Overview

PLA2G6-associated neurodegeneration (PLAN), also referred to as NAD or PARK14, is caused by mutations in the gene encoding calcium-independent phospholipase A2 (PLA2G6) (Figs 19.6a and 19.6b). The disease can manifest as classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (NAD), and PLA2G6-related dystonia-parkinsonism (Kurian and Hayflick, 2013).

Clinical Presentation

• Classic Infantile Neuroaxonal Dystrophy (INAD):

  • Onset typically occurs between 14 and 18 months of age.
  • Affected children never achieve independent walking (Adams and Lyon, 1982a).
  • Initial developmental arrest is followed by regression of language and motor skills.
  • Symptoms include a combination of upper and lower motor neuron signs, leading to the loss of reflexes, profound hypotonia, and marked leg wasting.
  • Additional features include optic atrophy resulting in blindness, progressive dementia, and sometimes seizures.
  • EEG may show prominent fast activity.
  • Dystonia is generally milder compared to PKAN.

• Atypical Neuroaxonal Dystrophy (NAD):

  • May present more with ataxia rather than spasticity.
  • The phenotype is less severe compared to the infantile form.

• PLA2G6-Related Dystonia-Parkinsonism:

  • Adult form presenting with dystonia-parkinsonism and spasticity.
  • Cognitive and psychiatric features are also observed (Paisan-Ruiz et al., 2009).
  • Initial good response to L-dopa may be followed by disabling dyskinesias.

Neuroimaging Findings

• Cerebellar Atrophy:

  • Most common neuroimaging finding in both INAD and atypical NAD.
  • Present in most patients early in the disease and in nearly all well-established INAD cases (Hogarth, 2015).

• Iron Accumulation:

  • May not be observed on MRI in early-onset cases.
  • In later-onset cases, the substantia nigra may be more heavily involved than the globus pallidus.

References

• Adams R, Lyon G (1982a) Neuroaxonal degeneration. In: Adams RD and Lyon G. (eds) Neurology of Hereditary Metabolic Diseases of Children. McGraw Hill Book Company, pp. 127–30.
• Hogarth P (2015) Neurodegeneration with brain iron accumulation: diagnosis and management. J Mov Disord 8: 1–13.
• Kurian M, Hayflick SJ (2013) Pantothenate kinase-associated neurodegeneration (PKAN) and PLA2G6-associated neurodegeneration (PLAN): Review of two major neurodegenerations with brain iron accumulation (NBIA) phenotypes. Int Rev Neurobiol 110: 85–95
• Paisan-Ruiz C, Bhatia KP, Li A, et al. (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 65: 19–23.