfPCmBo/DIEAClXuAoIZRMApGwSgYBXgBAL2eTct4+SgkAAAAAElFTkSuQmCC","orcid":"","institution":"Sana Clinics Duisburg","correspondingAuthor":true,"prefix":"","firstName":"Simone","middleName":"","lastName":"Schwarz","suffix":""},{"id":452668728,"identity":"03378624-199f-4d8a-8055-61b03971b624","order_by":1,"name":"Sylke J. 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14:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6572580/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6572580/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83913307,"identity":"0055a7b9-c938-4401-a3b8-9a1f86f31ee3","added_by":"auto","created_at":"2025-06-04 12:19:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2339451,"visible":true,"origin":"","legend":"\u003cp\u003eCranial ultrasound on DOL 11\u003c/p\u003e\n\u003cp\u003eIncrease of white matter echogenicity with very fine, homogeneous echo texture (two asterisks) with frontal predominance (a-e), volume expansion of the fornix area (arrow) (b), the area of the optic chiasma between optic recess and infundubulum of the third ventricle (arrow head) (d), and midbrain involvement (asterisk) (f).\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-6572580/v1/ce35409686515bfb2ce39a45.png"},{"id":83913309,"identity":"31ef55ff-45fa-401f-93ed-46fe1903343a","added_by":"auto","created_at":"2025-06-04 12:19:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2396557,"visible":true,"origin":"","legend":"\u003cp\u003eCranial ultrasound on DOL 32\u003c/p\u003e\n\u003cp\u003eProgressive increase of white matter echogenicity with very fine, homogeneous echo texture (two asterisks) with frontal predominance (a-e), volume expansion of the fornix area (arrow) \u0026nbsp;(b), the area of the optic chiasma between optic recess and infundubulum of the third ventricle (arrow head) (d), and midbrain involvement (asterisk) (f) with obstructive hydrocephalus (a-f).\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-6572580/v1/85ce13afd0637da3d20d3988.png"},{"id":83913308,"identity":"25850871-b49c-49f7-a5f0-d7522c55e5e6","added_by":"auto","created_at":"2025-06-04 12:19:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1626698,"visible":true,"origin":"","legend":"\u003cp\u003eMR imaging on DOL 12\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003e T2W image with white matter abnormalities with frontal predominance (two asterisks), involvement of head of caudate nucleus (open arrow head), and thickened fornix (arrow). \u0026nbsp;\u003cstrong\u003eb\u003c/strong\u003e Contrast enhancement on T1W image with enhancement of frontal white matter, head of caudate nucleus and fornix. \u003cstrong\u003ec\u003c/strong\u003e Contrast enhancement on T1W subtraction image with enhancement of frontal white matter, head of caudate nucleus and fornix, and cerebral white matter spots. \u003cstrong\u003ed\u003c/strong\u003e Involvement of the midbrain with volume expansion (asterisk) on sagittal T2W image \u003cstrong\u003ee\u003c/strong\u003e Periventrikular rim of low signal (arrow heads) and involvement of the midbrain (asterisk) on T2W image. \u003cstrong\u003ef\u003c/strong\u003e Periventrikular rim of high signal on T1W image (arrow heads).\u003c/p\u003e","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-6572580/v1/85238153da11d4968404968e.png"},{"id":83914447,"identity":"c7ac61bf-c158-483e-b0aa-4496083e2b78","added_by":"auto","created_at":"2025-06-04 12:27:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7233941,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6572580/v1/55f88aec-555a-41c1-9a21-44245e0d47b8.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rapid Progression and Early Mortality in Neonatal-Onset Alexander Disease: Association between Clinical Deterioration, Cranial Ultrasound and Magnetic Resonance Imaging","fulltext":[{"header":"Background","content":"\u003cp\u003eAlexander Disease (AxD) is a very rare genetic leukodystrophy caused by dominant gain of function mutation in the glial fibrillary acidic protein (GFAP) gene on chromosome 17q21 [1]. GFAP as the major intermediate filament of astrocytes is involved in the morphology and motility of astrocytes and in the interaction between astrocytes and oligodendrocytes [2]. Overexpression and reduced degeneration of GFAP along with upregulation of heat shock proteins cause accumulation of filaments in the cytoplasm of astrocytes, called \u0026quot;Rosenthal fibers\u0026quot;, leading to astrocyte dysfunction [3, 4]. The spectrum of clinical manifestations of AxD and the severity of the disease are closely related to the age of onset [5].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCases with neonatal manifestation are characterized by rapid onset and progression within the first month of life, leading to severe disability and death mostly within two years [6]. Frequent and intractable seizures occur as an early and obligatory symptom in combination with severe motor and cognitive impairment. Obstructive hydrocephalus due to aqueductal stenosis is caused by typical progressive volume increase of periaqueductal white matter accompanied by increased cerebrospinal fluid protein content [6]. In the neonatal period, disease progression manifests as progressive muscle hypotonia and loss of the ability to suck [7]. Cranial magnetic resonance (MR) imaging shows typical white matter abnormalities with frontal predominance, extensive periventricular enhancement, and involvement of the basal ganglia and cerebellum. To date, 21 cases of neonatal-onset AxD have been described, with survival ranging from 1.5 months to more than 7.5 years, making parental counseling complex [2, 3, 8, 9]. Some studies have suggested an association between genotype and disease severity, which may partially explain the variation of survival times [5, 9].