User:Gmk625/sandbox
Alexander Disease Review
[edit]Yes the article has appropriate and reliable sources. I checked a few sources and some pages were not found KatieWilhelmus (talk) 02:17, 8 November 2016 (UTC)Katie Wilhelmus
Topics to consider adding: -age of onset -mode of inheritance -ethnic/racial bias -explain symptoms in lay terms Gmk625 (talk) 02:36, 8 November 2016 (UTC)
I added to treatment since there was not a lot of information there to begin with: Hydrocephaly may been seen in younger patients and can be relieved with surgery or implanting a shunt to relieve pressure[17]. " [1] KatieWilhelmus (talk) 19:52, 15 November 2016 (UTC)KatieWilhelmusKatieWilhelmus (talk) 19:52, 15 November 2016 (UTC)
General Description
[edit]Alexander disease was first reported in 1949 by a physician named W. Stewart Alexander.[2] The discovery of the genetic base of Alexander disease was what really showed that this disorder is of a CNS cell type.[3] Alexander disease is a form of leukodystrophy that progressively affects cerebral white matter of the brain.[4][5] It has been shown that there are many astrocytic accumulations of eosinophilic cytoplasmic inclusions.[3] These were leveled as Rosenthal fibers by pathologists[3] The dominant gain of function mutations in the glial fibrillary acidic protein (GFAP) gene cause Alexander disease.[3] The clinical presentations of Alexander disease are varied depending on the age of onset.[4] The first reported patient was a 16-month old boy who died from progressive development of megalencephaly, hydrocephalus, and psychomotor delays.[3] The clinical hallmark of Alexander disease is close to that of Canavan disease.[6] Infant will commonly show a development of megalencephaly along with spasticity and dementia.[6] The later–onset cases of Alexander disease often show a slower clinical progression.[4] In infants this variety encompasses apporoximatly 42% of the afflicted, and the juvenile form roughly 22%, meanwhile the adult form contains approximately 33%.[4] Kny1216 (talk) 22:47, 30 November 2016 (UTC)Kny1216 (talk) 01:45, 1 December 2016 (UTC)
Modes of Inheritance and Symptoms
[edit]Alexander Disease is a rare autosomal dominant genetic disorder of the nervous system that involves destructing the myelin and other nervous system functions. Autosomal Dominant means that the mutated gene is located on an autosome, which is not a sex chromosome, and is dominant to the normal allele.[6] There are three types of Alexander disease, which are diagnosed by the difference in the age of onset, but most cases are seen before age 2.[6]
The most common symptoms seen with Alexander disease are delays in physical, mental and behavioral development, seizures and an enlarged brain. [2] There is usually both mental and physical developmental delays, such as lack of developmental milestones.[7] Alexander disease is characterized by homogeneous eosinophilic masses called Rosenthal fibers. These fibers usually form throughout the surfaces of the brain and brain-stem.[2] The Rosenthal fibers are located in astrocytes, which are cells that mimic blood vessels. These fibers produce a toxic a key feature of Alexander disease, which is demyelination of the brain.[2] KatieWilhelmus (talk) 20:10, 15 November 2016 (UTC)KatieWilhelmus
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Kny1216 (talk) 17:39, 30 November 2016 (UTC)
Prevalence
[edit]Alexander disease is very rare.[4] The estimated frequency of occurrence is about 1 in 1 million.[2] To date, there have been over 550 cases of Alexander disease reported.[4] However there are not any actual frequency of occurrence statistics published. There is no indication that Alexander disease has an ethnic, geographic, racial, or gender bias.[2][3] At first, Alexander disease appeared to primarily occur in the early onset. However, it is now being seen in almost all age groups with approximately the same frequency.[2] Kny1216 (talk) 16:24, 30 November 2016 (UTC) Kny1216 (talk) 17:46, 30 November 2016 (UTC)
Genetic Testing
