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This report presents a case of Alexander disease showing clinical characteristics mimicking progressive supranuclear palsy (PSP). A 67-year-old woman complaining of motor disturbance exhibited severe atrophy of medulla, spinal cord, and midbrain tegmentum, as well as periventricular hyperintensity on cerebral MRI. Genetic analysis identified a novel in-frame deletion/insertion mutation in the exon 3 of the GFAP gene. Interestingly, neurological findings and decreased striatal uptake in dopamine transporter SPECT were suggestive of PSP. A novel GFAP gene mutation found in the present case may cause the unique clinical phenotype, which should be differentiated from PSP., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Objectives: Alexander disease (AxD) is a rare progressive leukodystrophy caused by autosomal dominant mutations in the Glial Fibrillary Acidic Protein (GFAP) gene. Three main disease classifications are currently in use, the traditional one defined by the age of onset, and two other based on clinical features at onset and brain MRI findings. Recently, we proposed a new classification, which is based on taking into consideration not only the presenting features, but also data related to the clinical course. In this study, we tried to apply this modified classification system to the cases of pediatric-onset AxD described in literature., Methods: A literature review was conducted in PubMed for articles published between 1949 to date. Articles that reported no patient's medical history and the articles about Adult-onset AxD were excluded. We included patients with a confirmed diagnosis of pediatric-onset AxD and of whom information about age and symptoms at onset, developmental milestones and loss of motor and language skills was available., Results: Clinical data from 205 patients affected with pediatric-onset AxD were retrospectively reviewed. Among these, we identified 65 patients, of whom we had enough information about the clinical course and developmental milestones, and we assessed their disease evolutionary trajectories over time., Discussion: Our results confirm that patients with Type I AxD might be classified into four subgroups (Ia, Ib, Ic, Id) basing on follow up data. In fact, despite the great variability of phenotypes in AxD, there are some shared trajectories of the disease evolution over time., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Alexander disease (AxD) is a rare leukodystrophy with an autosomal dominant inheritance mode. Variants in GFAP lead to this disorder and it is classified into three distinguishable subgroups: infantile, juvenile, and adult-onset types., Objective: The aim of this study is to report a novel variant causing AxD and collect all the associated variants with juvenile and adult-onset as well., Methods: We report a 2-year-old female with infantile AxD. All relevant clinical and genetic data were evaluated. Search strategy for all AxD types was performed on PubMed. The extracted data include total recruited patients, number of patients carrying a GFAP variant, nucleotide and protein change, zygosity and all the clinical symptoms., Results: A novel de novo variant c.217A > G: p. Met73Val was found in our case by whole-exome sequencing. In silico analysis categorized this variant as pathogenic. Totally 377 patients clinically diagnosed with juvenile or adult-onset forms were recruited in these articles, among them 212 patients were affected with juvenile or adult-onset form carrier of an alteration in GFAP. A total of 98 variants were collected. Among these variants c.262C > T 11/212 (5.18%), c.1246C > T 9/212 (4.24%), c.827G > T 8/212 (3.77%), c.232G > A 6/212 (2.83%) account for the majority of reported variants., Conclusion: This study highlighted the role of genetic in AxD diagnosing. It also helps to provide more information in order to expand the genetic spectrum of Iranian patients with AxD. Our literature review is beneficial in defining a better genotype-phenotype correlation of AxD disorder., (© 2022. The Author(s).)

Alexander disease (AxD) is a neurodegenerative astrogliopathy caused by mutation in the glial fibrillary acidic protein (GFAP) gene. A 42-year-old Korean man presented with temporary gait disturbance and psychiatric regression after a minor head trauma in the absence of bulbar symptoms and signs. Magnetic resonance images of the brain and spinal cord showed significant atrophy of the medulla oblongata and the entire spinal cord as well as contrast-enhanced T2 hypointensity in the basal ganglia. DNA sequencing revealed a novel 33-bp in-frame deletion mutation (p.Glu138_Leu148del) within the 1B rod domain of GFAP, which was predicted to be deleterious by PROVEAN analysis. To test whether the deletion mutant is disease-causing, we performed in vitro GFAP assembly and sedimentation assays, and GFAP aggregation assays in human adrenal carcinoma SW13 (Vim - ) cells and rat primary astrocytes. All the assays revealed that GFAP p.Glu138_Leu148del is aggregation prone. Based on these findings, we diagnosed the patient with Type II AxD. This is a report that demonstrates the pathogenicity of InDel mutation of GFAP through functional studies. This patient's atypical presentation as well as the discrepancy between clinical symptoms and radiologic findings may extend the scope of AxD., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

