n.81 – MOLECULAR SCREENING OF DYSTONIA GENES IN PATIENTS WITHOUT DOPAMINERGIC DEFICIT (SWEDDS): A NEW PATHOGENIC MUTATION IN THE DYT11 GENE



Abstract

BACKGROUND-AIM
Up to 15% of patients with a clinical diagnosis of Parkinson’s disease (PD) who performed dopamine transporter (DAT) SPECT imaging may have a scan without evidence of dopaminergic deficit (SWEDD). Subsequent clinical and electrophysiological findings in such patients suggested a dystonic etiology.
METHODS
We retrospectively reviewed clinical and imaging data of 1,106 patients with clinical diagnosis of PD assessed at our tertiary movement disorder clinic ) from April 2002 to April 2011, who consecutively underwent DAT SPECT between 2002 and 2011. Molecular screening of dystonia genes (DYT1, DYT5, DYT6, DYT11 and DYT16) was then performed in all cases who met the following criteria: (1) clinical diagnosis of idiopathic PD; (2) asymmetric tremor at rest, with or without postural/kinetic component; (3) ≥12-month follow-up; (4) normal DAT SPECT imaging; (5) absence of major abnormalities at brain MRI; (6) absence of overt dystonic features at the time of SPECT.
To minimize possible methodological bias and obtain accurate semiquantitative data, we included only those scans obtained using the same protocol of image acquisition and applying a standardized semiquantitative analysis of binding values using the Basal Ganglia software.
RESULTS
We found normal DATSCAN in thirty-five patients, but only twenty-three subjects with SWEDD (9M/14F) have been finally enrolled in the study according to our inclusion/exclusion criteria and underwent molecular analysis.
We found a heterozygous frameshift mutation in DYT11 gene (c.1058-1062 delCACCA/p.Gln352fsX376). Electrophysiologic study of tremor revealed that the main contributor was a 5-6 Hz pseudo-rhythmic myoclonus, primarily involving extensor muscles. In 2 brothers, we found a missense variant in the DYT5 gene (c.334A>G; p.Thr112Ala) of uncertain pathogenicity in humans.
CONCLUSION
This is the first study molecular screening of genes for dystonia in a relatively large cohort of patients with clinical diagnosis of PD from a movement disorder tertiary referral centre. We found a new mutation in DYT11 gene, that has been associated with clinical features of dystonia and myoclonic jerks so far. Our findings provide further support to the hypothesis that adult-onset monogenic dystonia may underlie a “PD look-alike” clinical phenotype. In addition to dystonic tremor, pseudorhythmic myoclonus may be mischaracterized as “rest tremor.”

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