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PLA2G6-Associated Neurodegeneration

Synonyms: NBIA2, PLA2G6-Related Disorders, PLAN

, MS, CGC, , MA, MRCPCH, PhD, , BSc, MBBS, MRCPCH, PhD, , MD, , MD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: April 14, 2026.

Estimated reading time: 40 minutes

Summary

Clinical characteristics.

PLA2G6-associated neurodegeneration (PLAN) is an age-related continuum from infancy to adulthood comprising three broad age-related phenotypes: infantile PLAN, juvenile PLAN, and adult PLAN. Some individuals have intermediate phenotypes, suggesting that PLAN is more of a spectrum of disease rather than discrete phenotypes.

Infantile PLAN usually begins between ages six months and three years, presenting with truncal hypotonia, psychomotor delay, and plateauing or loss of previously acquired milestones. Most individuals have speech difficulties and do not achieve independent ambulation and/or initially have gait disturbance. Over time, affected persons develop both weakness and symmetric spastic tetraparesis that can cause discomfort, interfere with bracing or positioning, and often lead to contractures and scoliosis. Limb dystonia can also be present. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid; many children do not survive beyond their first decade.

Juvenile PLAN shows more phenotypic variability than infantile PLAN. In general, onset is in early childhood but can be as late as the end of the second decade. 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 common. Although the disease course is fairly stable during early childhood, resembling static encephalopathy, it is followed by neurologic deterioration between ages seven and 12 years. Although life span is not known, it is expected to be longer than that of infantile PLAN.

Adult PLAN 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 PLAN is established in a proband with suggestive findings and biallelic pathogenic variants in PLA2G6 identified by molecular genetic testing.

Management.

Treatment of manifestations: Supportive care for individuals with infantile PLAN and juvenile PLAN is best managed by a multidisciplinary care team of educators for developmental delay and intellectual disability; an experienced neurologist for anti-seizure medications and pharmacologic treatment of dystonia and spasticity; treatment by a psychiatrist for those with later-onset neuropsychiatric manifestations; fiber supplements and/or stool softeners to treat constipation; control of secretions with transdermal scopolamine patch as needed; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition. For individuals with adult PLAN, consider treatment with dopaminergic agents; treatment of neuropsychiatric manifestations by a psychiatrist; early care by a physical therapist and orthopedist to manage postural instability and gait difficulties and to prevent contractures as the disease progresses; occupational therapy to assist with activities of daily living; feeding modifications as needed to prevent aspiration pneumonia and achieve adequate nutrition.

Surveillance: Periodic assessments per treating clinicians to monitor abnormalities in tone and movement, other musculoskeletal issues, cognitive issues, seizure control, vision and hearing to determine level of sensory deficits, pulmonary needs (especially later in the disease course), feeding and nutrition, and family need for social support.

Genetic counseling.

PLAN 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 and prenatal/preimplantation genetic testing are possible if the pathogenic variants in the family are known.

GeneReview Scope

PLA2G6-Associated Neurodegeneration: Age-Related Phenotypic Continuum
  • Infantile PLAN (infantile neuroaxonal dystrophy [INAD])
  • Juvenile PLAN (atypical neuroaxonal dystrophy)
  • Adult PLAN (PLA2G6-related dystonia-parkinsonism; PARK14)

For synonyms and outdated names see Nomenclature.

1.

Diagnosis

No consensus clinical diagnostic criteria for PLA2G6-associated neurodegeneration (PLAN) have been published.

Suggestive Findings

PLAN should be considered in probands with the following clinical, supportive laboratory, neurophysiologic, and imaging findings by age-related phenotype and family history.

Infantile PLAN

Clinical findings

  • Global developmental delay or developmental plateau and eventual neuroregression (the most common presenting feature) before age three years. Development may be normal until age six to 18 months. Only around one third of individuals with infantile PLAN learn to walk independently.
  • Early truncal hypotonia is followed by spastic tetraparesis (usually with hyperreflexia in early disease stages with progression to areflexia later in the disease course).
  • Dystonia may also be present.
  • Visual abnormalities can include strabismus, nystagmus, and optic atrophy that may be observed early as optic nerve pallor; thin optic chiasm and tracts have also been reported on brain MRI [Farina et al 1999].
  • Seizures can occur early or late in the disease course [Wu et al 2009].