Alexander disease (AxD) is a rare, autosomal dominant genetic disorder with an incidence of approximately 1 in 27,00.000. It is caused by a missense mutation in the GFAP gene encoding the glial fibrillary acidic protein. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an X-linked dominant genetic disease, usually caused by a pre-mutation: an unmethylated expansion in the range of 50-200 CGG repeats in the fragile X mental retardation 1 (FMR1) gene. The clinical manifestations of these two diseases are complex and have some similarities. Both type II AxD and FXTAS may have ataxia as the first symptom. Here, we describe a case of type II AxD with ataxia as the first symptom accompanying a hemizygous mutation in the FMR1 gene (NM_001185081, exon13, c 0.1256C>T, p.T419M, g 0.147026507C>T). A sporadic genetic mutation led us to misdiagnose the patient with FXTAS initially. Whole-genome sequencing confirmed a heterozygous mutation in the GFAP gene (NM_002055.5, exon4, c 0.1158C>A, p.N386K, g 0.6310C>A). This report indicates that when the patient's clinical manifestation is ataxia, and imaging results suggest that the midbrain, medulla oblongata, and other subcerebellar structures are atrophied, AxD should be considered. Whole-genome sequencing is thus feasible to avoid missed diagnoses and misdiagnoses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent-offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.

A 50-year-old woman developed gait disturbances and dysarthria since the past 2 years. She also presented with dystonia and hypokinesia of her left lower limb, and orthostatic hypotension. The dopamine transporter SPECT with 123 I ioflupane showed abnormal scans in bilateral striatum. Cerebral MRI revealed atrophy and signal changes in the medulla and spinal cord, from which Alexander disease (AxD) was suspected. Consequently, we checked the Glial fibrillary acidic protein (GFAP) gene. The analysis of the gene detected a heterozygous c.219G>T mutation, which was the first mutation reported in Japan, and finally she was diagnosed with AxD. Dystonia is relatively rare in AxD patients, but this case demonstrated that AxD should be listed in the differential diagnosis of extrapyramidal syndromes with abnormalities of the medulla and spinal cord on MRI.

Alexander disease (ALXDRD) is a primary astrocyte disease caused by GFAP gene mutation. The clinical features of ALXDRD vary from infantile-onset cerebral white matter involvement to adult-onset brainstem involvement. Several studies revealed that the level of GFAP overexpression is correlated with disease severity, and basic research on therapies to reduce abnormal GFAP accumulation has recently been published. Therefore, the accumulation of clinical data to advance understanding of the natural history is essential for clinical trials expected in the future. This review focuses on the clinical characteristics of ALXDRD including the clinical symptoms, imaging findings and genetics to provide diagnostic information useful in daily clinical practice.

Alexander disease (ALXDRD) is a primary astrocyte disease caused by glial fibrillary acidic protein (GFAP) gene mutation. ALXDRD had been clinically regarded as a cerebral white matter disease that affects only children for about 50 years since the initial report in 1949; however, in the early part of the 21st century, case reports of adult-onset ALXDRD with medulla and spinal cord lesions increased. Basic research on therapies to reduce abnormal GFAP accumulation, such as drug-repositioning and antisense oligonucleotide suppression, has recently been published. The accumulation of clinical data to advance understanding of natural history is essential for clinical trials expected in the future. In this review, I classified ALXDRD into two subtypes: early-onset and late-onset, and detail the clinical symptoms, imaging findings, and genetic characteristics as well as the epidemiology and historical changes in the clinical classification described in the literature. The diagnostic criteria based on Japanese ALXDRD patients that are useful in daily clinical practice are also mentioned.