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAxD, like other genetic white matter disorders, has pathognomonic MR imaging features that allow non-invasive diagnosis based on pattern recognition [10-12]. Even in the era of readily available genetic testing such as whole-exome sequencing, pattern recognition continues to play an important role in narrowing down possible diagnoses. The relevance of neuroimaging and the potential role of bedside ultrasound for diagnosis and prognostic prediction in neonatal onset AxD are evaluated in the present case study.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical report\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe girl was born at 39+1 weeks' gestation by uncomplicated vaginal delivery as the third child of non-consanguineous parents (weight 3.59 kg (50.-75. percentile), height 53 cm (75.-90. percentile), head circumference 35 cm (25.-50. percentile)). Pregnancy and family history were unremarkable. On her first day of life, she presented with muscular hypotonia and respiratory failure requiring admission to the local neonatal intensive care unit (NICU). Seizures began on DOL 2, on DOL 8 the girl was transferred to our NICU with suspected congenital infection. Symptoms progressed rapidly with loss of spontaneous movements and inability to suck. She became lethargic, hypothermic and bradypnoeic until she died at 8 weeks of age. During these 8 weeks, a continuous increase of the head circumference caused by an obstructive hydrocephalus was observed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCerebrospinal fluid protein was elevated, but in-depth laboratory tests were unremarkable. The rapid clinical deterioration and morphologic imaging findings mimicked an inflammatory process, suggesting congenital infection as a potential and common cause. Metabolic and genetic diseases with leukoencephalopathy, especially mitochondrial diseases such as Leigh syndrome, were also considered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCranial ultrasound\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe first abnormality on CUS was symmetrical increase of white matter echogenicity with frontal predominance and transition to the anterior corpus callosum and septum pellucidum/septal nuclei extending to basal forebrain structures and striatum (Figure 1a-e). More detailed examinations revealed midbrain involvement (Figure 1f). Rapid progression of imaging abnormalities was observed on serial CUS with increasing echogenicity and volume increase/swelling of the aforementioned structures, including the midbrain with occlusion of the aqueduct and development of internal hydrocephalus (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMR imaging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMR imaging showed typical signs of AxD with 5/5 criteria fulfilled + 1/10 additional criterion for the diagnosis of AxD on DOL 4 with rapid progression to 5/5 criteria + 4/10 additional criteria on DOL 12 (Figure 3, Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRetrospective comparison of cranial ultrasound and MR imaging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvaluation of CUS imaging revealed typical signs of AxD with 4/5 criteria and 3/10 additional criteria for the diagnosis of AxD fulfilled on DOL 11 and 3/5 criteria and 5/10 additional criteria on DOL 32 with rapid progression of the extant of most abnormalities (Table 1). The agreement between MRI and ultrasound was almost perfect with Cohen's Kappa = 0.93 between the examinations on DOL 11/12 with less than 24 hours’ time difference between the two examinations. CUS was inferior to MR imaging for detailed assessment of brainstem and posterior fossa structures, resulting in inapplicable criteria for some imaging features (Table 1). In addition, no comparison could be made with MRI findings using gadolinium as a contrast agent because there is currently no comparable application for ultrasound. However, ultrasound revealed additional abnormalities in follow-up examinations that may also be helpful to characterize the pattern of affected cerebral structures (Figure 1+2, Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic testing\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA heterozygous, pathogenic \u003cem\u003ede novo\u003c/em\u003e point mutation c.1106T\u0026gt;C; p.(Leu369Pro) located in the coil 2B area of GFAP was identified via trio whole exome sequencing from peripheral blood samples of the infant and her parents. This variant has been previously described in one patient with neonatal-onset AxD and early death (Table 3) [9]. No other clinically relevant variant could be identified, including analysis of mitochondrial DNA.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case study highlights the interplay between clinical presentation, imaging features and genetic testing for diagnosis and prognostication in rare neonatal diseases like genetic leukodystrophies. We present the first direct comparison between high-resolution CUS, the first-line imaging modality in neonates, and MR imaging, the established imaging method for diagnosing AxD, in neonatal onset AxD. Showing an almost perfect agreement between pattern recognition in MR imaging and ultrasound using the AxD criteria described by van der Knaap et al. [12] this case may help in pattern recognition using bedside CUS.