Alexander disease (AxD) is a rare neurodegenerative disorder characterized by white matter degeneration and formation of cytoplasmic inclusions. Glial fibrillary acidic protein (GFAP) mutations have been reported in various forms of AxD since 2001. However, a definitive diagnosis remains difficult because of uncertain prevalence, and different clinical features seen in infantile AxD and adult AxD may lead to confusion and misdiagnosis. Here we report an epidemiological study conducted in Japan. Two nationwide questionnaire-based surveys were conducted using tentative diagnostic criteria. We gathered information regarding prevalence, neurological findings, magnetic resonance imaging (MRI) findings, electrophysiological findings, genetic information, and the results of therapeutic interventions and home care. Prevalence of various forms of AxD was determined as 27.3% (infantile), 24.2% (juvenile), and 48.5% (adult). Prevalence of AxD in Japan was estimated to be approximately 1 case per 2.7 million individuals. The main characteristics of infantile and juvenile AxD include delayed psychomotor development or mental retardation, convulsions, macrocephaly, and predominant cerebral white matter abnormalities in the frontal lobe on brain MRI. The main characteristics of adult AxD include bulbar signs, muscle weakness with hyperreflexia, and signal abnormalities and/or atrophy of medulla oblongata and cervical spinal cord on MRI. To ensure correct diagnosis of AxD, the physician should understand the importance of the process of GFAP genetic testing, which provides definitive diagnosis. Therefore, we propose new clinical guidelines for diagnosing AxD based on simplified classifications: cerebral AxD (type 1), bulbospinal AxD (type 2), and intermediate form (type 3).

BACKGROUND AND PURPOSE:The relationship between the MR imaging features and clinical outcomes in patients with hypoglycemic encephalopathy has always been evaluated retrospectively. The aim of this study was to prospectively evaluate whether MR imaging features of patients presenting with hypoglycemic coma are predictive of short-term (1-week) outcomes.

Mutations in the fused in sarcoma/translated in liposarcoma gene (FUS/TLS, FUS) have been identified in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). FUS is an RNA-binding protein that is normally localized in the nucleus, but is mislocalized to the cytoplasm in ALS, and comprises cytoplasmic inclusions in ALS-affected areas. However, it is still unknown whether the neurodegeneration that occurs in ALS is caused by the loss of FUS nuclear function, or by the gain of toxic function due to cytoplasmic FUS aggregation. Cabeza (Caz) is a Drosophila orthologue of human FUS. Here, we generated Drosophila models with Caz knockdown, and investigated their phenotypes. In wild-type Drosophila, Caz was strongly expressed in the central nervous system of larvae and adults. Caz did not colocalize with a presynaptic marker, suggesting that Caz physiologically functions in neuronal cell bodies and/or their axons. Fly models with neuron-specific Caz knockdown exhibited reduced climbing ability in adulthood and anatomical defects in presynaptic terminals of motoneurons in third instar larvae. Our results demonstrated that decreased expression of Drosophila Caz is sufficient to cause degeneration of motoneurons and locomotive disability in the absence of abnormal cytoplasmic Caz aggregates, suggesting that the pathogenic mechanism underlying FUS-related ALS should be ascribed more to the loss of physiological FUS functions in the nucleus than to the toxicity of cytoplasmic FUS aggregates. Since the Caz-knockdown Drosophila model we presented recapitulates key features of human ALS, it would be a suitable animal model for the screening of genes and chemicals that might modify the pathogenic processes that lead to the degeneration of motoneurons in ALS.

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. Since GFAP mutation has been confirmed in reported cases of AxD, clinical or experimental research is being conducted on the relationship between GFAP mutation and the onset pathology as well as the clinical form. We conducted a nationwide survey and a clinical study, and classified AxD into three types: cerebral AxD (type 1), which primarily has an infantile onset with presence of seizures, psychomotor developmental retardation, macrocephaly, and abnormalities in the superior frontal cerebral white matter observed in a brain MRI; bulbospinal AxD (type 2), which primarily has an adult onset with presence of muscle weakness, hyperreflexia, bulbar or pseudobulbar symptoms, signal abnormalities, and atrophy observed in an MRI of the medulla oblongata and upper cervical spinal cord; and an intermediate form (type 3) which has the characteristics of both. A research on GFAP mutations and aggregate formation concluded that GFAP mutations decreased the solubility of GFAP. According to our cell model experiment, the formation of mutant GFAP aggravates depending on the site of the GFAP mutation. Furthermore, there is a possibility that polymorphism in the GFAP promoter gene regulates the degree to which GFAP is expressed; it may have an effect on clinical heterogeneity. Recent research using cell and animal models suggests that the pathology of AxD involves not only mere functional abnormalities in intermediate filaments but also functional abnormalities in astrocytes as well as in neurons. Clarification of the glia-neuron interactions will prove the disease to be very interesting.

Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca . Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis.