Loss of paraplegin drives spasticity rather than ataxia in a cohort of 241 patients with SPG7.
Coarelli, Giulia MD; Schule, Rebecca MD; van de Warrenburg, Bart P.C. MD, PhD; De Jonghe, Peter MD, PhD; Ewenczyk, Claire MD, PhD; Martinuzzi, Andrea MD, PhD; Synofzik, Matthis MD; Hamer, Elisa G. MD; Baets, Jonathan MD, PhD; Anheim, Mathieu MD, PhD; Schols, Ludger MD; Deconinck, Tine MSci; Masrori, Pegah MD; Fontaine, Bertrand MD, PhD; Klockgether, Thomas MD, PhD; D'Angelo, Maria Grazia MD, PhD; Monin, Marie-Lorraine MD; De Bleecker, Jan MD, PhD; Migeotte, Isabelle MD, PhD; Charles, Perrine MD, PhD; Bassi, Maria Teresa PhD; Klopstock, Thomas MD; Mochel, Fanny MD, PhD; Ollagnon-Roman, Elisabeth MD, PhD; D'Hooghe, Marc MD; Kamm, Christoph MD; Kurzwelly, Delia MD; Papin, Melanie MS; Davoine, Claire-Sophie BS; Banneau, Guillaume PhD; Tezenas du Montcel, Sophie MD, PhD; Seilhean, Danielle MD, PhD; Brice, Alexis MD; Duyckaerts, Charles MD, PhD; Stevanin, Giovanni PhD; Durr, Alexandra MD, PhD
92(23):e2679-e2690, June 4, 2019.
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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.
(C) 2019 American Academy of Neurology