\u003c/p\u003e\n\u003cp\u003eDiagnosis of neonatal AxD can be made based on clinical symptoms and typical brain imaging findings and subsequently confirmed by genetics \u0026nbsp;[12]. Prior to the availability of genetic diagnosis, MRI criteria established by von der Knaap et al. allowed the diagnosis of AxD without cranial biopsy [12]. The diagnosis is confirmed when 4 out of 5 main criteria are present with very limited data in neonatal onset AxD. In this case, a pediatric neuroradiologist aware of these criteria suggested the diagnosis, which was confirmed by whole exome sequencing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCerebral pathologies in AxD are mainly caused by the accumulation of intracytoplasmic proteinaceous inclusions in astrocytes with varying degrees in different brain regions, causing pathologies first in areas with high GFAP content [13]. Like in the presented case neonatal onset AxD is characterized by expansion of the periaqueductal white matter leading to aqueductal stenosis and obstructive hydrocephalus, presumably caused by protein accumulation especially in these areas of the midbrain [3]. The increase in periaqueductal white matter volume detected on DOL 32 was associated with increased echogenicity on CUS with a very fine, homogeneous echo texture, similar to the previously observed frontal pathologies. Other affected structures exhibited progressive volume expansion with increasingly irregular morphology of the lateral and third ventricles, suggesting rapid accumulation of pathological intracytoplasmic proteins that correlated with rapid clinical deterioration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSeveral studies have reported a strong genotype-phenotype association in AxD [5, 9]. Especially in neonatal onset AxD mutations in the coil 2B domain seem to be linked to early death [9]. To date, only one other case with the same point mutation c.1106T\u0026gt;C; p.(Leu369Pro) in coil2B of the GFAP gene has been described [9]. The clinical course was identical, with progressive white matter lesions on cranial imaging, occlusive hydrocephalus due to aqueductal stenosis, rapid clinical deterioration and death at 6 weeks of age.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePresumably, certain mutations like the point mutation c.1106T\u0026gt;C;p.(Leu369Pro) lead to particularly rapid accumulation of GFAP in astrocytes and thus to neonatal presentation. This is consistent with animal studies where mice with the highest GFAP expression died at 3-5 weeks due to early seizures characteristic for neonatal onset AxD [13]. Increasing echogenicity and volume expansion of the affected areas on CUS accompanied by clinical deterioration suggests that GFAP accumulation could possibly be monitored using high-resolution ultrasound.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eModern high-resolution, high-end ultrasound equipment allows improved visualization of intracranial structures with high spatial and temporal resolution. In this study, the progression of morphological changes associated with protein deposition was monitored via point-of-care ultrasound and showed excellent intermodal agreement with MR imaging. Point-of-care CUS can be performed serially, is broadly available around the clock and does not require transport and/or sedation. As a relevant limitation, the brain stem and the posterior fossa can only be partially visualized and there is no equivalent to gadolinium contrast agent. Nonetheless, high-resolution ultrasound may be a cost-effective non-invasive bedside alternative to MRI for diagnosis and serial monitoring of white matter abnormalities. In low-income countries, imaging may be a target for even lower-cost genetic testing.\u003c/p\u003e\n\u003cp\u003eIn neonatal-onset AxD, integrating multimodal data from clinical assessments, imaging studies, and genetic analyses enables monitoring of disease progression, facilitating prognostication of life expectancy, which in turn informs treatment planning and parental counseling. Early prognostication could enable timely palliative care discussions with parents, avoid unnecessary invasive diagnostics and interventions and facilitate home discharge, allowing the family quality time together.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eDesign and study setting\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective case study conducted at Sana Hospital Duisburg aims to elaborate on the prognostic interplay of clinical parameters, cerebral imaging progression and the underlying mutation\u0026nbsp;for outcome prediction in neonatal onset AxD. We collected clinical, genetic and longitudinal imaging findings, compared these data with other published cases and drew conclusions for outcome prediction.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCerebral imaging\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCranial ultrasound (CUS) was performed serially using a high-end ultrasound device (GE Logiq E10s R3, GE Healthcare, Boston MA, USA) equipped with high-resolution mini-curved and linear transducers (GE C3-10-D, GE ML4-20-D), according to recommended standards , with the highest quality of the examination being obtained on day of life (DOL) 11 and 32. These images were retrospectively analyzed by two independent experts (LSDV, SJS) using the AxD MRI diagnostic criteria according to van der Knaap et al [11, 12].\u003c/p\u003e\n\u003cp\u003eMRI was performed on DOL 4 and 12, including T1- and T2-weighted images with and without gadolinium contrast, diffusion-weighted images, and susceptibility-weighted images. These images were also retrospectively analyzed by experienced neuroradiologists (KS, NRD) blinded to the CUS studies using the same AxD MRI diagnostic criteria by van der Knaap.