Alexander Disease

Alexander disease is a very rare, progressively fatal disorder of the central nervous system due to severe astrocytic dysfunction as a result of cytoskeletal protein mutations. Infantile, juvenile and adult forms are described and clinical presentation varies amongst the patients in these three groups. However, growth, psychomotor retardation, and seizures are common features of all three groups. The diagnosis is made by MRI and genetic testing. Treatment is only supportive.

  • Processes: congenital
  • Incidence: 1 / 100.000

Overview

Alexander disease is a very rare but universally fatal central nervous system disease that belongs to the group of leukodystrophies associated with demyelination. Since it's initial discovery at the end of the first half of the 20th century [1], it was established that the main pathological event is the accumulation of eosinophilic cytoplasmic inclusions in astrocytes, known as Rosenthal fibers, which significantly impair their function. It was subsequently determined that Rosenthal fibers are composed of mutated glial fibrillary acidic proteins (GFAP), the most important intermediate filaments of astrocytes, together with other proteins such as αB-crystallin and heat-shock protein (Hsp) 27 [2]. More than 95% of individuals harbor mutations in genes that encode GFAP and almost all of them appear de novo, implying that this genetic defect is the principal factor in the pathogenesis of Alexander disease [3]. Accumulation of Rosenthal fibers significantly impairs the process of myelination, particularly in the white matter [4]. The vast majority of patients develop symptoms in early childhood, but in general, three clinical subtypes of Alexander disease are described [5]. Type I (early) is characterized by an onset up to 2 years of age and presence of megalencephaly, psychomotor retardation, failure to thrive, hydrocephalus, and encephalopathy. Type II (juvenile) develops in patients from 2-14 years of age and is characterized by hyperreflexia, ataxia, somewhat preserved psychomotor development and bulbar symptoms. Type III (adult) implies a late onset consisting of bulbar signs and spasticity, but symptoms may vary from patient to patient [5]. However, type II and III are often classified together due to their similar clinical characteristics and symptoms may overlap from patient to patient. Magnetic resonance imaging (MRI) performed to diagnose the condition, can show specific changes. Leukodystrophy of the frontal lobe, atrophy of the medulla and basal ganglia, as well as brain stem abnormalities, are some of the main findings in these patients [3] [6]. A biopsy of the brain, however, is the definite diagnostic method. It confirms the presence of accumulated Rosenthal fibers in astrocytes. Currently, there is no cure for this disorder and treatment principles include only supportive measures. Unfortunately, this disease is universally fatal. Survival rates have shown to be substantially better for late-onset than early onset, averaging about 25 and 17 years, respectively [5].

Etiology

The cause of Alexander disease is established to be a genetic mutation of GFAP genes that are located on chromosome 17q21 [3]. The vast majority of mutations appear de novo and they occur as gain-of-function mutations, but certain studies have established an autosomal dominant pattern of inheritance [7]. GFAP is one of the main intermediate filaments of astrocytes, which are important cytoskeletal proteins that keep the structural integrity of the cell. Additionally, other astrocytic functions, such as regulation of glutamate action, formation of the blood-brain barrier and signal conduction, are impaired as well [8]. The exact effects that lead to GFAP gene mutations, however, remain unknown.

Epidemiology

Because of its very rare occurrence in medical practice, very few epidemiological studies have been conducted. One large survey indicates that this condition occurs in approximately 1 per 2.7 million individuals [9]. Additionally, the same study evaluated the frequency of different subtypes, with the most common form being the adult form (48.5%), followed by infantile (27.3%) and juvenile (24.2%) forms [9]. So far, neither risk factors, nor gender or ethnic predilection, have been established.

