An Interesting Case of Young-Onset Parkinsonism Due to PLA2G6 Gene Mutation-Related Dystonia Parkinsonism

Sir, Phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN) is a rare genetically heterogeneous disorder due to mutations in the PLA2G6 gene resulting in progressive deposition of iron in the basal ganglia and different regions of the brain, clinically characterized by various extrapyramidal symptoms, such as parkinsonism and dystonia. Age of onset, disease severity, and cognitive impairment are variable depending on genetic and clinical heterogeneity. A 30-year-old right-handed gentleman born out of non-consanguineous marriage, with normal birth and developmental history, has presented with insidious-onset progressive bradykinesia for 3 years, with almost symmetrical rigidity of both upper and lower limbs and distal predominant resting tremors. After 6 months of symptom onset, he also developed gait instability and postural disturbances in the form of recurrent backward falls. There is also a history of change in behavior in the form of anger outbursts, aggression, psychiatric symptoms, and difficulties in planning and execution of tasks. Apart from that, he also has complaints of urinary problems in the form of increased frequency and hesitancy. There is no history of motor weakness or any history suggestive of cranial nerve, sensory, or cerebellar involvement. His family history is insignificant. His past illness and medication history are unremarkable. On examination, a general survey revealed masked facies with infrequent blinks. On nervous system examination, MMSE is 20/30 and MoCA score is 18/30. On a detailed higher mental function examination, impaired attention and executive dysfunction are found. Verbal fluency is reduced. Calculation and judgment are impaired. The speech appears to be slow, monotonous, and without dysarthria. The cranial nerve examination is normal, including all extraocular and supranuclear eye movements. Neuro-ophthalmological examination is normal without any evidence of KF ring or retinitis pigmentosa. Bilateral extrapyramidal signs in the form of bilateral symmetric bradykinesia with coarse rest tremors of fingers, wrists, and toes are noted. There is evidence of symmetrical appendicular as well as axial rigidity. Note is made of truncal dystonia without any evidence of limb dystonia. His gait is short-stepping with a symmetrical reduced arm swing and a tendency to fall backwards, with occasional dystonic posturing of the trunk. No signs of corticospinal, sensory, or cerebellar involvement were found. His autonomic nervous system exam was also normal. In view of early-onset symmetrical parkinsonism with cognitive decline and truncal dystonia, secondary causes of early-onset parkinsonism are thoroughly evaluated. The routine hematological and biochemical investigations are normal. Human Immunodeficiency Virus (HIV) serology and Venereal disease research laboratory (VDRL) tests are negative. Wilson’s disease workup is also negative. The Nerve Conduction Study (NCS) and Electromyography (EMG) studies were unremarkable. EEG brain revealed some nonspecific theta range slowing of background rhythm The magnetic resonance (MR) imaging of the brain revealed markedly hypointense T2 and FLAIR signals in bilateral caudate heads, putamen, globus pallidi, and left substantia nigra [see Figures 1 and 2]. SWI images show blooming in the corresponding regions [see Figure 3]. Note is made of generalized mild cerebral atrophy as evidenced by mild prominence of the frontoparietal cortical sulcal spaces and cerebellar atrophy is also found [see Figures 1 and 4]. The temporal lobe volume appears to be well preserved. Sagittal images show mild drooping of the splenium of corpus callosum although there is no claval hypertrophy [see Figure 1]. Considering his clinical features and MRI brain appearance, NBIA was kept as a primary possibility, and the genetic workup for NBIA was sent. On targeted gene sequencing, a homozygous missense variation in exon 16 of the PLA2G6 gene (chr22:g.38508565C>T; Depth: 31x) that results in the amino acid substitution of Glutamine for Arginine at codon 741 (p.Arg741Gln; ENST00000332509.3) was detected. The mutation was previously described as pathogenic (rs121908686) and is present in the ExAC database with a very low frequency (0.0002277). The observed variation has previously been reported in patients affected by DP.