Objective: We here report on clinical features and course of disease in a novel CCDC88C mutation causing spinocerebellar ataxia type 40 (SCA40).

Background: SCA40 is a novel form of autosomal dominant spinocerebellar ataxia and has recently been linked to the coiled-coil domain containing 88C (CCDC88C) gene in a Chinese family. CCDC88C protein is involved in the JNK pathway, cleavage of caspase 3 and apoptosis.

Methods: The family consists of 5 affected subjects out of 3 generations. Neurological work-up was extensive in 2 affected brothers, especially in the index patient who has been followed-up at regular intervals for more than 5 years. Clinical assessment consisted of repeated evaluation including ataxia rating scales such as the Scale for the Assessment and Rating of Ataxia (SARA), magnetic resonance imaging (MRI), as well as neurophysiological and neuropsychological testing. Genetic confirmation was obtained by ordinary available genetic testing in affected and unaffected family members.

Results: The index patient is a 55-year-old male subject who developed first clinical signs in terms of unsteadiness while walking within his thirties. Gait ataxia remained mild without the need of walking devices but was slowly progressive over time. Clinical evaluation more than 20 years after disease onset revealed only a mild cerebellar syndrome with predominant gait ataxia and gaze evocated nystagmus. MR imaging showed isolated cerebellar atrophy with emphasis of the superior vermis. Notably, on concomitant disease he developed hepatolienal siderosis and non Hodgkin B-cell lymphoma. His brother had a similar disease onset. His SARA score at first evaluation with 36 years of age was 9 out 40 with more obvious dysarthria. Further course of disease was slowly progressive with only slight increase in SARA score. Neurophysiological and neuropsychological investigations were unremarkable in these patients. Genetic testing revealed a novel CCDC88C missense mutation (c.956G>A), which was not evident in healthy family members.

Conclusions: Clinical evaluations and additional findings show an isolated cerebellar ataxia as clinical phenotype in our SCA40 family. Disease onset is late with only mild progression and preserved walking abilities for decades. In the light of CCDC88C involvement in embryonic development, malignant disease may be associated with SCA40 and warrant further investigations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/clinical-characteristics-of-a-family-harbouring-a-novel-ccdc88c-mutation-sca40/