A case of drug-induced parkinsonism and tardive akathisia with e1143g polymerase γ mutation-innocent bystander or a culprit?

Background and Aim: Polymerase γ (POLG) is a protein that plays a pivotal role in the replication of the mitochondrial genome. POLG-related disorders constitute a sequence of overlying phenotypes that can present from early infancy to late adulthood. Parkinsonism is the most common movement disorder associated with POLG mutation. We also summarize all reported cases of POLG-related Parkinsonism, along with a literature review. Case Description: We present the case of an 80-year-old male presented with complaints of episodic confusion, tremors, and restlessness. He has been on risperidone for psychosis. A normal DaT scan ruled out Parkinson’s disease, and molecular analysis for POLG was positive (E1143G). He was diagnosed with drug-induced Parkinsonism and tardive akathisia with an incidental POLG mutation. Conclusions: A literature search revealed 55 cases of “POLG-related Parkinsonism” that met our criteria. These mutations can clinically affect multiple organ systems. Parkinsonism is the most common movement disorder reported in association with POLG mutations. We conducted a molecular analysis in our patient due to his Parkinsonism and recurrent episodes of encephalopathy. E1143G mutation found in our case was coincidental and reported a non-pathogenic or benign variant in literature. Relevance for Patients: E1143G is a non-pathogenic variant and multiple studies have shown that its co-occurrence with other POLG mutations can aggravate disease occurrence and severity. Literature findings and the experience from our own case indicate that the pathogenicity of E1143G is debatable, and future studies involving this particular variant may help understand its pathological consequences.


Introduction
A group of proteins replicates the mitochondrial deoxyribonucleic acid (mtDNA), a major one being DNA polymerase γ (POLG). POLG-related disorders constitute a continuum of overlying phenotypes that can present from early infancy to late adulthood. The most common movement disorder found in association with POLG mutation is Parkinsonism. These patients usually show clinical symptoms at a young age and are commonly associated with progressive external ophthalmoplegia (PEO). We present an 80-year-old male with drug-induced Parkinsonism and tardive akathisia with an incidental POLG mutation. We performed a literature search to summarize all reported cases of POLG-related Parkinsonism.
The episodic confusion was associated with apparent auditory/ visual hallucination and delusions and typically occurred at night. The inciting event was a recognized infection during most episodes. He was started on risperidone to be used intermittently during these attacks to control the psychotic symptoms. According to his wife, he has taken risperidone only a few times after beginning the medication.
The restlessness comprised repeated crossing and uncrossing legs, sitting and standing, and moving his arms around. It began 3 years after initiating antipsychotic medications. Around the same time, he also developed tremors in his hands bilaterally (right >left). It has remained stable, is present predominantly at rest, and does not affect his day-to-day activities. He denied any loss of sense of smell, change in facial expression, voice change, drooling, constipation, and orthostatic symptoms. He also reported no similar complaints among his family members.
On examination, he had symmetric, akinetic, rigid Parkinsonism, and prominent akathisia. His total Movement Disorders Society Unified Parkinson's Disease Rating Scale score was 46/104. Sensory examination showed impaired vibration sense in bilateral lower limbs. We advised him to avoid risperidone, as this could explain his Parkinsonism. When there was no noticeable improvement, we started him on a trial of Sinemet. A DaT scan was normal, ruling out Parkinson's disease. We prompted genetic testing due to the occurrence of marked encephalopathy from minor infections and Parkinsonism from low and intermittent doses of risperidone. Molecular analysis was positive for a heterozygous POLG mutation-c.3428 A >G, p. Glu1143Gly (E1143G).
At 85 years of age, follow-up demonstrated a good response to Sinemet. The patient denied any new delirium episodes and mentions his tremors and akathisia is still present but improving. He was diagnosed with drug-induced Parkinsonism and tardive akathisia, with an incidental POLG mutation and peripheral neuropathy, most likely due to poor diabetic control.

