Clinical Guidance

Genotype correlates with phenotype to a limited extent:

• All individuals with two null alleles of PLA2G6 have INAD.

• The less severe atypical NAD phenotype is caused almost exclusively by pathogenic missense variants.

• Common pathogenic variants associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with PLA2G6-related dystonia-parkinsonism did not .

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"

Diagnostic Criteria

Suggestive Findings

PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features:

• Infantile neuroaxonal dystrophy (INAD)

• Atypical neuroaxonal dystrophy (atypical NAD)

• PLA2G6-related dystonia-parkinsonism

Infantile Neuroaxonal Dystrophy (INAD)

PLA2G6-associated INAD should be suspected in individuals with the following clinical, laboratory, radiographic, and neurophysiologic features.

Clinical

• Onset before age three years

• Psychomotor regression (most common presenting feature)

• Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course)

• Visual abnormalities: strabismus, nystagmus, optic atrophy

Laboratory

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"

Differential Diagnosis

Infantile Neuroaxonal Dystrophy (INAD)

Early diagnosis is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions. The observation of an elevated aspartate aminotransferase / alanine aminotransferase ratio and elevated lactate dehydrogenase in combination with these findings is more suspicious for INAD . The degree of weakness early in the disease course may initially direct the clinician toward a myopathy or spinal muscular atrophy. Cerebellar atrophy can be detected by brain MRI before age two years in some children .

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PLA2G6-associated neurodegeneration (PLAN), the following evaluations are recommended if they have not already been completed:

• Thorough ophthalmologic examination to assess for optic atrophy

• EEG for the possibility of unrecognized seizure activity

• Consultation with a clinical geneticist and/or genetic counselor

Note: The extent of disease is often well characterized by the time of diagnosis, since the diagnostic workup frequently includes neurophysiologic studies (EEG, EMG, nerve conduction studies, ERG [electroretinogram], and/or VEP) and brain MRI.

Treatment of Manifestations

The following treatments for infantile neuroaxonal dystrophy (INAD) and atypical NAD are palliative:

• Pharmacologic treatment of spasticity and seizures

• Trial of oral or intrathecal baclofen for those with atypical INAD who have significant dystonia (See Dystonia Overview.)

Deep brain stimulation has been successfully utilized in one individual with atypical NAD who had intractable dystonia .

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"

Therapies Under Investigation

Because some individuals with PLAN have high brain iron and this disorder falls into the category of NBIA, the option of chelation therapy is sometimes raised. The chelator deferiprone is currently under investigation for the PKAN form of NBIA. Results may inform its use in PLAN and/or lead to additional trials. A proof-of-concept gene therapy strategy is currently under investigation in murine disease models of PLAN [Dr. Manju Kurian, personal communication]. Development of small molecule therapies is also under investigation in cell and murine disease models [Dr. Paul Kotzbauer, personal communication]. Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"

Surveillance Guidelines

Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits.

Source: GeneReviews — "PLA2G6-Associated Neurodegeneration"