Adult-onset Alexander Disease Research Articles

Adult-onset Alexander's disease mimicking degenerative disease

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...

Autonomic dysfunction in adult-onset alexander disease

Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.

Familial adult-onset Alexander disease with a novel mutation (D78N) in the glial fibrillary acidic protein gene with unusual bilateral basal ganglia involvement

In this report, we describe the case of a new Japanese family (32 to 64years old; 2 females and 1 male) affected by adult-onset Alexander disease. Clinically, one member (age at onset, 56years old) developed cerebellar ataxia, another (age at onset, 55years old) showed cerebellar ataxia and pseudobulbar signs, and one member (32years 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.

Acute onset of adult Alexander disease

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.

Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant

BackgroundWe studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander’s disease (AOAD), suggesting different expression of the same, genetically determined, condition.MethodsSince mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells.ResultsExome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene.ConclusionsExome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.

耳クリック音をみとめたprogressive ataxia and palatal tremor（PAPT）の一例

A 71-year-old man noted clicking sounds in the ear. At the age of 75, he developed progressive unsteadiness of gait and became unable to walk without assistance at the age of 76. There was no family history of neurologic illness. Neurological examination revealed truncal ataxia and 1-2 Hz rhythmic palatal tremor, which persisted during sleep. Consistently, brain magnetic resonance imaging showed mild cerebellar atrophy and increased signal intensity of bilateral inferior olivary nuclei on T2-weighted image. progressive ataxia and palatal tremor (PAPT) has recently been described as a rare sporadic neurodegenerative disease and the features of our case consistent with those of PAPT. However, for correct diagnosis of PAPT, multiple system atrophy, spinocerebellar ataxia, progressive supranuclear palsy or adult-onset Alexander's disease should be carefully ruled out.

Adult-onset Alexander disease with an R66Q mutation in GFAP presented with severe vocal cord paralysis during sleep

Adult-onset Alexander disease (AOAD) is clinically characterized by slowly progressive bulbar palsy, pyramidal signs, spastic paresis and cerebellar ataxia with atrophy of the medulla oblongata and upper cervical cord, and the glial fibrillary acidic protein (GFAP) gene has been identified to be the causative gene for Alexander disease [3]. So far, some reports have mentioned that AOAD presents with sleep apnea [1, 4, 5, 8–10, 12], but the apnea mechanism is not sufficiently known. Here, we report an AOAD patient presented with vocal cord paralysis during sleep. This is the first report indicating that AOAD presented with vocal cord abductor paralysis, followed by the rapid progression of vocal cord dysfunction. A 61-year-old woman was admitted to our hospital because of gait disturbance over a 4-year period. She has been described as ‘‘round shouldered’’ since childhood and would snore loudly while sleeping since her early 30 s. Her family history revealed that even her mother snored loudly and died because of unknown reason at 54 years of age. The patient had a short neck and cervical kyphosis. Neurological examination revealed slurred speech, spasticities of all extremities, and bilateral extensor Babinski signs. MRI findings revealed atrophy of the upper cervical cord and medulla oblongata. Axial imaging of the medulla oblongata showed multiple T2-weighted high-intensity lesions. Her cerebral blood flow on ECD-SPECT was reported previously [7]. Mutational analysis revealed a previously reported heterozygous missense mutation at exon 1 of GFAP, c.197G[A, which involved the substitution of glutamine for arginine at the 66th codon (R66Q) (Fig. 1a) [11]. We confirmed the diagnosis of AOAD. Polysomnography revealed obstructive sleep apnea syndrome with 292 apneic episodes at night (245 obstructivetype and 47 mixed-type). Although her mean percutaneous oxygen saturation during wakefulness was 94 %, her mean saturation during sleep was 84 %. Her apnea–hypopnea index (AHI) was 52.2/h indicating severe apnea syndrome. To investigate the mechanism of her apnea, we examined her laryngeal movement during wakefulness and sleep induced by intravenous administration of diazepam [6]. Awake-laryngofiberscopy showed mild vocal cord abduction restriction during inspiration. After intravenous diazepam administration (5 mg), the vocal cords showed paradoxical movement with obstruction during inspiration. To avoid fatal outcome Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6540-4) contains supplementary material, which is available to authorized users.

The Ocular Motor Features of Adult-Onset Alexander Disease: A Case and Review of the Literature

A 51-year-old Chinese man presented with gaze-evoked nystagmus, impaired smooth pursuit and vestibular ocular reflex cancellation, and saccadic dysmetria, along with a family history suggestive of late-onset autosomal dominant parkinsonism. MRI revealed abnormalities of the medulla and cervical spinal cord typical of adult-onset Alexander disease, and genetic testing showed homozygosity for the p.D295N polymorphic allele in the gene encoding the glial fibrillary acidic protein. A review of the literature shows that ocular signs are frequent in adult-onset Alexander disease, most commonly gaze-evoked nystagmus, pendular nystagmus, and/or oculopalatal myoclonus, and less commonly ptosis, miosis, and saccadic dysmetria. These signs are consistent with the propensity of adult-onset Alexander disease to cause medullary abnormalities on neuroimaging.

