Neurobehavioral characterization of adult-onset Alexander disease: A family study.
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SUBMITTER: Lichtenstein ML
PROVIDER: S-EPMC5874457 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC4909559 | biostudies-literature
Project description:Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0-2 years), juvenile (2-13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.
| S-EPMC6851058 | biostudies-literature
Project description:Alexander disease (AxD) is a rare neurological disease, especially in adults. It shows variable clinical and radiological features.We diagnosed a female with AxD presenting with paroxysmal numbness of the limbs at the onset age of 28-year-old, progressing gradually to spastic paraparesis at age 30. One year later, she had ataxia, bulbar paralysis, bowel and bladder urgency. Her mother had a similar neurological symptoms and died within 2 years after onset (at the age of 47), and her maternal aunt also had similar but mild symptoms at the onset age of 54-year-old. Her brain magnetic resonance imaging (MRI) showed abnormal signals in periventricular white matter with severe atrophy in the medulla oblongata and thoracic spinal cord, and mild atrophy in cervical spinal cord, which is unusual in the adult form of AxD. She and her daughter's glial fibrillary acidic protein (GFAP) gene analysis revealed the same heterozygous missense mutation, c.1246C?>?T, p.R416W, despite of no neurological symptoms in her daughter.Our case report enriches the understanding of the familial adult AxD. Genetic analysis is necessary when patients have the above mentioned symptoms and signs, MRI findings, especially with family history.
| S-EPMC5097349 | biostudies-literature
Project description:IntroductionAlexander disease is caused by mutations in GFAP, the glial fibrillary acidic protein gene. External laryngeal tremor has not been reported in adult-onset Alexander disease (AOAxD). The aims of this work were to report one such case and to review the literature on palatopharyngeal tremor and AOAxD.Case presentationA 43-year-old man experienced involuntary movements at the front of his neck. Continuous, rhythmic vertical movements of the laryngeal skeleton, soft palate and tongue, and lower limb dysmetria were observed. The pathogenic GFAP variant c.994G>A; p.(Glu332Lys) was found. MRI demonstrated spinal cord and medulla oblongata atrophy and hyperintensities at the cerebellum and cerebral white matter.ConclusionExternal laryngeal, palatopharyngeal tremor and cerebellar ataxia constituted a mild phenotype, as expected from this variant, herein reported in isolation for the third time. Imaging was consistent with AOAxD, including the so-called tadpole sign. Additional studies are necessary to define this infrequent disease.
| S-EPMC11249790 | biostudies-literature
Project description:ObjectiveTo characterize Alexander disease (AxD) phenotypes and determine correlations with age at onset (AAO) and genetic mutation. AxD is an astrogliopathy usually characterized on MRI by leukodystrophy and caused by glial fibrillary acidic protein (GFAP) mutations.MethodsWe present 30 new cases of AxD and reviewed 185 previously reported cases. We conducted Wilcoxon rank sum tests to identify variables scaling with AAO, survival analysis to identify predictors of mortality, and ?(2) tests to assess the effects of common GFAP mutations. Finally, we performed latent class analysis (LCA) to statistically define AxD subtypes.ResultsLCA identified 2 classes of AxD. Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features. Type II is characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features. Survival analysis predicted a nearly 2-fold increase in mortality among patients with type I AxD relative to those with type II. R79 and R239 GFAP mutations were most common (16.6% and 20.3% of all cases, respectively). These common mutations predicted distinct clinical outcomes, with R239 predicting the most aggressive course.ConclusionsAAO and the GFAP mutation site are important clinical predictors in AxD, with clear correlations to defined patterns of phenotypic expression. We propose revised AxD subtypes, type I and type II, based on analysis of statistically defined patient groups.
| S-EPMC3179649 | biostudies-literature
Project description:ObjectiveTo describe the imaging and clinical features in type II (late-onset) Alexander disease (AxD).MethodsWe 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.ResultsThirteen 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.ConclusionsOur 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.
| S-EPMC3873623 | biostudies-literature
Project description: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.
| S-EPMC10864087 | biostudies-literature
Project description:BackgroundKrabbe disease (KD) is a rare autosomal recessive lysosomal storage disorder caused by deficiency of the galactocerebrosidase (GALC) enzyme. The adult-onset KD is infrequent, and often presenting with slowly progressive spastic paraplegia. Herein, we describe a two-generation concomitant Chinese pedigree of adult-onset KD in which the proband presented with acute hemiplegia at onset.MethodsWe collected the clinical and neuroimaging data of the pedigree. GALC enzyme activity detection and gene analysis were performed to confirm the diagnosis. Moreover, we reviewed all studies available on PubMed to understand the correlationship between phenotype and genotype of the identified mutations.ResultsThe proband presented with sudden-onset weakness of left limbs with selective pyramidal tract involvement on diffusion-weighted imaging (DWI) of brain MRI. The GALC enzyme activity of him was low, and the GALC gene analysis revealed compound heterozygous pathogenic mutations of c.1901T>C and c.1901delT. More interestingly, the homozygous c.1901T>C mutations were found in the proband's asymptomatic father and two paternal uncles. Meanwhile, the literature review revealed the c.1901T>C mutation was only found in the late-onset form of KD.ConclusionsThese observations, combined with previous reports, indicate that KD should be considered in the adult patients presenting selective pyramidal tract impairment even with sudden onset.
| S-EPMC5994525 | biostudies-literature
Project description:Alexander disease (AD) is an autosomal dominant leukodystrophy which predominantly affects infants and children. The infantile form comprises the most common form of AD. It presents before two years of age and characterized by macrocephaly, psychomotor regression, spasticity, pyramidal sign, ataxia and seizures. The diagnosis is based on magnetic resonance imaging (MRI) findings and confirmed by Glial fibrillary acidic protein (GFAP) gene molecular testing. We report an Indian case with normal head circumference.
| S-EPMC4290301 | biostudies-literature
Project description:We 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.Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-?, 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.Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-?, 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.Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.
| S-EPMC3654953 | biostudies-literature