Supportive laboratory findings

  • Often elevated aspartate aminotransferase with normal alanine aminotransferase
  • Often elevated lactate dehydrogenase

Neurophysiologic findings

  • Electromyogram (EMG) shows evidence of denervation.
  • Electroencephalogram (EEG) shows fast rhythms.
  • Visual evoked potential (VEP) is delayed with reduced amplitudes.
  • Nerve conduction velocity (NCV) tests show distal axonal-type sensorimotor neuropathy.

The neurophysiology findings may not be present early on in the disease course, and some individuals do not have these abnormalities on testing.

Juvenile PLAN

Clinical

  • Age of regression onset after age three years and before age 18 years with usually slower progression than infantile PLAN
  • Gait difficulties (most common presenting feature) that can be ataxic and/or spastic/dystonic
  • Psychomotor regression
  • Prominent expressive language difficulties
  • Neurobehavioral/psychiatric manifestations including impulsivity, poor attention span, hyperactivity, emotional lability, and autistic features
  • Visual abnormalities including optic atrophy, nystagmus, and strabismus
  • Spasticity, dystonia, and dysarthria (without preceding hypotonia)
  • Seizures (later in the disease course)

Brain imaging findings

  • Cerebellar atrophy
  • T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation)

Neurophysiologic

  • VEP is delayed with reduced amplitudes.
  • NCV tests show distal axonal-type sensorimotor neuropathy.
  • EMG shows evidence of denervation.

Adult PLAN

Clinical

  • Onset in young adulthood (median age of onset 20 years)
  • Neurobehavioral/psychiatric manifestations including depression, personality changes, aggression, delusions, and/or paranoia
  • Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses)
  • Dystonia
  • Dysarthria
  • Cognitive decline
  • Initial dramatic response to levodopa treatment followed by early development of dyskinesias

Brain imaging findings

  • In adult PLAN, about 25% of individuals have abnormal iron accumulation and 47% have cortical atrophy.
  • Many adults who have undergone presynaptic dopaminergic terminal imaging as part of their diagnostic workup have had abnormal results [Karkheiran et al 2015, Chu et al 2020, Magrinelli et al 2022].

All PLAN Phenotypes

Brain imaging findings

  • Abnormal iron accumulation (see Figure 1A) that is similar in extent in both the globus pallidus and substantia nigra is a hallmark of PLAN. Although it may not be present early in the disease course, it becomes more prominent with age in infantile and juvenile PLAN [Kurian et al 2008].
  • Cerebellar atrophy (see Figure 1B) is common in all three age-related PLAN phenotypes. While nearly universal in symptomatic children, cerebellar atrophy is observed in only about 40% of individuals with adult PLAN.
  • Other common findings across the PLAN spectrum are (1) apparent hypertrophy of the clava (gracile tubercle); (2) a thin and vertically oriented splenium of the corpus callosum (see Figure 1); (3) T2 hyperintensity in the cerebellar cortex, dentate nuclei, or supratentorial white matter [Illingworth et al 2014, Al-Maawali et al 2016]; and (4) cerebral atrophy.
Figure 1. A.

Figure 1

A. Left axial image shows high brain iron in the globus pallidus (see arrow) on T2-weighted MRI. B. Right sagittal image shows cerebellar atrophy (see arrow).

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of PLAN is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in PLA2G6 identified by molecular genetic testing (see Table 1).

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic PLA2G6 variants of uncertain significance (or of one known PLA2G6 pathogenic variant and one PLA2G6 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of PLA2G6 followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended unless there is compelling clinical and radiographic evidence for PLAN without a PLA2G6 pathogenic variant identified by exome or genome sequencing. The phenotype for PLAN can be so specific that PLA2G6 variants are highly suspected despite negative comprehensive genomic testing. In this instance, single-gene testing with targeted enrichment may detect a pathogenic variant [A Gregory, personal observation].

Option 1

A multigene panel that includes PLA2G6 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which genes are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of PLA2G6 pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. For rare situations when the clinical suspicion for PLAN is very high but exome sequencing identifies only one or no PLA2G6 pathogenic variants, genome sequencing should be considered.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

PLA2G6-Associated Neurodegeneration: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
PLA2G6 Sequence analysis 3~85% 4
Gene-targeted deletion/duplication analysis 5≤12.5% 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Of all individuals identified with PLA2G6 pathogenic variants, approximately 10% have only one pathogenic variant identified [NBIA International Mutation Database, unpublished data].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Deletion and duplication of multiple exons have been identified [Crompton et al 2010].

