POLG-Related Parkinsonism with Good Response to Deep Brain Stimulation

Résumé fourni par la source

A 42-year-old woman, diagnosed with young-onset PD and with negative family history for neurological diseases, was referred for evaluation of DBS. At age 30, she had developed akinetic-rigid parkinsonism with a good response to levodopa. Later on, motor fluctuations emerged, with levodopa-induced dyskinesias and marked OFF freezing of gait (FOG) with 2 h OFF period per day. Upon clinical evaluation 12 years after symptom onset, she had asymmetric, akinetic-rigid parkinsonism (Movement Disorder Society–Unified Parkinson's Disease Rating Scale [MDS-UPDRS] motor score, part III: 29 points). She was of short stature and additionally exhibited bilateral ptosis (for which she had previously received corrective left eyelid surgery), external ophthalmoplegia, blepharospasm, proximal muscle weakness, reduced deep tendon reflexes and gait ataxia (Video 1). These findings raised suspicion of a mitochondrial disorder, further strengthened by a history of bilateral cataract surgery. Genetic testing revealed a rare heterozygous pathogenic variant in mitochondrial polymerase gamma (POLG; c.2828G) > A (p.Arg943His)3. Clinical features characteristic of POLG-related disorder. The patient exhibits bilateral ptosis and external ophthalmoplegia, accompanied by proximal muscle weakness affecting the neck, upper, and lower limbs. Additional features include short stature and gait ataxia. Dystonia is present in form of blepharospasm. Dopamine Transporter Scan (DaTSCAN) imaging showed a symmetrical decrease in tracer uptake. Brain MRI showed mild general atrophy. Other investigations, including non-ischemic forearm exercise test (NIFET), sub-anaerobic threshold exercise test (SATET), electroencephalogram (EEG), cerebrospinal fluid, polysomnography and electroneuromyography, were non-contributory. Neuropsychological testing revealed predominantly fronto-subcortical and possibly mesiotemporal, dysfunction characterized by verbosity, disinhibition, and deficits in attentional, mnestic, and executive subdomains. A levodopa challenge with 250 mg levodopa demonstrated good dopa-responsiveness (MDS-UPDRS part III: OFF 54 points; ON 23 points; Video 2a: OFF, 2b: ON), with troublesome dyskinesias. Based on the PD-like characteristics of her parkinsonism, given the normal MoCA score (28 points), the informant report indicating no cognitive difficulties in daily life, and the patient's clear wish to reduce medication a joint decision for DBS in the STN was made. Directional brain electrodes were implanted stereotactically in each STN (Medtronic B35200, Percept PC, Sensight electrodes B33005). Six months post-DBS, there were no longer OFF periods or FOG, and reduction of levodopa led to a nearly complete cessation of dyskinesias (Video 2c). To date, 48 months post-DBS, occasional dyskinesias are present but not perceived by the patient, who takes levodopa only in the evening (Video 2d). The only complaint 6 months after the surgery was mild gait ataxia, which persists at 48 months, along with occasional—partially levodopa responsive—freezing of gait in crowded environments. Although neuropsychological testing revealed a marked decline in attention, memory, and executive functions even before the surgery, with further deterioration across all functional domains postoperatively, the patient has not reported, and does not currently experience, any limitations in daily life, nor have any been noted by relatives. Further details on the clinical course and stimulation parameters are provided in Table 1.

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