The patient was a 65-year-old woman who became gradually more prone to falling from age 30 and who was visiting the hospital on an outpatient basis following a diagnosis of multiple system atrophy, cerebellar type. While eating, she started choking as a result of aspiration and was transported to our hospital by ambulance. Head magnetic resonance imaging (MRI) revealed tadpole-like atrophy of the brainstem, i.e. marked atrophy of the medulla oblongata and cervical spinal cord with disproportionately slight atrophy of the pons. Her eldest son also had the same symptoms, suggesting Alexander disease. A search of the glial fibrillary acidic protein gene revealed the previously unreported mutation Y242N. The same MRI findings and genetic mutation were confirmed in her 38-year-old son. Adult onset Alexander disease is a rare condition with very few reported familial cases. We hereby report this case with a discussion of the literature.
A 65-year-old woman had no clear developmental abnormalities from birth. From age 30, the patient noticed that she was prone to falling during exercise. From around age 37, she found she was prone to falling even in daily life, so she visited her previous doctor who diagnosed her with spinocerebellar ataxia. Thereafter, from around age 50, the patient developed difficulty walking and became wheelchair bound. At age 55, she visited our department and was diagnosed with MSA, cerebellar type. Around age 60, the patient developed sleep apnea syndrome and dysphagia. In August 2014, she choked while eating and was subsequently transported to our hospital for suffocation treatment.
A biochemical test revealed elevated levels of C-reactive protein (10.2 mg/dL). Neurological examination revealed E4V2M6 consciousness on the Glasgow Coma Scale. Eye movement was saccadic, and bilateral horizontal nystagmus in the direction of gaze and advanced dysarthria were observed. Tongue protrusion was possible without displacement, and no palatal myoclonus was noted. Muscle weakness was observed. The left-sided Babinski sign was observed. Dysuria and constipation were noted.
MRI (Fig. 1A) revealed peculiar tadpole-like atrophy of the brainstem, that is, marked atrophy from the medulla oblongata to the upper cervical spinal cord with disproportionately slight atrophy of the pons. White matter lesions in the anterior lateral ventricle and atrophy of the cerebellum were also observed (Fig. 1B). Bilaterally symmetrical high-signal-intensity lesions were observed on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging of the ventral pons (Fig. 1C). Videofluorography revealed a disorder of transporting food in the oral cavity, and no swallowing reflex was triggered.
Figure 1. Head MRI. (A–C) Case 1. (D–F) Case 2. (A) Sagittal view: Marked atrophy can be seen from the medulla oblongata to the upper cervical spinal cord. (B) FLAIR imaging: White matter lesions in the anterior lateral ventricle and atrophy of the cerebellum were also observed. (C) T2-weighted imaging: Bilaterally symmetrical high-signal-intensity lesions can be seen in the lower ventral pons of the brainstem. (D) Sagittal view: Marked atrophy from the medulla oblongata to the upper cervical spinal cord can be seen in both images, with no remarkable changes. (E and F) T2-weighted imaging: Bilaterally symmetrical high-signal-intensity lesions can be seen from the lower ventral pons of the brainstem to the ventral horn of the cervical spinal cord.
Course After Admission
Antibiotic treatment was initiated, which gradually improved the inflammatory response. The patient's diagnosis was revised because of the MRI findings, and analysis of the glial fibrillary acidic protein (GFAP) gene using the Sequencher program (Gene Codes Corp, Ann Arbor, MI) was performed with the family's consent. Analysis revealed a pY242N substitution, consistent with Alexander disease.
A 38-year-old man, the son of case 1, had no clear developmental abnormalities from birth, but was only able to pull himself up to stand after 1 year of age. Then the patient performed exercise poorly from around the time he entered high school. At age 20, he was diagnosed with a developmental disorder resulting from an inability to adapt to social life. At age 35, he noticed that he became lightheaded and was prone to falling and visited our department.
On neurological examination, eye movement was saccadic. Dysphagia, dysarthria, and limb ataxia were observed, but palatal myoclonus was not observed. Deep tendon reflexes were enhanced in the lower limbs, but no pathological reflex was observed in the upper or lower limbs. Autonomic nervous system disorders included dysuria and constipation.
MRI (Fig. 1D) revealed marked atrophy from the medulla oblongata to the upper cervical spinal cord, and T2-weighted and FLAIR imaging revealed bilaterally symmetrical high-signal-intensity lesions from the lower ventral pons to the ventral horn of the cervical spinal cord (Fig. 1E,F). Alexander disease was suspected from the patient's family history and imaging findings. A GFAP gene test was performed, which revealed the same substitution as that observed in the mother pY242N.
Since William Stewart Alexander, a New Zealand pathologist, in 1949 first reported an affected infant aged 15 months. Alexander disease (AD) has been described as a disease predominantly affecting infants and exhibiting psychomotor regression, spasticity, ataxia, and seizure, usually leading to death in a few years. This rare disease is pathologically characterized by Rosenthal fibers (RFs), but true incidence and prevalence of AD are unknown. Recently, patients with the same pathological findings but having different ages of onset and clinical symptoms have been reported; GFAP was determined to be the responsible gene, indicating that these cases had the same disease (AD).[4, 5]
The symptoms of the adult form of AD are extremely varied, and its prognosis ranges from several years to several decades from onset. Dysarthria and dysphagia are the most common clinical symptoms. Other reported symptoms with a high frequency in the adult form are pyramidal tract symptoms, ataxia, eye movement disorders, and dysautonomia.
Although palatal myoclonus is observed in approximately 40% of adult cases, it is not observed in infants or juveniles, indicating that symptoms differ according to age of onset. In case 1, videofluorography demonstrated the complete lack of a swallowing reflex. However, tongue protrusion was possible, and the hypoglossal nerve had been preserved, which suggested that this patient was suffering from marked impairment of the nucleus of the solitary tract and nucleus ambiguus in the medulla oblongata. Past reports have found that RFs are common in the deep white matter of the frontal lobe and on the ventral and lateral sides of the brainstem and spinal cord.
Signal changes and atrophy from the medulla oblongata to the upper cervical spinal cord are the most common imaging findings in adult onset. In contrast, the volume and shape of the pons are relatively preserved, and because this looks like a tadpole on imaging, this characteristic finding as a “tadpole-like appearance.” It is throught that the presence of signal abnormalities or atrophy in the medulla oblongata or cervical spinal cord are sufficient grounds for conducting GFAP gene test.
Of the 110 different pathogenic variants of GFAP gene that have been identified, 90 are single missense mutations involving 61 different amino acid residues. An analysis of the present cases revealed a Y242N substitution. To our knowledge, the first familial case of AD was reported in 1988; however, GFAP gene had not been identified at the time, so no testing was conducted. Since its discovery, familial cases of GFAP mutations have been reported worldwide.
The present cases had rare, familial adult-onset AD from a novel GFAP mutation. This mother-son pair with AD illustrates phenotypic variability from the same mutation within a single family. When characteristic MRI findings are observed, adult-onset AD should be suspected and GFAP gene test should be performed. This will allow more cases to be identified, leading to further understanding of AD and the establishment of better treatment and prevention strategies.