Autonomic dysfunction in hereditary spastic paraplegia type 4

Abstract

Background and purpose SPAST mutations are the most common cause of hereditary spastic paraplegia (SPG4‐HSP), which is characterized by progressive lower limb weakness, spasticity and hyperreflexia. There are few studies about non‐motor manifestations in this disease and none about autonomic involvement. Therefore, the aim was to determine the frequency and pattern of autonomic complaints in patients with SPG4‐HSP, as well as to determine the clinical relevance and the possible factors associated with these manifestations. Methods Thirty‐four molecularly confirmed SPG4 patients were recruited in a multicenter cross‐sectional study, of whom 26 underwent detailed neurophysiological testing (heart rate variability, sympathetic skin response and the Quantitative Sudomotor Axonal Reflex Test). The Scales for Outcomes in Parkinson's Disease – Autonomic Questionnaire (SCOPA‐AUT) was applied to quantify the severity of autonomic symptoms. Results were compared with 44 age‐ and gender‐matched healthy controls using non‐parametric tests. P values <0.05 were considered significant. Results In the SPG4‐HSP group, there were 18 men with a mean age of 47.7 ± 12.6 years. SCOPA‐AUT scores were similar between patients and controls (P = 0.238). Only the urinary domain subscore was significantly higher amongst patients (4 vs. 2.5, P = 0.05). Absent sympathetic skin response in the hands and feet was more frequent amongst patients (20% vs. 0%, P < 0.001, and 64% vs. 0%, P = 0.006, respectively). Quantitative Sudomotor Axonal Reflex Test responses were also smaller throughout all recording regions in the SPG4‐HSP group. Conclusion Our results indicate that SPG4‐HSP patients have sudomotor dysfunction caused by damaged small post‐ganglionic cholinergic fibers. Damage in SPG4‐HSP extends to the peripheral nervous system.

New spinocerebellar ataxia subtype caused bySAMD9Lmutation triggering mitochondrial dysregulation (SCA49)

“…Interestingly, patients with mutations in the SPAST gene associated with spastic paraplegia type 4 (SPG4) also present with SSR alterations and sudomotor dysfunction. 102 Relevantly, like our patients, some SPG4 patients also show hyperreflexia and pyramidal signs with cerebellar ataxia. 103 Some mutations in spastin protein causing SPG4 have been associated with microtubules and lysosomal trafficking, 104 and it contains an AAA-ATPase domain predicted to be significant similar with the AAA-ATPase domain in SAMD9L identified in this study.…”