MDS-PAS School for Young Neurologists Video Dinner February 21, 2015 Maria Eliza T. Freitas, MD...

MDS-PAS School for

Young NeurologistsVideo Dinner

February 21, 2015

Maria Eliza T. Freitas, MDClinical Fellow In Movement Disorder

University of TorontoToronto 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

Video

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 39-40 years

• Mean 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 phase Combined 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