PLA2G6-Associated Neurodegeneration

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

1. Infantile neuroaxonal dystrophy (INAD)

2. Atypical neuroaxonal dystrophy (atypical NAD)

3. PLA2G6-related dystonia-parkinsonism

INAD usually begins between ages six months and three years with psychomotor regression or delay, hypotonia, and progressive spastic tetraparesis. Many affected children never learn to walk or lose the ability shortly after attaining it. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid, resulting in severe spasticity, progressive cognitive decline, and visual impairment. Many affected children do not survive beyond their first decade.

Atypical NAD shows more phenotypic variability than INAD. In general, onset is in early childhood but can be as late as the end of the second decade. The presenting signs may be gait instability, ataxia, or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. Strabismus, nystagmus, and optic atrophy are common. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years.

PLA2G6-related dystonia-parkinsonism has a variable age of onset, but most individuals present in early adulthood with gait disturbance or neuropsychiatric changes. Affected individuals consistently develop dystonia and parkinsonism (which may be accompanied by rapid cognitive decline) in their late teens to early twenties. Dystonia is most common in the hands and feet but may be more generalized. The most common features of parkinsonism in these individuals are bradykinesia, resting tremor, rigidity, and postural instability.

Diagnosis/testing: The diagnosis of PLA2G6-associated neurodegeneration is established in a proband by identification of biallelic pathogenic variants in PLA2G6 on molecular genetic testing. The diagnosis of INAD or atypical NAD can be established in a proband with no identified PLA2G6 pathogenic variants by electron microscopic examination of nerve biopsies for dystrophic axons (axonal spheroids).

Management: Treatment of manifestations:

1. Individuals with INAD and atypical NAD. Routine pharmacologic treatment of spasticity and seizures; trial of oral or intrathecal baclofen for dystonia associated with atypical INAD; treatment by a psychiatrist for those with later-onset neuropsychiatric symptoms; fiber supplements and/or stool softener treatment for constipation; control of secretions with transdermal scopolamine patch as needed; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition.

2. Individuals with PLA2G6-related dystonia-parkinsonism. Consider treatment with dopaminergic agents; treatment of neuropsychiatric symptoms by a psychiatrist; evaluation by physical therapy for management of postural instability and gait difficulties; occupational therapy to assist with activities of daily living; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition.

Prevention of secondary complications: Early physical therapy and orthopedic management to prevent contractures as the disease progresses; body temperature monitors may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature.

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

Genetic counseling: PLA2G6-associated neurodegeneration is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the pathogenic variants in the family are known.