Objective: To describe two cases of young-onset parkinsonism (YOP; case 1 with mitochondrial membrane protein associated neurodegeneration (MPAN) due to a heterozygous mutation in C19orf12; Case 2 with a heterozygous pathogenic variant in mitochondrial polymerase gamma (POLG; c.2828G > A (p.Arg943His)) treated with bilateral STN-DBS surgery at the University Hospital Zurich.

Background: MPAN or POLG-related YOP is very rare (1,2), and STN-DBS outcomes have not yet been reported. Given the rarity of such conditions, trials are not feasible and case reports are relevant to better understand treatment options.

Method: Chart review.

Results: Case 1: This Caucasian male developed right-sided tremor and clumsiness at the age of 32. Two years later, he developed attention deficit, slurred speech, and parkinsonism with right-sided resting and postural tremor partly responsive to levodopa. Due to motor fluctuations and psychotic symptoms less than a year later, STN-DBS was performed. 6 years later, levodopa remains markedly reduced, there are no motor fluctuations, and psychiatric symptoms are well controlled. DBS wash-out is currently associated with a 22% worsening in MDS-UPDRS III. However, there is a disease progress with severe myoclonus, and deterioration of parkinsonism, cognition and speech.

Case 2: This Caucasian female presented with akinetic-rigid parkinsonism at the age of 42, and had additional features of mitochondrial disease (short stature, external ophthalmoplegia, proximal myopathy). 12 years into the disease course, she had severe motor fluctuations with freezing of gait and dyskinesias, and was treated with STN-DBS. 6 weeks post DBS, levodopa was reduced by 50% and motor fluctuations are no longer present.

Conclusion: To the best of our knowledge, these are the first cases of MPAN or POLG-related disease treated with STN-DBS. In MPAN-YOP, DBS had a favorable effect not only on the severity of motor but also of psychiatric symptoms as it allowed reducing levodopa. The main limiting factors were, however, overall disease progression with cognitive worsening. In POLG-YOP, there was a favorable response without any adverse effects of STN-DBS in the short term.

References: 1. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, et al. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011 Oct 7;89(4):543–50.
2. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase gamma mutations: clinical and molecular genetic study. Lancet Lond Engl. 2004 Sep 4;364(9437):875–82.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/to-stimulate-or-not-to-stimulate-bilateral-subthalamic-stn-deep-brain-stimulation-dbs-in-cases-of-young-onset-parkinsonism-with-mitochondrial-dysfunction-induced-neurodegeneration/