A Rosenthal Fiber Encephalomyelopathy Resembling Alexander’s Disease in 3 Sheep

We report an encephalomyelopathy in three 18-month-old Merino sheep with features of adult-onset Alexander's disease (AD), a human primary astrocytic disorder. The signature histologic finding was the presence of numerous hypereosinophilic, intra-astrocytic inclusions (Rosenthal fibers), mainly in perivascular, subpial, and subependymal sites, especially in the caudal brain stem and spinal cord. Although AD usually results from mutations in the glial fibrillary acidic protein (GFAP) gene, no such mutation was detected in these sheep. However, the annual clinical presentation of this disorder in a few sheep in the affected flock is suggestive of a familial pattern of occurrence.

MS-like presentation of Alexander disease with multifocal lesions and oligoclonal bands

Alexander disease is a leukodystrophy characterized by Rosenthal fiber accumulation, which is caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP) [1]. Depending on the age at onset, three subtypes (infantile-, juvenile-, and adult-onset) can be distinguished [1], characterized by different phenotypes. Once considered a rare condition, recent studies reveal an increasing number of cases of the adult-onset condition with pseudobulbar signs, ataxia, and spasticity and abnormalities in the medulla and upper cervical cord on neuroimaging [2, 3]. We present MR imaging of a patient with a novel mutation in the GFAP gene and CSF inflammatory signs that broadens the clinical spectrum of adult-onset Alexander disease. A 43 year old woman was admitted to the Department of Neurology at the University Hospital Bonn complaining about recurrent singultus for 1 year and left-sided tonic seizures for 1 month. Cerebrospinal fluid analysis revealed CSF-specific oligoclonal bands without pleocytosis. MRI showed hyperintense T2 and FLAIR signal in the brainstem (Fig. 1a–e) and cervical cord (Fig. 1g) and a contrast-enhancing lesion in the medulla oblongata (Fig. 1f). Taking into account the CSF results, the diagnosis of a chronic inflammatory CNS disease was discussed. However, the patient did not respond to an i.v. course of methylprednisolone. The patient’s condition deteriorated slowly over the next year. She subsequently developed dysphagia, and recurrent vomiting. Repeated brain MRIs over 11 months did not show relevant change. Based on the MRI imaging, adult-onset Alexander disease was suspected. Subsequent genetic analysis of the GFAP gene revealed a novel missense mutation in exon 6 (c.1051G [ C; p.D351H positions according to RefSeq NM_002055) in heterozygous state. This mutation results in an amino acid exchange in codon 351 from aspartate to histidine and it was not detected in 1,038 control chromosomes in a cohort of ethnically matched healthy blood donors from Germany. Analysis of this new amino acid exchange is predicted as ‘‘disease causing’’ using the web-based mutation taster analysis tool [4]. In addition, one sequence variant in intron 3 in heterozygous state (c.619-35_-21del; 1/965 control chromosomes) as well as one polymorphism in exon 2 in heterozygous state (rs59291670) were detected, for which pathogenic impact is unlikely. H. J. Tschampa (&) S. Greschus H. Urbach Departments of Radiology and Neuroradiology, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany e-mail: Henriette.Tschampa@ukb.uni-bonn.de

Glial fibrillary acidic protein mutations in adult-onset Alexander disease: clinical features observed in 12 Japanese patients

To clarify the clinical manifestations of adult-onset Alexander disease (AOAD) in Japanese patients with glial fibrillary acidic protein (GFAP) gene mutations. Twelve patients of AOAD with GFAP mutations detected in our centre were examined for neurological and magnetic resonance imaging (MRI) findings. Major symptoms were pyramidal and bulbar signs. In addition, three patients presented abnormal behaviour and/or memory disturbance. Two of the three patients also had Parkinsonism and had been diagnosed with fronto-temporal dementia or progressive supranuclear palsy until GFAP mutations were detected. Abnormalities of the medulla oblongata and cervical spinal cord were observed on MRI in all patients. Patients presenting with pyramidal and/or bulbar signs with abnormalities of the medulla oblongata and cervical spinal cord on MRI should be considered for GFAP analysis as this is the typical presentation of AOAD. Abnormal behaviour and cognitive disorders including deterioration of memory were rare symptoms but could be an obstacle to diagnosing Alexander disease.

Poster 242: A Case Report of Adult Onset Alexander's Disease in an Acute Inpatient Rehabilitation Setting: A Case Report

Poster 242: A Case Report of Adult Onset Alexander's Disease in an Acute Inpatient Rehabilitation Setting: A Case Report

Adult-onset Alexander disease with typical "tadpole" brainstem atrophy and unusual bilateral basal ganglia involvement: a case report and review of the literature

BackgroundAlexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in GFAP that cause this disease, cases of adult-onset ALX have been increasingly reported.Case PresentationWe present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the GFAP gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX.ConclusionThe typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the GFAP gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.

