Early Ataxia and Subsequent Parkinsonism: PLA2G6 Mutations Cause a Continuum Rather Than Three Discrete Phenotypes

Abstract

PLA2G6-associated neurodegeneration comprises a heterogeneous spectrum of age-related phenotypes, with three forms classically recognized, including infantile neuroaxonal dystrophy (INAD) with onset in infancy, atypical neuroaxonal dystrophy (atypical NAD) with onset in childhood, and dystoniaparkinsonism (PARK14) with onset in early adulthood. We describe 3 cases that challenge this view, discuss the related literature, and suggest that PLA2G6 mutations cause a phenotypic continuum rather than three discrete phenotypes, further ensuing clinical implications.Fueled by the advances in the field of genetics, our understanding of the clinical presentations and the underlying pathophysiology of syndromes summarized as neurodegeneration with brain iron accumulation (NBIA) has expanded considerably. 1 PLA2G6-associated neurodegeneration (PLAN; also referred to as NBIA2) is one of the major subtypes of NBIA and comprises a heterogeneous spectrum of age-related phenotypes (Table 1), with three forms recognized, which include infantile neuroaxonal dystrophy (INAD) with onset in infancy, atypical neuroaxonal dystrophy (atypical NAD) including Karak syndrome (e.g., slowly progressive ataxia associated with cognitive decline) with onset in childhood, and dystonia-parkinsonism (PARK14) in the absence of prominent ataxia or sensory disturbances with onset in adulthood. [1][2][3][4] Infantile presentation accounts for the majority of cases (up to 85%), whereas other phenotypes, particularly atypical NAD, are much less frequently described. 1-3Although such clinical classification can be useful on practical grounds, it has been increasingly recognized that PLAN can manifest with intermediate phenotypes, 1-5 which only partially match those classically associated with this disorder. Here, we describe three cases, which suggest a phenotypic continuum rather than a discrete presentation of one form, and discuss the related literature ensuing clinical implications. Case 1This currently 24-year-old man attained normal milestones during the first 2 years of life, but was noticed to be clumsy and prone to fall. By the age of 6, he also started having learning and behavioral difficulties, though he could attend normal primary schools. His gait progressively worsened and he sought medical advice at the age of 13 years. Examination revealed ataxia of gait and unsteady stance. Finger-nose-finger test was mildly abnormal on both sides (right>left), and reflexes were brisk bilaterally. A brain MRI showed marked atrophy of the cerebellum, with associated hypointensity of the globus pallidus

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

“…P-values that compare individual characteristics between groups with dystonia-parkinsonism and early-onset PD were evaluated with an analysis of variance. Variables without a normal distribution were compared with the Kruskal-Wallis test, the non-parametric equivalent of the independent sample t-test levodopa-responsive EOPD (25,30). Consistent with initial reports, our two patients with this same mutation had comparable phenotypes and there were no signs of iron accumulation in the globus pallidus in brain MRIs.…”

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.…”

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

“…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 . Reports suggest that PLA2G6 mutations cause a phenotypic continuum rather than three discrete phenotypes, further ensuing clinical implications . We report two siblings with NBIA2 with a striking disparity in presentation: one as INAD and the second as atypical neuroaxonal dystrophy.…”

“…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.…”