\u003c/p\u003e\n\u003cp\u003eBecause the comparison of CUS on DOL 11 and MRI on DOL 12 yielded consistent results, further imaging progression was monitored with CUS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCohen's Kappa [15] was calculated to determine the agreement between MRI and CUS findings using Python 3.13 (Python Software Foundation, Beaverton, USA) in a Jupyter Lab environment (Version 4.3.4; Project Jupyter) [16]. Ratings categorized as \"not applicable\" were excluded from the analyses. This was determined when the corresponding structures could not be evaluated due to image quality or were not visible in the stored images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe infant's parents provided written informed consent for publication.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the parents for their permission to publish this case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSS designed the study, carried out data retrieval, extracted literature, interpreted the results, wrote the initial draft, and created figures. LSDV and SJS scored the CUS images. KS and NRD scored the MR images. NB carried out statistical analyses, interpreted the results, and revised the initial draft. LSDV, MHL, FB, TR interpreted the patient imaging data regarding the initial diagnosis. JL carried out genetic analysis. All authors revised the initial draft, and read/approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets supporting the conclusions of this article are included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests related to this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVazquez E, Macaya A, Mayolas N et al. Neonatal Alexander disease: MR imaging prenatal diagnosis. AJNR Am J Neuroradiol 2008; 29: 1973-1975. DOI: 10.3174/ajnr.A1215\u003c/li\u003e\n\u003cli\u003ePaprocka J, Nowak M, Machnikowska-Sokolowska M et al. Leukodystrophy with Macrocephaly, Refractory Epilepsy, and Severe Hyponatremia-The Neonatal Type of Alexander Disease. Genes (Basel) 2024; 15. DOI: 10.3390/genes15030350\u003c/li\u003e\n\u003cli\u003eTakeuchi H, Higurashi N, Kawame H et al. GFAP variant p. Tyr366Cys demonstrated widespread brain cavitation in neonatal Alexander disease. Radiol Case Rep 2022; 17: 771-774. DOI: 10.1016/j.radcr.2021.11.066\u003c/li\u003e\n\u003cli\u003eLi R, Johnson AB, Salomons G et al. Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 2005; 57: 310-326. DOI: 10.1002/ana.20406\u003c/li\u003e\n\u003cli\u003ePrust M, Wang J, Morizono H et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology 2011; 77: 1287-1294. DOI: 10.1212/WNL.0b013e3182309f72\u003c/li\u003e\n\u003cli\u003eSpringer S, Erlewein R, Naegele T et al. Alexander disease--classification revisited and isolation of a neonatal form. Neuropediatrics 2000; 31: 86-92. DOI: 10.1055/s-2000-7479\u003c/li\u003e\n\u003cli\u003eSingh N, Bixby C, Etienne D et al. Alexander\u0026apos;s disease: reassessment of a neonatal form. Childs Nerv Syst 2012; 28: 2029-2031. DOI: 10.1007/s00381-012-1868-8\u003c/li\u003e\n\u003cli\u003eMura E, Nicita F, Masnada S et al. Alexander disease evolution over time: data from an Italian cohort of pediatric-onset patients. Mol Genet Metab 2021; 134: 353-358. DOI: 10.1016/j.ymgme.2021.11.009\u003c/li\u003e\n\u003cli\u003eKnuutinen O, Kousi M, Suo-Palosaari M et al. Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases. Neuropediatrics 2018; 49: 256-261. DOI: 10.1055/s-0038-1649500\u003c/li\u003e\n\u003cli\u003eOikarainen JH, Knuutinen OA, Kangas SM et al. Brain MRI findings in paediatric genetic disorders associated with white matter abnormalities. Dev Med Child Neurol 2024. DOI: 10.1111/dmcn.16036\u003c/li\u003e\n\u003cli\u003evan der Knaap MS, Salomons GS, Li R et al. Unusual variants of Alexander\u0026apos;s disease. Ann Neurol 2005; 57: 327-338. DOI: 10.1002/ana.20381\u003c/li\u003e\n\u003cli\u003evan der Knaap MS, Naidu S, Breiter SN et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22: 541-552.\u003c/li\u003e\n\u003cli\u003eMessing A, Brenner M, Feany MB et al. Alexander disease. J Neurosci 2012; 32: 5017-5023. DOI: 10.1523/JNEUROSCI.5384-11.2012\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1:\u0026nbsp;\u003c/strong\u003eCriteria for AxD in MRI and CUS\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCriterion\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRI DOL 4\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMRI DOL 12\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCUS DOL 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCUS DOL 32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCiterion 1: WM abnormalities and frontal preponderance\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eWM abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eFrontal predominance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eInvolvement of periventr. WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eInvolvement of deep WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eInvolvement of subcortical WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eSwelling of the abnormal WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eAtrophy of the abnormal WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eCystic degeneration of the abnormal WM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCiterion \u0026nbsp;2: Periventricular rim\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(+)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eperiventricular