Adult-onset Alexander Disease Research Articles

Tadpole Brainstem Atrophy in Adult-Onset Alexander Disease: A Case Report and Review of Literature.

Tadpole Brainstem Atrophy in Adult-Onset Alexander Disease: A Case Report and Review of Literature.

Adult-Onset Alexander Disease With Late-Presenting Vestibulopathy: A Case Report.

Adult-Onset Alexander Disease With Late-Presenting Vestibulopathy: A Case Report.

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 mutationc.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.

A Familial Cohort of Adult-Onset Alexander Disease (P12-3.016)

<h3>Objective:</h3> To describe a familial cohort of adult-onset Alexander Disease. <h3>Background:</h3> Leukodystrophies are a group of rare, hereditary disorders characterized by abnormal myelination. Each leukodystrophy is caused by abnormalities in one or more genes leading to abnormal production of myelin (hypomyelination) or destruction (demyelination). Leukodystrophies are also classified by the region of the brain or in some cases peripheral nerves that are affected. Alexander Disease is a leukodystrophy characterized by a confluent pattern of demyelination. It is caused by autosomal dominant gain-of-function mutation in the <i>GFAP (glial fibrillary acidic protein)</i> gene. <i>GFAP</i> serves an intermediate filament protein of mature astrocytes; incorrect formation of the protein can lead to astrocyte cytoskeletal collapse and abnormal protein aggregation. Clinically, this can lead to innumerable neurologic manifestations in the affected individual. Alexander Disease predominantly affects neonates, infants, children and rarely adults. We describe a familial cohort of adult-onset Alexander Disease associated with a c.758C&gt;G (p.A253G) mutation of GFAP. This mutation has previously been described in neonates. In this case series we describe the clinical and radiologic features of three sisters with adult-onset symptoms. The first patient is a 53-year-old female who presented with progressive myelopathy and later developed bulbar symptoms. Her 51-year-old sister developed progressive, bilateral leg weakness and gait disturbance. She progressed to have profound cognitive dysfunction. The MRI features include T2 hyperintensities with atrophy in the midbrain and upper cervical spine with peripheral rim brainstem and periventricular garlands. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> These cases describe the clinical and radiologic features of a familial cohort of adult-onset Alexander disease in a mutation previously described only in childhood onset. This also illustrates the importance of considering a diagnosis of Alexander Disease in adult patients and the necessity of genetic analysis of patients and their family members. <b>Disclosure:</b> Dr. Wolf has nothing to disclose. Dr. Gettings has nothing to disclose. Dr. Goodrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono.

Type I Alexander disease: Update and validation of the clinical evolution-based classification.

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. 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. 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. 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.

Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene.

ObjectivesAlexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in GFAP that caused a phenotype of adult-onset AD (AOAD).MethodsIn our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in GFAP to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity.ResultsThe brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in GFAP (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates.DiscussionWe have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.

Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease.

Background and ObjectiveAlexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation.MethodsGenetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed.ResultsThe patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5′ end of the exon 4.DiscussionGFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Pearls & Oy-sters: Adult-Onset Alexander Disease With Transient Swelling of the Medulla Oblongata.

Alexander disease should be considered in patients of all ages, especially in juveniles and adults, with contrast-enhancing lesions in the lower brainstem or upper spinal cord.

Adult-onset Alexander disease mimicking multiple system atrophy predominant cerebellar ataxia

•We report a patient with adult-onset Alexander disease (AOAD) mimicking MSA-C. •Cerebellar ataxia, spasticity, bradykinesia and urinary disturbance were observed. •The patient showed striatal dopaminergic deficit on DAT SPECT. •We should recognize that AOAD can affect striatal dopaminergic systems.

Blended phenotype of adult-onset Alexander disease and spinocerebellar ataxia type 6.

Alexander disease is an autosomal dominant hereditary disease characterized by progressive spastic paraplegia, ataxia, and bulbar symptoms caused by mutations in the glial fibrillary acidic protein ( GFAP ) gene. Previous nation-wide surveillance revealed that the prevalence rate in Japan is estimated at 1 in 2.7 million people.1 Meanwhile, SCA6 is an autosomal dominant spinocerebellar ataxia characterized by adult-onset pure cerebellar ataxia. The prevalence of SCA6 is estimated to be 1 in 100,000 people in Japan.2 Here, we report an extremely rare case presenting with a blended phenotype of adult-onset Alexander disease and SCA6. The authors thank Shoko Watanabe, PhD, for technical assistance including mutational analysis.

