Unusual Presentation of PLA2G6‐Related Neurodegeneration with Retinal Vasculitis

Phospholipase A2 Group VI (PLA2G6)‐related neurodegeneration (PLAN) is a form of neurodegeneration with brain iron accumulation (NBIA), which displays genetic and phenotypic heterogeneity. It can present in the following 4 different forms depending on the age of onset and varied clinical features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), adult‐onset dystonia‐parkinsonism, and autosomal recessive early‐onset parkinsonism. ¹ Neuroophthalmological involvement is well known in pantothenate kinase‐associated neurodegeneration, the most common form of NBIA, and includes retinal degeneration (pigmentary retinopathy), optic neuropathy, and oculomotor abnormalities. ² Visual dysfunction also occur in PLAN in the form of optic atrophy predominantly in the INAD and ANAD subtypes. ³ We report an unusual presentation of retinal vasculitis in a patient of adult‐onset PLAN.

A 27‐year‐old male product of third‐degree consanguinity presented with difficulty in walking for 9 months in the form of dragging of feet and right eye visual loss for the past 1 month. There was associated extensor posturing of the trunk with a tendency to fall backward and progressive slowness in activities of daily living. Nonmotor symptoms included apathy, history of urinary frequency and urgency, rapid eye movement sleep behavioral disorder, and constipation.

The patient noted acute‐onset, painless progressive visual loss in his right eye of 1 month duration. The patient had a similar history of painless progressive visual loss (no perception of light) in the left eye. He was diagnosed with a retinal detachment in 2014 attributed to posterior uveitis and underwent pars plana vitrectomy elsewhere. The patient had a poor postsurgical outcome with loss of vision and phthisis bulbi.

On examination at our center, he was unable to perceive light in the left eye, and the acuity was 6/36 in the right eye. Fundus examination revealed pale disc edema with multiple superficial non‐necrotizing retinitis patches. Fluorescein angiography revealed attenuated vessels with capillaritis and leakage of dye suggestive of active retinal vasculitis (Fig. 1). There was significant dye leakage from the vessels in the late phase. There were capillary nonperfusion areas in the periphery suggestive of occlusive retinal vasculitis. Examination of extraocular eye movements revealed the presence of square wave jerks with broken pursuits and normal saccades.

FIG 1.

(A) Hazy media with pale disc associated with yellow retinal patches suggestive of retinitis on fundus examination. (B) Fundus fluorescein angiogram shows features of small vessel vasculitis (beading of vessels with leakage of dye). (C,D) Optical coherence tomography showing patches of active retinitis.

Tone was spastic with 3+ deep tendon reflexes in the lower limbs and bilateral extensor plantar reflex. Extrapyramidal system examination revealed mask‐like facies, decreased blink rate, and slow hypophonic speech. Bradykinesia was present with reduced arm swing bilaterally. There was dystonia predominantly affecting the trunk, hands, and feet (Video S1). Patient was investigated to look for the etiology of retinal vasculitis. Cerebrospinal fluid (CSF) analysis was noncontributory, including negative results for CSF gram stain, acid‐fast bacilli (AFB), and venereal disease research laboratory test (VDRL). Viral markers, including human immunodeficiency virus (HIV), were negative. Serum VDRL and Treponema pallidum hemagglutination assay was negative. Work up for autoimmune causes including erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA) quantitative profile (ANA, anti Jo‐1, Anti Ro/LA, anti‐Smith, Anti Scl‐70, anti‐centromere, and anti U1RNP), and human leukocyte antigen B51 (HLA B51) to rule out Behcet's disease was normal. Serum protein electrophoresis did not show M band. Nerve conduction studies were normal. Brain magnetic resonance imaging revealed diffuse cerebral atrophy with iron deposition in the bilateral globus pallidus in susceptibility weighted imaging sequences with left optic nerve atrophy (Fig. 2). Genetic tests consisting of screening for spinocerebellar ataxia (SCA) (1, 2, 3, 5, 6, 7, 8, 11, 14, 17, 23), fragile X tremor ataxia syndrome (FXTAS), dentatorubral‐pallidoluysian atrophy (DRPLA), and mitochondrial disorders were normal. Clinical exome sequencing revealed a homozygous missense mutation (NM_003560.2: C.2222 G>A; p. Arg 741 Gln) on chromosome 22 suggestive of PLAN. This variant was identified to be damaging by in silico prediction tools (mutation transfer, Eigen PC, Deleterious Annotation of genetic variants using Neural Networks (DANN), and Rare Exome Variant Ensemble Learner (REVEL)). The variant is novel as per gnomAD database and is previously reported in Clinvar (rs121908686) as pathogenic. This was confirmed using Sanger sequencing (Fig. 3). This variant has been previously reported from Saudi Arabia, Pakistan, and India with possible geographical clustering. ⁴ , ⁵

Video S1.

