Data from: Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7

Objective: We took advantage of a large multinational recruitment to
delineate genotype-phenotype correlations in a large, trans-European
multicenter cohort of patients with spastic paraplegia gene 7 (SPG7).
Methods: We analyzed clinical and genetic data from 241 patients with
SPG7, integrating neurologic follow-up data. One case was examined
neuropathologically. Results: Patients with SPG7 had a mean age of 35.5 ±
14.3 years (n = 233) at onset and presented with spasticity (n = 89),
ataxia (n = 74), or both (n = 45). At the first visit, patients with a
longer disease duration (>20 years, n = 62) showed more cerebellar
dysarthria (p < 0.05), deep sensory loss (p < 0.01), muscle
wasting (p < 0.01), ophthalmoplegia (p < 0.05), and
sphincter dysfunction (p < 0.05) than those with a shorter duration
(<10 years, n = 93). Progression, measured by Scale for the
Assessment and Rating of Ataxia evaluations, showed a mean annual increase
of 1.0 ± 1.4 points in a subgroup of 30 patients. Patients homozygous for
loss of function (LOF) variants (n = 65) presented significantly more
often with pyramidal signs (p < 0.05), diminished visual acuity due
to optic atrophy (p < 0.0001), and deep sensory loss (p <
0.0001) than those with at least 1 missense variant (n = 176). Patients
with at least 1 Ala510Val variant (58%) were older (age 37.6 ± 13.7 vs
32.8 ± 14.6 years, p < 0.05) and showed ataxia at onset (p <
0.05). Neuropathologic examination revealed reduction of the pyramidal
tract in the medulla oblongata and moderate loss of Purkinje cells and
substantia nigra neurons. Conclusions: This is the largest SPG7 cohort
study to date and shows a spasticity-predominant phenotype of LOF variants
and more frequent cerebellar ataxia and later onset in patients carrying
at least 1 Ala510Val variant.