Brainstem Chipmunk Sign: A Diagnostic Imaging Clue across All Subtypes of Alexander Disease.

BACKGROUND AND PURPOSE: While classic brain MR imaging features of Alexander disease have been well-documented, lesional patterns can overlap with other leukodystrophies, especially in the early stages of the disease or in milder phenotypes. We aimed to assess the utility of a new neuroimaging sign to help increase the diagnostic specificity of Alexander disease. MATERIALS AND METHODS: A peculiar bilateral symmetric hyperintense signal on T2-weighted images affecting the medulla oblongata was identified in an index patient with type I Alexander disease. Subsequently, 5 observers performed a systematic MR imaging review for this pattern by examining 55 subjects with Alexander disease and 74 subjects with other leukodystrophies. Interobserver agreement was assessed by the κ index. Sensitivity, specificity, and receiver operating characteristic curves were determined. RESULTS: The identified pattern was present in 87% of subjects with Alexander disease and 14% of those without Alexander disease leukodystrophy (P < .001), 3 with vanishing white matter, 4 with adult polyglucosan body disease, and 3 others. It was found equally in both type I and type II Alexander disease (28/32, 88% versus 18/21, 86%; P = .851) and in subjects with unusual disease features (2/2). Sensitivity (87.3%; 95% CI, 76.0%-93.7%), specificity (86.5%; 95% CI, 76.9%-92.5%), and interobserver agreement (κ index = 0.82) were high. CONCLUSIONS: The identified pattern in the medulla oblongata, called the chipmunk sign due to its resemblance to the face of this rodent, is extremely common in subjects with Alexander disease and represents a diagnostic tool that can aid in early diagnosis, especially in subjects with otherwise atypical MR imaging findings and/or clinical features.

Alexander disease with a novel GFAP insertion-deletion mutation mimicking progressive supranuclear palsy.

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.

Substitution of Glu to Lys at Codon 332 on the GFAP Gene Alone Is Causative for Adult-onset Alexander Disease.

A 57-year-old man whose mother had been pathologically diagnosed with Alexander disease (ALXDRD), presented with cerebellar ataxia, pyramidal signs, and mild dysarthria. Brain magnetic resonance imaging revealed typical ALXDRD alterations, such as atrophy of the medulla oblongata (MO) and cervical spinal cord, a reduced sagittal diameter of the MO, and garland-like hyperintensity signals along the lateral ventricular walls. A genetic analysis of GFAP by Sanger sequencing revealed a single heterozygous mutation of Glu to Lys at codon 332 (c.994G>A) in the GFAP gene. Our results newly confirmed that p.E332K alone is the pathogenic causative mutation for adult-onset ALXDRD.

Acquisition and Loss of Developmental Milestones and Time to Disease-Related Outcomes in Cerebral Alexander Disease.

Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 [94%], mean age 0.58 years), compared to an initial seizure (N = 41 [80%], mean age 2.80 years), and macrocephaly (N = 28 [55%], mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.

Adult-onset Alexander disease among patients of Jewish Syrian descent.

Alexander disease (AxD) is a rare autosomal dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acid protein (GFAP) gene. The age of symptoms onset ranges from infancy to adulthood, with variable clinical and radiological manifestations. Adult-onset AxD manifests as a chronic and progressive condition, characterized by bulbar, motor, cerebellar, and other clinical signs and symptoms. Neuroradiological findings typically involve the brainstem and cervical spinal cord. Adult-onset AxD has been described in diverse populations but is rare in Israel. We present a series of patients diagnosed with adult-onset AxD from three families, all of Jewish Syrian descent. Five patients (4 females) were diagnosed with adult-onset AxD due to the heterozygous mutation c.219G > A, p.Met73Ile in GFAP. Age at symptoms onset ranged from 48 to 61 years. Clinical characteristics were typical and involved progressive bulbar and gait disturbance, followed by pyramidal and cerebellar impairment, dysautonomia, and cognitive decline. Imaging findings included medullary and cervical spinal atrophy and mostly infratentorial white matter hyperintensities. A newly recognized cluster of adult-onset AxD in Jews of Syrian origin is presented. This disorder should be considered in differential diagnosis in appropriate circumstances. Genetic counselling for family members is required in order to discuss options for future family planning.

Fetal-onset Alexander disease with radiological-neuropathological correlation.

