Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature

Abstract

Alexander disease (AD) in its typical form is an infantile lethal leucodystrophy, characterized pathologically by Rosenthal fibre accumulation. Following the identification of glial fibrillary acidic protein (GFAP) gene as the causative gene, cases of adult-onset AD (AOAD) are being described with increasing frequency. AOAD has a different clinical and neuroradiological presentation with respect to early-onset AD, as abnormalities are mainly concentrated in the brainstem^spinal cord junction. We report detailed clinical and genetic data of 11 cases of AOAD, observed over a 4 -year period, and a review of the previously reported 25 cases of genetically confirmed AOAD. In our series, onset occurred as late as age 62, and up to 71 in an affected deceased relative. Most cases appeared sporadic, but family history may be misleading.The most frequent symptoms were related to bulbar dysfunctionçwith dysarthria, dysphagia, dysphonia (seven patients)ç, pyramidal involvement (seven patients) and cerebellar ataxia (seven patients). Four patients had palatal myoclonus. Sleep disorders were also observed (four cases). Bulbar symptoms, however, were infrequent at onset and two symptomatic patients had an almost pure pyramidal involvement. Two subjects were asymptomatic. Misdiagnosis at presentation was frequent and MRI was instrumental in suggesting the correct diagnosis by showing, in all cases, mild to severe atrophy of the medulla oblongata extending caudally to the cervical spinal cord. In ten patients, molecular studies revealed six novel missense mutations and three previously reported changes in GFAP. The last typical patient carried no definitely pathogenic mutation, but a missense variant (p.D157N), supposedly a rare polymorphism. Revision of the literature and the present series indicate that the clinical picture is not specific, but AOAD must be considered in patients of any age with lower brainstem signs.When present, palatal myoclonus is strongly suggestive. Pyramidal involvement, cerebellar ataxia and urinary disturbances are common. Less frequent findings include sleep disorders and dysautonomia. Fluctuations may occur. The course is variable, usually slowly progressive and less severe than the AD forms with earlier onset. AOAD is more common than previously thought and might even be the most common form of AD. The diagnosis is strongly suggested by MRI and confirmed by GFAP gene analysis.Keywords: Alexander disease; GFAP; brainstem diseases; medulla oblongata atrophy; palatal myoclonus Abbreviations: AD = Alexander disease; AOAD = adult-onset AD; FLAIR = fluid-attenuated inversion recovery; GFAP = glial fibrillary acidic protein

Late onset Alexander’s disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene

“…In accordance with previous reports of AOAD, clinical progression in our patient was relatively slow compared with that seen in childhood onset of AD [1,[4][5][6]. In summary, sequencing of the GFAP gene should be considered in cases of late onset cerebellar ataxia, in particular in the presence of MRI findings compatible with AD.…”

“…Nearly all AD mutations involve amino acid substitutions, and a dominant toxic or gain-of-function effect for mutant GFAP protein was hypothesized [2,3]. While AD in infants and children typically presents with psychomotor retardation, seizures, ataxia and progressive spasticity leading to death within a few years [1,2], clinical phenotypes with AOAD vary considerably and the clinical course is more protracted [4][5][6]. MRI criteria have been proposed for the diagnosis of AD [7].…”

“…MRI criteria have been proposed for the diagnosis of AD [7]. However, more recent case series of patients with AOAD involving individuals with atypical clinical and MRI features not fully meeting the above diagnostic criteria, suggest that the spectrum of clinical phenotypes of AOAD may be broader than previously expected [4][5][6]8].…”

“…More than 60 different mutations within the coding region of GFAP have been identified in association with AD [1] but only few studies have systematically investigated GFAP mutations in AOAD [4]. The differential diagnosis of adult onset cerebellar ataxia involves a wide spectrum of disorders including SCA, autosomal recessive ataxias such as Friedreich's ataxia, X-linked cerebellar ataxias such as ataxia teleangiectasia and fragile X-associated tremor/ataxia syndrome (FXTAS), abetalipoproteinemia, Refsum disease, late-onset GM2 gangliosidosis, cerebrotendinous xanthomatosis, autosomal dominant mitochondrial heredoataxias as well as multisystem atrophy, vitamin B 12 and vitamin E deficiencies, primary progressive multiple sclerosis and adult manifestations of leukodystrophies [10][11][12].…”

Sleep disorders in cerebellar ataxias

“…Detailed clinical and genetic data from one study of 11 cases of adult-onset AD showed that the most frequent symptoms were related to bulbar dysfunction with dysarthria, dysphagia, dysphonia, pyramidal involvement and cerebellar ataxia. Sleep disorders were also observed in four cases 29 . Sporadic fatal insomnia is a rare prion disease that has recently been recognized and is characterized by loss of sleep, oneiric stupor with autonomic/motor hyperactivity and somato-motor abnormalities, including pyramidal signs, myoclonus, dysarthria, dysphagia and ataxia 30 .…”