Adult Alexander Disease With Autosomal Dominant Transmission

Abstract

The present study is the first demonstration of a mutation in GFAP that causes an autosomal dominant form of Alexander disease and establishes the existence of the adult variant. Clinical evaluation in individuals carrying mutation in the GFAP gene allowed a better definition of this heterogeneous clinical syndrome and will help increase its recognition in neurological practice.

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

“…In addition, GJA1 mRNA level, which is expressed mainly by astrocytes in neocortical areas (Yamamoto, Ochalski, Hertzberg, & Nagy, 1990), was higher in the combined psychiatric subjects than in controls, but not correlated with miR-21. Differences between control and psychiatric subjects regarding GFAP and GJA1 mRNA levels in WM, although in opposite directions, are consistent with the known roles of astrocytes in support of oligodendrocyte maturation and physiology, and the known myelin-destabilizing effects of GFAP alterations or astrocyte gap junction disturbance (Li, Giaume, & Xiao, 2014; Liedtke et al, 1996; Magnotti, Goodenough, & Paul, 2011; Sargiannidou, Markoullis, & Kleopa, 2010; Stumpf et al, 2003). Whether the correlation of GFAP mRNA and miR-21 levels reflects a causal relationship between these two factors or just a dependence on other depression related alterations remains to be determined.…”

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

“…In addition, GJA1 mRNA level, which is expressed mainly by astrocytes in neocortical areas (Yamamoto, Ochalski, Hertzberg, & Nagy, 1990), was higher in the combined psychiatric subjects than in controls, but not correlated with miR-21. Differences between control and psychiatric subjects regarding GFAP and GJA1 mRNA levels in WM, although in opposite directions, are consistent with the known roles of astrocytes in support of oligodendrocyte maturation and physiology, and the known myelin-destabilizing effects of GFAP alterations or astrocyte gap junction disturbance (Li, Giaume, & Xiao, 2014; Liedtke et al, 1996; Magnotti, Goodenough, & Paul, 2011; Sargiannidou, Markoullis, & Kleopa, 2010; Stumpf et al, 2003). Whether the correlation of GFAP mRNA and miR-21 levels reflects a causal relationship between these two factors or just a dependence on other depression related alterations remains to be determined.…”

Does genetic anticipation occur in familial Alexander disease?

“…An intriguing aspect of this family is that the age of symptom onset in the mother was greater than in the daughter by over two decades. Variable expressivity occurs in AxD [3,4], but here both mother and daughter had strikingly similar phenotypes. Whilst variable penetrance of the GFAP mutation could explain the daughter's much earlier age of onset, another possibility is genetic anticipation.…”

Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease

“…Though penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms, in adult-onset forms penetrance of GFAP variants is less clear and harder to study given the range in age of onset and phenotypic presentation. In a review of 293 individuals, 10 (3%) of those with an identifiable GFAP pathogenic variant were reported to be asymptomatic during the period of observation 11 31 65 93 94. Our study suggests that the penetrance of GFAP variants is incomplete, that there is under recognition or misdiagnosis of milder phenotypes of late-onset Alexander disease, or both.…”

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

“…In addition, GJA1 mRNA level, which is expressed mainly by astrocytes in neocortical areas (Yamamoto, Ochalski, Hertzberg, & Nagy, 1990), was higher in the combined psychiatric subjects than in controls, but not correlated with miR-21. Differences between control and psychiatric subjects regarding GFAP and GJA1 mRNA levels in WM, although in opposite directions, are consistent with the known roles of astrocytes in support of oligodendrocyte maturation and physiology, and the known myelin-destabilizing effects of GFAP alterations or astrocyte gap junction disturbance (Li, Giaume, & Xiao, 2014; Liedtke et al, 1996; Magnotti, Goodenough, & Paul, 2011; Sargiannidou, Markoullis, & Kleopa, 2010; Stumpf et al, 2003). Whether the correlation of GFAP mRNA and miR-21 levels reflects a causal relationship between these two factors or just a dependence on other depression related alterations remains to be determined.…”

Does genetic anticipation occur in familial Alexander disease?

“…An intriguing aspect of this family is that the age of symptom onset in the mother was greater than in the daughter by over two decades. Variable expressivity occurs in AxD [3,4], but here both mother and daughter had strikingly similar phenotypes. Whilst variable penetrance of the GFAP mutation could explain the daughter's much earlier age of onset, another possibility is genetic anticipation.…”

Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease

“…Though penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms, in adult-onset forms penetrance of GFAP variants is less clear and harder to study given the range in age of onset and phenotypic presentation. In a review of 293 individuals, 10 (3%) of those with an identifiable GFAP pathogenic variant were reported to be asymptomatic during the period of observation 11 31 65 93 94. Our study suggests that the penetrance of GFAP variants is incomplete, that there is under recognition or misdiagnosis of milder phenotypes of late-onset Alexander disease, or both.…”

MicroRNA-21: Expression in oligodendrocytes and correlation with low myelin mRNAs in depression and alcoholism

“…In addition, GJA1 mRNA level, which is expressed mainly by astrocytes in neocortical areas (Yamamoto, Ochalski, Hertzberg, & Nagy, 1990), was higher in the combined psychiatric subjects than in controls, but not correlated with miR-21. Differences between control and psychiatric subjects regarding GFAP and GJA1 mRNA levels in WM, although in opposite directions, are consistent with the known roles of astrocytes in support of oligodendrocyte maturation and physiology, and the known myelin-destabilizing effects of GFAP alterations or astrocyte gap junction disturbance (Li, Giaume, & Xiao, 2014; Liedtke et al, 1996; Magnotti, Goodenough, & Paul, 2011; Sargiannidou, Markoullis, & Kleopa, 2010; Stumpf et al, 2003). Whether the correlation of GFAP mRNA and miR-21 levels reflects a causal relationship between these two factors or just a dependence on other depression related alterations remains to be determined.…”

Does genetic anticipation occur in familial Alexander disease?

“…An intriguing aspect of this family is that the age of symptom onset in the mother was greater than in the daughter by over two decades. Variable expressivity occurs in AxD [3,4], but here both mother and daughter had strikingly similar phenotypes. Whilst variable penetrance of the GFAP mutation could explain the daughter's much earlier age of onset, another possibility is genetic anticipation.…”

Analysis of GFAP variants in UK Biobank suggests underdiagnosis or incomplete penetrance of adult-onset Alexander disease

“…Though penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms, in adult-onset forms penetrance of GFAP variants is less clear and harder to study given the range in age of onset and phenotypic presentation. In a review of 293 individuals, 10 (3%) of those with an identifiable GFAP pathogenic variant were reported to be asymptomatic during the period of observation 11 31 65 93 94. Our study suggests that the penetrance of GFAP variants is incomplete, that there is under recognition or misdiagnosis of milder phenotypes of late-onset Alexander disease, or both.…”