The <scp>Ala53Thr</scp> Mutation in the <scp>α‐Synuclein</scp> Gene in an Indian Patient with <scp>Young‐Onset</scp> Parkinson's Disease

The Ala53Thr mutation in the α-synuclein gene (SNCA) was the first genetic mutation reported to cause autosomal-dominant Parkinson's disease (PD).1 The clinical profile of SNCA gene mutations tend to have early-onset PD, with a remarkable levodopa response initially.2 The disease may worsen relatively more rapidly than idiopathic PD and cognitive, psychiatric, and autonomic disorders are frequently observed.2 Here we report a patient with young-onset PD attributed to the Ala53Thr mutation in the SNCA gene; to the best of our knowledge, this is the first report from India. A 38-year-old right-handed male, presented with complaints of slowness in his daily activities and stiffness of the right side of the body for the past 1½ years. He had anosmia and constipation for 5 to 6 years before the onset of these symptoms. He had a history of anxiety and depression in the past. There was no history of any cognitive decline, falls, freezing episodes, sleep disorder, or any autonomic disturbances. However, his family history was very significant (Fig. 1-i). He had 2 brothers, and both had a similar history of early-onset PD; his eldest sibling died at an early age. His mother also had a similar history at the age of 45 years, and she died at the age of 52 years. One of his maternal cousins also had similar complaints and also died at the age of 25 years. He is a Kumauni Brahmin originally from Uttarakhand, and his family later migrated to Nepal. On examination, his Montreal cognitive assessment score was 28/30, and his speech was monotonous. He had facial hypomimia, bradykinesia, and rigidity predominantly on the right side with a decreased arm swing of his right arm and leg on walking (see Video 1). His Movement Disorder Society–Unified Parkinson's Disease Rating Scale (MDS-UPDRS; Part III off) score was 20. He was treated with tablets of levodopa + carbidopa (100 + 25 mg 5 times daily), but the response was poor (MDS-UPDRS Part III on score was 18). His blood and urine investigations, including workup for metabolic disorders and the magnetic resonance imaging of the brain, were normal. Given his clinical presentation and strong positive family history, whole-exome sequencing was done, which detected a heterozygous missense variant in exon 3 of the SNCA gene (chr4:g.90749300C>T; depth: 37x) that results in the amino acid substitution of threonine for alanine at codon 53 (p.Ala53Thr; ENST00000394986.1; Fig. 1-ii). The observed variation lies in the synuclein domain of the SNCA protein and has previously been reported in patients affected with PD.3 The detection of the p.A53T mutation in the SNCA gene in patients with PD marked a turning point in the genetics of PD. Since its first description in 1997 in the large Contursi kindred, this mutation has been reported mostly with Greek and Italian backgrounds due to the existence of a founder effect.1 Our case is the first reported case of PD attributed to the mutation in the SNCA gene from India. In a recent study, we performed whole-exome sequencing in 250 patients with PD, and only 1 patient had a heterozygous variant of unknown significance in the SNCA gene (4:90743416 T>C:p.K96R).4 The phenotype of patients with PD with SNCA mutations resembles sporadic PD but with early-onset and atypical features such as psychiatric symptoms, cognitive decline, and autonomic dysfunction. Our patient had psychiatric symptoms, but he did not have any cognitive decline or autonomic dysfunction. The SNCA mutations usually display a high penetrance and rapidly progressive course, very similar to our family where multiple family members were affected, and many of them had early deaths. However, there are reports where affected members with the p.A53T mutation showed a longer disease duration and marked intrafamilial variability regarding the age of onset, disease severity, and clinical symptoms, including nonmotor features.2 Response to levodopa in SNCA-gene–related PD is usually good, but our patient had a poor response. His elder brother who died at a very young age also had a poor response to levodopa, and he underwent bilateral subthalamic deep brain stimulation with no significant improvement. In a recent study from France, Lesage et al reported a patient with PD with both the SNCA Ala53Thr and heterozygous PRKN Thr240Met variants with a poor response to levodopa.5 He rapidly developed motor fluctuations and impulse control disorders, but he did not have cognitive decline. In this study, 2 other patients carrying the Ala53Thr mutation had a good response to levodopa. To conclude, our patient from India is a case of young-onset PD attributed to the Ala53Thr mutation in the SNCA gene, with some unusual features such as normal cognition and poor response to levodopa. However, future studies are required to know the exact prevalence of SNCA gene mutations in the Indian population. (1) Conception and Design of the Study, (2) Acquisition and Analysis of Data; (3) Drafting a Significant Portion of the Manuscript and Figures. S.P.: 1, 2, 3 L.R.T.: 1, 2, 3 The authors confirm that the approval of an institutional review board was not required for this work. We also confirm that the patient has given written informed consent for the publication of Video 1. We confirm that we have read the Journal's position on issues involved in the ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report.

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