[1] The genetic screening of the other healthy family members was also offered but they didn’t give consent for that due to social stigma. Finally, the patient has been diagnosed with PLA2G6 gene mutation-related dystonia parkinsonism and started on oral levodopa replacement therapy. The dose of levodopa was slowly uptitrated to a total daily dose of 375 mg combined levodopa-carbidopa tablets in three divided doses and over the next six months of follow-up his MDS UPDRS score improved significantly from 58 at baseline to 49 after 6 months.Figure 1: T2 Images-Axial cuts (upper row) showing hypointense signals in the midbrain and basal ganglia regions (red arrow). T2 Sagittal images (lower row) showing mild cerebellar atrophy (prominence of cerebellar folia marked as yellow arrow) and mild drooping of the splenium of corpus callosum (green arrow)Figure 2: T2 FLAIR image showing hypointensity in bilateral basal banglia at putamen and globus pallidus (red arrow)Figure 3: SWI images showing blooming in bilateral caudate heads (yellow arrow) and putamen (red arrow)Figure 4: Axial T1 images showing mild generalised cerebral atrophy as evidenced by mild prominence of sulcal spaces in frontoparietal region (image on the left) although temporal volume is well preserved (image on the right)PLA2G6 encodes a group of calcium-independent phospholipase A2 proteins that are involved in the metabolism of glycerophospholipids responsible for inner mitochondrial membrane homeostasis. PLAN is a rare genetically heterogeneous disorder with variable mutation regions and types leading to clinically distinct phenotypes. PLAN has been classified as NBIA type-2.[2,3] The classification of PLAN includes infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), adult-onset dystonia parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP).[4] INAD and ANAD present early in childhood, manifesting as progressive worsening of psychomotor functions, spasticity, ataxia, axial dystonia, and optic atrophy, in a few. In most of the cases of INAD, MRI shows evidence of iron deposition in the globus pallidus and/or the substantia nigra[5] with advanced cerebellar atrophy in some cases. MRI evidence of iron accumulation can be picked up by the susceptibility-weighted imaging (SWI) sequences. Patients with DP and AREP present as adults and usually have normal births and early developmental milestones. They present with clinical features of complex parkinsonian syndromes such as bradykinesia, tremors, and dystonia, as well as progressive neurocognitive decline and instability of gait. Unlike in INAD MRI, evidence of brain iron deposition may not always be present in adult-onset DP.[6] Variability among the clinical subtypes is substantially high, but the age of onset and clinical presentations can help differentiate the subtypes of PLAN. Earlier in the year 2006, the PLA2G6 gene was identified in INAD patients from two Israeli families, which included consanguineous marriages in both.[7] The PLA2G6 gene mutation was found to have an association with parkinsonism for the first time in 2010.[8] Mutations in different regions and even at the same position may cause phenotypic heterogeneities. Previously, Kapoor et al.[9] had reviewed the genetic analysis of PLA2G6 in an Indian context among 22 Indian families with PLAN. As per the description by Paisan-Ruiz et al.[1] out of 23 patients with PLAN-DP, features of dystonia and parkinsonism were seen almost uniformly. Autonomic dysfunction, specifically urinary symptoms, has been observed frequently. The treatment of PLA2G6-related DP in adults primarily focuses on symptom management and supportive care, as there is currently no curative therapy for this rare genetic disorder. However, various pharmacological and non-pharmacological interventions may help alleviate symptoms and improve quality of life. Among the pharmacological therapy levodopa remains the mainstay of treatment to alleviate the parkinsonian symptoms. Anticholinergic drugs as well as botulinum toxin injections are useful to some extent for controlling associated dystonia. Selective serotonin reuptake inhibitors (SSRIs) or benzodiazepines may be prescribed to manage associated mood disorders or anxiety. Non-pharmacological interventions such as physical therapy, occupational therapy, and speech therapy can help to prevent early disability. Participation in clinical trials investigating novel therapeutic approaches, including gene therapies or disease-modifying agents, may offer potential benefits for individuals with PLA2G6-related DP. PLAN is a rare and highly variable disease lacking specific clinical criteria for diagnosis. Suspicion for PLAN arises based on the age of presentation and clinical features, prompting consideration for genetic testing to confirm the subtype. The PLAN-DP subtype typically manifests in adults with early-onset complex parkinsonism, alongside dystonia, psychiatric symptoms, cognitive changes, and autonomic dysfunction. The MRI appearance of iron accumulation is not consistent in DP in comparison with INAD, unlike in our case, which shows significantly distinct iron accumulation in bilateral basal ganglia. Identifying genetically confirmed cases of PLAN is crucial for raising awareness and understanding of the disease, facilitating improved diagnostics, and potential therapeutic planning. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.