Category: Spasticity
Objective: to describe a Croatian family presenting with late-onset spastic paraparesis and cognitive decline associated with a distinct amino acid substitution.
Background: Variants in CCDC88C have been associated with autosomal dominant spinocerebellar ataxia type 40 (SCA40) and early-onset pure hereditary spastic paraplegia (HSP). Previously reported variants encode Arg→Gln (SCA40; c.1886G>A) or Glu→Lys (early-onset HSP; c.1993G>A)
Method: Two symptomatic sisters (onset at 55 and 60 years) and one asymptomatic sister underwent neurological examination and clinical exome sequencing. Brain and whole neuroaxis MRI and brain SPECT were performed in affected individuals. Family history was assessed across two generations
Results: Initial symptoms included unilateral tremor, ataxia, leg weakness, instability and dysphagia. Within five years, both sisters required a walker; after ten years, they developed marked cognitive impairment. Neurological examination revealed severe spastic paraparesis, hyperreflexia with ankle clonus, intention tremor, ataxia, dysphagia, and cognitive deficit. MRI was unremarkable, while SPECT showed diffuse cortical hypoperfusion. Exome sequencing identified a heterozygous missense variant in CCDC88C (c.4384G>A; p.Ala1462Thr) in both affected sisters, absent in the asymptomatic sibling. The mother, her sister, and her brother had similar late-onset gait disturbances. Compared to previously reported variants, our variant encodes alanine-to-threonine at position 1462, in contrast to Arg→Gln at 629 (SCA40) and Glu→Lys at 665 (early-onset HSP)
Conclusion: This family supports autosomal dominant inheritance and highlights that different CCDC88C missense substitutions may result in distinct clinical phenotypes. Our report extends the spectrum of CCDC88C-related disease to include late-onset spastic paraparesis with dysphagia and cognitive decline, emphasizing the importance of considering this gene in adult-onset complex spastic paraplegia
To cite this abstract in AMA style:
I. Sarac, H. Sarac, F. Borovecki. Late-Onset Ataxia, Tremor and Spastic Paraparesis associated with the a Novel CCDC88C Variant: Expanding the Phenotypic Spectrum of mutation in the CCDC88C gene [abstract]. Mov Disord. 2026; 41 (suppl 1). https://www.mdsabstracts.org/abstract/late-onset-ataxia-tremor-and-spastic-paraparesis-associated-with-the-a-novel-ccdc88c-variant-expanding-the-phenotypic-spectrum-of-mutation-in-the-ccdc88c-gene/. Accessed October 1, 2026.« Back to 2026 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/late-onset-ataxia-tremor-and-spastic-paraparesis-associated-with-the-a-novel-ccdc88c-variant-expanding-the-phenotypic-spectrum-of-mutation-in-the-ccdc88c-gene/