Does genetic anticipation occur in familial Alexander disease?

AbstractAlexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent–offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.

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Alexander Disease

Journal of Child Neurology ◽

10.1177/0883073816673263 ◽

2016 ◽

Vol 32 (2) ◽

pp. 184-187 ◽

Cited By ~ 6

Author(s):

Ali Tavasoli ◽

Thais Armangue ◽

Cheng-Ying Ho ◽

Matthew Whitehead ◽

Miriam Bornhorst ◽

...

Keyword(s):

White Matter ◽

Glial Fibrillary Acidic Protein ◽

Structural Changes ◽

Correct Diagnosis ◽

Alexander Disease ◽

Acidic Protein ◽

Missense Mutations ◽

Focal Lesions ◽

Gene Encoding ◽

Protein Mutation

Alexander disease is a leukodystrophy caused by dominant missense mutations in the gene encoding the glial fibrillary acidic protein. Individuals with this disorder often present with a typical neuroradiologic pattern including white matter abnormalities with brainstem involvement, selective contrast enhancement, and structural changes to the basal ganglia/thalamus. In rare cases, focal lesions have been seen and cause concern for primary malignancies. Here the authors present an infant initially diagnosed with a chiasmatic astrocytoma that was later identified as having glial fibrillary acidic protein mutation-confirmed Alexander disease. Pathologic and radiologic considerations that were helpful in arriving at the correct diagnosis are discussed.

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Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease

Annals of Neurology ◽

10.1002/ana.20406 ◽

2005 ◽

Vol 57 (3) ◽

pp. 310-326 ◽

Cited By ~ 158

Author(s):

Rong Li ◽

Anne B. Johnson ◽

Gajja Salomons ◽

James E. Goldman ◽

Sakkubai Naidu ◽

...

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Alexander Disease ◽

Acidic Protein ◽

Protein Mutations

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Glial fibrillary acidic protein exhibits altered turnover kinetics in a mouse model of Alexander disease

Journal of Biological Chemistry ◽

10.1074/jbc.m116.772020 ◽

2017 ◽

Vol 292 (14) ◽

pp. 5814-5824 ◽

Cited By ~ 12

Author(s):

Laura R. Moody ◽

Gregory A. Barrett-Wilt ◽

Michael R. Sussman ◽

Albee Messing

Keyword(s):

Mouse Model ◽

Glial Fibrillary Acidic Protein ◽

Alexander Disease ◽

Acidic Protein

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Alexander Disease: Role of Glial Fibrillary Acidic Protein

Tumors of the Central Nervous System - Tumors of the Central Nervous System, Volume 13 ◽

10.1007/978-94-007-7602-9_22 ◽

2013 ◽

pp. 215-221

Author(s):

Tomokatsu Yoshida ◽

Masanori Nakagawa

Keyword(s):

Glial Fibrillary Acidic Protein ◽

Alexander Disease ◽

Acidic Protein

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Refining the concept of GFAP toxicity in Alexander disease

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-019-9290-0 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 4

Author(s):

Albee Messing

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glial Fibrillary Acidic Protein ◽

Intermediate Filament ◽

Alexander Disease ◽

Acidic Protein ◽

Sequence Variants ◽

Main Body ◽

Gain Of Function ◽

The Central Nervous System

Abstract Background Alexander disease is caused by dominantly acting mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes in the central nervous system. Main body In addition to the sequence variants that represent the origin of disease, GFAP accumulation also takes place, together leading to a gain-of-function that has sometimes been referred to as “GFAP toxicity.” Whether the nature of GFAP toxicity in patients, who have mixtures of both mutant and normal protein, is the same as that produced by simple GFAP excess, is not yet clear. Conclusion The implications of these questions for the design of effective treatments are discussed.

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