Four-month-old male Labrador retriever, (Canis familiaris).A 3-month-old Labrador retriever pup developed progressively worsening tetraparesis with a spastic swimming-puppy-like position of the thoracic limbs and a flattened chest. One month later mild vestibular signs and myoclonic jerks in the head and cervical region became obvious. General clinical examination was within normal limits. Neurological examination revealed absent patellar reflexes, weakness on the 4 limbs with an abnormal spasticity of the thoracic limbs and mild generalized muscle atrophy. During the second visit a vestibular strabismus in the right eye, a mild right-sided head tilt and regular myoclonic jerks at the head and thoracic limbs were noticed.

Electrophysiological examination was normal. RX of the thorax only confirmed the dorsoventral flattening of the thorax. Due to the worsening neurological signs further examinations were declined by the owner and the pup was euthanized at the age of 4.5 months.

Gross Description:  

Except for the dorso-ventral flattening of the thorax, no gross abnormalities were noted at necropsy.

Histopathologic Description:

Cerebrum: Within the white and gray matter of the brain, some blood vessels are surrounded by numerous short, perpendicularly oriented, hypereosinophilic, amorphous intraastro-cytic accumulations,  varying in diameter from 4 to 20 µm (Rosenthal fibers). These Rosenthal fibers are also found in the astrocytic endfeet in the subpial tissue and to a lesser extend throughout the parenchyma. Mainly in the white matter, there is proliferation of abnormal astrocytes with large nuclei, prominent nucleoli and glassy eosinophilic to pale cytoplasm. Occasionally, there are binucleated astrocytes. GFAP-staining: All Rosenthal fibers are strongly immunopositive for GFAP.

Morphologic Diagnosis:  

Cerebrum, gray and white matter, encephalopathy, multifocal, chronic, moderate, perivascular and subpial accumulation of Rosenthal fibers, astro-cytosis and astrocytic hypertrophy.

Lab Results:  

Blood examination and cerebrospinal fluid analysis were within normal limits.


Astroglial dystrophy with Rosenthal fibers

Contributor Comment:  

In humans, Rosenthal fibers are found in Alexander disease (AxD), and, albeit in greatly reduced numbers in chronic reactive astrocytosis and low-grade astrocytomas.4,5 They are seldom encountered in animal neuropathology. Alexander disease, or fibrinoid leuko-dystrophy, is a rare neurodegenerative disorder of astrocyte dysfunction in human. In veterinary medicine, Alexander disease is very rare and has been reported in  a few dogs (two Labrador Retrievers, one Scottish Terrier dog, one Miniature Poodle, three Bernese Mountain dogs, one  Bernese Mountain cross breed, one French bulldog, and one Chihuahua) and four sheep (one white Alpine sheep and three Merino sheep).1-7

There are no specific gross lesions of AxD. The classic histological lesions are Rosen-thal fibers. These fibers are deeply eosinophilic, irregularly shaped, elongated,  round to oval intra-astrocytic aggregates. Rosenthal fibers have been shown to be ubiquinated aggregates of GFAP, αβ-crystalin and HSP27.3,4

In humans AxD is classified based on the age of onset as infantile, juvenile and adult. Recently, Prust et al. proposed a reclassification in two age-dependent clinical subtypes: type I, characterized by an early age of onset, seizures, macrocephaly, encephalopathy, developmental delay, paroxysmal deterioration, failure to thrive and typical MRI features, and type II, characterized by a later age of onset, autonomic dysfunction, bulbar symptoms, ocular movement abnormalities and atypical MRI features.5 The characteristic pathological feature of both types of AxD are widespread and abundant Rosenthal fibers. All known genetic causes of AxD are attributed to GFAP mutations (explaining more than 95% of the cases), mostly de novo dominant missense mutations with hotspots at R79 and R239, the latter one inducing the most aggressive form.1

JPC Diagnosis:  

Cerebrum: Astroglial dystrophy, diffuse, severe, with marked subpial, subependymal, and perivascular Rosenthal fiber formation, Labrador retriever, Canis familiaris.

Conference Comment:  

The contributor provides a concise review of Alexander disease (AxD), a rare neurodegenerative disorder previously reported in dogs, sheep, and humans.1-7 Conference participants identified the large brightly eosinophilic and irregularly shaped Rosenthal fibers (RF) with astrocytes scattered throughout the white matter and aggregated in the subpial, subependymal, and perivascular spaces. This is the classic histologic lesion distribution associated with previously reported cases of AxD in all reported species.1,7  As mentioned by the contributor,  these accumulated fibers consist of large aggregates of glial fibrillary acidic protein (GFAP), αB-crystallin, heat shock protein (hsp-27) and ubiquitin, within markedly expanded astrocytic processes distributed throughout the central nervous system.1,4,7 Prior to the conference, the Joint Pathology Center ran a GFAP immunohistochemical stain which demonstrated intense immuno-staining of the RF surrounding vessels and in the subpial and subependymal areas. RF have also been reported to be immuno-positive for ubiquitin. The presence of RF is not pathognomonic for AxD and has been reported in glial scars and multiple sclerosis in humans; however, the distribution of the RF in the subpial, subependymal, and perivascular areas in this and other reported cases is unique to AxD. In addition to Rs, other common histologic lesions of AxD include white matter demyelination and astrogliosis.1,7

As mentioned by the contributor, it is thought that a mutation in GFAP leads to glial intermediate filament disorganization, decreased solubility, and defective degradation of the protein.1,3,7 This results in accumulation of the aberrant and misfolded protein, leading to cellular stress and the unfolded protein response (UPR) in the endoplasmic reticulum. Cellular stress and the resulting UPR are postulated to be the initiating factor for the production of ubiquitin and heat shock proteins (αB-crystallin, hsp-27) accumulating with GFAP and forming the RFs seen histologically.1,4,7 Accumulation of these insoluble fibers is likely progressively toxic to astrocytes and degrades oligodendrocyte function, affecting myelin formation in the white matter.

As a result, animals affected with AxD typically present as juveniles with rapidly progressive depression, ataxia, paresis, generalized tremors, decreased spinal reflexes, and seizures.1 


1. Aleman N, Marcaccini A, Espino L, et al. Rosenthal fiber encephalopathy in a dog resembling Alexander disease in humans. Vet. Pathol. 2006; 43: 1025-1028.
2. Gruber A, Pakodzy A, Leschnik M, et al. Morbus Alexander: 4 Fälle bei Hunden in Österreich. Wien. Tierärztl. Mschr. Vet Med Austria. 2010; 97:1-4.
3. Ito T, Uchida K, Nakamura M, et al. Fibrinoid leukodystrophy (Alex-ander's disease-like disorder) in a young adult French bulldog. J Vet Med Sci. 2010; 72:1387-1390.
4. Kessell A, Finnie J, Manavis J, et al. A Rosenthal fiber encephalo-myelopathy resembling Alexander's disease in three sheep. Vet Pathol. 2012; 49: 248-254.
5. Prust M, Wang J, Morizono H, et al. GFAP mutations, age at onset, and clinical subtypes in Alexander disease. Neurology. 2011; 77: 1287-1294.
6. Richardson J, Tang K, Burns D. Myeloencephalopathy with Rosen-thal fiber formation in a Miniature Poodle. Vet Pathol. 1991; 28: 536-538.
7. Wrzosek M, Giza E, Płonek M et al. Alexander disease in a dog: Case presentation of electrodiagnostic, magnetic resonance imaging and histopathologic findings with review of literature. BMC Vet Res. 2015; 11:115.

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4-1. Cerebrum, puppy.

4-2. Cerebrum, puppy.

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