LAUSR

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of inherited neurological disorders that are characterized by pyramidal tract affection and variable other neurological manifestations [2]. Mutations in the CAPN1 gene have recently been identified as causative for SPG76 [4]. Homozygous and compound-heterozygous CAPN1 mutations were also found in pedigrees with an overlapping ataxia-spasticity syndrome with or without additional mild cognitive decline and mild axonal peripheral involvement [6]. In addition, a missense CAPN1 mutation was previously associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed [3]. Our 39-year-old female index patient noticed first symptoms of a slowly progressive gait disorder at the age of 29 years (Fig. 1a). Neurological examination revealed mild dysarthria, slightly slowed saccades, spastic tetraparesis predominantly affecting the legs. Muscle tone was severely increased causing action-induced pes equinovarus bilaterally. Finger-to-nose tests were slightly and heel-toknee tests were moderately ataxic. Gait was wide-based and moderately spastic-ataxic without use of assistive devices. The patient scored 4/40 on the Scale for the Assessment and Rating of Ataxia (SARA). Baclofen, tizanidine and tolperisone were not tolerated or inefficacious but she responded to botulinum toxin injections with a mean improvement of 40–50%. Her cranial MRI showed very mild cerebellar vermal atrophy, whereas spinal cord imaging was unremarkable (Fig. 1b). Her 37-year-old sister reported that her gait had become less smooth over the last 4 years, particularly when climbing stairs. Her medical history comprised autosomal recessively inherited familial Mediterranean fever (FMF) [1]. Upon neurological examination, she had mildly increased muscle tendon reflexes and clonus in feet but muscle tone was normal. Babinski sign was suspicious on the left side, and negative on the right. Finger-to-nose tests showed mild limb ataxia and a slight intention tremor. All subjects gave written informed consent prior to inclusion into the genetic study which was approved by the Ethics Committee of the University of Lübeck. By wholeexome sequencing, a previously unreported homozygous variant in the CAPN1 gene, c.759?1G[A, affecting the invariant position ?1 of a donor splice site, was detected in both sisters (Fig. 1a, c). Both unaffected parents carried the variant in the heterozygous state. We further demonstrated that this mutation results in aberrant splicing by leaving out exon 6 from the transcript (Fig. 1c). This exon skipping results in a frameshift and a premature stop mutation (Ser198Valfs*5). In addition, the 37-year-old sister harbored a compound heterozygous mutation in the MEFV gene, M680I and V726A, which was present in the heterozygous state in the parents. Mutations in the MEFV gene are causative for FMF [1]. To date, three families affected by complex HSP and four pedigrees with an ataxia-spasticity overlap syndrome were reported harboring mutations in the CAPN1 gene [4, 6]. Given the strong phenotypic overlap between the symptoms of our two patients and previously reported cases, we consider the detected variant as causative and confirmed a genetic diagnosis of an ataxia& Norbert Brüggemann [email protected]