Adult-onset Alexander's disease is a rare leukodystrophy that can present later in life in a variety of ways, often mimicking more common neurodegenerative conditions. We present two cases with novel mutations, diagnosed from their characteristic MR scan findings. Even in much older people, clinicians should have a high clinical suspicion if there are typical imaging findings.
Statistics from Altmetric.com
Adult-onset Alexander's disease is a rare leukodystrophy that typically presents with progressive spasticity, weakness, bulbar dysfunction and other brainstem features. Often there is also autonomic involvement. Late presentations are often initially misdiagnosed as other neurodegenerative disorders. There are three clinical subtypes based on age of onset: the infantile form is often fatal within a few years, whereas the juvenile and adult forms (which present similarly) can have a more protracted course. Transmission is autosomal dominant and the pathological hallmark is Rosenthal fibre deposition within astrocytes.1 With the discovery of causative mutations in the glial fibrillary acidic protein (GFAP) gene, there are more reports of the adult variety. Here we present two cases with novel GFAP gene mutations, each both initially misdiagnosed as other disorders.
A 64-year-old woman gave a 5-year history of progressive gait disturbance, swallowing difficulty and bladder disturbance with mild urinary urgency and frequency. Her initial diagnosis was multiple system atrophy, based on her gait disorder and mild postural hypotension. One year before her presentation, she had developed hand dexterity problems and horizontal diplopia. On examination, she had mild postural hypotension, torsional bidirectional nystagmus and left sixth cranial nerve palsy. There was mild dysarthria but no hypomimia or palatal tremor. She had a spastic quadriparesis, hyperreflexia and mild lower limb weakness.
MR scan of brain (figure 1) showed severe medullary atrophy, with signal change extending to the upper cervical cord. This primarily involved the corticospinal tracts but also with signal changes in the dentate nuclei and scattered white matter lesions in the cerebral hemispheres. Genetic testing for GFAP gene identified an Asp284Tyr missense mutation, confirming adult-onset Alexander's disease. No other family members had relevant clinical features and none chose to undergo genetic testing.
An 80-year-old man gave a 1-year history of slurred speech and dysphagia. The dysphagia was mild but he took care with liquids and solids. His speech disturbance was consistent with pseudobulbar palsy and he had sialorrhoea. He also had mild loss of balance and needed a walking stick. There was no bladder disturbance or postural dizziness. On examination, there was a spastic dysarthria and rotational nystagmus on horizontal gaze. His gait was slightly wide based but the remaining examination was normal. His initial diagnosis was bulbar-onset motor neurone disease. Electromyography showed chronic denervation in the tongue only. MR scan of brain showed T2-signal alteration within the medulla with significant atrophy (figure 1). There were prominent periventricular white matter lesions within the cerebral hemispheres. Based on the MR scan findings, we revised his diagnosis and arranged GFAP mutation testing, which found a missense mutation in Arg276Cys. There were no similar presentations in his family, who declined genetic testing.
We present two new cases of adult-onset Alexander's disease, each with novel mutations in GFAP. The Asp284Tyr and Arg276Cys mutations add to the 110 mutations so far identified within the GFAP coding region. These cases expand the current clinical spectrum to include presentation very late in life. Case 2's symptoms began at age 79 years, the latest age of onset so far described. The diagnosis of adult-onset Alexander's disease requires a high index of suspicion, as the presentation often resembles other neurodegenerative disorders; these cases highlight the difficulty. Its most frequent manifestations are bulbar dysfunction, pyramidal involvement and ataxia; less frequent manifestations include autonomic failure, palatal myoclonus and oculomotor abnormalities.2 ,3
Neither case had palatal myoclonus or prominent ataxia and each was eventually diagnosed from their characteristic MRI findings. The only common findings in these cases were bulbar palsy and oculomotor abnormalities. The clinical features that most commonly occur in Alexander's disease—prompting consideration of this rare disorder—are bulbar palsy (87%), ataxia (82%), pyramidal signs (75%), oculomotor abnormalities (59%) and autonomic dysfunction (45%).4
With recent improvements in MRI, the diagnosis of the adult-onset form has become easier. The most consistent finding is signal change in the medulla with atrophy in the upper cervical cord.5 In many cases, including these, the medullary signal change is selective with sparing of the inferior olives, contributing to the ‘tadpole sign’.6 In some cases, there is also brainstem enhancement with contrast. Periventricular white matter abnormality is common, whereas extensive cerebral white matter abnormalities develop with infantile and juvenile cases.
The discovery of mutations in GFAP has substantially increased the number of reported adult cases.7 ,8 By 2015, there have been 96 adult cases reported in the literature.9 ,10 Adult cases show the most variation in expression to the extent that imaging or postmortem may identify asymptomatic cases. Only a minority of adult cases are familial and most probably result from de novo mutations. Because of this, the risk of inheriting the mutation in siblings is <0.5% although the risk in offspring is still 50%.10 Genetic testing should ideally be performed not only in offspring but also in parents and siblings to prove segregation. Predictions regarding phenotype of Alexander's disease are difficult as some mutations can cause all three forms.11 ,12 The age of onset seems the most important factor determining clinical presentation and prognosis. As is evident from these cases, this can be very late in life.
Late onset Alexander's disease can mimic more common neurodegenerative disorders.
The most common clinical features are bulbar dysfunction, ataxia, pyramidal signs and oculomotor abnormalities.
Medullary atrophy, giving the ‘tadpole sign’ on MR brain imaging, is characteristic.
Identification of mutations in GFAP will clarify the diagnosis.
Twitter Follow Dominic Rowe at @cinimodewor
Contributors OA: study concept and design, sourcing of case. DBR: study supervision, critical revision of manuscript, sourcing of case.
Competing interests None declared.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by Henry Houlden, London, UK.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.