Alexander disease is a leukodystrophy caused by mutations in the GFAP gene, primarily affecting the astrocytes. This report describes the prenatal and post-mortem neuroimaging findings in a case of genetically confirmed, fetal-onset Alexander disease with pathological correlation after termination of pregnancy. The additional value of fetal brain magnetic resonance imaging in the third trimester as a complementary evaluation tool to neurosonography is shown for suspected cases of fetal-onset Alexander disease. Diffuse signal abnormalities of the periventricular white matter in association with thickening of the fornix and optic chiasm can point towards the diagnosis. Furthermore, the presence of atypical imaging findings such as microcephaly and cortical folding abnormalities in this case broadens our understanding of the phenotypic variability of Alexander disease.

Adult-onset Alexander disease with brainstem and cervical cord enhancing lesions.

Leukodystrophies are a group of genetic diseases with diverse clinical features and prominent involvement of the central nervous system white matter. We describe a 27-year-old man who presented with a progressive neurological disease, and striking involvement of the brainstem and symmetrical white matter lesions on MR scanning. Having excluded several other causes of leukodystrophy, we confirmed Alexander disease when a genetic panel showed a probable pathogenic variant in GFAP: p.Leu359Pro. Clinicians should suspect Alexander disease in people with a progressive neurological motor decline who has pyramidal and bulbar signs and compatible neuroimaging.

Diagnostic features of type II fibrinoid leukodystrophy (Alexander disease) in a juvenile Beagle dog.

A 3-month-old female entire Beagle presented with a progressive history of caudotentorial encephalopathy. Reactive encephalopathies were ruled out and tests for the most common infectious diseases agents were negative. Magnetic resonance imaging of the brain using a 1.5 Tesla scanner showed diffuse, bilateral, T2-weighted and T2-weighted-FLAIR hyperintense, T1-weighted hypointense, noncontrast-enhancing lesions involving the white matter of the cerebellum, brainstem, spinal cord, and forebrain to a lesser extent. There was cerebellar enlargement. Abnormalities were not detected on cerebrospinal fluid examination. Given the progressive nature of the disease and suspected poor prognosis the dog was euthanized. Histopathological analysis of the brain was consistent with fibrinoid leukodystrophy, also known as Alexander disease. Based on the classification used in humans, this is a description of MRI of a case of type II Alexander disease in veterinary medicine, with characteristics different to other described leukoencephalopathies in dogs.

Identification of association fibers using ex vivo diffusion tractography in Alexander disease brains.

BACKGROUND AND PURPOSE: Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings.

Clinical and radiological characteristics of older-adult-onset Alexander disease.

BACKGROUND: Alexander disease (ALXDRD) affects a wide range of ages from infancy to adulthood. However, only a few cases involving patients with older-adult onset over 65 years of age have been reported. In contrast, regarding in-house data, 10.6% of 85 cases with the identification of GFAP mutations demonstrated older-adult onset. This discrepancy may be due to poor awareness of such cases. METHODS: The subjects included 9 older-adult-onset cases, with an onset age of 65 years or older. We characterized older-adult-onset ALXDRD by assessing neurological findings and several magnetic resonance imaging (MRI) parameters. RESULTS: The age at onset, mean age at diagnosis, and mean period from onset to diagnosis were 68.2 years, 70.4 years, and 2.2 years, respectively. The main neurological features at diagnosis included pyramidal signs with muscle weakness and/or cerebellar ataxia. Two-thirds of cases were dependent, and the dependence was significantly correlated with a longer period from onset to diagnosis. Quantitative MRI evaluation for brainstem atrophy demonstrated distinctive morphological features of bulbospinal ALXDRD. The corpus callosum index tended to be negatively correlated with the period from onset to diagnosis. CONCLUSIONS: Although neurological and MRI findings of older-adult-onset ALXDRD patients showed typical features of bulbospinal ALXDRD, their disease progression was more severe than that in younger-adult-onset ALXDRD, and patients developed dependence within 2 years from onset. Cerebral white matter damage tended to progress in proportion to the duration of illness. Our case study may help to advance understanding of the clinical spectrum of ALXDRD.

A report of two cases of bulbospinal form Alexander disease and preliminary exploration of the disease.

