A 68-year-old male with ataxia
A 68-year-old Korean man (proband; subject II.1 in Fig. 1b), who exhibited slowly progressive gait disturbance with tendency to fall for several months, was referred to our hospital. Albeit self-ambulatory, the proband suffered from unsteady gait due to ataxia. His medical history was unremarkable except for mild hypertension. The proband had no family history of neurological diseases or consanguineous marriage. Neurological examination revealed dysphagia, dysarthria, dysphonia, wide-based truncal ataxia, bilateral gaze-evoked nystagmus and exaggerated deep tendon reflexes with bilaterally positive Babinski and Hoffman signs, indicating dysfunctions in the brainstem, cerebellum or cervical cord. The proband did not present with sensory disturbance, palatal myoclonus, and abnormal mental or emotional status. To determine the etiology of ataxia, extensive workup was carried out including somatosensory evoked potential recording, blood and urine chemistry tests, assay of serum levels of vitamin B12 and thyroid hormones, venereal disease research laboratory (VDRL) test, anti-human immunodeficiency virus (HIV) antibody test and genetic studies for spinocerebellar ataxia (types 1, 2, 3, 6, 7 and 8), Friedreich ataxia and dentato-rubro-pallido-luysian atrophy. All of these tests were negative, however.
The brain MR images revealed marked atrophy of the medulla oblongata and upper cervical cord, and mild atrophy of the cerebellar hemisphere on both sagittal T2- and T1-weighted images (Fig. 1c and d, respectively). Moreover, fluid-attenuated inversion recovery (FLAIR) imaging illustrated hyperintense lesions in the bilateral cerebellar dentate nuclei (Fig. 1e). These MRI findings suggested adult AxD. Therefore, we had the proband’s GFAP sequenced and found a heterozygous mutation, c.382G > A, which was absent in the GFAP sequences from 200 normal controls. This substitution was predicted to lead to p.Asp128Asn (Fig. 1f and g). Sequencing of the GFAP of the proband’s family members suggested Mendelian inheritance of the mutation (Fig. 1b). Out of the other family members with p.Asp128Asn, subjects II.3, III.2, and III.5 showed hyperreflexia of the upper and lower extremities with positive Babinski and Hoffman signs and without evidence of neurological symptoms (Fig. 1b), indicating early stage of adult onset AxD or various degrees of penetrance.
p.Asp128Asn was reported in two cases of AxD, and Rosenthal fibers in the brain were observed posthumously in one of the cases [32, 33]. Albeit characteristic, Rosenthal fibers are not pathognomonic of AxD [3, 15]. As such, we turned to a zebrafish model to test if p.Asp128Asn GFAP is disease-causing.