[edit]Since Alexander Disease is an autosomal dominant disorder, any child of an affected parent has a 50% chance of inheriting that particular GFAP variant. However, if this disease came about in a child due to a de novo mutation and not due to an affected parent, the likelihood of other siblings within that family also having Alexander Disease is significantly less [4]. Prenatal testing is available to those who have already had a child with the disease and were able to determine the particular mutation that caused the disease.[2]Gmk625 (talk) Gmk625 (talk) 17:20, 25 November 2016 (UTC)
Therapy and Treatment
[edit]Unfortunately, there is no cure for Alexander Disease [7] As far as treatment goes, it is pretty variable among patients due to the fact that patients may experience a subset of an assortment of symptoms. Along with this variability, patients may also experience systems at different periods throughout their lifetime than other patients[7]. Gmk625 (talk) 17:38, 25 November 2016 (UTC)
Supportive treatment of this disease usually requires special attention to overall care and nutritional status of the patient. Especially concerned with proper growth, regular check-ups to examine strength and mobility are essential. While physical and occupational therapy are used accordingly to help with day-to-day hurdles, cognitive assessments are also important to determine communication and learning disabilities[4]. Since seizures are another common symptom to manifest in Alexander patients, special antiepileptic drugs can be prescribed to help with this neurological ailment[4]. Gmk625 (talk) 17:38, 25 November 2016 (UTC)
A few other alternative strategies for treatment may also be available. The initial approach would be to avoid the disease all together by reducing the build-up of GFAP[3]. Since toxicity becomes an issue with the accumulation of GFAP, another approach would be to target the downstream effects of GFAP, such as the reduction in expression of another gene, GLT-1. A clinical trial for ALS used the antibiotic ceftriaxone to help drive GLT-1 expression, and other researchers are thinking this drug may be yet another appropriate approach to help Alexander patients [8]. Gmk625 (talk) 17:35, 25 November 2016 (UTC)Kny1216 (talk) 01:55, 1 December 2016 (UTC)
Gene Name/ Protein Name
[edit]Alexander Syndrome is caused by a de novo (spontaneous) mutation in a gene called GFAP [9]. The GFAP gene codes for a protein called glial fibrillary acidic protein[10]. GFAP is a 432 amino acid protein that has a molecular weight of 55kDa and consists of 9 exons[10]. (talk: blaketd) Blaketd (talk) 16:43, 30 November 2016 (UTC)
Normal Function of GFAP
[edit]The GFAP gene encodes for the glial fibrillary acidic protein. Glial fibrillary acidic proteins are intermediate filaments found in astroglial cells [11]. Astroglial cells are important to the stability and maintenance of cells in the brain and spinal cord [11]. Normally when spinal cord cells and brain cells are damaged, astroglial cells repair the damaged cells by overproduction of glial fibrillary acidic proteins[11]. (talk: blaketd) Blaketd (talk) 16:43, 30 November 2016 (UTC)
Molecular Explanation for Phenotype
[edit]In the majority of cases of Alexander disease, the expression of an abnormal phenotype is due to de novo, dominant mutations in the coding region of GFAP, resulting in the dysfunction of astrocytes and the formation of cytoplasmic inclusions named Rosenthal fibers[12]. Rosenthal fibers are located within astrocytes, and contain GFAP[12]. GFAP is a type III intermediate filament protein that is conserved across human and rodent genomes, and is responsible for producing α-GFAP, which is highly expressed in astrocytes of the CNS[13]. Mutations in the GFAP protein do not prevent synthesis of a complete protein; rather, they affect the later steps of polymerization by partially inhibiting filament formation[14]. As such, this partial inhibition leads to the accumulation of a toxic polymerization intermediate that ultimately compromises astrocyte function[14]. Sjq94 (talk) 18:06, 30 November 2016 (UTC)
Types of Mutations
