PLA2G6 ‐Associated Neurodegeneration: Report of a Novel Mutation in Two Siblings with Strikingly Different Clinical Presentation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of hereditary heterogeneous disorders (most of them autosomal recessive) characterized by the presence of an extrapyramidal progressive dysfunction and excess iron accumulation in different locations in the brain. Overall, it remains unclear whether increased brain iron content, documented in many neurodegenerative diseases, is a direct cause of neurodegeneration, a secondary event in a pathophysiologic cascade, or just a nonspecific marker of neurodegeneration. NBIA disorders present a wide spectrum of clinical manifestations such as progressive hypo-and/ or hyperkinetic movement disorders, and a variable degree of pyramidal, cerebellar, peripheral nerve, autonomic, cognitive, and psychiatric involvement, and visual dysfunction. The responsible mutated gene defines each syndrome.1 The second most common types of NBIA after pantothenate kinase-associated neurodegeneration (PKAN), are PLA2G6-related disorders. PLA2G6 encodes iPLA2-VI, a calcium-independent phospholipase. Traditionally mutations on this gene were thought to cause progressive neurodegeneration with miscellaneous manifestations in three phenotypes: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and late-onset dystonia/parkinsonism starting in adolescence or early adulthood. 2 Reports suggest that PLA2G6 mutations cause a phenotypic continuum rather than three discrete phenotypes, further ensuing clinical implications. 3 We report two siblings with NBIA2 with a striking disparity in presentation: one as INAD and the second as atypical neuroaxonal dystrophy. Case ReportThe kindred included two siblings from nonconsanguineous parents. Family history was unremarkable except for the presence of Parkinson's disease (PD) in their grandmother.Case III-1Our index case, a 20-year-old woman had normal development up to the age of 9 when she begun to experience subtle difficulties in school, social withdrawal, and progressive clumsiness. A few years later she began neurological evaluations that included several MRIs, but up to age 16, brain iron accumulation was not sufficiently detected by MRI to raise the suspicion of PLA2G6 mutation. She had a tonic-clonic seizure at the age of 19. At age 20, she had normal height and weight, marked ataxia, intention tremor, and slurring speech (Video S1). Examination showed generalized hyperreflexia, gait disturbance, slight dystonic signs such as mild torticollis, and cognitive impairment. EEG was normal and since she was 16, several MRIs showed hypointensity in the substantia nigra and globus pallidus (Fig. 1). There was also a marked cerebellar atrophy in MRI. Case III-2Patient III-1 had a 32-year-old sister. She had been born after a normal pregnancy with Apgar 10. In her first months she had weak cry and frequently adopted opisthotonus posture so she was evaluated throughout her first year with normal EEG, cranial CT, and CSF. A diagnosis of cerebral palsy had been made shortly after birth. She was ab...

Genetic Dystonia‐ataxia Syndromes: Clinical Spectrum, Diagnostic Approach, and Treatment Options

“…Most important useful handles in guiding diagnosis with the herein proposed clinical algorithms for dystonia‐ataxia syndromes include the age of disease onset, some associated clinical clues and particular imaging findings. However, major criticism to clinical algorithms arise on the clinical and genetic heterogeneity (e.g., many entities or combined syndromes are not distinct conditions), but may represent a continuum between different phenotypes, as is the case for ATP1A3‐, or PLA2G6‐related disorders . In addition, clinical algorithms may not fit for atypical phenotypes or be useless if they are too simplistic or rigid, as they may delay or obstruct the identification of the underlying genetic cause in a determined patient .…”

Unusual Presentation of PLA2G6‐Related Neurodegeneration with Retinal Vasculitis

“…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.…”

Moving Beyond Syndromic Classifications in Neurodegenerative Disease: The Example of PLA2G6

“…Two recent case series have now demonstrated that syndromes caused by biallelic mutations in phospholipase A2 group VI ( PLA2G6 ) (Online Mendelian Inheritance in Man no. 60360) also are examples of this general insight.…”

“…• X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and nonsyndromic sensorineural deafness (DFN2) are continuous allelic phenotypic clusters caused by phosphoribosyl pyrophosphate synthetase 1 (PRPS1) mutations. 8 Two recent case series 9,10 have now demonstrated that syndromes caused by biallelic mutations in phospholipase A2 group VI (PLA2G6) (Online Mendelian Inheritance in Man no. 60360) also are examples of this general insight.…”