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

Alexander disease (AxD) is an autosomal-dominant leukodystrophy caused by heterozygous mutations in the glial fibrillary acidic protein (GFAP) gene. The objective of this report is to characterize the clinical phenotype and identify the genetic mutation associated with adult-onset AxD. 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. 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. 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.

A case report of adult-onset Alexander disease clinically presenting as Parkinson\u2019s disease: is the comorbidity associated with genetic susceptibility?

BackgroundAlexander disease is a rare neurological disease characterized by progressive spastic quadriparesis and bulbar palsy. Moreover, certain patients with adult-onset Alexander disease were often misdiagnosed as other neurodegenerative disorders.Case presentationHerein, we report an adult a 58-year-old woman presented with typical parkinsonism with good levodopa-responsiveness. The patient’s dopamine transporter scanning showed significant striatal depletion, while her brain magnetic resonance imaging revealed bilateral tadpole shape of medulla oblongata and bilateral high signal intensity at both cerebellar dentate nuclei in T2-weighted images, suggesting the possibility of a genetic disorder beyond Parkinson’s disease. The patient’s genetic test resulted in known pathogenic glial fibrillary acidic protein variant, indicating Alexander disease.ConclusionThis unique case highlights genetically diagnosed Alexander disease may present with clinical Parkinson’s disease.

C.1289G>A (p.Arg430His) variant in the epsilon isoform of the GFAP gene in a patient with adult onset Alexander disease

Alexander disease (AD) is a rare form of leukodystrophy caused by pathogenic variants in the GFAP gene. In young children the condition is fatal, while adults have variable neurological symptoms and prognosis. On magnetic resonance imaging, a pattern of atrophy of the medulla oblongata and cervical spinal cord with a ‘tadpole’ appearance is highly suggestive of adult-onset Alexander disease (AOAD). GFAP gene sequencing is used to confirm the diagnosis. Pre-mRNA of this gene undergoes alternative splicing resulting in formation of at least 8 different protein isoforms. Most patients with AD described to date have a pathogenic variant in the coding sequence of the main and the most abundant gene isoform, the GFAPα. Recently, two half-siblings with neurological symptoms and radiological signs of AOAD were reported and were not found to have any pathogenic variants in the GFAPα gene while further genetic testing by next generation sequencing revealed a c.1289G>A (p.Arg430His) variant in the alternative exon 7A of the GFAPε isoform.Here we present a case of another patient with symptoms and brain MRI pattern suggestive of AOAD. Similarly to the previously described patients, this patient did not have any pathogenic variants in the main gene isoform and had the same c.1289G>A (p.Arg430His) variant in the GFAPε. This report contributes to evidence of pathogenicity of the c.1289G>A (p.Arg430His) variant in the GFAPε.

Atypical Alexander disease with dystonia, retinopathy, and a brain mass mimicking astrocytoma.

Alexander disease (AD) is an autosomal dominant progressive astrogliopathy caused by pathogenic variants in glial fibrillary acidic protein (GFAP).1 Clinical presentation of AD includes infantile AD, characterized by psychomotor retardation, seizures, pyramidal signs, and megalencephaly; juvenile AD, characterized by bulbar/pseudobulbar signs, hyperreflexia, lower limb spasticity, ataxia, loss of intellectual function, and macrocephaly; and adult-onset AD, characterized by progressive bulbar symptoms, ataxia, palatal myoclonus, bladder dysfunction, and spastic paraparesis.1 The authors thank the patient and her family for participating in this research. They thank Alyssa Tran, Deanna Erwin, and Alex Espana in the Molecular and Human Genetics Department, Baylor College of Medicine for administrative assistance.

Rosenthal fiber encephalopathy and Alexander disease

Background: Numerous Rosenthal fibers were revealed both adult onset Alexander disease (AOAD) and Rosenthal fiber encephalopathy (RFE). Rosenthal fibers usually showed the area of perivascular, periventricular and brainstem. Alexander disease is associated with mutations in GFAP gene. However, RFE has not detected mutation of GFAP gene.It remains obscure in what condition Rosenthal fibers are formed and how different RF formation in both AOAD and RFE. We are made some special reference about this presentation.

