Phospholipase-associated Neurodegeneration (PLAN) with PLA2G6 mutation comprises a continuum of three phenotypes with overlapping clinical and radiological features. The spectrum comprises typical Infantile neuroaxonal dystrophy (INAD) also known as Seitelberger disease, atypical neuroaxonal dystrophy (ANAD) and more recently described entity PLA2G6-associated dystonia parkinsonism (PLAN-DP). We, herein, report an adolescent with PLAN-DP.

A 14-year-old boy, product of a non-consanguineous marriage and with a normal birth and developmental history, presented with difficulty in walking from last one year. Parents noticed dragging of the left leg while walking with short steps. This was followed by stiffness of both the legs and arms with frequent falls on left side while walking along with dystonic posturing of left leg. Patient developed generalized slowness with decreased arm swing, unable to close fist and poor interest in surroundings. Patient was unable to sit and stand after one year of onset of illness along with poor speech in form of decreased phonation and articulation. There were no psychiatric or behavioral changes. There were no other affected family members with a similar illness.

On examination, patient was conscious and oriented but lacking emotional expression on the face. Generalized bradykinesia was present involving trunk and all four limbs. Motor examination revealed cogwheel rigidity with exaggerated deep tendon reflexes and positive Babinski sign. Sensory, cranial nerve and cerebellar examination were normal. Kayser-Fleischer ring was not detected, and fundus evaluation was normal. Patient developed urgency and incontinence of urine during his course of illness. On the basis of clinical diagnosis of neurodegeneration with extra pyramidal symptoms a differential diagnosis of Wilson disease, dopa-responsive dystonia (Segawa disease), panto-thenate kinase-associated neurodegeneration (PKAN), hypo-parathyroidism and mitochondrial disorder were considered and evaluated for.

Brains magnetic resonance imaging MRI showed T2 hyper intense shadow in the insular cortex and some part of temporal lobe but no evidence of T2-weighted hypo-intensities in the basal ganglion and substantial nigra. There was no evidence of cerebellar atrophy or brainstem involvement. All laboratory tests including serum biochemistry, liver and thyroid function test, serum ceruloplasmin, and 24-hour urinary copper excretion were within normal limits. Direct gene sequencing revealed a homozygous missense variation in exon 16 of the PLA2G6 gene (chr22:g.38508565C>T; Depth: 315x) which resulted in the amino acid substitution of Glutamine for Arginine at a codon 741(p.Arg741Gln; ENT00000332509.3). The mutation was previously described as pathogenic (rs121908686) and is present in ExAC database with very low frequency (0.0002277). Patient was put on levodopa which resulted in dramatic improvement in motor symptoms and speech. He is under follow-up and sustaining good response to drugs.

Paisan-Ruiz, et al. [4] described 23 patients of PLAN-DP from 16 pedigrees [3,4], with youngest age of onset of 4 years and the oldest 37 years. Dystonia and parkinsonism were seen uniformly but neuropsychiatric and cognitive decline were seen invariably as initial presentation in adult-onset disease. Autonomic dysfunction, specifically urinary symptoms have been observed frequently as in this case and may be an important clue in diagnosis. Kapoor, et al. [5] in a review discussed the genetic analysis of PLA2G6 in 22 Indian families with phospholipase-2 associated neurodegeneration. This mutation was found in 12/22 (54.55%) families with INAD and ANAD which again suggest variable phenotypic expression of this disorder. Majority of families presented with INAD/ANAD and only one family presented with PLAN-DP, but was negative for this mutation.

In our patient, MRI showed no evidence of hypointensity in globus pallidus and substansia nigra; although, PLAN has been consistently reported to have neurodegeneration with brain iron accumulation. Iron accumulation was found in only eight patients (33%) in a previous review of 23 patients, which is less than what is reported in INAD (40-50%). The process of iron accumulation; however, is not well described.

The protein product of PLA2G6, phospholipase–A2 group VI (iPLA2-IVA) is an enzyme involved in the metabolism of glycerophospholipids and it plays an important role in inner mitochondrial membrane homeostasis [8].

In conclusion, PLAN-DP is characterized by remarkably heterogeneity in presentation and at present no specific clinical criteria are there to pinpoint the diagnosis but the early onset dystonia parkinsonism with psychiatric symptoms, speech deterioration, cognitive changes, autonomic dysfunction, iron deposition in MRI and response to levodopa is suggestive towards this differential diagnosis and these children should be evaluated for PLA2G6 mutation.

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3. Karkherian S, Shahidi GA, Walker RH, Paisan-Ruiz. PLA2G6-associated dystonia-Parkinsonism: Case report and literature review. Tremor Other Hyperkinet Mov. 2015;5:317.

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5. Kapoor S, Shah MH, Singh N, et al. Genetic analysis of PLA2G6 in 22 Indian families with infantile neuroaxonal dystrophy, atypical late onset neuroaxonal dystrophy and dystonia parkinsonism complex. PLoS One. 2016;19:11.

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7. Paisan-Ruiz C, Li A, Susanne A, et al. Widespread Lewy body and Tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutation. Neurobiol Aging. 2012;33:814-23.

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