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