rim of low signal on T2 and high signal T1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e(+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003erim of low echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCriterion 3: basal ganglia and thalami\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eInvolvement of central nuclei\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eHead of caudate nucleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003ePutamen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eGlobus pallidus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eThalamus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eAspect of central nuclei\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eabnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eabnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eabnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eabnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eElevated signal on T2W images\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eElevated signal on T1W images\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eSwelling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eAtrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCriterion 4: brainstem lesions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eBrainstem lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eMidbrain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003ePons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eMedulla\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eNodular lesions with mass effect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eBrainstem atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCriterion 5: contrast enhancement\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e++\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ena\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ena\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eContrast enhancement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eCerebral WM spots\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eEpendymal lining\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eBrainstem lesions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eLesions middle cerebellar peduncles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eDentate nucleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eChiasm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eFornix\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eExtra features\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eEnlargement of lateral ventricles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eInvolvment of cerebellar structures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e(+)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003eFlattened hemispheres\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eCerebellar hemispheric WM abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eHilus of the dentate nucleus abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eDentate nucleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eMiddle cerebellar peduncles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eCerebellar swelling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eCerebellar atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eThickened fornix\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e(+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e(++)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eThickened septal grey nuclei/Septum pellucidum/fornix area\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003eThickened chiasm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e(+)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e(++)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 215px;\"\u003e\n \u003cp\u003eSpace-occupying lesion in the area of the optic chiasma between optic recess and infundubulum of the third ventricle\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCUS = cranial ultrasound, DOL = day of life, MRI = magnetic resonance imaging, na = not applicable, WM = white matter\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2:\u0026nbsp;\u003c/strong\u003eAdditional findings on cerebral ultrasound compared to MRI\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCUS findings\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCUS DOL 11\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCUS DOL 32\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eVery fine, homogeneous echo texture of affected structures with increased echogenicity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 366px;\"\u003e\n \u003cp\u003eVolume expansion of affected structures including midbrain with compression of the aqueduct\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e++\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCUS = cranial ultrasound, DOL = day of life\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTable 3:\u003c/strong\u003e Neonatal-onset AxD caused by mutation in the coil 2B area of GFAP\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"989\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eCase study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eKnuutinen et al (9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003ePaprocka et al (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eMura et al (8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eTakeuchi et al (3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 