An adult-onset, slowly progressive ataxic syndrome characterizes the phenotype of SCA13 related to the KCNC3
p.Arg420His mutation with a widely ranging age at onset. The clinical signs were primarily purely cerebellar, though no oculomotor pathologies related to cerebellar degeneration were detected. Brisk deep tendon reflexes were found in less than half of the subjects without associated marked spasticity or upper motor neuron signs suggestive of upper motor neuron dysfunction. Half of the subjects had diminished vibration sense in the toes though two of them were diabetic and the others were over 50 years of age, confounding the determination of mutation causality. No evidence for extrapyramidal or anterior horn cell involvement was found. Nerve conduction studies performed on three subjects were entirely normal with no evidence for peripheral neuropathy. None of the individuals had seizures or episodic symptoms.
Though limited descriptions of SCA13p.Arg420His have been published previously, this report provides an in-depth phenotypic characterization of the largest sample group to date including cognitive assessment, formal ataxia scale ratings, functional staging, and self-assessed quality of life indicators in presymptomatic, early, middle-, and late-stage patients. This report is limited in that it describes these features in a single kindred, though strengthened in that it includes two pedigree branches and four generations of subjects. Moreover, it provides an important foundation on which the natural history of SCA13p.Arg420His may be characterized as it includes examination of presymptomatic patients as well as those with SARA severity scales ranging from 1 to 32.5, functional staging of 0.5 to 5, and disease duration of 1 to 48 years.
Other reports of this SCA13 allele include four individuals from three different lineages, all discovered by large-scale DNA sequencing from unknown ataxia repositories [3]. One individual was described similarly to the current cohort with a disease duration of approximately 20 years at age 43, cerebellar signs, ataxic gait, and clear progression of symptoms. A small kindred, one aged 66 years with onset at 42 years, and their offspring with a 3-year duration at age 31 years also shared cerebellar signs, gait ataxia, and disease progression but were also observed to have pyramidal signs and, in the younger subject, a seizure disorder [10]. This observation potentially extends the phenotype to include epilepsy, which has been described in the p.Arg423His allelic form of SCA13 [11]. The final patient, aged 57 years with 6 years of symptoms, shared cerebellar and pyramidal signs and gait ataxia. No follow-up was available to assess for disease progression. Though the number of affected symptomatic individuals in the pedigree is too small to perform definitive studies on genetic modifiers of SCA13p.Arg420His, the number of at-risk individuals in this family, as well as the potential discovery of additional pedigrees, may provide the opportunity for this type of analysis in the future.
SCA13p.Arg420His is slowly progressive. The annual increase in SARA score based on this cross-sectional examination was much slower than for other SCAs associated with extracerebellar signs such as SCAs 1, 2, and 3 [12]. Only three individuals used a cane, and only one was wheelchair-bound despite mean disease duration of 17.6 years. The minimal decrease in the mean UHDRS IV functional score reinforces the slow progression.
Contrary to the initial impression that this mutation is not associated with cognitive impairment, we found evidence for mild abnormalities in a number of affected individuals. Seven of 12 subjects scored in the abnormal range with deficits in delayed recall, verbal fluency, and visuospatial tasks.
The mutation-positive but asymptomatic subjects generally had normal examinations excepting brisk tendon reflexes in four. However, a slight tremor, mild heel-to-shin ataxia, and minimal spastic catches were also observed. Additionally, imaging evidence suggests that cerebellar atrophy may significantly precede overt clinical symptomatology. Thus, though referencing SCA13p.Arg420His as an adult-onset, slowly progressive neurodegenerative phenotype is clinically accurate, it may underestimate the actual onset of disease pathology. The evolution of ataxic features and when these subjects become frankly symptomatic remains to be determined.