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

[alexander disease]

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 dysfunction-with dysarthria , dysphagia , dysphonia (seven patients )-, 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 .D 157 N ), 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 .

Diseases
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Diseases presenting "almost pure pyramidal involvement" symptom

alexander disease

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