Adult-onset Alexander disease with an R66Q mutation in GFAP presented with severe vocal cord paralysis during sleep

Abstract

Adult-onset Alexander disease (AOAD) is clinically characterized by slowly progressive bulbar palsy, pyramidal signs, spastic paresis and cerebellar ataxia with atrophy of the medulla oblongata and upper cervical cord, and the glial fibrillary acidic protein (GFAP) gene has been identified to be the causative gene for Alexander disease [3]. So far, some reports have mentioned that AOAD presents with sleep apnea [1, 4, 5, 8–10, 12], but the apnea mechanism is not sufficiently known. Here, we report an AOAD patient presented with vocal cord paralysis during sleep. This is the first report indicating that AOAD presented with vocal cord abductor paralysis, followed by the rapid progression of vocal cord dysfunction. A 61-year-old woman was admitted to our hospital because of gait disturbance over a 4-year period. She has been described as ‘‘round shouldered’’ since childhood and would snore loudly while sleeping since her early 30 s. Her family history revealed that even her mother snored loudly and died because of unknown reason at 54 years of age. The patient had a short neck and cervical kyphosis. Neurological examination revealed slurred speech, spasticities of all extremities, and bilateral extensor Babinski signs. MRI findings revealed atrophy of the upper cervical cord and medulla oblongata. Axial imaging of the medulla oblongata showed multiple T2-weighted high-intensity lesions. Her cerebral blood flow on ECD-SPECT was reported previously [7]. Mutational analysis revealed a previously reported heterozygous missense mutation at exon 1 of GFAP, c.197G[A, which involved the substitution of glutamine for arginine at the 66th codon (R66Q) (Fig. 1a) [11]. We confirmed the diagnosis of AOAD. Polysomnography revealed obstructive sleep apnea syndrome with 292 apneic episodes at night (245 obstructivetype and 47 mixed-type). Although her mean percutaneous oxygen saturation during wakefulness was 94 %, her mean saturation during sleep was 84 %. Her apnea–hypopnea index (AHI) was 52.2/h indicating severe apnea syndrome. To investigate the mechanism of her apnea, we examined her laryngeal movement during wakefulness and sleep induced by intravenous administration of diazepam [6]. Awake-laryngofiberscopy showed mild vocal cord abduction restriction during inspiration. After intravenous diazepam administration (5 mg), the vocal cords showed paradoxical movement with obstruction during inspiration. To avoid fatal outcome Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6540-4) contains supplementary material, which is available to authorized users.