An infantile case of Alexander disease unusual for its MRI features and a GFAP allele carrying both the p.Arg79His mutation and the p.Glu223Gln coding variant

An infantile case of Alexander disease unusual for its MRI features and a GFAP allele carrying both the p.Arg79His mutation and the p.Glu223Gln coding variant

Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature

Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem-spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4-year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading. The most frequent symptoms were related to bulbar dysfunction-with dysarthria, dysphagia, dysphonia (seven patients)-, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.

Can MR Imaging Diagnose Adult-Onset Alexander Disease?

In recent years, the discovery that mutations in the glial fibrillary acidic protein gene (GFAP) were responsible for Alexander disease (AD) brought recognition of adult cases. The purpose of this study was to demonstrate that MR imaging allows identification of cases of AD with adult onset (AOAD), which are remarkably different from infantile cases. In this retrospective study, brain and spinal cord MR imaging studies of 11 patients with AOAD (7 men, 4 women; age range, 26-64 years; mean age, 43.6 years), all but 1 genetically confirmed, were reviewed. Diffusion and spectroscopic investigations were available in 6 patients each. Atrophy and changes in signal intensity in the medulla oblongata and upper cervical spinal cord were present in 11 of 11 cases and were the diagnostic features of AOAD. Minimal to moderate supratentorial periventricular abnormalities were seen in 8 patients but were absent in the 3 oldest patients. In these patients, postcontrast enhancement was also absent. Mean diffusivity was not altered except in abnormal white matter (WM). Increase in myo-inositol (mIns) was also restricted to abnormal periventricular WM. Awareness of the MR pattern described allows an effective selection of the patients who need genetic investigations for the GFAP gene. This MR pattern even led to identification of asymptomatic cases and should be regarded as highly characteristic of AOAD.

Adult‐onset Alexander disease with palatal myoclonus and intraventricular tumour

Adult‐onset Alexander disease with palatal myoclonus and intraventricular tumour

Mild functional effects of a novel GFAP mutant allele identified in a familial case of adult-onset Alexander disease

Alexander disease is a neurological genetic disorder characterized by progressive white-matter degeneration, with astrocytes containing cytoplasmic aggregates, called Rosenthal fibers, including the intermediate filament glial fibrillary acidic protein (GFAP). The age of onset of the disease defines three different forms, infantile, juvenile and adult, all due to heterozygous GFAP mutations and characterized by a progressive less severe phenotype from infantile to adult forms. In an Italian family with a recurrent mild adult onset of Alexander disease, we have identified two GFAP mutations, coupled on a same allele, leading to p.[R330G; E332K]. Functional studies on this complex allele revealed less severe aggregation patterns compared to those observed with p.R239C GFAP mutant, associated with a severe Alexander disease phenotype. Moreover, in addition to confirming the involvement of the ubiquitin-proteasome system in cleaning cells from aggregates and a dominant effect of the novel mutant protein, in cells expressing the mild p.[R330G; E332K] mutant we have observed that indirect alphaB-crystallin overexpression, induced by high extracellular potassium concentration, could completely rescue the correct filament organization while, under the same experimental conditions, in cells expressing the severe p.R239C mutant only a partial rescue effect could be achieved.

Adult‐onset Alexander disease with progressive ataxia and palatal tremor

A novel glial fibrillary acidic protein (GFAP) mutation, Y257C, is reported in a patient with adult-onset Alexander disease. This is the oldest reported case with confirmation of a GFAP mutation. Onset was late in the sixth decade. Genetic analysis of the GFAP gene is recommended in cases of progressive ataxia and palatal tremor.

Adult-onset Alexander disease

Pathogenic, dominant, de novo missense mutations in the glial fibrillary acidic protein (GFAP) have been found in the three subtypes of infantile, juvenile and adult Alexander disease. Here we describe four members of an Italian family (32 to 66-yearsold, 2 women and 2 men) affected by adult Alexander disease, the least common and the most clinically variable form. Direct sequencing of all coding regions of the GFAP gene, neurological examination and brain MRI were performed. Two novel missense mutations were found involving two very close codons, c.[988C > G, 994G > A], leading to p.[Arg330Gly, Glu332Lys]. Clinically, two members exhibited pseudo-bulbar signs, gait ataxia and spasticity, one showed a severe cranial sensory symptomatology, and one subject was asymptomatic.Medulla and cervical cord atrophy was present in all of them on MRI. Although adult Alexander disease shows a wide clinical variability, a more frequent pattern can be identified characterized by bulbar or pseudo-bulbar signs, gait ataxia, and spasticity, and including on MRI medulla and cervical cord atrophy. Our findings also confirm that the clinical spectrum of adult Alexander disease includes cases without overt neurological involvement and with minimal brain MRI alterations.