Background: Alexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP . Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist., Methods: A family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line., Results: The novel variant in GFAP (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models., Conclusion: We suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAP analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Alexander disease (AxD) is a fatal neurodegenerative disorder caused by mutations in glial fibrillary acidic protein (GFAP), which supports the structural integrity of astrocytes. Over 70 GFAP missense mutations cause AxD, but the mechanism linking different mutations to disease-relevant phenotypes remains unknown. We used AxD patient brain tissue and induced pluripotent stem cell (iPSC)-derived astrocytes to investigate the hypothesis that AxD-causing mutations perturb key post-translational modifications (PTMs) on GFAP. Our findings reveal selective phosphorylation of GFAP-Ser13 in patients who died young, independently of the mutation they carried. AxD iPSC-astrocytes accumulated pSer13-GFAP in cytoplasmic aggregates within deep nuclear invaginations, resembling the hallmark Rosenthal fibers observed in vivo. Ser13 phosphorylation facilitated GFAP aggregation and was associated with increased GFAP proteolysis by caspase-6. Furthermore, caspase-6 was selectively expressed in young AxD patients, and correlated with the presence of cleaved GFAP. We reveal a novel PTM signature linking different GFAP mutations in infantile AxD., Competing Interests: RB, AB, SD, RD, JR, PK, LH, VM, RQ, JG, MP, MI No competing interests declared, NR, EW, RN are paid employees of ThermoFisher Scientific, whose products were used to complete parts of the study. ThermoFisher Scientific had no role in the study design, data analysis, decision to publish, or preparation of the manuscript. NS is a member of the Scientific Advisory Board for Elise's Corner Fund, which supported part of this work, (© 2019, Battaglia et al.)

The various forms of Alexander disease (AD) have been linked to heterozygous point mutations in the coding region of the human Glial Fibrillary Acidic Protein (GFAP) gene. The aim of this study was to confirm and characterise an adult variant of AD based on the presence of Rosenthal fibres, which were identified at brain autopsy. We performed histological and immunohistochemical studies and mutation screening by cycle sequencing of exons 1, 4, 6, and 8. A heterozygous D128N GFAP mutation, previously described in three other cases of adult-onset AD (AOAD), was genetically confirmed. The mutation was seemingly sporadic. Symptoms of the female, 65-year-old patient started with occasionally asymmetric motor impairment and concluded, 23 months later, with a lack of spontaneous movement in all four limbs, reduced consciousness, an acute respiratory problem, and eventually lethal exitus. The most striking characteristics were a cerebellar syndrome with subsequent clinical signs due to brainstem and spinal cord involvement. The final diagnosis was based on a complete autopsy, detection of Rosenthal fibres, GFAP, vimentin, alpha B-crystallin, ubiquitin, hsp27, neurofilament, and synaptophysin, and the identification of the corresponding GFAP gene mutation. Blood analyses were positive for ANA and rheumatoid factor. In conclusion, this work describes sporadic, rapidly advancing AOAD in a female patient and links it with other published cases with the same mutation. Reflections are provided on the influence of vasculitis and ANA in AD as well as the presence of Rosenthal fibres in the neurohypophysis.

A 51-year-old woman presented with progressive weakness of the neck extensor muscles and gait disturbances since the past 6 years. In addition, she presented with symptoms such as dysarthria, dysphagia, bladder, and rectal disturbances. Bilateral plantar reflex was positive. Her gait was short-stepped-spastic. Brain and cervical MRI showed atrophy of the medulla and spinal cord. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. We identified a heterozygous c.368T>C missense mutation of the GFAP gene in the patient. This was the first case of the mutation in Japanese patients, and subsequently, she was diagnosed with AxD type 2. There are a few studies which reported that patients with AxD complained of dropped head syndrome. Dropped head syndrome can be the initial manifestation of AxD.

