MDS-PAS School for Young Neurologists Video Dinner February 21, 2015 Maria Eliza T. Freitas, MD Clinical Fellow In Movement Disorder University of Toronto Toronto Western Hospital

History 40 year-old male, right-handed Age of onset: 35 years Tremor and lack of dexterity in both hands Worse in the left side Slow and unsteady gait (2 falls) He denied: - Symptoms of dysautonomia, - Cognitive/ behavior impairment - Dysarthria, dysphagia Past medical history: hypertension, dyslipidemia and gout Current medications: Crestor, Atenolol, Allopurinol

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Physical Exam No cognitive impairment or apraxia. Cranial nerves: Eye movements were full. There were slow saccades and normal pursuit/VOR. No nystagmus. Motor exam showed normal muscle bulk and strength throughout. Reflexes were normal. Moderate rigidity in the upper limbs (worse in the left side). Mild rigidity in the lower limbs. No sensory abnormalities.

Differential Diagnosis Brain MRI: Normal Normal copper studies Investigation Early onset Parkinsonism: Parkin (PARK2) PINK1 (PARK6) DJ-1-associated parkinsonism (PARK7) Neurodegeneration with brain iron accumulation (NBIA) Spinocerebellar atrophy (SCA) types 2 and 3 X-linked dystonia-parkinsonism/Lubag (DYT3) Wilson’s disease Dopa-responsive dystonia (DYT5)

Summary Early onset Parkinsonism (35yo) Asymmetric rest, postural and kinetic tremor (atypical tremor - dystonic) Postural instability Levodopa reduced hand tremor (no benefit for others symptoms) Not aware of on-off motor fluctuations Diphasic dyskinesia Mode of inheritance: Sex-linked recessive disorder History of ancestral roots from Panay Islands (Philippines)

Final Diagnosis Target mutation analysis found the disease-specific single-nucleotide change 3 (DSC3) in the TAF1/DYT3 gene: X-linked recessive Dystonia-Parkinsonism: DYT3 or Lubag Disease

Phenomenology of the Tremor Marsden’s Book of Movement Disorders, 2011

DYT3 - Lubag Lee et al (2011): reviewed 505 cases Age of onset is years M ean duration of illness is 16 years and mean age at death is 55.6 years. Onset with dystonia: 94.3% (focal) Onset with parkinsonism: 5.7% Focal dystonia spreads in 97% of the time and generalizes within 5 years in 84% Dyskinesia are unusual: levodopa-induced x clinical feature of Lubag Women: milder course and different phenotype Diagnosis: DSC3 mutation on Xq13 Treatment: oral medications, Botulinum toxin, DBS Dystonic phaseCombined dystonia-Parkinsonian phase parkinsonian phase Pasco et al, 2011 Lee et al, 2011

Taking Home Messages DYT3 is a sex-linked recessive dystonia-parkinsonism This case has shown mainly parkinsonian symptoms with atypical features: dystonic tremor but no clear focal dystonia and also unusual dyskinesia (levodopa-induced or Lubag's dyskinesia?) DYT3 should be considered in men with progressive dystonia/parkinsonism, positive family history and ancestral roots from Philippine. Parkinsonism may be the only early feature in male patients with XDP preceding the onset of dystonia. Symptomatic carriers (women) have a milder phenotype, older age of onset, and mild parkinsonism with or without dystonia. Evidente et al., 2004