Year: 2022
Type: article
Abstract: To the Editor: Alexander disease (AxD) is a rare and often fatal demyelinating disorder of white matter that occurs most commonly in infants. There are currently several classification systems used to categorize the various subtypes of this autosomal dominant leukodystrophy (1, 2). The most common model utilizes age of onset to discern different groups (3). This model separates AxD into an infantile group (under 2 years of age), a juvenile group (2–12 years of age), and an adult group (12 years and older) (1–3). Each group is typically characterized by different clinical manifestations (2). Infant-type AxD is characterized by encephalitis, seizures, dysphagia, poor coordination, loss of motor control, hydrocephalus, developmental delays, and cognitive impairments (2). Juvenile-type AxD often presents with symptoms of bulbar involvement, ataxia, loss of motor control, and cognitive delays (2). Individuals diagnosed with adult-onset AxD typically display a variety of clinical symptoms ranging from bulbar dysfunction, dysphagia, dyspnea, dysarthria, palatal myoclonus, macrocephaly, and seizures (1, 2). Given that the survival rate increases as the age of onset increases, fatality is most common in infantile-type AxD (2). However, given the rarity of documented adult-onset AxD cases, there is relatively little information known regarding this specific subtype. A second classification system relies on the neurologic location of lesions to categorize AxD subtypes (1, 2). Lesions located in the frontal lobe/supratentorial are considered to be Type I AxD and often correspond to an early-onset, aggressive symptoms, and high mortality rates. Lesions located in the hindbrain are classified as Type II AxD and are associated with late-onset and mild symptoms (1, 2). Here, we report the pathologic and genetic findings supporting an adult-onset AxD with a novel GFAP c.1054C>G, p. L352V heterozygous missense mutation. The patient presented as a 33-year-old woman with progressive symptoms of headaches, dysarthria, left-sided extremity weakness, dizziness, and difficulty walking. A magnetic resonance imaging (MRI) of the head revealed a third intraventricular tumor in addition to brainstem and cerebellar peduncle lesions (Fig. 1A–C). A biopsy of the intraventricular tumor/lesion was obtained and pathologic findings showed a mildly cellular glial lesion with numerous Rosenthal fibers consistent with a diagnosis of pilocytic astrocytoma (Fig. 2A, B). Over the next 3 years, the patient’s symptoms worsened. She subsequently was found to have bilateral vocal cord paralysis and was admitted for a tracheostomy. She had longstanding headaches and noted worsening dizziness and difficulty with ambulation. She also stated recent decreases in global leg strength with an associated subjective hip weakness; she ambulated with a cane for balance. She had an ataxic gait and diplopia. A subsequent MRI of the head showed similar increased signal abnormalities in the brainstem and cerebellar peduncles (Fig. 1D). Magnetic resonance imaging. (A–C) First scan of third intraventricular mass lesion (red arrows in A and B), and abnormalities in brainstem and cerebellar peduncles (white arrow in B). (D) Second scan of brainstem and cerebellar peduncles. Histological features of brain lesions. (A, B) Intraventricular mass lesion with mildly increased glial cellularity and numerous Rosenthal fibers (arrows). (C–E) Peduncle lesion with “piloid glial features” (C, D), containing demyelinating components demonstrated by loss of myelin on LFB staining (E). Focal chronic lymphocytic aggregate (F). Given the concern for disease progression, a left retrosigmoid craniotomy was performed and a biopsy of the cerebellar peduncle was obtained which showed a lesion with glial fibrillary acidic protein (GFAP)-positive “piloid glial features” (Fig. 2C, D). Loss of myelin was demonstrated by Luxol fast blue (LFB) staining (Fig. 2E), with relative preservation of axons (not shown). There was a focal chronic lymphocytic aggregate (Fig. 2F). In addition to the clinical symptoms, the identification of cerebellar peduncle piloid glial lesion with demyelinating features in conjunction with the pathologic presence of Rosenthal fibers in the original third intraventricular lesion biopsy gave cause to consider adult-onset AxD as a possible diagnosis. Family history