Introduction

The Gordon-Holmes syndromes (GHS) is a rare condition characterized by cerebellar ataxia/atrophy and reproductive problems, such as the hypogonadotropic, cognitive decline, dementia, and movement disorders1. GHS can be caused by mutations in genes of RNF216, PNPLA6, OTUD4, STUB1, and POLR3A/3B/1C2. The previous study has reported the whole brain white matter hyperintensity and global white matter integrity loss in GHS patients3. In our present study, two patients were diagnosed with GHS, and the tracking based analysis was used to determine the specific white matter pathway alteration quantitatively.

Methods

MRI acquisition and participants MRI data were acquired on a 3T scanner (Simens Prisma). The DTI data was scanning with simultaneous multislice (SMS) imaging techniques, totally 90 diffusion directions (b value =1500,3000 s/mm2) and 10 b0 image was acquired with an isotropic 1.5mm resolution. Two patients and five age-matched healthy controls were included in our study. Patient 1 (male, 35 years old) presented with onset slurring and slow speech, developed cerebellar syndrome and cognitive impairment, with a history of azoospermia at age of 28. Screening of patient’s DNA for genes related to neurological disease revealed one novel homozygous nonsense variant in gene RNF216, c.1948G>T; p.E650X. Patient 2 (female, 32 years old) started to choreatic movements of both hands, slowly progressing to head, face, and four extremities, with prominent cognitive deterioration. We found a homozygous deletion on exon 2 of RNF216. White matter lesions in cerebral hemispheres and brainstem, cerebellar atrophy and low gonadotropin serum levels could be demonstrated in both patients. DTI deterministic tractography Firstly, the diffusion data were reconstructed in the MNI space using q-space diffeomorphic reconstruction4 to obtain the spin distribution function. A deterministic fiber tracking algorithm was used5. The anisotropy threshold was 0.2. The angular threshold was 60 degrees. The step size was 0.25 mm. Tracks with the length shorter than 30 or longer than 300 mm were discarded. A total of 50000 seeds were placed for each seed tracking. The anatomy prior to a tractography atlas6 was used to determine the specific tracts. The mean FA, fiber number, axial diffusivity, radial diffusivity were used to investigate the GHS patients' white matter characteristics.

Results

The T2-weighted image indicates the multiple cerebral white matter and cortical change in the whole brain, such as the cerebellar atrophy and global white matter hyperintensities (figure.1). The tracking based analysis revealed a significant change of diffusion properties in each atlas specific pathway. Here, three main white matter pathways were performed in our present article, including the corpus callosum, cortical striatal pathway, and the arcuate fasciculus (figure.2-4). The changes in diffusion parameters were shown in each pathway (table.1).

Discussion

The results indicate the whole brain white matter abnormal in our case. The reduce of FA and increase of RD suggest the impairment of integrity and the demyelination of patients’ white matter. The increase of AD suggests the early aging process has occurred in GHS patients7. The distribution parameter maps may help to locate the possible white matter abnormal origin.

Acknowledgements

This work was supported by Shanghai Municipal Science and Technology Major Project (No.2017SHZDZX01), Shanghai Municipal Science and Technology Major Project (No.2018SHZDZX01) and ZJLab, Shanghai Natural Science Foundation (No. 17ZR1401600) and the National Natural Science Foundation of China (No. 81971583).

References

1. Topaloglu, A.K., et al., Loss-of-Function Mutations in PNPLA6 Encoding Neuropathy Target Esterase Underlie Pubertal Failure and Neurological Deficits in Gordon Holmes Syndrome. J Clin Endocrinol Metab. 99(10): p. E2067-E2075. 2. Calandra, C.R., et al., Gordon Holmes Syndrome caused by RNF216 novel mutation in 2 Argentinean siblings. Movement Disorders Clinical Practice, 2018. 3. Hayer, S.N., et al., STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. Orphanet Journal of Rare Diseases. 12(1): p. 31. 4. Yeh, F.C. and W.-Y.I. Tseng, NTU-90: A high angular resolution brain atlas constructed by q-space diffeomorphic reconstruction. 58(1): p. 91-99. 5. Fang-Cheng, Y., et al., Deterministic Diffusion Fiber Tracking Improved by Quantitative Anisotropy. Plos One. 8(11): p. e80713-. 6. Fang-Cheng, Y., et al., Population-averaged atlas of the macroscale human structural connectome and its network topology. Neuroimage. 178: p. 57-68. 7. Nir, T.M., et al., Effectiveness of regional DTI measures in distinguishing Alzheimer\"s disease, MCI, and normal aging. Neuroimage Clinical. 3: p. 180-195.