Pathophysiology

The pathogenesis of Alexander disease invariably starts with GFAP gene mutations that result in accumulation of these proteins inside astrocytes in various regions of the brain and concomitant inability to preserve proper nerve conduction signaling [10]. Abundant formation of proteins in the cytoplasm, defined as Rosenthal fibers, cause significant intracellular structural changes, as these proteins are one of the main cytoskeletal filaments. The exact event that triggers mutations of GFAP genes and subsequent formation of these fibers remain unknown [11]. It is shown that the deep white matter, optic nerves, brain stem, periventricular zones, as well as the spinal cord are the sites where this phenomenon can be identified on imaging studies, which can partly explain the range of symptoms that are seen in patients suffering from this disease [6].

Prognosis

The prognosis is poor, as the disease causes progressive neurodegeneration, coupled with the fact that there is no cure for this disease. In virtually all cases, fatal outcomes are expected. Survival rates have shown to vary significantly between subtypes. From the onset of symptoms, median survival rates for type I (infantile) were approximately 17 years, while juvenile and adult forms showed median survival rates of approximately 25 years, indicating a somewhat better prognosis [5]. It is observed that patients who develop this disease in adulthood have a much milder clinical course and disease progression in comparison to infantile forms.

Presentation

Currently, the clinical presentation depends on the age of onset, as three distinct subtypes have been identified:

  • Infantile (0-2 years) - This form is seen in neonates and infants and is termed to be the most severe subtype. Most common symptoms include megalencephaly [12], growth and psychomotor retardation, seizures and spasticity. Symptom progression is usually rapid.
  • Juvenile (2-12 years) - Some studies report symptoms that are similar to infantile forms, but with much milder psychomotor retardation and a markedly slower progression of symptoms [6]. On the other hand, symptoms characteristic for adult forms such as hyperreflexia, bulbar symptoms, ataxia and others can also be observed [5].
  • Adult - Muscle weakness, spastic paraparesis, palatal myoclonus, as well as bulbar symptoms, hyperreflexia and ataxia are reported to develop in this form [5].

Since a clear overlap between symptoms exists across different subtypes, the diagnosis cannot be made on clinical grounds. Imaging techniques and other procedures are necessary to confirm the diagnosis.

Workup

The diagnosis of Alexander disease rests on the findings of imaging studies, mainly MRI. Several findings are termed to be diagnostic for this disease [6]:

  • White matter abnormalities such as atrophy, cystic degeneration or swelling, most commonly in the frontal cortex
  • Reduced signal intensity on T2 images in the form of a periventricular rim, while T1-weighed images will show increased intensity in the same area
  • Pathological appearance of basal ganglia
  • Brain stem findings such as signal alterations in the midbrain and medulla
  • Contrast enhancement of various structures including the cortex, optic chiasma, thalamus, brain stem and a few others.

Depending on the clinical subtype, significant changes in MRI findings may be observed. In adult forms, atrophy of the cervical spinal cord and brainstem may be observed together with other previously mentioned findings [13]. In addition to imaging studies, attempts to find biochemical markers of this disease have been made, including GFAP in serum and cerebrospinal fluid, as well as various other parameters that are thought to be indicators of astrocytic injury [2]. Genetic testing is available and may be performed to determine the presence of GFAP mutations. Brain biopsy may be considered in patients with inconclusive results.

Treatment

Current treatment strategies are aimed at supportive management only, as there is no cure for this disorder [14]. Symptomatic therapy comprises adequate nutritional support and management of underlying symptoms such as seizures. Isolated studies have attempted to treat patients with non-conventional techniques, such as bone marrow transplantation, administration of thyrotropin-releasing hormone (TRH) and ceftriaxone [15] [16] [17]. Bone marrow transplantation was without success, but the use of TRH and ceftriaxone, through partially understood mechanisms, has shown to reduce the severity of symptoms, although further studies are necessary to determine their efficacy.

Prevention

At this point, measures to prevent this disease and its occurrence do not exist. Keeping in mind the fact that the vast majority of patients develop this condition without a positive family history, familial screening may not prove to be beneficial.