We describe the rare condition known as Alexander's disease or Alexander's leukodystrophy, which is essentially a childhood dementia. We then present the case of Louise Davies (we are using Louise's real name with the permission and special request of her mother), a woman who was diagnosed with this disease at the age of 5 years and is still alive at the age of 38, making her the longest known survivor of this condition. Although now severely impaired, both physically and mentally, and able to do very little, she has lived far longer than expected. We present some neuropsychological results from her childhood before measuring her decline over the past four years. We conclude by considering whether or not the diagnosis was correct and why she has lived so long.

Sleep apnoea and respiratory difficulties are reported in adult-onset Alexander's disease (AOAD), an autosomal-dominant leukodystrophy that presents mainly with progressive ataxia. We demonstrate for the first time that the respiratory symptoms can result from association of palatal tremor with a similar tremor of laryngeal and respiratory muscles that interrupts normal inspiration and expiration.A 60-year-old woman presented with progressive ataxia, palatal tremor and breathlessness. MRI revealed medullary atrophy, bilateral T2 hyperintensities in the dentate nuclei and hypertrophic olivary degeneration (HOD). AOAD was confirmed genetically with a positive glial fibrillary acidic protein (GFAP) mutation. Electrophysiological study revealed 1.5 Hz rhythmic laryngeal and respiratory muscle activity. Her respiratory symptoms were significantly improved at night with variable positive pressure ventilation.This case illustrates that palatal tremor in AOAD, and potentially in other conditions, may be associated with treatable breathlessness due to a similar tremor of respiratory muscles., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Alexander disease is a leukodystrophy caused by dominant missense mutations in the gene encoding the glial fibrillary acidic protein. Individuals with this disorder often present with a typical neuroradiologic pattern including white matter abnormalities with brainstem involvement, selective contrast enhancement, and structural changes to the basal ganglia/thalamus. In rare cases, focal lesions have been seen and cause concern for primary malignancies. Here the authors present an infant initially diagnosed with a chiasmatic astrocytoma that was later identified as having glial fibrillary acidic protein mutation-confirmed Alexander disease. Pathologic and radiologic considerations that were helpful in arriving at the correct diagnosis are discussed.

Astrocytes play crucial roles in maintaining brain homeostasis and in orchestrating neural development, all through tightly coordinated steps that cooperate to maintain the balance needed for normal development. Here, we review the alterations in astrocyte functions that contribute to a variety of developmental neurometabolic disorders and provide additional data on the predominant role of astrocyte dysfunction in the neurometabolic neurodegenerative disease glutaric acidemia type I. Finally, we describe some of the therapeutical approaches directed to neurometabolic diseases and discuss if astrocytes can be possible therapeutic targets for treating these disorders.

Alexander disease, less commoniy known as fibrinoid leukodystrophy is an extremely rare, non- familial, progressive, lethal leukodystrophy which is characterized predominantly by abnormalities of white matter in bilateral frontal regions. It usually presents early within first 2 years of life with clinical features of macrocephaly, recurrent seizures and psychomotor retardation. Diagnosis of this white matter disorder is possible with certain features seen on magnetic resonance imaging (MRI), even without the need for histological confirmation. Our case is a one year old male infant who presented with repeated episodes of focal seizures to the paediatrician. He was referred for an MRI and subsequently based on typical MRI findings the diagnosis of Alexander disease was made.

