Dear Sir, Weight changes in Parkinson’s disease (PD) are a complex issue that can occur even before the onset of motor symptoms. Individuals who undergo deep brain stimulation (DBS) of the bilateral subthalamic nucleus (STN) for PD have also reported weight changes.1 The literature reveals weight gain as the most common outcome in PD patients after undergoing DBS of the STN, with multifaceted mechanisms. These include reduced energy expenditure, improved motor function, changes in eating behaviors, and alterations in hormones and neurotransmitters.2 Here, we present a case of long-standing young-onset PD with a PARK2 mutation in a patient who experienced progressive weight loss since the onset of PD and whose weight loss persisted even after undergoing DBS; this was ultimately attributed to a systemic cause rather than disease progression. A 42-year-old male presented with parkinsonism—characterized by asymmetric bradykinesia and rigidity—for 10 years (since the age of 32 years), which gradually progressed and was associated with tremors for the past 6 years. He had left-sided dystonic posturing of the limbs during the night, along with constipation and unintentional weight loss. He was born to second-degree consanguineous parents and had an unremarkable birth and developmental history Figure 1A. He had a sibling (II-5) with a similar illness. Finally, he was diagnosed with young-onset PD with hemi-dystonia. He demonstrated significant improvement in the levodopa challenge test, as indicated by the Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores, which improved from 54 (OFF state) to 12 (ON state) when assessed at presentation to our clinic (8 years after disease onset). The Montreal Cognitive Assessment was normal. Blood investigations—including complete blood count, serum copper, ceruloplasmin, thyroid, renal, and liver parameters—were normal. Brain magnetic resonance imaging was normal. He was started on a combination of levodopa (100 mg) and carbidopa (25 mg) four times per day, along with trihexyphenidyl and pramipexole. Initially, his motor symptoms improved, but later his dystonia showed an inadequate response to levodopa, with ON-time dyskinesias lasting 1–2 hours after taking levodopa for the past 4 years. Given the young-onset parkinsonism and consanguineous parentage, we performed whole-exome sequencing, which revealed disease-causing homozygous deletions of exon 1 of the PARK2 (ENST00000366898) and exon 1 and exon 2 of the PACRG (ENST00000337019.3) genes.Figure 1: (A). Pedigree of the proband. Computed tomography of the abdomen: (B) axial (C) and sagittal sections. Long-segment enhancing irregular polypoidal wall thickening of the rectum, 5 cm from the anal verge (lining in red).He had a gradual weight loss of nearly 8 kg accompanied by significant constipation. Initially, there was no evidence of recurrent fevers, abdominal pain, altered bowel habits, rectal bleeding, vomiting, anemia, or other red flags prompting consideration of alternative diagnoses. Hence, the weight loss was considered probably secondary to the disease process and medication-related. Trihexyphenidyl was stopped, and safinamide (100 mg) was started once daily. Despite this, his constipation and weight loss continued to progress, and further evaluation showed unremarkable blood parameters. The gastroenterologist evaluated him at two different times using abdominal ultrasound and colonoscopy, both of which were normal. We considered the symptoms to be probably secondary to PD progression, as well as medication-induced at this stage, and gradually tapered and stopped safinamide. Because of advanced PD, he underwent DBS of the bilateral STN in 2021, 10 years after disease onset. Following this, he showed improvement in motor symptoms with no dyskinesias. Post-DBS, he continued to experience persistent and progressive constipation, along with significant weight loss of 12 kg from baseline. He presented with acute abdominal pain and vomiting. Subsequent evaluation with colonoscopy revealed polypoidal infiltrative growth with areas of necrosis, located 5 cm to 12 cm from the anal verge. This finding was confirmed by contrast-enhanced computed tomography of the abdomen, which also showed multiple small-volume peri-rectal lymph nodes with no evidence of metastasis Figure 1B and C. Biopsy of the lesion was suggestive of well-differentiated adenocarcinoma of the rectum. He underwent preoperative radiotherapy for 1 month, followed by abdominoperineal resection and adjuvant chemotherapy with capecitabine for 4 months. After treatment, his gastrointestinal symptoms resolved, accompanied by a remarkable weight gain of 10 kg. Currently, he is on levodopa (100 mg)–carbidopa (25 mg), pramipexole, safinamide, and lorazepam. He performs activities of daily living independently, although OFF dystonia persists and is partially relieved with lorazepam. Genetics and PD involve different mechanisms, including mitochondrial, lysosomal, and synaptic dysfunctions, all of which contribute to dopaminergic dysfunction and neuronal cell death.3 Monogenic PD accounts for approximately 5%–10% of all PD cases, with PARK2 being the most common.4 Mutations in the Parkin gene (PARK2) cause early-onset autosomal recessive PD characterized by dystonia, slow progression, early-onset dyskinesias, and a sustained response to levodopa.5 Nonmotor symptoms in individuals with PARK2 variants more commonly include anxiety, depression, and panic attacks than gastrointestinal symptoms.6 A study by Yamamura et al.7 showed constipation in 48% of PARK2 variant cases, suggesting significant gastrointestinal dysfunction in these patients. Parkin has diverse functions that contribute to various cellular processes. Among them, notable ones include its role in protein turnover through ubiquitin-proteasome pathways, which facilitate protein degradation and clearance, and mitophagy, which involves the clearance of damaged mitochondria by autophagy. These processes are critical for maintaining homeostasis and, in turn, can prevent the accumulation of damaged proteins and organelles, which may lead to neurodegeneration.8 Parkin is activated by PINK1 (phosphatase and tensin homolog-induced kinase 1) or through neuronal depolarization (in a PINK1-independent manner), regulating synaptic vesicle (SV) endocytosis and recycling, which is crucial for dopamine regulation. In Parkin PD, SV recycling is impaired, leading to the accumulation of oxidized dopamine in SVs and neurodegeneration.3 Furthermore, Parkin serves as a tumour-suppressor gene.9 In malignancies, Parkin becomes deregulated at both mRNA and protein levels, contributing to the aggressiveness and metastatic nature of these diseases.10 Its association with breast cancer, colorectal cancer, squamous cell lung carcinoma, and gastric cancer has been reported.11 Unintentional weight loss is commonly seen in 30%–70% of PD cases (sporadic or genetic) and typically begins much earlier than the onset of motor symptoms. It is primarily based on factors such as advanced age, duration of illness, higher Hoehn and Yahn staging, UPDRS III, and nonmotor symptom scores.12 Following DBS, patients ideally gain weight within the first year after surgery. Then, it remains static or stable with increasing longevity, depending on unilateral and bilateral stimulation of the STN or globus pallidus internus for PD.13 Hence, when weight loss with persistent and progressive gastrointestinal symptoms occurs despite DBS and appropriate medical management in PD—especially in PARK2-related PD, where its association with malignancy has been reported, —we suggest a timely and comprehensive evaluation for secondary causes other than disease progression. This evaluation should include consideration of endocrinal abnormalities (hyperthyroidism, diabetes mellitus, adrenal insufficiency); infections such as tuberculosis and human immunodeficiency virus (especially in endemic countries like India); psychiatric conditions like depression; gastrointestinal pathologies; and malignancies, particularly those associated with Parkin. Early and appropriate intervention measures can significantly improve the quality of life in PD individuals. Acknowledgement We thank the patient and the patient’s family for their cooperation. Author contribution A. Research project: Conception: Karri Madhavi, Rukmini M. Kandadai, Rupam Borgohain, Sruthi Kola, Rajesh Alugolu, Vanukuru Prasad Organization: Karri Madhavi, Rukmini M. Kandadai, Rupam Borgohain, Vanukuru Prasad Execution: Karri Madhavi, Rukmini M. Kandadai, Vanukuru Prasad B. Statistical analysis: Design: Karri Madhavi, Rukmini M. Kandadai, Aditya P. Kumar Kanteti Execution: Karri Madhavi, Rukmini M. Kandadai, Vanukuru Prasad, Aditya P. Kumar Kanteti, Srikanth Nallam Review and Critique: Karri Madhavi, Rukmini M. Kandadai C. Manuscript preparation: Writing of the first draft: Karri Madhavi Review and Critique: Karri Madhavi, Rukmini M. Kandadai, Rupam Borgohain, Sruthi Kola, Rajesh Alugolu, Vanukuru Prasad, Aditya P. Kumar Kanteti, Srikanth Nallam Ethical compliance statement All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. The authors confirm that this work did not require ethical approval from the institutional review board. Verbal and written consent was obtained from the patient to publish this case study. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Madhavi et al. (Thu,) studied this question.