Objective: The aim of this work was to delineate the clinical phenotype of SPG7 patients, integrating genetic data and follow-up examinations, taking advantage of a large multinational recruitment.

Background: The SPG7 gene was the first identified gene for inherited spastic paraplegia (HSP)1. Actually, SPG7 is a common cause of adult onset spastic ataxia 2, variably presenting either predominantly with ataxia or spasticity. It is not known whether genetic factors and/or neuropathology account for these differences.

Methods: We analyzed clinical and genetic data from 238 SPG7 patients. Neuropathological examination was performed in one case.

Results: SPG7 was a late onset (35.2± 14.6 years, n=230) and slowly progressive disease with annual SARA progression of 0.64. At onset, ataxia was present in 71 patients. Disease durations of more than 20 years (n=58) showed significantly increased cerebellar dysarthria (p=.02), deep sensory loss (p=<.001), wasting (p=.001) and ophthalmoplegia (p=.04). Brain MRI showed cerebellar atrophy in 63% of the patients. We did not find a cluster of mutations along the gene nor phenotype correlations based on the location of the mutations in case of missense. Patients homozygous for loss of function (LOF) mutations (n=63) versus those with missense variants or composite missense and LOF mutations (n=173), presented significantly more often with pyramidal signs (p=.01), pes cavus (p=.04) and diminished visual acuity (p=<.0001). The missense variant A510V was the most frequent mutation (58% of patients). The presence of at least one A510V mutation was associated with later age at onset (37.14± 14 vs 32.67± 15, p=.02) and cerebellar signs at onset (p=.04), but no differences in disease severity was observed compared to patients carrying other mutations. Apparently dominant inheritance was found in 11 families (6%), more often reported in patients that had cerebellar symptoms at onset (p=.02). Neuropathological examination in a SPG7 patient (c.1749G>C; c.2181+2dup) who died at age 56, revealed a 20% pyramidal tract reduction, moderate loss of Purkinje cells, moderate neuronal loss in the substantia nigra without Lewy Body.

Conclusions: This is the first longitudinal follow-up study of a large cohort of 238 SPG7 patients, showing that LOF mutations was associated more often to spastic predominance and that at least one A510V mutation more often to cerebellar ataxia and later onset.

References: 1. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Dürr A, Fontaine B, Ballabio A. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998; 93: 973–83. 2. Pfeffer G, Pyle A, Griffin H, Miller J, Wilson V, Turnbull L, Fawcett K, Sims D, Eglon G, Hadjivassiliou M, Horvath R, Németh A, Chinnery PF. SPG7 mutations are a common cause of undiagnosed ataxia. Neurology. 2015 Mar 17;84(11):1174-6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-paraplegin-drives-spasticity-rather-than-ataxia-in-spg7-a-european-cohort-analysis-of-238-patients/