Adult-onset Alexander's disease is a rare leukodystrophy that can present later in life in a variety of ways, often mimicking more common neurodegenerative conditions. We present two cases with novel mutations, diagnosed from their characteristic MR scan findings. Even in much older people, clinicians should have a high clinical suspicion if there are typical imaging findings., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Alexander disease (AxD), a fatal degenerative leukoencephalopathy, is caused by de novo heterozygous missense mutations in the Glial Fibrillary Acidic Protein (GFAP) gene. The pathological hallmark of the disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes, composed mainly of GFAP, αB-crystallin and HSP27. To date, several patients with a typical presentation of the disease or displaying characteristic Rosenthal fibers in brain material have been reported with no GFAP mutation. Recently, several studies have demonstrated a correlation between Rosenthal fiber formation and wild-type GFAP overexpression, despite the absence of mutations. We tested the hypothesis that a GFAP gene rearrangement could modulate AxD severity or promote GFAP overexpression and aggregation, resulting in leukoencephalopathy. A QMPSF assay was validated for 11 exonic fragments: 3 in control genes (CFTR, DSCR1, F9) and 8 corresponding to GFAP exons. A total of 97 patients suspected of AxD were analyzed: 28 with a GFAP mutation; 69 with clinical and magnetic resonance imaging criteria compatible with the disease. Neither duplications nor deletions of GFAP were found, suggesting that GFAP coding-region rearrangements may not be involved in AxD or Alexander-related leukoencephalopathies. In addition, 80 patients with undetermined leukodystrophies, and negative for PLP1, GJA12, Sox10 and MCT8 mutations and PLP1 and Lamin B1 rearrangements, were tested. These patients were also negative for GFAP rearrangements. Other hypotheses should be investigated for a molecular diagnosis in patients with undetermined leukoencephalopathy: mutations in GFAP isoforms, splicing sites or regulatory regions, or defaults in genes encoding molecular partners of GFAP., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Alexander disease is a rare neurodegenerative disorder that has not often been described in dogs. None of the existing descriptions include electrodiagnostic or magnetic resonance imaging workup. This is the first presentation of the results of an electrodiagnostic evaluation including electromyography, motor nerve conduction velocity, F-wave, the brainstem auditory evoked response and magnetic resonance imaging of a dog with Alexander disease., Case Presentation: A six month old male entire Bernese mountain dog was presented with central nervous system symptoms of generalized tremor, general stiffness, decreased proprioceptive positioning, a reduced menace response, decreased physiological nystagmus, myotonic spasms and increased spinal reflexes which progressed to lateral recumbency. The electromyography revealed normal muscle activity and a decreased motor nerve conduction velocity, temporal dispersion of the compound muscle action potential, prolonged F-wave minimal latency, lowered F-ratio, decreased latency, and lowered amplitude of the brainstem auditory evoked potentials. The magnetic resonance imaging examination revealed ventriculomegaly and linear hyperintensity on the border of the cortical grey and white matter. The histopathological examination confirmed the presence of diffuse degenerative changes of the white matter throughout the neuraxis. A proliferation of abnormal astrocytes was found at the border between the white matter and cortex. There was also a massive accumulation of eosinophilic Rosenthal fibers as well as diffuse proliferation of abnormally large astrocytes and unaffected neurons., Conclusion: This is the first histopathologically confirmed case of Alexander disease in a dog with a full neurological workup. The results of the electrodiagnostic and magnetic resonance imaging examinations allow for a high-probability antemortem diagnosis of this neurodegenerative disorder in dogs.

Alexander disease (AxD) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP. We found a novel nonsense mutation (c.1000 G>T, p.(Glu312Ter); also termed p.(E312*)) within a rod domain of GFAP in a 67-year-old Korean man with a history of memory impairment and leukoencephalopathy. This mutation, GFAP p.(E312*), removes part of the 2B rod domain and the whole tail domain from the GFAP. We characterized GFAP p.(E312*) using western blotting, in vitro assembly and sedimentation assay, and transient transfection of human adrenal cortex carcinoma SW13 (Vim(+)) cells with plasmids encoding GFAP p.(E312*). The GFAP p.(E312*) protein, either alone or in combination with wild-type GFAP, elicited self-aggregation. In addition, the assembled GFAP p.(E312*) aggregated into paracrystal-like structures, and GFAP p.(E312*) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW13 (Vim(+)) cells. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation.

