PLA2G6-Associated Neuroderation, Infantile Neuroaxonal Dystrophy and Parkinson Disease via the PLA2G6 Gene

PLA2G6-associated neurodegeneration (PLAN): This is the second most common disorder in neurodegeneration with brain iron accumulation (NBIA). It has variable phenotypes including infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (NAD), and PLA2G6-related Parkinsonism. Onset can be infantile, juvenile or late onset. The main manifestations include hypotonia, spasticity, dystonia, parkinsonism, cerebellar ataxia, motor and mental retardation. In both INAD and atypical NAD, cerebellar atrophy and optic atrophy are hallmark features. The most common and earliest signs in Brain MRI is cerebellar atrophy and claval hypertrophy, while cerebellar cortex hyperintensity and increased iron deposition in the globus pallidus are later findings (Salih et al 2013; Romani et al 2015; Arber et al. 2016).

Infantile Neuroaxonal Dystrophy (INAD): This is an early onset type from six months to three years with developmental regression, hypotonia, visual disturbance, optic atrophy, progressive spastic tetraparesis and motor and mental retardation (Salih et al 2013; Levi and Finazzi et al 2014).

PLA2G6-related Parkinsonism: This is a levodopa-responsive Parkinsonism with pyramidal signs and additional clinical features such as neuropsychiatric symptoms, emotional liability, autonomic symptoms and sleep disorders (Bohlega et al. 2016).

PLA2G6-associated Neurodegeneration, Infantile Neuroaxonal Dystrophy and PLA2G6-related Parkinsonism are inherited in an autosomal recessive manner and are caused by pathogenic variants in the PLA2G6 gene which encodes a calcium-independent phospholipase A2 group VI. This phospholipase catalyzes hydrolysis of the sn-2 acyl-ester bonds in phospholipids. Null alleles in PLA2G6 result in Infantile Neuroaxonal Dystrophy. Pathogenic variants in PLA2G6 gene include missense, nonsense, small deletion and insertion, and splice pathogenic variants, as well as large deletion/duplications across the PLA2G6 locus (Salih et al 2013; Romani et al 2015, Davids et al 2016; Human Gene Mutation Database).

It has been estimated that pathogenic variants in PLA2G6 account for 20% cases of neurodegeneration with brain iron accumulation (Arber et al. 2016).

For PLA2G6, mutation detection rate for large deletions and duplications in patients with neurodegeneration with brain iron accumulation is unavailable in the literature.

This test provides full coverage of all coding exons of the PLA2G6 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).