Literature Review
A literature search was done on PubMed using the keyword "POLG-related Parkinsonism." We included all reported cases in the English language in our review and excluded those without the relevant documentation. A total of 55 patients met our criteria.
• The age of onset of clinical symptoms ranged from 10 to 80 years, with an average onset between the 3 rd and 4 th decade.

Discussion
The mitochondria are known as the cell's powerhouse, generating adenosine triphosphate. Through the electron transport chain, this allows the proper functioning of cells, including the neurons. Multiple proteins that make up the system are derived from the mitochondrial genome, consisting of circular mtDNA.
POLG is a major DNA-binding protein involved in mDNA replication. POLG-related disorders can present with clinically overlapping symptoms in affected individuals. However, they are characterized into six clinical forms-• Alpers-Huttenlocher syndrome-severe progressive encephalopathy, intractable epilepsy, and liver failure.
Parkinsonism is the most common movement disorder associated with POLG mutations. The exact mechanism by which mitochondrial dysfunction leads to Parkinsonism is still not well understood. The existing hypothesis indicates that an alteration  in the mtDNA can result in impaired protein synthesis resulting in mitochondrial dysfunction in the dopaminergic neurons [13]. Parkinsonism has been associated with both autosomal dominant and recessive POLG mutations and has an early age of onset, typically around the 3 rd -4 th decade [14]. Although patients with POLG-related Parkinsonism have associated PEO, studies have reported its occurrence without PEO [9]. Tzoulis et al. described 11 patients with POLG-related encephalopathy. The patients had no signs of Parkinsonism; however, DaT scans indicated severe nigrostriatal neuronal loss [15]. Degeneration of the nigrostriatal dopaminergic pigment neurons is evident on DaT scans, and most cases respond to treatment with dopaminergic medications. In 2004, Luoma et al. studied seven families, and for the 1 st time, described a significant link between Parkinsonism and POLG mutations [16]. The extent to which POLG variants play a role in the development of Parkinson's disease is still not established. Studies of patients with idiopathic Parkinson's disease have shown an increase in mtDNA deletions and impairment of oxidative phosphorylation in nigrostriatal neurons [17]. Luoma et al. also conducted a post-mortem examination on two patients with POLG mutation. This revealed loss of pigmented dopaminergic neurons in the substantia nigra, though Lewy bodies were not seen [16]. Betts-Henderson et al. performed an autopsy on a patient with multiple heterozygous POLG mutations. Microscopic examination of the brain showed a severe neuronal loss in the substantia nigra and Lewy bodies' presence in the remaining nigral neurons [18].
E1143G mutation is a non-pathogenic variant found at varying frequencies in different population subgroups (https://www.ncbi. nlm.nih.gov/snp/rs2307441#frequency%20tab). The mutation is rendered benign due to its occurrence outside the identified pathogenic cluster [19]. Sequence analysis of the E1143G variant by computer-based algorithms has yielded mixed results. While one indicated a benign mutation (http://www.snps3d.org/), another program predicted it to be damaging protein structure and function (http://genetics.bwh.harvard.edu/pph/). The commonly encountered pathogenic POLG variants include A467T, W748S, G848S, and T251I-P587L [20]. Studies have shown that the cooccurrence of E1143G with other POLG variants may aggravate the disease's occurrence and clinical severity. Horvath et al. reported five patients with E1143G mutation, of which two individuals had compound mutations-A467T/E1143G and S433C/E1143G [21]. Chan et al. investigated the biochemical consequences of POLG proteins with E1143G polymorphism. They described that the occurrence of W748S in cis with E1143 mutation could modulate the former's phenotypic effects [22].
Our patient was positive for a heterozygous POLG mutation-c.3428 A >G, p. Glu1143Gly (E1143G). The variant probably remained silent till the dopamine blocking effects of risperidone were in effect. It could also be contributing to his episodic encephalopathy and amplifying his drug-induced Parkinsonism.

Conclusion
The mutation identified in our patient, a benign heterozygous POLG variant (E1143G), was incidental. The pathogenicity of E1143G is debatable, and future studies involving this particular variant may help understand the pathological consequences when it occurs as single or compound mutations.