Monday, September 21, 2015

Alexander disease

Mahajnah, Muhammad; Abu-Rashid, Muhammad; Lerman-Sagie, Tally; Goikhman, Igor; Zelnik, Nathanel.  Alexander Disease in Israel: Megalencephaly and Leukoencephalopathy and Its Differential Diagnosis.  Journal of Pediatric Neurology (J PEDIATR NEUROL), 2015; 13 (3): 121-5.
Alexander disease (AD) is a rare leukodystrophy caused by overexpression of glial fibrillary acidic protein and heat shock proteins, which accumulate in the astrocytes and appear as Rosenthal fibers. Clinically, there are three main phenotypes: infantile, juvenile, and adult forms, with a highly variable clinical course. The classical, and most common phenotype, is the infantile form, which occurs during the first 2 years of life. The diagnosis of AD is based on clinical findings and, supported by magnetic resonance imaging, should be suspected in infants with leukoencephalopathy associated with progressive megalencephaly. In this article, we report two additional patients. Their mutations were already reported; however, while one of them is a common hotspot of the severe infantile-onset phenotype, the other is uncommon and was not yet reported in early infantile-onset AD. To the best of our knowledge, these are the first cases of AD reported from Israel. AD was reported anecdotally in a few other Middle Eastern countries but, since they are usually de novo sporadic mutations, they are not affected by consanguineous marriages, and do not tend to cluster in isolated ethnic populations.
Ebrahimi-Fakhari D, Wahlster L, Hoffmann GF, Kölker S. Emerging role of
autophagy in pediatric neurodegenerative and neurometabolic diseases. Pediatr
Res. 2014 Jan;75(1-2):217-26.
Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review.
Rodriguez D. Leukodystrophies with astrocytic dysfunction. Handb Clin Neurol.
Astrocytic dysfunctions have been recently identified in four leukosdystrophies without peripheral nervous system myelin involvement. Alexander disease, the first primary genetic astrocytic disorder identified, is due to dominant GFAP mutations. The presence of Rosenthal fibers throughout the CNS is the pathological hallmark of this disease. Neurological degradation, megalencephaly, and typical MRI pattern are characteristic of infantile sporadic patients. Nevertheless, clinical and MRI expression is large, including late onset forms which can be familial. Spongiform or cystic white matter CNS degeneration is present in the other three recessive disorders. The visualization of a white matter cystic breakdown on MRI has led to the identification of CACH/VWM and MLC diseases. CACH/VWM is due to mutations in one of the five subunits of EIF2B which compromise the astrocytic lineage. The clinical spectrum is large, from antenatal to adult forms, and several extraneurological organs can be affected. Mutations in MLC1, which is mainly expressed in astrocyte endfeet, produce megalencephaly, whereas the mild clinical course contrasts with severe MRI features. An increased concentration of NAA in the urine is sufficient to diagnose Canavan disease, which is due to mutations of the ASPA gene. These disorders highlight the role of astrocytes in myelination or myelin maintenance.

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