Demonstrates slow stiff gait with decreased arm swing bilaterally. Dystonia is evident in the form of extension posturing of the trunk with slight bending to the left as well as bilateral hands. Bradykinesia is present on both sides (right > left).

FIG 2.

(A–D) Brain magnetic resonance imaging (MRI) showing cerebral and cerebellar atrophy; (E,F) iron deposition in bilateral globus pallidus in susceptibility weighted imaging images; and (G,H) brain MRI with optic nerve cuts showing relatively thinned left optic nerve with no enhancement.

FIG 3.

Targeted mutational analysis of the PLA2G6 gene by polymerase chain reaction and bidirectional sanger sequencing.

Patient demonstrated significant improvement in bradykinesia and dystonia with levodopa/carbidopa (100/25 mg thrice a day; Video S2). He was also started on immunomodulatory therapy in the form of corticosteroids and azathioprine for posterior uveitis in the right eye. Clinical examination at 6 months revealed stable visual acuity in the right eye and mild interval reduction in retinal vasculitis (Fig. 4).

Video S2.

Demonstrates improvement in bradykinesia and dystonia with the presence of oro‐buccolingual dyskinesias after 1 month of levodopa therapy.

FIG 4.

(A) Follow‐up fundus imaging of the patient after 6 months of treatment shows healing of the yellow retinitis patches after initiation of therapy. (B) The fluorescein angiography shows significantly reduced retinal vascular leakage and improvement in the vasculitis. There is an ill‐defined hyperfluorescence in the mid‐periphery attributed to atrophy of the retinal pigment epithelium. There is no retinal neovascularization.

Ocular manifestations, including optic atrophy, strabismus, and nystagmus have been described predominantly in INAD and ANAD subtypes compared with adult‐onset PLAN. ⁶ , ⁷ Eye movement abnormalities can also occur and include poor convergence, saccadic pursuit, and saccadic intrusions. Visual‐evoked potentials and electroretinograms are usually abnormal especially when performed in the later stages of the disease. Optic pathway atrophy is an important imaging finding apart from cerebellar atrophy and iron deposition in globus pallidus. ⁸

The PLA2G6 gene encodes a calcium‐independent phospholipase enzyme iPLA2‐VIA that catalyzes the hydrolysis of glycerophospholipids. PLA2G6 plays a potential role in neuronal development. The expression of PLA2G6 has been demonstrated in various neuronal and nonneuronal tissues in the fetus using in situ hybridization tecniques. ⁹ In the eye, it is expressed in lens, neurosensory retina, and optic nerve. Kolko et al demonstrated the role of calcium‐independent phospholipase A2 in the regulation of retinal pigment epithelium proliferation. ¹⁰ There are reports of pigmentary retinopathy in the PLA2G6 mutation, and the underlying cause could be decreased rate of proliferation of retinal cells attributed to inhibited activity of iPLA2‐VIA. ¹¹

Retinal vasculitis is a potential sight‐threatening inflammatory eye condition and can occur as an isolated idiopathic condition, as a manifestation of infectious disease, or as a part of systemic immune‐mediated disease. ¹² To the best of our knowledge, retinal vasculitis has not been described in PLAN. One may speculate the findings of retinal vasculitis in a neurodegenerative condition such as PLAN to be a chance association. However, the absence of PLA2G6 can lead to neuroinflammation in the form of activation of microglia and the release of proinflammatory cytokines such as tumor necrosis factor alpha and interleukin 1 beta (TNF‐α and IL‐1β) as demonstrated by a mice model in which genetic ablation of PLA2G6 led to cerebellar atrophy characterized by Purkinje cell loss and glial cell activation. ¹³ Plasmalogens or ether phospholipids account for 13% of retinal phospholipids and play a crucial role in retinal vascular development. ¹⁴ Plasmalogen deficient and iPLA2‐inhibited mice exhibit defects in retinal vasculature with high macroglial activity and an overproduction of fibronectin. The inflammatory process may be related to increased macroglial activity, astrocytic proliferation, and fibronectin production secondary to hypoxia, leading to a retinal vasculitis–like picture. The mild reduction in retinal vasculitis after immunomodulatory therapy may be attributed to suppression of the inflammation occurring secondary to this abnormal vascular development.

To summarize, we report a novel association of retinal vasculitis with PLAN, although further cases need to be reported before a definite causal association can be established.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of Final Draft, B. Review and Critique.S.M.: 1A, 1B, 1C, 2A, 2B

A.T.: 1B, 1C, 2B

D.S.: 1B, 1C

A.A.: 1B, 1C, 2A, 2B

V.L.: 1A, 1B, 1C, 2B

Disclosures

Ethical Compliance Statement: The authors confirm that the Ethics board clearance was not required for this work. The subject has provided written video consent. 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 guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.

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