355px;\"\u003e\n \u003cp\u003eLi et al (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ePat. 32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ePat. 33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ePat. 35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ePat. 36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003ecDNA\u003c/p\u003e\n \u003cp\u003emutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ec.1106T\u0026gt;C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ec.1106T\u0026gt;C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003ec.1187C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ec.1187C\u0026gt;T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ec.1097A\u0026gt;G\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ec.1049_1050insCTTGCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ec.1055T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ec.1090G\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ec.1096T\u0026gt;C\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003cp\u003emutation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ep.(Leu369Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003ep.(Leu369Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003ep.(Thr396Ile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ep.(Thr396Ile)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ep.(Tyr366Cys)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ep.(Tyr349_Gln350insHisLeu)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ep.(Leu352Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ep.(Ala364Pro)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ep.(Tyr366His)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eProtein structure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eCoil2B\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eAge of onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e1. DOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4. DOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e1. week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e1. month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eventriculomegaly at 36 weeks of gestation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eonset at 1 month of age\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1. DOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e1. month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003e1. month\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eFirst signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003emuscular hypotonia,\u003c/p\u003e\n \u003cp\u003erespiratory failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003edrug-resistant seizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eincreasing apathy, severely limited spontaneous activity, lack of eye tracking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eHydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003esevere vomiting,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eintractable seizures\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003efeeding problems\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eSeizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2. DOL, drug resistent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e4. DOL, drug resistent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003edrug resistant seizures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003edrug resistent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003erapid progression with seizures, adynamie, loss of spontaneous movements and inability to suck,\u003c/p\u003e\n \u003cp\u003emakrocrania with hydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003erapid progression with lethargy and prolonged\u003c/p\u003e\n \u003cp\u003eseizures, makrocrania with hydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003erapid progression, drug resistant seizures, makrocrania with hydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003every severe rapidly evolving course with absence of postural acquisition, hydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003epsychomotor development significantly impaired, no neck control, no vocalization, lack of eye tracking, makrocrania with hydrocephalus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003edevastating\u003c/p\u003e\n \u003cp\u003ecourse, macrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003erapid progression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003emacrocephaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eFirst MRI findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eSee table 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eWM loss and hydrocephalus, caused by aqueductal\u003c/p\u003e\n \u003cp\u003estenosis due to enlargement of the tectum,\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eextensive signal abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003edecreased T1 and increased\u003c/p\u003e\n \u003cp\u003eT2 WM signals in both hemispheres with frontal domination, midbrain,\u003c/p\u003e\n \u003cp\u003ecortico-spinal tracts, and enlarged basal ganglia with heterogeneous signals and enhancement, DWI with generalized abnormality and\u0026nbsp;\u003c/p\u003e\n \u003cp\u003esignal with increased diffusivity in the frontal white matter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003etypical MRI features with prominent cerebral WM abnormalities with antero-posterior gradient and basal ganglia involvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003enarrow aqueductus