The packet lists PLA2G6 (chromosome 22) as the gene associated with this condition. A ClinGen validity classification is not supplied in the packet. The inheritance pattern given is autosomal recessive, and GeneReviews states that PLAN is inherited in an autosomal recessive manner. According to GeneReviews, parents of an affected individual are obligate heterozygous carriers, and carriers are described as asymptomatic. For siblings of an affected individual, GeneReviews gives a 25 percent chance of being affected, a 50 percent chance of being an asymptomatic carrier, and a 25 percent chance of being unaffected and not a carrier at conception.

GeneReviews describes limited genotype-phenotype correlation. Individuals with two null alleles of PLA2G6 are reported to all have INAD, while the less severe atypical neuroaxonal dystrophy phenotype is described as caused almost exclusively by pathogenic missense variants. Common pathogenic variants associated with INAD are described as impairing the catalytic activity of the PLA2G6 protein, whereas three pathogenic variants associated with PLA2G6-related dystonia-parkinsonism did not. A molecular-mechanism field is not supplied in the packet beyond these GeneReviews statements.

According to GeneReviews, the diagnosis of PLAN is established in a proband by identification of biallelic pathogenic or likely pathogenic variants in PLA2G6 on molecular genetic testing. The same source lists suggestive findings for INAD, including onset before age three years, psychomotor regression as the most common presenting feature, early truncal hypotonia followed by spastic tetraparesis, and visual abnormalities such as strabismus, nystagmus, and optic atrophy. Laboratory features listed include an elevated aspartate aminotransferase to alanine aminotransferase ratio and elevated lactate dehydrogenase.

Radiographic findings described include cerebellar atrophy and, on T2-weighted brain MRI, a hypointense globus pallidus indicating iron accumulation, cerebellar cortical hyperintensities consistent with gliosis, white matter abnormalities, and a thin, vertically oriented corpus callosum. Neurophysiologic findings listed include denervation on EMG, fast rhythms on EEG, delayed visual evoked potentials with reduced amplitudes, and a distal axonal sensorimotor neuropathy on nerve conduction studies. GeneReviews states that an estimated 40 to 50 percent of individuals with INAD have abnormal basal ganglia iron accumulation and that an eye-of-the-tiger sign has not been found in INAD, in contrast to pantothenate kinase-associated neurodegeneration. For atypical neuroaxonal dystrophy and dystonia-parkinsonism, the source lists distinct clinical and radiographic features, and notes that brain iron findings in dystonia-parkinsonism are variable and may not be evident until late in the disease course.

The packet does not certify an FDA-approved therapy for this condition. The orphan drug records attached to the packet, including approved records for deferasirox and acetylcysteine, list indications unrelated to this condition and are not treatments for it. Orphan designation is not approval, and the designated and withdrawn records in the packet carry no approval for this condition.

According to GeneReviews, the treatments for INAD and atypical neuroaxonal dystrophy are palliative. The source describes pharmacologic treatment of spasticity and seizures, a trial of oral or intrathecal baclofen in atypical disease with significant dystonia, deep brain stimulation reported in one individual with atypical disease and intractable dystonia, psychiatric treatment for neuropsychiatric symptoms in later-onset disease, fiber supplements or stool softeners for constipation, a transdermal scopolamine patch for excessive secretions, and gastric feeding tube or tracheostomy placement as needed to prevent aspiration pneumonia. For dystonia-parkinsonism, GeneReviews describes a response to dopaminergic agents that may be dramatic initially and diminishes over time, with early dyskinesias reported.

GeneReviews also describes early rehabilitation with physical therapy and orthopedic management to prevent contractures in individuals who are permanently nonambulatory, body temperature monitors used for progressive autonomic involvement, and periodic assessment of vision and hearing in nonverbal children as surveillance. The source states that early diagnosis is not likely to significantly reduce morbidity or mortality.

According to GeneReviews, the progression of INAD is usually rapid. Many affected children never learn to walk or lose the ability shortly after attaining it. In end stages, severe spasticity, progressive cognitive decline, and visual impairment are described as resulting in a vegetative state, and death is described as occurring through secondary illnesses such as aspiration pneumonia associated with bulbar dysfunction. The source states that many affected children do not survive beyond their first decade, while some survive into their teens or later, and that supportive care can contribute to a longer life span by reducing the risk of infection and other complications. For atypical neuroaxonal dystrophy, GeneReviews states that the life span is not known but is expected to be longer than in classic disease, with disease progression slower than in INAD. Individual outcomes are not certified in this packet.

The packet lists one ClinicalTrials.gov record, NCT03570931, a phase 2 study of RT001 in infantile neuroaxonal dystrophy sponsored by Biojiva LLC, with status active, not recruiting, a start date of 2018-11-05, and a listed completion date of 2022-06-30. The packet classifies its intervention type as drug therapy; the title does not establish efficacy or approval. GeneReviews describes therapies under investigation, stating that chelation therapy is sometimes raised because some individuals have high brain iron, that the chelator deferiprone was under investigation for the PKAN form of neurodegeneration with brain iron accumulation with results that may inform its use in PLAN, and that a proof-of-concept gene therapy strategy and small molecule therapies were under investigation in cell and murine disease models.