Abstract
Background
Spinal cerebellar ataxia 11 (SCA11) is a rare disease, characterized by progressive cerebellar ataxia, abnormal eye sign. Four families have been reported in the past. We report on China’s first family with spinocerebellar ataxia 11.
Methods
A careful investigation of the clinical manifestations, brain imaging, and exome and Sanger sequencing were utilized to identify pathogenic genetic variants in a three-generation pedigree that includes 5 affected individuals.
Results
The proband and affected members began to develop cerebellar ataxia, dysarthria, nystagmus, and strabismus at approximately age 40 for no apparent reason. The lifespan of patients in the family is shortened. Brain MRIs showed cerebellar atrophy and slight atrophy of the bulbar medulla. Electromyography showed extensive neurogenic damage. Sensory evoked potentials of lower limbs showed damage to the spinal-brainstem-cortical conduction pathway. Genetic analysis revealed a novel point mutation (c.3290T>C) in the TTBK2 gene encoding tau-microtubule kinase 2, which led to an amino acid exchange (p.Val1097Ala). The missense mutation segregated with the phenotype. The mutation has a very low mutation rate in the population, the variant amino acids are highly conserved among species, and protein function damage prediction at the mutation site is detrimental and is highly likely to cause protein damage. The pathogenicity prediction of the mutation site shows that it is likely to cause disease. This variation is consistent with the diagnosis of SCA11.
Conclusion
The first SCA11-affected family in China was characterized by gait instability, movement disorders and dysarthria with obvious cerebellar atrophy. The pathogenic allele was a c.3290T>C mutation in the TTBK2 gene.
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Abbreviations
- SCA11:
-
Spinocerebellar ataxia 11
- SCA3:
-
Spinocerebellar ataxia 3
- ADCA:
-
Autosomal dominant cerebellar ataxia
- TTBK2:
-
tau-tubulin kinase2
- IP3:
-
inositol triphosphate
- gsk-3β:
-
Glycogen synthase kinase-3β
- MRI:
-
Magnetic resonance imaging
- NGS:
-
next-generation sequencing
- EMG:
-
electromyography
- CK:
-
creatinine kinase
- ATXN7 :
-
The pathogenic gene of spinocerebellar ataxia-7
- DARS2 :
-
Pathogenic genes of leukocephalopathy with brain stem and spinal cord involvement and lactate elevation
- MRA:
-
Magnetic resonance angiography
- EMG:
-
Electromyography
- RNS:
-
repeated nerve stimulation
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Acknowledgments
The authors wish to thank the patient and her family members for cooperation.
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The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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YD, JF, and YZ performed the acquisition of data and analytical studies, and wrote the manuscript; XQ and MZ conducted and performed the periodic clinical monitoring; XQ planned the study, checked the final form of the manuscript, and approved the final manuscript. All authors read and approved the final manuscript.
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This study was approved by the ethics committee of The Second Affiliated Hospital of Nanchang University. A written informed consent form was obtained from each study participant.
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Deng, Y., Fu, J., Zhong, Y. et al. First finding of familial spinal cerebellar Ataxia11 in China: clinical, imaging and genetic features. Neurol Sci 41, 155–160 (2020). https://doi.org/10.1007/s10072-019-04052-6
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DOI: https://doi.org/10.1007/s10072-019-04052-6