cerebri, ventriculomegaly, abnormal WM signal intensity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003etypical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003etypical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003etypical\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eFollow-up MRI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eSee table 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e\u003cu\u003e1-week follow-up\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003egeneralized WM T2\u003c/p\u003e\n \u003cp\u003ehyperintensity with a low signal rim around ventricles, marked symmetrical perivascular spaces in\u003c/p\u003e\n \u003cp\u003einternal capsules\u003c/p\u003e\n \u003cp\u003e\u003cu\u003e4-month follow-up\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003eprogression of abnormal, diffused, increased\u003c/p\u003e\n \u003cp\u003esignal of WM with frontal domination, periventricular narrow bands of high T1 and low T2 signals, inhomogeneous signals from the basal nuclei with the most intense changes in the heads of the caudate nuclei, lenticular nuclei, and anteromedial parts of the thalamus, post-contrast enhancement of subcortical nuclei and along the cortico-spinal tracts\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ehydrocephalus, early and rapid cystic degeneration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cu\u003e5-month follow-up\u003c/u\u003e\u003c/p\u003e\n \u003cp\u003ehypomyelination and periventricular cavitation localized to the frontal area\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eCUS findings\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003eSee table 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eHydrocephalus, increasing WM abnormalities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003eenlarged supratentorial ventricular system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ena\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eTime point of death\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e8 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e6 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 126px;\"\u003e\n \u003cp\u003e4 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003ewithin second year\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eAlive with 1 year of life\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3.5 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e38 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e4 month\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 81px;\"\u003e\n \u003cp\u003ewith 1.5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCUS = cranial ultrasound, DOL = day of life, MRI = magnetic resonance imaging, na = not applicable, WM = white matter\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neonatal leukodystrophy, Neonatal onset Alexander disease, Cranial ultrasound, White matter disease, Neonatal seizures","lastPublishedDoi":"10.21203/rs.3.rs-6572580/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6572580/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlexander disease represents a rare genetic leukodystrophy caused by abnormal astrocytic accumulations of intracytoplasmic proteinaceous inclusions with astrocyte dysfunction. With neonatal onset, survival ranges from 1.5 months to more than 7.5 years, with a possible association between the underlying point mutation, the level of protein accumulation in the cerebral white matter, disease progression, and survival time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe describe the clinical and cerebral imaging features of a female newborn with neonatal-onset Alexander disease caused by a heterozygous de novo point mutation c.1106T\u0026gt;C; p.(Leu369Pro) located in the coil 2B area of the glial fibrillary acidic protein (GFAP). Early-onset seizures, lethargy, and rapid loss of spontaneous movements were accompanied by rapidly evolving brain morphologic abnormalities and early death. The progression of cerebral abnormalities was monitored by MR imaging and serial cranial ultrasound exams.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs shown in this case study and accompanied literature review, rapid accumulation of GFAP, as indicated by volume expansion of affected structures on brain imaging, combined with early onset of seizures, and rapid clinical deterioration seems to be associated with poor prognosis. In this case high-resolution ultrasound offered an easy accessible, serial bedside imaging tool for the detection and follow-up of pathognomonic features of Alexander disease.\u003c/p\u003e","manuscriptTitle":"Rapid Progression and Early Mortality in Neonatal-Onset Alexander Disease: Association between Clinical Deterioration, Cranial Ultrasound and Magnetic Resonance Imaging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-04 12:19:05","doi":"10.21203/rs.3.rs-6572580/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"97b31ced-2bc8-4414-b0dc-abc465c51bbc","owner":[],"postedDate":"June 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48140390,"name":"Health sciences/Diseases"},{"id":48140391,"name":"Health sciences/Medical research"},{"id":48140392,"name":"Health sciences/Neurology"},{"id":48140393,"name":"Health sciences/Signs and symptoms"}],"tags":[],"updatedAt":"2025-06-04T12:19:06+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-04 12:19:05","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6572580","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6572580","identity":"rs-6572580","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}