How is a PLA2G6 mutation diagnosed and what samples are used?

Diagnosis is confirmed by sequencing the PLA2G6 gene, usually through a targeted NGS panel for neurodegenerative disorders or whole‑exome sequencing. A blood sample is sufficient; in some cases, a skin biopsy for fibroblast culture may be requested to assess enzyme activity.

What clinical features should prompt evaluation for infantile neuroaxonal dystrophy (INAD) related to PLA2G6 mutations?

INAD typically presents with developmental regression after a period of normal development, progressive motor difficulties (ataxia, spasticity), intellectual disability, and sometimes vision loss. Early onset seizures and abnormal gait are also common. If these symptoms appear, a neurologist should consider genetic testing for PLA2G6.

Are there any disease‑modifying treatments or clinical trials for PLA2G6‑related disorders?

Currently, treatment is supportive: physical therapy, speech therapy, and management of seizures. Some patients are enrolled in clinical trials investigating neuroprotective agents or gene‑replacement strategies, but these are experimental and not widely available. Patients should discuss trial options with a specialist in neurogenetics.

How does PLA2G6 deficiency affect iron metabolism and what monitoring is recommended?

PLA2G6 mutations can lead to abnormal iron accumulation in the brain, detectable by MRI T2* or susceptibility‑weighted imaging. Routine monitoring includes periodic MRI scans, serum ferritin, and transferrin saturation levels. Early detection of iron overload may guide iron‑chelation therapy, although evidence for benefit is limited; decisions should be individualized with a neurologist and a hematologist.

PLA2G6 Gene

The PLA2G6 gene encodes a calcium‑independent phospholipase A2 that regulates phospholipid metabolism; mutations disrupt enzyme function and are linked to several neurodegenerative disorders, most notably infantile neuroaxonal dystrophy.

Overview

The PLA2G6 gene provides instructions for making a type of enzyme called an A2 phospholipase. This enzyme is involved in breaking down (metabolizing) fats called phospholipids. Phospholipid metabolism is important for many body processes, including helping to maintain the integrity of the cell membrane. Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine, which is abundant in the cell membrane.

Health Conditions Related to Genetic Changes

Infantile Neuroaxonal Dystrophy

At least 50 mutations in the PLA2G6 gene have been identified in people with infantile neuroaxonal dystrophy, a progressive neurological disorder that causes intellectual disability and movement problems. Mutations in the PLA2G6 gene eliminate or severely impair the function of the PLA2 group VI enzyme. Impairment of PLA2 group VI enzyme function may disrupt cell membrane maintenance and contribute to the development of swellings called spheroid bodies in the axons, which are fibers that extend from nerve cells (neurons) and transmit impulses to muscles and other neurons.

Although it is unknown how changes in this enzyme's function lead to the signs and symptoms of infantile neuroaxonal dystrophy, phospholipid metabolism problems have been seen in both this disorder and a similar disorder called pantothenate kinase‑associated neurodegeneration. These disorders, as well as the more common Alzheimer’s disease and Parkinson’s disease, also are associated with changes in brain iron metabolism. Researchers are studying the links between phospholipid defects, brain iron, and damage to nerve cells, but have not determined how the iron accumulation that occurs in some individuals with infantile neuroaxonal dystrophy may contribute to the features of this disorder.

Melanoma

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Other Disorders

PLA2G6 gene mutations can also cause atypical neuroaxonal dystrophy and PLA2G6-related dystonia‑parkinsonism, which are conditions in which deterioration of neurological function (neurodegeneration) occurs later in life. The term PLA2G6-associated neurodegeneration (PLAN) is often used to include the entire spectrum of neurodegenerative disorders caused by mutations in PLA2G6.

Atypical neuroaxonal dystrophy (atypical NAD) is a disorder with signs and symptoms that are similar to those of infantile neuroaxonal dystrophy but that occur later and progress more slowly. Atypical NAD usually appears in early childhood but in some cases is not evident until the teenage years.

PLA2G6-related dystonia‑parkinsonism is also caused by PLA2G6 gene mutations and involves movement abnormalities that occur in adulthood. Dystonia is involuntary tensing of the muscles, and parkinsonism comprises a group of movement problems including unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability).

Both of these later‑onset conditions are caused by PLA2G6 gene mutations that are believed to have a less severe effect on PLA2 group VI enzyme function than the mutations that cause infantile neuroaxonal dystrophy.

Other Names for This Gene

CaI-PLA2
calcium-independent phospholipase A2
cytosolic, calcium-independent phospholipase A2
GVI
INAD1
iPLA2
iPLA2beta
NBIA2
OTTHUMP00000028877
PA2G6_HUMAN
PARK14
patatin-like phospholipase domain containing 9
phospholipase A2, group VI
phospholipase A2, group VI (cytosolic, calcium-independent)
PLA2
PNPLA9

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Tests of PLA2G6

Scientific Articles on PubMed

PubMed

Catalog of Genes and Diseases from OMIM

PHOSPHOLIPASE A2, GROUP VI; PLA2G6

Gene and Variant Databases

NCBI Gene
ClinVar

Genomic Location

The PLA2G6 gene is found on chromosome 22.

References

Engel LA, Jing Z, O'Brien DE, Sun M, Kotzbauer PT. Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia‑parkinsonism. PLoS One. 2010 Sep 23;5(9):e12897. doi:10.1371/journal.pone.0012897.
Hayflick SJ. Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Semin Pediatr Neurol. 2006 Sep;13(3):182-5. doi:10.1016/j.spen.2006.08.007.
Khateeb S, Flusser H, Ofir R, et al. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. Am J Hum Genet. 2006 Nov;79(5):942-8. doi:10.1086/508572.
Kurian MA, Morgan NV, MacPherson L, et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008 Apr 29;70(18):1623-9. doi:10.1212/01.wnl.0000310986.48286.8e.
McNeill A, Chinnery PF. Neurodegeneration with brain iron accumulation. Handb Clin Neurol. 2011;100:161-72. doi:10.1016/B978-0-444-52014-2.00009-4.
Morgan NV, Westaway SK, Morton JE, et al. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006 Jul;38(7):752-4. doi:10.1038/ng1826.
Polster B, Crosier M, Lindsay S, Hayflick S. Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy. Brain Res Bull. 2010 Nov 20;83(6):374-9. doi:10.1016/j.brainresbull.2010.08.011.
Schneider SA, Bhatia KP. Rare causes of dystonia parkinsonism. Curr Neurol Neurosci Rep. 2010 Nov;10(6):431-9. doi:10.1007/s11910-010-0136-0.
Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov Disord. 2012 Jan;27(1):42-53. doi:10.1002/mds.23971.
Wu Y, Jiang Y, Gao Z, et al. Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy. Eur J Neurol. 2009 Feb;16(2):240-5. doi:10.1111/j.1468-1331.2008.02397.x.