Late-onset Alexander disease with a V87L mutation in glial fibrillary acidic protein (GFAP) and calcifying lesions in the sub-cortex and cortex

Suzuki, Hidekazu; Yoshida, Tomokatsu; Kitada, Mari; Ichihashi, Juri; Sasayama, Hiroshi; Nishikawa, Yoshiro; Mistui, Yoshiyuki; Nakagawa, Masanori; Kusunoki, Susumu

doi:10.1007/s00415-011-6201-z

Cited by 6 publications

(3 citation statements)

References 13 publications

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“…As we said cerebral calcification represent a useful diagnostic hint, but they should be carefully evaluated when found in advanced disease stages because in these cases it could become a confounding factor. Calcium deposition indeed can be secondary to white matter degeneration and can be observed in advanced stages of some leukodystrophies not usually characterized by cerebral calcification such as X-linked adrenoleukodystrophy [ 24 – 26 ] or Alexander disease [ 27 – 30 ]. This was the case of one patient of our series who was referred for diagnostic work-up of a severe leukodystrophy with cerebral calcification.…”

Section: Discussionmentioning

confidence: 99%

Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Tonduti

Panteghini

Pichiecchio³

et al. 2018

Orphanet J Rare Dis

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BackgroundWe present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses.MethodsWe collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification.ResultsWe collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two.ConclusionsGenetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

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Section: Discussionmentioning

confidence: 99%

Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Tonduti

Panteghini

Pichiecchio³

et al. 2018

Orphanet J Rare Dis

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“…Further recognized causes of a PAPT syndrome such as GFAP mutations[14, 15] and celiac disease[16] were excluded in our patient, whereas SCA20[17] is unlikely in our patient, as there was no family history, and imaging in SCA20 shows isolated dentate calcification (“dark dentate disease”).…”

mentioning

confidence: 91%

Progressive ataxia and palatal tremor associated with dense pontine calcification: A unique case

Stamelou

Adams

Davagnanam³

et al. 2013

Movement Disorders

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“…According to the American College of Medical Genetics and Genomic Guidelines, this variant can be classified as likely pathogenic (13). Indeed, i) the c.260T > A in GFAP we found in the proband and her mother has never been described to date, either in general population or AxD cases (pathogenic moderate criteria 2, PM2); ii) it is in a mutational hot spot domain of the protein (pathogenic moderate criteria 1, PM1), iii) it is considered pathogenic by the most relevant pathogenicity scores (MetaLR 0.94; Revel 0.93) (pathogenic supporting criteria 3, (PP3); iv) different amino acidic changes at the same codon (p. Val87Ile; p.Val87Leu; p.Val87Gly) were previously described in late-onset AxD patients (pathogenic moderate criteria 5, PM5) (8,(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Case report: A novel mutation of glial fibrillary acidic protein gene causing juvenile-onset Alexander disease

Romano,

Morena,

Petrucci

et al. 2024

Front. Neurol.

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Alexander disease (AxD) is a rare inherited autosomal dominant (AD) disease with different clinical phenotypes according to the age of onset. It is caused by mutations in the glial fibrillary acid protein (GFAP) gene, which causes GFAP accumulation in astrocytes. A wide spectrum of mutations has been described. For some variants, genotype–phenotype correlations have been described, although variable expressivity has also been reported in late-onset cases among members of the same family. We present the case of a 19-year-old girl who developed gait ataxia and subtle involuntary movements, preceded by a history of enuresis and severe scoliosis. Her mother has been affected by ataxia since her childhood, which was then complicated by pyramidal signs and heavily worsened through the years. Beyond her mother, no other known relatives suffered from neurologic syndromes. The scenario was further complicated by a complex brain and spinal cord magnetic resonance imaging (MRI) pattern in both mother and daughter. However, the similar clinical phenotype made an inherited cause highly probable. Both AD and autosomal recessive (AR) ataxic syndromes were considered, lacking a part of the proband’s pedigree, but no causative genetic alterations were found. Considering the strong suspicion for an inherited condition, we performed clinical exome sequencing (CES), which analyzes more than 4,500 genes associated with diseases. CES evidenced the new heterozygous missense variant c.260 T > A in exon 1 of the glial fibrillary acidic protein (GFAP) gene (NM_002055.4), which causes the valine to aspartate amino acid substitution at codon 87 (p. Val87Asp) in the GFAP. The same heterozygous variant was detected in her mother. This mutation has never been described before in the literature. This case should raise awareness for this rare and under-recognized disease in juvenile–adult cases.

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Late-onset Alexander disease with a V87L mutation in glial fibrillary acidic protein (GFAP) and calcifying lesions in the sub-cortex and cortex

Cited by 6 publications

References 13 publications

Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Encephalopathies with intracranial calcification in children: clinical and genetic characterization

Progressive ataxia and palatal tremor associated with dense pontine calcification: A unique case

Case report: A novel mutation of glial fibrillary acidic protein gene causing juvenile-onset Alexander disease

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