Objective: To characterize phenotype-genotype correlation in patients with two SPG7 variants, supported by a post mortem study.

Background: The SPG7 gene was the first identified gene for inherited spastic paraplegia (HSP)¹. Clinical variability is well reported in SPG7 patients. In addition to complicated form of HSP, a role in hereditary ataxia has emerged². Explanations of different phenotypes by genetic and neuropathology are requested.

Methods: We analysed data of 81 SPG7 patients from the Spatax network. We compared clinical presentation of two groups based on the symptom at onset: ataxia or spasticity and the presence or absence of the A510V variant. Neuropathological examination was performed in one case.

Results: There were 81 patients, 37 women and 44 men with mean disease onset of 33.5±15 years and a mean age at examination of 48±15 years. Ataxia was the presenting symptom in 48 patients, spastic gait in 26, both in 4 and developmental delay in the remaining. Comparison between cerebellar versus spastic onset indicated a gender difference with more men in the former (p=.022) and a faster disease progression in women (p=.017). The presence of the A510V variant (n=55) was associated with later disease onset (36±13 vs 28.5±17 years, p=.022), more often cerebellar (p=.06), more diffused reflexes (85% vs 60%, p=.029) and intellectual difficulties (22% vs 4%, p=.011). Parkinsonism was rare (4%). A woman with SPG7 (c.1749G>C; c.2181+2dup) died at age 56 and microscopically, the cerebral cortex was normal except for the motor cortex, where one Betz cell was chromatolytic although there was no evidence of neuronal loss. In the substantia nigra, extracellular pigments evidenced a moderate neuronal loss without Lewy Body. The pars reticulata was involved with severe gliosis, although the pallidum appeared normal. The packing density of the neurons in the pontine nuclei was normal. In the medulla oblongata, moderate neuronal loss and marked astrogliosis were responsible for inferior olive pseudohypertrophy. The section volume of the pyramidal tract was reduced by approximately 20%.There was a moderate loss of Purkinje cells. Axonal torpedoes were seen in the molecular layer. The cerebellar dentate nucleus showed gliosis and moderate neuronal loss.

Conclusions: SPG7 is a frequent cause of spastic ataxia and is a rare example of a HSP entity with phenotype genotype correlations.

References:

1. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Casari G, De Fusco M, Ciarmatori S, Zeviani M, Mora M, Fernandez P, De Michele G, Filla A, Cocozza S, Marconi R, Durr A, Fontaine B, Ballabio A. Cell. 1998 Jun 12; 93(6):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. 2015 Mar 17;84(11):1174-6.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spg7-related-spastic-ataxia-differs-according-to-the-presence-of-the-a510v-variant/