External Laryngeal Tremor in Adult-Onset Alexander Disease: A Case Report

Alexander disease (AxD) is caused by mutations in the glial fibrillary acidic protein (GFAP) gene, GFAP. GFAP is a 432-amino acid neurofilament of intermediate molecular weight type III, essential in the structure of the astrocyte cell. Diagnosis relies on finding abnormal astrocytes (Rosenthal fibers) or a pathogenic variant in GFAP. Clinical manifestations vary depending on age at onset, evolution is progressive, and there is no curative treatment [1, 2].

External laryngeal tremor infrequently accompanies palatal tremor and has not been reported in adult-onset AxD (AOAxD), in which palatal tremor is a distinctive marker. The aims of this work were to report one such case and to make a review of the medical literature on palatopharyngeal tremor and AOAxD. This study was in accordance with the Institutional Ethics Committee and the 1964 Declaration of Helsinki. The CARE Checklist has been completed by the authors for this case report and attached as online supplementary material (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000539038).

A 43-year-old man experienced involuntary movements at the front of his neck during the last 2 years. He also noticed a spasmodic, faltering voice after prolonged lecturing. He denied tinnitus, ear clicking, dyspnea, dysphagia, or other neurologic symptoms.

On inspection, continuous and rhythmic vertical movements of the laryngeal skeleton were observed, together with simultaneous contractions of the soft palate, tongue, and pharyngeal walls, as displayed in the accompanying video recording. On examination, tandem gait was limited to two steps, and there was dysmetria in the heel-to-shin maneuver. Lateral gaze-evoked horizontal nystagmus and scandid dysarthria were present.

A fiberoptic laryngoscopic examination revealed a rhythmic and continuous vertical movement of the soft palate, tongue and epiglottis, together with adduction of the pharyngeal walls, arytenoid cartilages and vocal cords, without occlusion of the airway during respiration or phonation, visible in the video recording. Pharmacological treatment was declined due to symptomatic mildness.

The patient was the eldest of 3 male siblings. His late father suffered a dementing illness with behavioral disturbances, and a paternal uncle and a late paternal aunt were diagnosed with cerebellar ataxia of undetermined etiology at another medical center. His mother and youngest brother were both asymptomatic and had normal neurological examinations, but testing was not possible in other family members.

An MR showed atrophy of the medulla oblongata, a normal ventral pons, and hyperintensities at the hila of the dentate nuclei and cerebral periventricular white matter. A spinal MR revealed cord atrophy with hyperintense gray matter, shown in Figure 1. A surface electromyographic recording of the geniohyoid and thyrohyoid muscles registered simultaneous contractions at 2 Hz.

Whole-exome sequencing revealed a heterozygous missense variant in exon 6 of GFAP (NM_002055.5): c.994G>A; p.(Glu332Lys). It was registered as pathogenic in the ClinVar database (ID:66515), defined as likely pathogenic according to the American College of Medical Genetics criteria, and absent from the gnomAD database. The patient’s youngest brother displayed the same GFAP variant, albeit not so his mother.

External laryngeal tremor was the initial and most distinctive symptom in this case. Tremor limited to the external laryngeal muscles has been reported exceptionally, describing movements of the laryngeal skeleton, similar to those observed in this case [3]. Isolated laryngeal movements are extremely infrequent because they accompany palatal tremor in most cases. These may be caused by brainstem stroke, although posterior fossa structures may be normal on imaging studies in some cases [4]. Palato-pharyngo-laryngeal tremor can lead to altered phonation, dysphagia, and/or respiratory distress.

The palato-pharyngo-laryngeal movements observed herein could be clinically classified as palatal tremor, which may be essential or symptomatic. The essential type is diagnosed on finding involuntary palatal movements with an otherwise normal neurological examination and without structural lesions. Patients complain of rhythmic ear clicking, caused by contraction of the tensor veli palatini muscle innervated by the fifth cranial nerve, which opens the Eustachian tube and provokes a hearable sound. Its contraction is synchronous with the palatal movement, and its frequency ranges between 26 and 420 cycles/minute [5].

Symptomatic palatal tremor (SPT) is the only tremor related to an identified anatomical abnormality: hypertrophic degeneration of the inferior olivary nucleus, which is caused by a mechanism of transsynaptic degeneration [5]. SPT is caused by disruption of the segment from the dentate nucleus to the contralateral inferior olive via the superior cerebellar peduncle and central tegmental tract. The causative lesions remove the inhibitory influence from the cerebellum on spontaneous depolarization of the inferior olivary cells, whose normal firing frequency is 2 Hz, as found in this case [5]. SPT results from activation of the levator veli palatini, a muscle with innervation from the nucleus ambiguus that does not interact with the Eustachian tube: in consequence, ear clicking is absent. It involves extrapalatal muscles in at least 30% of cases, so that facial, lingual, laryngeal, diaphragmatic, head, limb tremor, and/or ocular nystagmus, synchronous with the palatal tremor, may occur [6].

The most frequent additional finding in SPT was a cerebellar syndrome, either inherited or acquired [5]. Known associations of hereditary palatal tremor and ataxia are cerebrotendinous xanthomatosis, progressive ataxia and palatal tremor, GM2 gangliosidosis, spinocerebellar ataxia type 20, POLG gene-related disorders, and AOAxD. AxD is an astrogliopathy characterized by myelin loss and accumulation of Rosenthal fibers, which are astrocytes laden with mutated GFAP and the small heat shock proteins HSP27 and αB-crystallin, localized in subpial, periventricular, and perivascular distributions [1, 2].