Introduction: There are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging., Patient and Methods: We present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed., Results: The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease., Conclusions: Alexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To describe the imaging and clinical features in type II (late-onset) Alexander disease (AxD)., Methods: We retrospectively identified all cases of type II AxD evaluated at Mayo Clinic, Rochester from January 1996 to February 2012. Clinical and neuroimaging data abstracted from the record included age at onset of symptoms, age at diagnosis, first symptom, neurologic symptoms, physical/neurologic findings on examination, genetic testing and/or biopsy (if performed), and MRI findings., Results: Thirteen patients with type II AxD were identified. Median age at onset was 38 years (range: 12-63). Five patients were female. Eleven of 13 patients had atrophy of the medulla while all 13 had medullary T2 hyperintensity. In 7 patients, these brainstem regions showed patchy enhancement. Five subjects had T2 signal change in the middle cerebellar peduncle, with associated contrast enhancement in 4 subjects. Eleven of 12 patients with T2 fluid-attenuated inversion recovery (FLAIR) imaging had pial FLAIR signal change in the medulla. Nine of 12 patients with spinal cord imaging had cord atrophy, and 3 of 9 of these evaluated with contrast had cervical cord enhancement., Conclusions: Our study confirms prior reports of atrophy and signal change of the medulla and spinal cord in late-onset AxD. We expand on previous imaging studies by identifying middle cerebellar peduncle and pial FLAIR signal changes as important diagnostic clues. Variable patchy enhancement may occur in regions of T2 hyperintensity, leading to diagnostic uncertainty. In addition, we demonstrate that previously emphasized clinical features such as palatal tremor may not be common. We affirm that age at onset predicts clinical phenotype and imaging findings.

Adult-onset Alexander disease (AOAD) is a rare leukoencephalopathy affecting predominantly the brainstem and cervical cord with insidious onset of clinical features. Acute onset is very rare and has yet been described only twice, to our knowledge. We report a 32-year-old hitherto healthy male who, after excessive consumption of alcohol, presented with stroke-like onset of symptoms including rigidospasticity, loss of consciousness, and bulbar dysfunction. MRI features comprised bilateral T2-hyperintensities of frontal white matter and basal ganglia as well as atrophy of medulla oblongata with a peculiar "tadpole" appearance, a pattern characteristic of AOAD. Mutation analysis of the GFAP gene revealed a heterozygous de novo 9-bp microduplication in exon 1. Adult Alexander disease may present with stroke-like features. MRI patterns of chronic neurodegenerative conditions may be recognizable even in acute neurological emergencies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In this report, we describe the case of a new Japanese family (32 to 64 years old; 2 females and 1 male) affected by adult-onset Alexander disease. Clinically, one member (age at onset, 56 years old) developed cerebellar ataxia, another (age at onset, 55 years old) showed cerebellar ataxia and pseudobulbar signs, and one member (32 years old) was asymptomatic. Marked atrophy of the medulla oblongata and spinal cord was detected in the two symptomatic patients by magnetic resonance imaging (MRI). However, in the asymptomatic patient, cervicomedullary atrophy was mild. Hyperintensity signals in the medulla oblongata were detected in the two symptomatic patients, but not in the asymptomatic patient. In addition, there are symmetrical hyperintensity signals in the posterior part of the globus pallidus on T2-weighted images in the two symptomatic patients, which are rarely observed in adult-onset Alexander disease. Molecular genetic analysis revealed a novel missense mutation (p. D78N) in the glial fibrillary acidic protein (GFAP) gene in this family. The typical atrophy of the medulla oblongata and upper cervical cord detected by MRI is the diagnostic feature of adult-onset Alexander disease. Genetic analysis of the GFAP gene is recommended for all patients with late-onset progressive ataxia and suspected of having adult-onset Alexander disease on the basis of MRI findings. Additionally, these characteristic MRI patterns might even lead to the identification of asymptomatic cases, as in one of our cases., (Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.)

Alexander disease is an autosomal dominant leukoencephalopathy characterized by developmental delay, macrocephaly, and characteristic neuroimaging abnormalities predominantly involving frontal lobes. We report a 6-year-old Indian boy with infantile-onset Alexander disease, who has an unusually mild clinical course and a de novo p.Leu359Val mutation in the glial fibrillary acidic protein gene.

