Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.
Brain. 2012-10-01; 135(10): 2980-2993
DOI: 10.1093/brain/aws240
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1. Brain. 2012 Oct;135(Pt 10):2980-93. doi: 10.1093/brain/aws240.
Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy.
Klebe S(1), Depienne C, Gerber S, Challe G, Anheim M, Charles P, Fedirko E,
Lejeune E, Cottineau J, Brusco A, Dollfus H, Chinnery PF, Mancini C, Ferrer X,
Sole G, Destée A, Mayer JM, Fontaine B, de Seze J, Clanet M, Ollagnon E, Busson
P, Cazeneuve C, Stevanin G, Kaplan J, Rozet JM, Brice A, Durr A.
Author information:
(1)INSERM, UMR_S975 – CRICM, F-75013 Paris, France.
Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are
responsible for autosomal recessive hereditary spasticity. We screened 135
unrelated index cases, selected in five different settings: SPG7-positive
patients detected during SPG31 analysis using SPG31/SPG7 multiplex
ligation-dependent probe amplification (n = 7); previously reported ambiguous
SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype
(spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on
magnetic resonance imaging/computer tomography scan and/or optic neuropathy and
without other signs) (n = 24); patients with hereditary spastic paraparesis
referred consecutively from attending neurologists and the national reference
centre in a diagnostic setting (n = 98); and the index case of a four-generation
family with autosomal dominant optic neuropathy but no spasticity linked to the
SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of
the patients selected according to phenotype but only 8% of those referred
directly. Our results confirm the pathogenicity of Ala510Val, which was the most
frequent mutation in our series (65%) and segregated at the homozygous state with
spastic paraparesis in a large family with autosomal recessive inheritance. All
SPG7-positive patients tested had optic neuropathy or abnormalities revealed by
optical coherence tomography, indicating that abnormalities in optical coherence
tomography could be a clinical biomarker for SPG7 testing. In addition, the
presence of late-onset very slowly progressive spastic gait (median age 39 years,
range 18-52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy
(47%) constitute, with abnormal optical coherence tomography, key features
pointing towards SPG7-testing. Interestingly, three relatives of patients with
heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral
neuropathy, but no spasticity of the lower limbs, suggesting that SPG7 mutations
at the heterozygous state might predispose to late-onset neurodegenerative
disorders, mimicking autosomal dominant inheritance. Finally, a novel missense
SPG7 mutation at the heterozygous state (Asp411Ala) was identified as the cause
of autosomal dominant optic neuropathy in a large family, indicating that some
SPG7 mutations can occasionally be dominantly inherited and be an uncommon cause
of isolated optic neuropathy. Altogether, these results emphasize the clinical
variability associated with SPG7 mutations, ranging from optic neuropathy to
spastic paraplegia, and support the view that SPG7 screening should be carried
out in both conditions.
DOI: 10.1093/brain/aws240
PMCID: PMC3470714
PMID: 23065789 [Indexed for MEDLINE]