Alexander Disease (Alexander's Disease)

Rare leukoencephalopathy with infantile-onset accumulation of Rosenthal fibers in the subpial, periventricular, and subependymal zones of the brain. Rosenthal fibers are GLIAL FIBRILLARY ACIDIC PROTEIN aggregates found in ASTROCYTES. Juvenile- and adult-onset types show progressive atrophy of the lower brainstem instead. De novo mutations in the GFAP gene are associated with the disease with propensity for paternal inheritance.

Also Known As:

Networked: 153 relevant articles (2 outcomes, 8 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Neurodegenerative Diseases (Neurodegenerative Disease)
2.	Brain Ischemia (Cerebral Ischemia)
3.	Multiple Sclerosis
4.	Leukoencephalopathies
5.	Nervous System Diseases (Neurological Disorders)

Experts

1.	Messing, Albee: 17 articles (09/2015 - 03/2005)
2.	Goldman, James E: 11 articles (05/2014 - 03/2005)
3.	Brenner, Michael: 9 articles (12/2015 - 10/2004)
4.	Ceccherini, Isabella: 9 articles (06/2013 - 01/2008)
5.	Hagemann, Tracy L: 8 articles (01/2015 - 10/2006)
6.	Balbi, Pietro: 8 articles (01/2013 - 01/2008)
7.	Kanazawa, Naomi: 7 articles (01/2008 - 03/2003)
8.	Tsujino, Seiichi: 7 articles (01/2008 - 03/2003)
9.	Sechi, GianPietro: 6 articles (01/2014 - 03/2010)
10.	Bachetti, Tiziana: 6 articles (01/2013 - 04/2008)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Alexander Disease:

