Objective: We aim to establish biological markers for the natural history and course of hereditary spastic paraplegia (HSP) type 11 (SPG11) using multiple readout parameters as a basis for upcoming therapeutical trials.

Background: SPG11 is a complicated form of HSP with autosomal-recessive transmission caused by loss of function mutations in the SPG11 gene encoding spatacsin. Additional features apart from spasticity and weakness of the lower limbs are severe mental impairment, thinning of the corpus callosum, and peripheral neuropathy. Until now there are only few biomarkers of the natural course of the disease and little is known about disease progression.

Methods: All patients underwent standardized clinical examination cross-sectionally and longitudinally for a period of two years. For neuropsychologic testing items of seven standardized tests (VLMT, FWIT, TMT A/B, FAB, d2-R, WAIS-IV, and RWT) were used. We additionally performed extensive electrophysiological measurements as well as video-supported posturography. Furthermore all subjects underwent optical coherence tomography (OCT) as potential biomarker of disease progression.

Results: 13 patients (6 females, 7 males) of 12 families all with compound heterozygous mutations were included in the study. Average age at onset was 15±7 years, identified anamnestically by the relatives as gait abnormalities and spasticity. Average disease duration at baseline was about 17±9 years. On the Spastic Paraplegia Rating Scale, which ranges from 0 to 52 points, patients scored 30.8±7.8 at baseline and 34.1±6.3 after 12 months, reflecting disease progression. Electrophysiologically patients showed severe axonal neuropathy and increased central motor conduction time. Posturography revealed a statistically significant difference in the number of extreme antero-posterior excursions of the Centre of Pressure. Cognitive testing showed a significant reduction of mental flexibility over time as measured by the ratio of the two Trail Making Test subitems. OCT revealed atrophy of retinal and optical nerve structures in most patients.

Conclusions: Our results provide multidimensional biomarkers for the biological course of SPG11 which can be used as reference in further therapeutic trials and close a gap in our knowledge of this disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/biological-course-and-natural-history-of-hereditary-spastic-paraplegia-type-11-spg11/