[edit]The abnormal phenotype of Alexander disease is caused by missense mutations in the central rod domain and variable tail region of GFAP to cause an accumulation of GFAP in Rosenthal fibers, ultimately leading to dysfunctional astrocytes[12]. The two most frequent mutations are the R79 and R239, with R79 patients expressing a less severe phenotype[15]. The R239 mutation is the result of a substitution to Cysteine, and it was present in 5 of the 11 patients that were screened; whereas the R79 mutation was present in 4 of the 11 screenings [13]. In each case, the patients were all heterozygous for the mutation, suggesting that these mutations are dominant and de novo[13]. Sjq94 (talk) 21:42, 30 November 2016 (UTC)
Future Directions
[edit]Although there is no current animal model for Alexander Disease, there are engineered mice with the same mutations of GFAP that have been known to cause the disease. Even though these mice do not exhibit all symptoms of Alexander Disease, they do form Rosenthal fibers and have seizures [7]. Gmk625 (talk) 17:42, 25 November 2016 (UTC)
Due to the lack of an animal model, researchers are determined to understand the mechanisms by which mutations of GFAP cause this particular disease, and of course, develop a better animal model for the disorder. One clinical study is underway to explore alternative treatment for Alexander Disease. To accomplish this, the team is trying to identify biomarkers of the disease by analyzing samples of blood or cerebrospinal fluid. Finding such biomarkers would change the way scientists could evaluate patients’ responses to any future treatments or clinical trials [7]. Gmk625 (talk) 17:42, 25 November 2016 (UTC)
- ^ "Alexander Disease - United Leukodystrophy Foundation United Leukodystrophy Foundation". ulf.org. Retrieved 2016-11-08. line feed character in |title= at position 53 (help)
- ^ a b c d e f g h Alexander Disease- NORD
- ^ a b c d e f g Messing, Albee; Brenner, Michael; Feany, Mel B.; Nedergaard, Maiken; Goldman, James E. (2012-04-11). "Alexander Disease".
{{cite journal}}: Cite journal requires|journal=(help) Cite error: The named reference ":Messing" was defined multiple times with different content (see the help page). - ^ a b c d e f g h i Alexander Disease- GeneReviews
- ^ Alexander Disease -Genetics Home Reference
- ^ a b c d Alexander Disease-OMIM
- ^ a b c d e Alexander Disease Information Page-NINDS
- ^ Rothstein, J (2005). "Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression". Nature. 433: 73–77.
- ^ Rodriguez, Diana; Gauthier, Fernande; Bertini, Enrico; Bugiani, Marianna; Brenner, Michael; N'guyen, Sylvie; Goizet, Cyril; Gelot, Antoinette; Surtees, Robert (2001-11-01). "Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation". The American Journal of Human Genetics. 69 (5): 1134–1140. doi:10.1086/323799. PMC 1274357. PMID 11567214.
- ^ a b Nielsen, Anders Lade; Holm, Ida E.; Johansen, Marianne; Bonven, Bjarne; Jørgensen, Poul; Jørgensen, Arne Lund (2002-08-16). "A New Splice Variant of Glial Fibrillary Acidic Protein, GFAPε, Interacts with the Presenilin Proteins". Journal of Biological Chemistry. 277 (33): 29983–29991. doi:10.1074/jbc.M112121200. ISSN 0021-9258. PMID 12058025.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b c Reference, Genetics Home. "GFAP gene". Genetics Home Reference. Retrieved 2016-11-30.
- ^ a b c Brenner, Michael; Johnson, Anne B.; Boespflug-Tanguy, Odile; Rodriguez, Diana; Goldman, James E.; Messing, Albee (2001-01-01). "Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease". Nature Genetics. 27 (1): 117–120. doi:10.1038/83679. ISSN 1061-4036.
- ^ a b c Quinlan, Roy A; Brenner, Michael; Goldman, James E.; Messing, Albee (2007-06-10). "GFAP and its role in Alexander Disease". Experimental cell research. 313 (10): 2077–2087. doi:10.1016/j.yexcr.2007.04.004. ISSN 0014-4827. PMC 2702672. PMID 17498694.
- ^ a b Li, Rong; Messing, Albee; Goldman, James E.; Brenner, Michael (2002-06-01). "GFAP mutations in Alexander disease". International Journal of Developmental Neuroscience. NICHD Mental Retardation Research Centers. 20 (3–5): 259–268. doi:10.1016/S0736-5748(02)00019-9.
- ^ Rodriguez, Diana (2001). "Infantile Alexander Disease: Spectrum of GFAP Mutations and Genotype-Phenotype Correlation". American Journal of Human Genetics. 69: 1134–1140.