included a son who had a pineal germinoma diagnosed in 2016 at the age of 17 years old. To pursue this line of inquire, a genetic analysis was performed on the patients’ blood (Athena Diagnostics, Marlborough, MA). The results using Sanger sequencing identified a C–G missense heterozygous mutation at nucleotide position 1054 leading to an amino acid modification from leucine to valine at codon 352 in the GFAP gene; this was classified as a variant of unknown significance. However, in the comment section of the report, it was stated that “the following data indicate that this variant may be more likely pathologic than benign” and supports a diagnosis of an adult-onset AxD (score of 5 based on 1 = benign to 7 = pathogenic). In addition, this mutation is unique and has not been described to date in the Athena Diagnostic multiethnic database. Both SIFT and PolyPhen-2.2.2(HumVar) predict that this variant is pathogenic. Most cases of AxD are pathologically characterized by the degeneration of subpial white matter and the presence of abnormal protein aggregation in astrocytes commonly known as Rosenthal fibers (1, 2, 4). Rosenthal fibers are cytoplasmic inclusions containing an abnormal abundance of the heat shock protein αB-crystallin. These eosinophilic fibers are located in hypertrophic astrocytes approximately 10–40 µm in diameter with a length of 100 µm (1, 4, 5). While the clinical symptoms and pathologic findings were suggestive of a tentative diagnosis of AxD, genetic analysis of the GFAP gene supports the interpretation that this case is on the spectrum of the disease. As of today, over 100 different GFAP mutations corresponding to AxD have been reported (1). The results in this patient are of particular scientific interest as the mutation identified is a novel mutation of unknown significance. Of all reported cases of AxD, 90% are caused by de novo heterozygous gain-of-function mutations in GFAP, which is located on chromosome 17 (1, 6–8). Mutations of GFAP often lead to the accumulation of intermediate filament proteins in astrocytes that can cause a range of larger-scale molecular changes to occur. Interestingly, at the same site described in this case, an L352P mutation has been reported in a patient who died in infancy (9). These changes include stress kinase activation, proteasome inhibition, and changes in cell morphology due to the inability to complete cytokinesis and mitosis (10). In turn, these multinucleated astrocytes lose efficiency at maintaining ion homeostasis, preserving the blood-brain barrier, and transmitting neurotransmitters; ultimately leading to astrocyte dysfunction and white matter degeneration (5, 10). AxD is an autosomal dominant genetic disease, however, most GFAP mutations arise spontaneously (1, 2). While clinical symptoms and pathologic findings are often instrumental in the detection of AxD, it is vital to screen the DNA from peripheral blood lymphocytes to identify a GFAP mutation and definitively confirm the diagnosis (11). At present, there are some potential treatment options for patients with AxD that are currently under investigation. One possible treatment involves reducing the expression of the GFAP gene; subsequently lowering GFAP protein accumulation and minimizing the manifestations of the disease (8, 12). Another potential approach focuses on testing the efficiency of the antibiotic ceftriaxone to minimize the symptoms caused by GFAP toxicity (8). Finally, it may be possible to alter either the stress pathways affecting αB-crystallin or epigenetic mechanisms in an effort to reduce the effects of GFAP dysfunction (8, 12). Given that genetic and pathologic findings are currently vital in confirming the diagnoses of AxD, it is necessary to report and analyze cases containing novel findings. Documentation of these unusual cases will hopefully assist the scientific community in fundamentally understanding the underlying cause and pathogenesis of AxD with the goal of ultimately developing an effective treatment. The compilation of case and molecular studies should provide the necessary foundation to define the subtypes of AxD. The authors declare no conflicts of interest at the time of submission except for the role of JML as JNEN Editor-in-Chief.
DOI: 10.1093/jnen/nlac014
Authors: Elayna Mork, Pouya Jamshidi, John M Lee
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4220906344