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A new SCA19/SCA22 family with the T377M variant in the KCND3 gene

Martin Paucar1*
  • 1 Karolinska University Hospital and Karolinska Institutet, Neurology and Clinical Neuroscience, Sweden

Introduction: SCA19 and SCA22 are allelic disorders that belong to the group of channelopathies. The disease is associated with mutations in the gene encoding the potassium channel KCND3. Mutations in this gene are also associated with Brugada syndrome (BRGDA9). Only 9 SCA19 families of diverse ethnicities have been described so far. The SCA19/SCA22 phenotype consists of adult-onset and slowly progressive cerebellar ataxia in most cases with varying degrees of myoclonus, polyneuropathy and cognitive impairment. The T377M variant in KCND3 has been described only once in a Japanese patient affected by pure cerebellar ataxia. Aim: To perform a comprehensive characterization of a new four generation SCA19 family consisting of 7 affected patients. Methods: The phenotype characterization includes physical examination, structural and functional imaging (FDG-PET), ENeG and cognitive assessment. Mass sequencing was performed in the index case (IV:1) after poly-Q and DRPLA were ruled out. Results: Four patients (III:1, III:2, IV:1 and V:1) were examined clinically and genotyped (Fig 2). Varying degrees of cerebellar ataxia, dysarthria, intellectual disability, polyneuropathy, atrophy of the vermis and white matter abnormalities were found. Widespread hypometabolism was found in case IV:1, her son (V:1) had hypometabolism in supratentorial regions but not in the cerebellum.Patient III:2 never sought medical care, she had a no-no head tremor for many years and clumsiness since childhood (unable to perform tandem gait since then). Her rate of progression was very slow, during the last years she has fallen and contracted several fractures. Case II:1 may have not progressed but there are not medical records to confirm this description. Whole exome sequencing revealed the T377M mutation in KCND3 in the index case, this variant segregated with disease in the family. None of the four affected had signs of Brugada syndrome. Conclusions: This is the first time functional imaging is described in SCA19. Also new is the early onset (childhood) and the ethnic background of this family. This is also to the best of our knowledge the first SCA19 family diagnosed in Sweden. All the studied subjects displayed atrophy of the vermis and varying degrees of white matter abnormalities (WMA). Differently to the described T377M Japanese SCA19 family we found polyneuropathy. However, this feature has to be interpreted with caution since diabetes is a condition commonly associated with damage to periphery nerves. The rate of disease progression in SCA19 is very slow three of the examined patients but not in the youngest one.

References

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Keywords: Spinocerebellar ataxia type 19, KCND3, FDG-PET, cerebellar atrophy, Intellectual Disability

Conference: The Cerebellum inside out: cells, circuits and functions , ERICE (Trapani), Italy, 1 Dec - 5 Dec, 2016.

Presentation Type: poster

Topic: Neuropathologies

Citation: Paucar M (2019). A new SCA19/SCA22 family with the T377M variant in the KCND3 gene. Conference Abstract: The Cerebellum inside out: cells, circuits and functions . doi: 10.3389/conf.fncel.2017.37.000021

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Received: 29 Nov 2016; Published Online: 25 Jan 2019.

* Correspondence: Dr. Martin Paucar, Karolinska University Hospital and Karolinska Institutet, Neurology and Clinical Neuroscience, Stockholm, 141 86, Sweden, martin.paucar-arce@regionstockholm.se