Her left eye was in the abduction position since she was about 1 year old. It is not a transient manifestation and it didn't recover after the other symptoms such as diminished vision and sustaining crying recovered. Other cranial nerve examinations revealed no further abnormalities. Ophthalmologic examinations yielded no indication of amblyopia, lateral rectus palsy, or other ophthalmologic problems. Her vision and visual field were normal.
EEG monitoring conducted over the course of 24 h found predominant theta and delta activity in bilateral hemispheres. With the increase in voltage from 30 to 485 muV, the frequency decreased from 6 to 2.5 Hz. (Figures 2A,B). The phenomenon acutely abolished after intravenous injection of diazepam and frequency of beta activity increased and finally recovered to normal EEG background (Figure 2D). The EEG of our patient is in accordance with the 4a EEG criteria of NCSE by Kaplan. In addition, the clinical symptoms recovered. The patient's crying subsided, her vision recovered and she was able to answer questions as usual. Our legend of Figure 2 further includes all relevant details.
Cranial MRI was performed using a 3.0-T magnetic resonance scanner (MAGNETOM Trio Tim, Siemens Healthcare, Erlangen, Germany). Conventional T1-weighted (T1WI), T2-weighted (T2WI), and fluid-attenuated inversion recovery (FLAIR) were obtained. Analysis of the imaging revealed mild atrophic changes in both hemispheres, as well as the cerebellum (Figure 3). Ventricular systems were generally enlarged. Cerebral sulcus and fissures widened in bilateral hemisphere and cerebellum.
The patient's gait was wide-based and unsteady. She could not complete the Romberg test with her eyes closed. Bilateral coordinated movement could not be successfully performed. Together with the mild atrophic cerebellum in MR imaging, these manifestations suggest cerebella ataxia.(Figure 3) The patient's parents could not remember the exact time point when her left eye was in abduction position. There was no proof of ophthalmological problems such as amblyopia or lateral rectus palsy. In addition, no lesions were found in her brainstem and CSF analysis were normal.
The cause of ophthalmoplegia is thus uncertain. The fact that this symptom has rarely been reported in patient with TBC1D24 mutations further confounds our analysis. It may, however, relate to the novel TBC1D24 mutation. Future research is needed to confirm this. Her parents' neurological examination results were normal.
We identified and confirmed two compound heterozygous mutations in TBC1D24 (NM_001199107.1) by using next-generation sequencing and Sanger sequencing, respectively: c.1416_1437del (p.Ser473Argfs*43) and c.1499C>T (p.Ala500Val; Figure 1B). The former mutation is novel, whereas the latter has been reported in a patient with infantile myoclonic epilepsy. Sequencing and haplotype construction of the parental DNA revealed that the mother was the heterozygous carrier of p.Ser473Argfs*43, and the father of p.Ala500Val. The p.Ser473Argfs*43 mutation occurred on exon 6, causing a frameshift. It is further predicted to introduce a premature stop codon at position 514, thereby truncating 45 amino acids at the C terminus of the TBC1D24 protein (ORF Finder predicted; Figure 1C). Mutation Taster classified the anomaly as "disease causing" that may induce nonsense mediated decay (NMD). The p.Ser473Argfs*43 mutation truncated the TLDc domain of the TBC1D24 protein, while p.Ala500Val was found to occur in the same region; both mutations were classified as "pathogenic" according to ACMG guidelines. PolyPhen2 classified the mutation as "probably damaging," and SIFT predicted it as "damaging." Across-species alignment of wild type TBC1D24 protein demonstrated that the p.Ala500 is highly conserved in humans, rhesus monkeys, cattle, rats, mice, and chickens.