The past decade has witnessed a burst of speculation and data about how astrocyte dysfunction contributes to the phenotypes of the well-known neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, as well as other types of disorders such as epilepsies and multiple sclerosis (Rempe and Nedergaard, 2010). However, these are complex syndromes that likely represent combined abnormalities of neurons, glia, and immune cells. The clearest example of astrocytes acting as the primary culprit in disease is Alexander disease, which is caused by dominant gain of function mutations in the glial fibrillary acidic protein (GFAP) gene (for an extensive review, see (Brenner et al., 2009)). Although this disorder is quite rare, the extent to which we can understand how astrocyte function is impaired in Alexander disease, and the strategies we can devise to restore astrocyte function, will have significant implications for how we deal with the many more common neurological diseases that confront us. The purpose of this review is to introduce the wider neuroscience audience to the unique research opportunities posed by this disease.
The first recognized patient was a 16-month old boy who died after a progressive course that included megalencephaly, hydrocephalus, and psychomotor delays (Alexander, 1949). Pathology revealed abundant astrocytic accumulations of eosinophilic cytoplasmic inclusions, recognized by neuropathologists as Rosenthal fibers (after the 19th century German pathologist who first described them in the context of an old astrocyte scar)(Rosenthal, 1898)(reviewed in (Wippold et al., 2006)) (Figure 1). During the subsequent 15 years additional individuals with similar pathology were reported, and in 1964 Friede suggested that these all represented a single disease, and recommended they be named after Alexander (Friede, 1964). Although the initial finding of prominent aggregates in astrocytes prompted Alexander himself to suggest that this might represent a primary disorder of astrocytes, it was the discovery of the genetic basis for the disease that established Alexander disease as a primary disorder of this major CNS cell type (Brenner et al., 2001).
Approximately 95% of patients harbor mutations in the GFAP gene, and no other genetic causes are known (Brenner et al., 2009). Only one population based survey has been conducted, arriving at an incidence of approximately 1:2.7 million (Yoshida et al., 2011), although this figure is likely an underestimate. The age of onset is quite variable, ranging from prenatal through the sixth decade. The most common classification divides patients into three categories based on age of onset, infantile (0–2 yrs), juvenile (2–12 yrs), and adult (>12)(Russo et al., 1976). More recently a different classification has been proposed, with only two categories of type I and type II, hinging more on distribution of lesions and clinical presentation rather than age of onset (all type I’s being early-onset, and type II’s occurring at all ages) (Prust et al., 2011). Early onset patients predominate in the literature, but this likely reflects ascertainment bias as the adult- onset patients in particular are frequently mis-diagnosed with other conditions. The early onset patients typically present with seizures, spasticity, or developmental delays, whereas the later onset patients more often have signs of hindbrain dysfunction such as ataxia, palatal myoclonus, and dysphagia or dysphonia (Russo et al., 1976). Diagnosis is usually suspected based on characteristic appearances on MRI, with a frontal leukodystrophy common in the younger patients and a hindbrain predominance of lesions, sometimes with atrophy of the medulla oblongata and cervical spinal cord, in the later onset patients (Figure 2) (van der Knaap et al., 2001; Namekawa et al., 2002; van der Knaap et al., 2005; van der Knaap et al., 2006). Lifespan is related to age of onset; type I patients have a median survival of 14 years, and type II patients a median survival of 25 years (Prust et al., 2011). Most of the initially discovered mutations occured de novo, but with sharpening tools for diagnoses of the more difficult to discern later onset form, increasing numbers of familial cases are being detected. When passed to progeny, the mutations have typical autosomal dominant inheritance with nearly 100% penetrance (see (Stumpf et al., 2003) and (Messing et al., 2011) for further discussion on the topic of penetrance). There is no predilection for any ethnic population, or any gender bias.