Late onset Alexander’s disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene

Schmidt, Saskia; Wattjes, Mike P.; Gerding, Wanda M.; Knaap, Marjo van der

doi:10.1007/s00415-010-5849-0

Cited by 13 publications

(5 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…15,16 Some atypical imaging features were reported, like focal lesions, abnormal signals in cerebellum and calcifying lesions in the sub-cortex and cortex. [17][18][19] The survival analysis in Prust's study revealed a mean survival of 25.0 ± 2.1 years. It was reported that half of the late-onset cases were familial, whereas familial cases are very rare in infantile type.…”

Section: Phenotype Of Patientsmentioning

confidence: 96%

Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations

et al. 2013

View full text Add to dashboard Cite

To delineate the phenotype and genotype in Chinese children with type I Alexander disease (AxD) and the parental origin of de novo glial fibrillary acidic protein (GFAP) mutations. Twenty-two children with clinically diagnosed type I AxD were followed up for 1.66-6.62 years. Allele-specific PCR was used for the analysis of parental origin of the allele harboring the de novo mutation. Phenotype of these patients were consistent with type I AxD described in other population, with developmental delay (motor delay in 81.82%, cognitive delay in 63.64%), macrocephaly (100%), seizures (95.45%), paroxysmal deterioration (27.27%) and typical brain magnetic resonance imaging (100%). Progression was slower than reported. At 8.55 years of age (5.29-13.25), all patients who underwent the second follow-up were alive. Eleven heterozygous missense mutations of GFAP were identified in 21 patients, with three novel mutations. Reported hot spot mutations, p.R79, p.R239 and p.R88, were also identified in Chinese patients. Mutations were de novo in all but one case. The mother of a proband was demonstrated to be a presymptomatic patient with type II AxD with a p.R79H mutation. Ninety percent of de novo mutations were on the paternal allele demonstrated by allele-specific PCR. This is the largest follow-up study on Chinese children with AxD. The phenotypes of these patients are consistent with reports in other populations. GFAP mutations were identified in 95.46% of Chinese children with clinically diagnosed type I AxD. Our data suggested a male germ-line transmission.

show abstract

Section: Phenotype Of Patientsmentioning

confidence: 96%

Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Detection of Rosenthal fibers through cerebral biopsy is considered to be one of the best diagnostic approaches. However, most putative AxD patients with GFAP mutations did not undergo cerebral biopsy [ 12 – 14 ] as it is an invasive procedure. In addition, Rosenthal fibers are not a pathognomonic feature of AxD because they are also occasionally found in astrocytic tumors, ependymoma, hamartomas, craniopharyngioma, pineal cysts, glial scars and multiple sclerosis [ 3 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model

et al. 2017

View full text Add to dashboard Cite

BackgroundAlexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient’ CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease-causing.MethodsWe found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year-old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos.ResultsThe most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP.ConclusionsThe p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing.

show abstract

“…Basal ganglia involvement is a diagnostic feature for infantile and juvenile forms of the disease but it is an uncommon finding in the adult-onset form of the disease, although it has been reported occasionally in the literature (6,11,12,13,14,15,16). Signal changes in the putamen and globus pallidus were observed bilaterally and unilaterally in the MRI of cases 1 and 3, respectively.…”

Section: Discussionmentioning

confidence: 91%

Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases

Elmalı

Çetinçelik²,

Işlak

et al. 2016

Arch Neuropsychiatr

View full text Add to dashboard Cite

The adult-onset Alexander disease (AOAD) dramatically differs from the early onset AD with respect to clinical and neuroradiological findings. Herein we report the detailed clinical and neuroradiological findings of a Turkish family with AOAD. In all three cases, magnetic resonance imaging revealed marked atrophy of the mesencephalon, bulbus, and cervical spinal cord accompanied with signal abnormalities in the same regions along with supratentorial white matter. Basal ganglia were affected in two cases. Molecular genetic analysis revealed heterozygous mutation in the 8th exon of the glial fibrillary acidic protein gene M451I (c.1245G>A), leading to the diagnosis of AOAD in all cases.

show abstract

Late onset Alexander’s disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene

Cited by 13 publications

References 11 publications

Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations

Follow-up study of 22 Chinese children with Alexander disease and analysis of parental origin of de novo GFAP mutations

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model

Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases

Contact Info

Product

Resources

About