Alexander disease (AxD) is a cerebral white matter disease affecting a wide range of ages, from infants to adults. In the present study, two cases of bulbospinal form AxD were reported, and a preliminary exploration of AxD was conducted thorough clinical, functional magnetic resonance imaging (fMRI) and functional analyses. In total, two de novo mutations in the glial fibrillary acidic protein (GFAP) gene (c.214G>A and c.1235C>T) were identified in unrelated patients (one in each patient). Both patients showed increased regional neural activity and functional connectivity in the cerebellum and posterior parietal cortex according to fMRI analysis. Notably, grey matter atrophy was discovered in the patient with c.214G>A variant. Functional experiments revealed aberrant accumulation of mutant GFAP and decreased solubility of c.1235C>T variant. Under pathological conditions, autophagic flux was activated for GFAP aggregate degradation. Moreover, transcriptional data of AxD and healthy human brain samples were obtained from the Gene Expression Omnibus database. Gene set enrichment analysis revealed an upregulation of immune­related responses and downregulation of ion transport, synaptic transmission and neurotransmitter homeostasis. Enrichment analysis of cell­specific differentially expressed genes also indicated a marked inflammatory environment in AxD. Overall, the clinical features of the two patients with bulbospinal form AxD were thoroughly described. To the best of our knowledge, the brain atrophy pattern and spontaneous brain functional network activity of patients with AxD were explored for the first time. Cytological experiments provided evidence of the pathogenicity of the identified variants. Furthermore, bioinformatics analysis found that inflammatory immune­related reactions may play a critical role in AxD, which may be conducive to the understanding of this disease.

[A case of Alexander disease presented with dystonia of lower limb and decreased dopaminergic uptake in dopamine transporter scintigraphy].

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 123I 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.

Recessively-Inherited Adult-Onset Alexander Disease Caused by a Homozygous Mutation in the GFAP Gene.

BACKGROUND: Alexander disease (AxD) is an autosomal-dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acidic protein (GFAP) gene. OBJECTIVES: The objective of this report is to characterize the clinical phenotype and identify the genetic mutation associated with adult-onset AxD. METHODS: A man presented with progressive unsteadiness since age 16. Magnetic resonance imaging findings revealed characteristic features of AxD. The GFAP gene was screened, and a candidate variant was functionally tested to evaluate causality. RESULTS: A homozygous c.197G > A (p.Arg66Gln) mutation was found in the proband, and his asymptomatic parents were heterozygous for the same mutation. This mutation affected GFAP solubility and promoted filament aggregation. The presence of the wild-type protein rescued mutational effects, consistent with the recessive nature of this mutation. CONCLUSIONS: This study is the first report of AxD caused by a homozygous mutation in GFAP. The clinical implication is while examining patients with characteristic features on suspicion of AxD, GFAP screening is recommended even without a supportive family history. © 2020 International Parkinson and Movement Disorder Society.

Severe worsening of adult-onset Alexander disease after minor head trauma: Report of two patients and review of the literature.

Alexander disease (ALXDRD) is a rare astrocytic leukodystrophy caused by GFAP mutations. The adult-onset (AO) variant is usually characterized by gradual onset of spastic ataxia and bulbar symptoms with slowly progressive course. We report two AO-ALXDRD cases with rapid worsening after minor head trauma. In one of them, the only post-traumatic neuroimaging change was revealed by diffusion tensor imaging study. Our observations support the link between head trauma and ALXDRD progression, and suggest that this progression may be ascribed to microstructural changes. Clinicians should inform ALXDRD patients to minimize the risk of head trauma.

[A case of Alexander disease with repeated loss of consciousness and with rapid aggravation of dysbasia by falling].

A 41-year-old woman presented with short-stepped gait from 20 years old and with repeated loss of consciousness from 21 years old. She had a deep cerebral white matter lesion on brain MRI at 34 years of age, but she did not reach a definitive diagnosis. At the age of 41, the gait disorder rapidly worsened after fall and fall-related head trauma. She had fixation nystagmus, dysphonia, speech disorder and exaggerated tendon reflexes. Her bilateral plantar reflex was positive, and she was not able to walk by herself. The brain and cervical MRI showed atrophy of the medulla and upper spinal cord and a deep cerebral white matter lesion. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. As a result, we identified a heterozygous p.R79H (c.250 G>A) missense mutation of the GFAP gene in the patient. This case suggests that loss of consciousness may be caused by autonomic disorder due to orthostatic hypotension and reflex syncope (vasovagal syncope), psychogenic non-epileptic seizures (PNES) by mental and physical stress. It is important to consider the pathophysiology and management of Alexander disease, in which the progression of gait disorder caused by pyramidal tract disorder is rapidly exacerbated by fall and head injury.