Patient Information

Alexander disease is a very rare fatal disorder of the central nervous system. It occurs as a result of gene mutations that encode certain intracellular parts of the astrocytes, cells that perform various functions in the brain, with the most important one being the transmission of nerve signals. Specific mutations of glial fibrillary acidic proteins (GFAP), one of the most important filaments that maintain the structural integrity of astrocytes, have been reported in this disease. Consequently, the mutation leads to their abundant accumulation inside the cell, leading to various pathological changes which ultimately disable normal functioning. Despite the fact that the pathogenesis of this disease is almost completely understood, the exact reason for such events remains unknown. Moreover, the majority of patients develop de novo mutations, meaning that a familial connection does not exist and some other factors are responsible for the mutations. As astrocytes play an important role in the nerve signaling pathway, various symptoms may be present. In infants and in children, growth, and mental retardation, failure to thrive and epilepsy are the most common symptoms. Adults, on the other hand, may present with speech abnormalities, muscle weakness, and paralysis. Diagnosis may be difficult, but magnetic resonance imaging (MRI) can identify changes in the white matter with very good precision and is often used as the sole diagnostic method. Genetic testing to confirm the presence of mutations is available, but biopsy of the brain may be required in some patients in whom the diagnosis is doubtful. There is no cure for this disease and treatment solely rests on supportive measures. The prognosis of patients with Alexander disease is poor since fatal outcomes are likely in virtually all patients. For unknown reasons, much more aggressive forms of the disease with significantly lower survival rates are observed in children as compared to adult forms. On average, infants and young children survive up to 17 years after the onset of symptoms, while adults can live up to 20 years after symptom onset.

References

  1. Alexander WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain. 1949;72:373–381.
  2. Jany PL, Agosta GE, Benko WS, et al. CSF and Blood Levels of GFAP in Alexander Disease. eNeuro. 2015;2(5):ENEURO.0080-15.2015.
  3. Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE. Alexander disease. J Neurosci. 2012;32(15):5017-5023.
  4. Li R, Messing A, Goldman JE, Brenner M. GFAP mutations in Alexander disease. Int J Dev Neurosci. 2002;20(3-5):259-268.
  5. Prust M, et al. GFAP mutations, age of onset, and clinical sub-types in Alexander disease. Neurology. 2011;77:1287–1294.
  6. van der Knaap MS, Naidu S, Breiter SN, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol. 2001;22(3):541-552.
  7. Stumpf E, Masson H, Duquette A, Berthelet F, McNabb J, Lortie A, et al. Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. Arch Neurol. 2003;60(9):1307-1212.
  8. Quinlan RA, Brenner M, Goldman JE, Messing A. GFAP and its role in Alexander disease. Exp Cell Res. 2007;313(10):2077-2087.
  9. Yoshida T, Sasaki M, Yoshida M, Namekawa M, Okamoto Y, Tsujino S, et al. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis. J Neurol. 2011;258(11):1998-2008.
  10. Farina L, Pareyson D, Minati L, et al. Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol. 2008;29(6):1190-1196.
  11. Wippold FJ 2nd, Perry A, Lennerz J. Neuropathology for the neuroradiologist: Rosenthal fibers. AJNR Am J Neuroradiol. 2006;27(5):958-961.
  12. Renaud DL. Clinical approach to leukoencephalopathies. Semin Neurol 2012;32:29–33.
  13. Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev. 2009;31(7):493-498.
  14. Messing A, LaPash Daniels CM, Hagemann TL. Strategies for treatment in Alexander disease. Neurotherapeutics. 2010;7(4):507-515.
  15. Staba MJ, Goldman S, Johnson FL, Huttenlocher PR. Allogeneic bone marrow transplantation for Alexander's disease. Bone Marrow Transplant. 1997;20(3):247-249.
  16. Ishigaki K, Ito Y, Sawaishi Y, et al. TRH therapy in a patient with juvenile Alexander disease. Brain Dev. 2006;28:663–667.
  17. Sechi G, Matta M, Deiana GA, et al. Ceftriaxone has a therapeutic role in Alexander disease. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2010;34:416–417.

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