Age at onset, clinical features, and prognosis vary widely. Congenital, infantile, juvenile, and adult (≥14 years) forms of AxD have been described. Prust et al. [1] reviewed 215 cases with the aim of analyzing variables associated with age at onset and survival, and their results allowed differentiation of two types of AxD. Type I AxD had an infantile onset, seizures, megalencephaly, episodes of paroxysmal deterioration, psychomotor delay, and limited survival [1].

Type II AxD was clinically milder, with onset along the whole lifespan but predominating in the fourth decade, and a variable rate of progression that did not compromise survival. Episodic clinical courses mimicking multiple sclerosis may occur, especially at early disease stages. Presentation could exceptionally be acute, attributed to excessive synthesis of abnormal GFAP induced by binge alcoholic exposure [7]. Disease duration was of up to 22 years in AOAxD [2], although patients over 45 years old at onset demonstrated more severe phenotypes than those with onset aged under 45 years. Rapid progression to dependence within 2 years was observed when onset was over 65 years of age [8].

The clinical expression was heterogeneous and characterized by bulbar or pseudobulbar palsy, ataxia, spasticity in a hemiparetic or tetraparetic distribution, and/or dysautonomia (orthostatic hypotension, constipation, impotence, episodes of hypothermia, or bladder dysfunction) [2, 6, 9]. Palatal tremor was suggestive of AOAxD, either isolated or accompanied by vocal cord, pharyngeal or lingual tremor, as in the present case. However, its absence should not prevent this diagnosis because its frequency ranged between 1/13, 1/3, and 41% of cases [5, 6].

Sleep disorders included apnoea, REM behaviour disorder and restless leg syndrome, and sensation was normal. Preserved cognition is characteristic in AOAxD, although dementia with behavioral disturbances was described in two subjects [10].

The MRI findings in AOAxD included atrophy of the medulla oblongata and spinal cord, and hyperintensities in the hila of the dentate nuclei, cerebral periventricular white matter, and central spinal cord [1], as observed in this case. A tadpole-like image, specific to AOAxD, is caused by the combination of an atrophic medulla oblongata extending to the upper spinal cord and a spared pontine base [11]. Besides, an association between medullary atrophy and periventricular white matter abnormalities should raise a diagnostic suspicion of AOAxD.

The finding of mutations in GFAP causing infantile and juvenile AxD preceded molecular diagnosis in adult-onset cases, and stimulated clinical research on this variant. AOAxD is mostly sporadic and caused by de novo heterozygous point mutations, but kindreds with dominant transmission have been reported, in which penetrance may be incomplete. Causative mutations are considered gain-of-function ones because GFAP-null mice did not develop disease [12].

The GFAP variant c.994G>A; p.(Glu332Lys) is located on the 2B domain of the central coiled-coil rod structure of the protein, which allows binding of GFAP molecules to form dimers, polymers, and filaments. It was found in a 61-year-old male with ataxia, spasticity, and dysautonomia [6] and in a 57-year-old male with ataxia, dysarthria, and spasticity [13]. It was also reported as part of the complex allele c.988C>G; p.(Arg330)Gly-c.G994A; p.(Glu332Lys) in four adults from the same kindred, without possible definition of the causative variant [14]. Nonetheless, human astrocytoma U-251-MG cells transfected with c.G994A; p.(Glu332Lys) expressed aggregation of mutated GFAP [15], confirming this variant as pathogenic and source of benign clinical pictures.

In conclusion, we present the third case of AxD caused by GFAP c.G994A; p.Glu332Lys in isolation. Its outstanding clinical feature was external laryngeal tremor, not hitherto described in AOAxD, which together with vocal cord and palatopharyngeal tremor, gaze-evoked nystagmus, and slight cerebellar ataxia constituted a mild phenotype as expected from this variant, in which palatal tremor has not been reported. An altered speech in the form of faltering voice was also noted. Based on the existence of ataxia and dementia with behavioral disturbances in the kindred, a dominant transmission was suspected albeit it could not be demonstrated, due to impaired access to clinical and molecular studies of the affected individuals. Imaging in the present case was consistent with that described in AOAxD, including the characteristic tadpole sign.

If penetrance were complete, the patient’s youngest brother would be in a presymptomatic phase; therefore, follow-up is necessary to detect disease onset. To our knowledge, AOAxD has not been described in the Spanish population yet. Additional studies are necessary to better define this most infrequent disease.

We thank Mrs. María Berciano Fernández for editing the supplementary material.

Ethical approval was not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of the details of his medical case and any accompanying images or video recording.

The authors have no conflicts of interest to declare.

No funding was received for the elaboration of this original article.

J. Gazulla: conception and design of the work; acquisition, analysis, and interpretation of data; drafted the work and revised it critically for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. Rodríguez-Valle: acquisition, analysis, and interpretation of data; drafted part of the work and revised it critically for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. L.M. Calatayud-Lallana: acquisition and interpretation of data; revised the manuscript critically for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J. Berciano: conception of work and acquisition and analysis of data; drafted part of the work and revised it critically for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.