Objective: To report a new family with combined spasticity and ataxia harboring mutations in the CAPN1 gene.

Background: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurological disorders that are characterized by pyramidal tract affection and variable other neurological manifestations. Mutations in the CAPN1 gene have recently been identified as causative for SPG76 and an overlapping ataxia-spasticity syndrome with or without additional mild cognitive decline.

Methods: Exome sequencing was performed in a consanguineous Turkish family with two sisters suffering from adult-onset, slowly progressive spastic paraplegia with mild cerebellar signs.

Results: The 39-year-old female index patient had a 10-year history of progressive dysarthria, slightly slowed saccades, spastic tetraparesis predominantly affecting the legs and a moderately spastic-ataxic, wide-based gait. Her 37-year old sister developed first symptoms of mild limb spasticity and cerebellar ataxia at the age of 33 years. Exome sequencing revealed a previously unreported, homozygous change in CAPN1, c.759+1G>A, affecting the invariant position +1 of a donor splice site in both sisters. This mutation results in aberrant splicing by leaving out exon 6 from the transcript. Both unaffected parents carried the variant in the heterozygous state. The cranial MRI of the index patient showed very mild cerebellar vermal atrophy whereas spinal cord imaging was unremarkable.

Conclusions: This new family independently confirms that both spasticity and cerebellar ataxia are associated with mutations in CAPN1. The phenotypic expression includes focal atrophy patterns and appears to vary depending on the underlying mutation and additional, not yet identified factors. Rather than distinguishing between HSP and an ataxia-spasticity syndrome, we suggest the clinical spectrum of this disorder be considered as CAPN1-associated neurodegeneration.

« Back to 2017 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/capn1-mutations-are-associated-with-a-syndrome-of-combined-spasticity-and-ataxia/