PLA2G6-associated neurodegeneration: A phenotypic continuum

Sir, PLA2G6-associated neurodegeneration (PLAN) is a subtype of Neurodegeneration with Brain Iron Accumulation (NBIA), caused by mutations in the PLA2G6 gene on chromosome 22q13.1. It traditionally manifests as three distinct phenotypes linked to age of onset: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophies (ANAD), and PLA2G6-related dystonia–parkinsonism (PLAN-DP).[1,2] We report an Indian case with childhood onset with features suggestive of an overlap of the phenotypes of PLAN. A 21-year-old boy presented with a history of insidious-onset cervical dystonia at 7 years of age after a short febrile illness. Five years later, he developed right upper limb dystonic hand tremor. He had average scholastic performance until the age of 20 years. He then presented to us at age 21 years with a 3-month history of subacute neurological worsening. The dystonia had generalized, and he complained of slowness of activities and sudden jerk-like involuntary movements. In addition, there was history of new cognitive and behavioral changes in the form of low mood, poor comprehension, difficulties in finding words, and navigational errors. The patient had second-degree consanguineous parentage, but no reported family history of similar illness. On examination, cognitive testing revealed impairments of attention, execution, working and recent memory, and visuospatial and constructional tasks. The Montreal Cognitive Assessment score was 12/30. He had generalized dystonia involving the cervical and hand and trunk regions with a dystonic neck and hand tremor, bradykinesia, and myoclonic jerks of the limbs [Video 1]. There were no pyramidal signs noted. Baseline part III motor score of the Unified Parkinson’s Disease Rating Scale (UPDRS) was 41 out of 108 and the Burke–Fahn–Marsden Dystonia Rating Scale (BFMD) score was 19. The possibility of recessive dystonia–parkinsonism was considered. Subacute cognitive and psychiatric symptoms could either reflect worsening of the underlying condition or be unrelated etiologies, possibly infectious, immune, or inflammatory. Investigations aimed to rule out the latter causes. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_3uhdi8l4"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Routine tests were normal. Brain magnetic resonance imaging (MRI) showed mild cerebral atrophy, but notably, no iron accumulation [Figures 1 and 2]. Cerebrospinal fluid analysis and whole-body positron emission tomography scan were unremarkable. Video electroencephalogram (EEG) showed generalized epileptiform discharges, although there was no clear history of seizures. Whole-exome sequencing revealed a homozygous missense variation c.2264G>A (p.Arg755Gln) in exon 16 of the PLA2G6 gene. The patient was treated with levodopa 300 mg per day and clonazepam 0.5 mg per day. Trihexyphenidyl was avoided in view of cognitive concerns. At follow-up, the UPDRS III motor score improved to 11 from 41 and the BFMD score improved to 9.5 from 19. There were no dyskinesias at the 1-year follow-up.Figure 1: MRI FLAIR image was normalFigure 2: Susceptibility Weighted Imaging did not show iron accumulationThe INAD phenotype of PLAN has infantile onset with psychomotor regression with early axial hypotonia, late spasticity, bulbar dysfunction, and dystonia with death by age 10 years. The ANAD phenotype presents later between 1.5 and 6.5 years with language difficulty and cerebellar, pyramidal, and extrapyramidal dysfunction with rapid deterioration at the end of first decade. The pathological hallmark of INAD and ANAD is axonal degeneration with distended axons present throughout the central and peripheral nervous system. Brain MRI shows characteristic iron deposition in the globus pallidus and/or substantia nigra.[1,2] The PLAN-DP variant usually presents between the late second and third decade. Presentation may be with isolated psychiatric symptoms at onset, prior to the appearance of extrapyramidal symptoms, making early diagnosis challenging. Parkinsonism usually develops in the second to third decade; it shows good levodopa responsiveness but may result in complications a few weeks to years later with “tell-tale” levodopa-induced dyskinesias. The other manifestations include dystonia, cortical myoclonus, ataxia, oculomotor involvement, and pyramidal signs. EEG abnormalities and iron deposition observed on imaging are infrequently noted in the adult-onset phenotype. Apart from symptomatic treatment with levodopa, deep brain stimulation targeting the subthalamic nucleus or globus pallidus internus has shown promising results. However, reporting bias and the lack of long-term outcome data are limiting factors, underscoring the need for further research to provide stronger evidence.[2] After ruling out possible contributors, this case was concluded to be PLAN with the following atypical features: 1) An initial first decade of dystonia is consistent with the presentation of ANAD 2) Motor onset in the first decade and neuropsychiatric issues only in third decade 3) EEG changes which are observed more commonly with INAD and ANAD than in the PLAN-DP phenotype 4) Absence of levodopa-induced dyskinesia, which is frequent in the PLAN-DP phenotype This mutation (c.2264G>A (p.Arg755Gln)) has been reported in an Indian family with INAD.[3] Moreover, the same mutation may have different phenotypes in the same pedigree, suggesting that factors other than the PLA2G6 gene may contribute to the disease course.[1-3] Table 1 summarizes previously described similar cases with overlapping features highlighted in the last rows.[1,4-6]Table 1: Review of cases with overlapping phenotypes of PLANThis case and the review of existing literature highlights that PLAN can present on a continuum of a spectrum rather than age-related rigid phenosubtypes. More literature on similar dystonia–parkinsonian disorders with a protracted course will help better understand such rare genetic disorders. 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. Acknowledgement We acknowledge the patient and his family for their consent and cooperation. Author contribution Each author contributed to the patient’s clinical treatment, the composition and writing of the manuscript, and provided critical revisions of the text. Research project: Conception: SG, KS Organization: SG, CHM, NS, KS Execution: Statistical analysis: Design: SG, KS Execution: SG, KS Review and Critique: CHM, NS, KS Manuscript preparation: Writing of the first draft: SG, KS Review and Critique: SG, CHM, NS, KS Ethical compliance statement This work was conducted in compliance with ethical standards, and institutional review board approval was not required. We have secured informed consent from the subject for the publication of this material. The authors have reviewed the journal’s ethical publication guidelines and attest that this submission adheres to them. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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