1.	Glial Fibrillary Acidic ProteinIBA 10/01/2010 - "Recent genetic studies identified heterozygous missense mutations in glial fibrillary acidic protein (GFAP), the major intermediate filament protein in astrocytes, as the cause of nearly all cases of Alexander disease. " 03/01/2003 - "Since the first report by Brenner et al. of mutations in the glial fibrillary acidic protein (GFAP) gene in patients with Alexander disease, several molecular genetic studies have been performed in different ethnic groups. " 12/01/2015 - "Alexander Disease (AxD) is a "gliopathy" caused by toxic, dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene. " 09/25/2014 - "Alexander disease (AxD) is the only known human pathology caused by mutations in an astrocyte-specific gene, glial fibrillary acidic protein (GFAP). " 07/01/2014 - "The child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease. "
2.	Proteins (Proteins, Gene)IBA 09/01/2009 - "These 20 kDa proteins have been implicated in neurodegenerative diseases like Alexander's disease, Creutzfeldt-Jacob disease, Alzheimer's disease, and Parkinson's disease. " 10/01/1991 - "The authors have analyzed the proteins of RFs from Alexander's disease and have found mono- and polyubiquitinated conjugates of alpha B-crystallin." 01/15/2014 - "The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander's disease. " 07/01/2008 - "The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). " 03/01/2015 - "Several of the most enriched proteins (plectin, glial fibrillar acidic protein, vimentin, Hsp 27, and ubiquitin) are known to form complex astrocytic inclusions, so-called Rosenthal fibers, in the neurodegenerative disorder Alexander disease. "
3.	Proteasome Endopeptidase Complex (Proteasome)IBA 04/02/2010 - "The accumulation of the intermediate filament protein, glial fibrillary acidic protein (GFAP), in astrocytes of Alexander disease (AxD) impairs proteasome function in astrocytes. " 12/15/2006 - "Synergistic effects of the SAPK/JNK and the proteasome pathway on glial fibrillary acidic protein (GFAP) accumulation in Alexander disease." 04/02/2010 - "Oligomers of mutant glial fibrillary acidic protein (GFAP) Inhibit the proteasome system in alexander disease astrocytes, and the small heat shock protein alphaB-crystallin reverses the inhibition." 07/01/2008 - "The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). " 08/01/2010 - "Alexander disease is a rare, untreatable and usually fatal neurodegenerative disorder caused by heterozygous mutations of the glial fibrillary acidic protein (GFAP) gene which ultimately lead to formation of aggregates, containing also alphaB-Crystallin, HSP27, ubiquitin and proteasome components. "
4.	Sirolimus (Rapamycin)FDA Link 07/01/2008 - "The proteasome system is responsible for unfolded, short-lived proteins, which precludes the clearance of oligomeric and aggregated proteins, whereas macroautophagy, a process generally referred to as autophagy, mediates mainly the bulk degradation of long-lived cytoplasmic proteins, large protein complexes or organelles.(1) Recently, the autophagy-lysosomal pathway has been implicated in neurodegenerative disorders as an important pathway for the clearance of abnormally accumulated intracellular proteins, such as huntingtin, tau and mutant and modified alpha-synuclein.(1-6) Our recent study illustrated the induction of adaptive autophagy in response to mutant glial fibrillary acidic protein (GFAP) accumulation in astrocytes, in the brains of patients with Alexander disease (AxD), and in mutant GFAP knock-in mouse brains.(7) This autophagic response is negatively regulated by mammalian target of rapamycin (mTOR). "
5.	Crystallins (Crystallin)IBA 04/01/2009 - "Suppression of GFAP toxicity by alphaB-crystallin in mouse models of Alexander disease." 02/01/2001 - "Ser-59 is the major phosphorylation site in alphaB-crystallin accumulated in the brains of patients with Alexander's disease." 02/01/2001 - "These results indicate that the major phosphorylation site in alphaB-crystallin in brains of patients with Alexander's disease or Alzheimer's disease as well as in aged controls is Ser-59." 10/17/2012 - "Recent studies have revealed that αB-crystallin plays a beneficial role in a mouse model of multiple sclerosis, brain ischemia, and Alexander disease. " 08/01/2012 - "Alexander disease (AxD) is pathologically characterized by the presence of Rosenthal fibers (RF), which are made up of GFAP, αB-crystallin and heat shock protein 27, in the cytoplasm of perivascular and subpial astrocyte endfeet. "
6.	Heat-Shock Proteins (Heat-Shock Protein)IBA 07/01/1995 - "In previous studies, an enhanced expression with abnormal phosphorylation of a low molecular weight heat shock protein, HSP27, was identified in reactive astrocytes and Rosenthal fibers in Alexander disease brain. " 08/01/1998 - "The increased amounts of stress proteins and GFAP results in the formation of Rosenthal fibers, similar to those found in Alexander's disease." 12/01/1993 - "Overexpression and abnormal modification of the stress proteins alpha B-crystallin and HSP27 in Alexander disease." 08/01/1993 - "In addition, Western blotting of Alexander's disease brain homogenates revealed that the 27-kd heat shock protein (HSP27), which is related to alpha B-crystallin, accumulates along with alpha B-crystallin. " 01/01/2014 - "Alexander disease (AxD) is a neurodegenerative disorder with prominent white matter degeneration and the presence of Rosenthal fibers containing aggregates of glial fibrillary acidic protein (GFAP), and small stress proteins HSP27 and αB-crystallin, and widespread reactive gliosis. "
7.	AntibodiesIBA 02/01/2001 - "Immunohistochemically, alphaB-crystallin was stained in Rosenthal fibers in brains of patients with Alexander's disease and their peripheral portions were immunostained with antibodies recognizing phosphorylated Ser-59. " 03/16/1998 - "In all the cases of Alexander's disease examined, strong immunolabeling of RF by the antibodies to 4-hydroxy-2-nonenal pyrrole adducts were noted. " 01/01/2010 - "Alexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). " 03/16/1998 - "In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. " 02/01/2001 - "The phosphorylation state of alphaB-crystallin accumulated in the brains of two patients with Alexander's disease (one infantile and one juvenile type) was determined by means of SDS-PAGE or isoelectric focusing of soluble and insoluble fractions of brain extracts and subsequent western blot analysis with specific antibodies against alphaB-crystallin and each of three phosphorylated serine residues. "
8.	Peroxidase (Myeloperoxidase)IBA 01/01/1983 - "Light- and electron-microscopic and immunohistochemical studies revealed that (1) the granular osmiophilic deposits (GOD) in Alexander's disease accumulate mainly in astrocytic processes to form Rosenthal fibers, (2) the Bergmann glia are different in this regard and accumulate the deposits primarily in their perikarya, (3) the Müller cells of retina (which closely resemble astrocytes) do not accumulate GOD, (4) the deposits are also not present in other glial cells and glial-like cells such as pituicytes and pineocytes, (5) the deposits are sparse in the retrobulbar optic nerves, and (6) the peroxidase-antiperoxidase and immunofluorescence studies do not demonstrate glial fibrillary acidic protein (GFAP), albumin, immunoglobulins, or fibrinogen in the astrocytic deposits. "
9.	Lysine (L-Lysine)FDA Link 03/16/1998 - "In this study, we immunohistochemically examined three cases of Alexander's disease using antibodies to a lysine-derived pyrrole modification arising from 4-hydroxy-2-nonenal, a highly cytotoxic reactive aldehyde produced by lipid peroxidation. "
10.	Immunoglobulins (Immunoglobulin)IBA 01/01/1983 - "Light- and electron-microscopic and immunohistochemical studies revealed that (1) the granular osmiophilic deposits (GOD) in Alexander's disease accumulate mainly in astrocytic processes to form Rosenthal fibers, (2) the Bergmann glia are different in this regard and accumulate the deposits primarily in their perikarya, (3) the Müller cells of retina (which closely resemble astrocytes) do not accumulate GOD, (4) the deposits are also not present in other glial cells and glial-like cells such as pituicytes and pineocytes, (5) the deposits are sparse in the retrobulbar optic nerves, and (6) the peroxidase-antiperoxidase and immunofluorescence studies do not demonstrate glial fibrillary acidic protein (GFAP), albumin, immunoglobulins, or fibrinogen in the astrocytic deposits. "

Therapies and Procedures

1.	Bone Marrow Transplantation (Transplantation, Bone Marrow) 08/01/1997 - "In this case report, we evaluate the efficacy of allogeneic bone marrow transplantation (BMT) in a 7-month-old female with the infantile form of Alexander's disease. " 08/01/1997 - "Allogeneic bone marrow transplantation for Alexander's disease."
2.	Ventriculoperitoneal Shunt 09/01/2003 - "A 20-month-old infant with hydrocephalus secondary to Alexander's disease developed erosion of her parieto-occipital ventriculoperitoneal shunt reservoir through an occipital decubitus scalp ulceration. "
3.	Transplantation (Transplant Recipients) 08/01/1997 - "Marrow transplantation was not effective in changing her prognosis with Alexander's disease." 08/01/1997 - "Based on research that describes Alexander's disease as a leukodystrophy which may result from an unidentified enzyme deficiency, we attempted marrow transplantation to reverse or arrest the patient's neurological deterioration. "