Alexander's leukodystrophy is a rare cerebral white matter disorder with an onset that can be infantile, juvenile, or occur in the adult years. It is thought to be demyelinative, but the pathogenesis is ill-defined. We report a 24-year-old woman with juvenile-onset Alexander disease, of 12 years duration, who underwent magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) serially as part of her care. The patient's latest MRI showed periventricular-increased signal intensity on T2 and fluid attenuation and inversion recovery sequences, which appeared stable when compared to her first study seven years ago. MRS revealed an elevated choline/creatine ratio with relative suppression of the n-acetyl aspartate peak, also similar to her previous MRS findings. MRS also showed elevation of myoinositol levels, best demonstrated with the short echo-time spectra. These findings support the primarily demyelinative characteristics of this leukodystrophy and may provide a surrogate marker of disease progression, as well as a potential response to therapeutic intervention when this becomes available.

Introduction: Alexander disease is a disorder caused by a mutation and accumulation of the glial fibrillary acidic protein. Currently, three subtypes are acknowledged: an infantile, a juvenile, and an adult form. However, onset early in infancy or in the prenatal period has been shown to present with a uniform pattern of symptoms-suggesting the presence of a distinct neonatal form of the disease., Results and Discussion: Though the neonatal form of Alexander disease is not well acknowledged, a uniform and distinct presentation of the disease in neonates has been observed, suggesting the need for a different course of identification and treatment. Clinical presentation of the neonatal form is distinguished by leukodystrophy and generalized, frequent, and intractable seizures. While the infantile form presents with ataxia, hyperreflexia, and other upper motor neuron symptoms, none of these has been observed in the neonatal form. In the diagnosis of neonatal Alexander disease, it is essential to rule out other causes of leukodystrophy and the presence of neoplasms.

A 2-month-old infant was admitted to hospital because of recurrent vomiting for 1 week, progressive apathy, and focal seizures. The cranial MRI showed a noticeable result.

Objective: To delineate the phenotype and genotype characteristics in 12 Chinese children with Alexander disease (AD), which is helpful for the molecular diagnosis and genetic counseling in China., Methods: Clinical diagnosis of AD was based on MRI criteria proposed by van der Knaarp in 2001. Included AD patients were followed up for 0.50 - 3.67 years. Mutations in GFAP were detected by DNA sequencing., Results: The 12 cases of AD were clinically diagnosed. Age of first visit was 4.87 years (0.75 - 12.00 years), with 3 types of chief complaints: developmental delay in 3, recurrent seizures in 7, unable to walk after falling in 2. Average head circumference was 52.34 cm (44 - 58 cm), which larger than age-matched average by 6.45% (1.80% - 13.95%). On the first visit, scaling according to Gross motor functional classification system (GMFCS) was performed, with GMFCSI in 8, II in 3, V in 1. Mild to severe cognitive dysfunction were found in 8, and seizures in 11 cases. The 12 patients were followed up for 0.50 - 3.67 years, their motor and cognitive function remained stable. Episodic aggravations provoked by fever or falling were observed in 5 cases (41.67%). Heterozygous missense mutations of GFAP were detected in 12 patients. All mutations were de novo; 3 out of 10 mutations identified were novel. R79 and R239 were hot mutations, which was consistent with previous reports. Mutations were located in exon 1 in 8 cases., Conclusions: The phenotype in these patients is characterized by slower progression compared with reports from other population and high incidence of seizures. And episodic aggravations provoked by fever or falling were more common. The genotype characteristics are consistent with previous reports. The results of this research expanded the number of patients with Alexander disease found to have GFAP coding mutations in China.

Alexander disease is a rare leukodystrophy that most often presents in infancy but also includes neonatal, juvenile, and adult variants. Juvenile Alexander disease presents primarily with bulbar symptoms between 2 and 12 years of age. The diagnosis is often suggested by the clinical course and brain magnetic resonance image pattern and then confirmed by the presence of a mutation in the glial fibrillary acidic protein gene. A young girl presented with globus sensation and magnetic resonance imaging of the brain revealed abnormalities mainly involving white matter tracts of the medulla oblongata and cerebellum. The presence of a mutation in the glial fibrillary acidic protein gene confirmed the diagnosis of juvenile Alexander disease. A high index of clinical suspicion is necessary for the diagnosis of late-onset presentations of Alexander disease.