Biochemical analysis of a novel frameshift mutant glial fibrillary acidic protein (GFAP) in adult onset Alexander disease

Biochemical analysis of a novel frameshift mutant glial fibrillary acidic protein (GFAP) in adult onset Alexander disease

A novel familial mutation in Alexander disease with marked variation in clinical severity

Objective: Alexander disease is a rare, often lethal disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein (GFAP). The disease typically results from dominant mutations in GFAP that arise de novo. However, series of familial cases with variable clinical manifestations have been described suggesting a potential recessive inheritance or germline mosaicism. We report a male infant with typical Alexander disease, inherited by his asymptomatic father with positive neuroimaging markers of the disease. Methods: Clinical histories were obtained and whole exome sequencing (WES) analyses in blood samples were performed through next generation sequencing. Results: We report a 6-month male, born of an uneventful term pregnancy, who presented with generalized hypotonia, chorioathetosis and drug-resistant seizures, without macrocephaly. Brain MRI showed symmetrical abnormalities of the basal ganglia, subcortical white matter abnormalities, mainly of the frontal area with contrast enhancement along with high intensity periventricular rim on T1. WES analysis of the patient revealed a heterozygous missense mutation, c.1120G>A (p.Glu374Lys) in GFAP gene, resulting in the substitution of the aminoacid glutamic acid with lysine at the protein level. Although this genetic change is novel, it was considered as pathogenic from in silico analysis. We therefore proceeded to genetic analyses of the remaining members of the family that revealed the same mutation in the asymptomatic father. A subsequent brain MRI showed white matter abnormalities suggestive of adult-onset Alexander disease. Conclusion: We present a familial case of Alexander disease caused by a novel mutation on GFAP gene. There is a marked discrepancy on clinical presentation between the father and the affected child imposing that there is a striking variation on penetrance of the mutated gene of unknown etiology. We suggest genetic analysis on parents of patients with Alexander disease even if asymptomatic.

Adult Onset Alexander Disease with Novel GFAP p.Ser385Cys Mutation (P1.079)

Adult Onset Alexander Disease with Novel GFAP p.Ser385Cys Mutation (P1.079)

Long-term follow-up of a case of adult-onset Alexander disease presenting with cognitive impairment as the initial symptom

Long-term follow-up of a case of adult-onset Alexander disease presenting with cognitive impairment as the initial symptom

Interactions of GFAP with ceftriaxone and phenytoin: SRCD and molecular docking and dynamic simulation

BackgroundGFAP is the major intermediate filament protein in mature astrocytes. Its increased expression and aggregation was firstly associated to Alexander's disease, and successively in different neurological diseases including scrapie, Alzheimer's and Creutzfeld–Jacob diseases. Recently, ceftriaxone a multi-potent β-lactam antibiotic able to overcome the blood–brain barrier, successfully eliminated the cellular toxic effects of misfolded mutated GFAP, similarly to phenytoin sodium, in a cellular model of Alexander's disease and inhibited α-synuclein aggregation protecting PC12 cells from the exposure to 6-hydroxydopamine. MethodsIn this study, synchrotron radiation circular dichroism spectroscopy has been used to obtain structural information about the GFAP-ceftriaxone (phenytoin) interactions, while computational methods allowed the identification of the relevant putative binding site of either ceftriaxone or phenytoin on the dimer structure of GFAP, permitting to rationalize the spectroscopic experimental results. ResultsWe found that GFAP exhibited enhanced stability upon the addition of two equivalents of each ligands with ceftriaxone imparting a more spontaneous interactions and a more ordered complex system than phenytoin. ConclusionsSRCD data and MD models indicate a stronger protective effect of ceftriaxone in neurological disorders characterized by an increased production and polymerization of GFAP. General significanceThis result, in addition to our previous works in which we documented that ceftriaxone interacts with α-synuclein inhibiting its pathological aggregation and that a cyclical treatment with this molecule in a patient with adult-onset Alexander's disease halted, and partly reversed, the progression of neurodegeneration, suggests the possibility of a chaperone-like effect of ceftriaxone on protein involved in specific neurodegenerative diseases.