SPG11‐related parkinsonism: Clinical profile, molecular imaging and l‐dopa response

Abstract

Background: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. Objectives: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l‐dopa. Methods: Patients and controls underwent single‐photon emission computed tomography imaging utilizing 99mTc‐TRODAT‐1 tracer. A single‐blind trial with 600 mg of l‐dopa was performed comparing UPDRS scores. Results: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l‐dopa intake during the trial. Conclusion: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

Janus-faced spatacsin (SPG11): involvement in neurodevelopment and multisystem neurodegeneration

“…A clinical study on a large patient cohort consisting of 22 SPG11 mutation carriers, reported degeneration of the substantia nigra and reduced dopamine transporter density as common findings in SPG11-HSP ( Faber et al , 2018 b ). The latter was indicative of a disruption of presynaptic dopaminergic pathways even in patients without extrapyramidal motor symptoms ( Faber et al , 2018 b ).…”

“…A clinical study on a large patient cohort consisting of 22 SPG11 mutation carriers, reported degeneration of the substantia nigra and reduced dopamine transporter density as common findings in SPG11-HSP ( Faber et al , 2018 b ). The latter was indicative of a disruption of presynaptic dopaminergic pathways even in patients without extrapyramidal motor symptoms ( Faber et al , 2018 b ). These observations are in line with reports of parkinsonism in SPG11-HSP patients, partly as a presenting symptom and partly with a positive l -DOPA response ( Anheim et al , 2009 ; Paisan-Ruiz et al , 2010 ; Guidubaldi et al , 2011 ; Vanderver et al , 2012 ; Wijemanne et al , 2015 ).…”

Neuroimaging in Hereditary Spastic Paraplegias: Current Use and Future Perspectives

“…Cerebral metabolism in HSP was assessed in a few studies using PET and the [18F]-Fluorodeoxyglucose tracer—Table 2 (53–63). Cortical hypometabolism was the usual finding, but the regions affected were rather heterogeneous across the different reports.…”

“…In a recent publication, Faber et al found reduced bilateral striatal DAT uptake to be a universal phenomenon in a cohort of 22 patients with SPG11 (Figure 6). Even patients without parkinsonism had clearly abnormal results (63).…”

Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy

“…Key clinical features, in addition to spasticity and spasticity‐related complications, include intellectual disability and later cognitive decline, retinal degeneration (then referred to as Kjelling syndrome), peripheral neuropathy, dysphagia, cerebellar signs including ataxia, and parkinsonism. Early‐onset parkinsonism in SPG11 is usually not responsive to levodopa . On brain magnetic resonance imaging (MRI), a thin corpus callosum is evident (Figure ), and a characteristic ‘ears of the lynx’ sign on FLAIR imaging has been described in both SPG11 and SPG15 .…”