Clinical Characteristics

Clinical Description

PLA2G6-associated neurodegeneration (PLAN) is an age-related continuum from infancy to adulthood that comprises three broad age-related phenotypes: infantile PLAN, juvenile PLAN, and adult PLAN. Some individuals have intermediate phenotypes, suggesting that PLAN is more of a spectrum of disease rather than discrete phenotypes [Wilson et al 2025] (see Figure 2).

Figure 2.

Figure 2.

PLA2G6-associated neurodegeneration (PLAN) clinical disease progression by phenotype

Infantile PLAN

Age at onset is usually between ages six months and three years, presenting with psychomotor delay and plateauing or regression of development (i.e., loss of previously acquired milestones). Most individuals with infantile PLAN have speech difficulties and do not achieve independent ambulation and/or have gait disturbance. One individual with neonatal onset was reported to have severe hypotonia and marked weakness [Fusco et al 2015].

Truncal hypotonia is observed from early in the disease course. Over time, affected persons develop both weakness and symmetric spastic tetraparesis that can cause discomfort and interfere with bracing or positioning, often leading to contractures and scoliosis. Although reflexes can be normal or brisk initially, as peripheral nerve involvement increases, lower limb reflexes can be absent in a length-dependent manner. Limb dystonia can also be present.

Children typically younger than age five years can have unexplained irritability [AKS Soo, personal observation]. Sleep disturbances are common.

Ophthalmologic manifestations are common. Strabismus and nystagmus are frequent early features. Later, optic atrophy with vision loss occurs in most individuals.

Hearing impairment was reported in five of 18 children with infantile disease in Iran based on brain stem auditory evoked response testing [Dehnavi et al 2023].

Seizures occur in a minority of individuals as a later manifestation [Nardocci et al 1999, Wu et al 2009]. Children with infantile PLAN may also have non-epileptic stiffening or jerking movements that resemble seizures.

Autonomic involvement may present early as constipation, cold extremities, or breath-holding spells (i.e., involuntary, brief episodes in which young children, typically ages six months to six years, stop breathing, often turning blue or pale and sometimes losing consciousness). With progression, some individuals develop hypo- or hyperthermia.

Prognosis. Progression of infantile PLAN is usually rapid. Most affected children never learn to walk or speak. Those who achieve these skills lose them shortly after attaining them. In the end stages of disease, severe spasticity, weakness, progressive cognitive decline, and visual impairment result in minimal spontaneous voluntary movements. However, children do continue to vocalize, laugh, and smile into the latest disease stages [Gregory et al 2026]. Death results from illnesses such as aspiration pneumonia due to bulbar dysfunction and respiratory insufficiency. Although many children do not survive beyond their first decade, some have survived into their teens or later. In a small prospective study of infantile PLAN, the median age of death was ten years eight months [Gregory et al 2026]. Supportive care including careful management of nutritional status can contribute to a longer life span by reducing the risk of infection and other complications.

Juvenile PLAN

The features of juvenile PLAN vary. In general, age at onset is early childhood but can be into the early teens. In their report of 13 individuals, Nardocci et al [1999] found that onset in four individuals was by age three years with a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years.

In their report of 14 individuals, Menicucci at al [2025] reported that all attained language skills, independent walking, and fine motor and social skills. Loss of ambulation and regression of speech both occurred at a median age of ten years (range: 3-19 and 3-21 years, respectively).

In a cohort of 62 individuals, the most common presenting features were gait difficulty and falls at a median age of three years with loss of ambulation at a median age of 6.5 years. The median age of survival was 39 years [A Soo, unpublished data].

The presenting manifestations in some individuals may be similar to those of infantile PLAN, including gait instability, ataxia, or spasticity. However, individuals may present with speech delay and autistic features that may be the only evidence of disease for a year or more [Gregory et al 2008].

Although spastic tetraparesis is common in juvenile PLAN, on occasion it is preceded by early truncal hypotonia. In contrast to infantile PLAN, extrapyramidal findings (i.e., dystonia and dysarthria) are more common in juvenile PLAN. Parkinsonism may develop later in the course of the disease. Eye findings are like those seen in infantile PLAN.

Neurobehavioral/psychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [Gregory et al 2008]. Social communication difficulties, autistic features, or autism spectrum disorder are also common.

Prognosis. The life span is not known; however, it is expected to be longer than that observed in infantile PLAN. In their study of 14 individuals with juvenile PLAN, Menicucci et al [2025] reported that five were adults (ages 18-25 years) at the time of data collection and two had died, one at age ten years and one at age 18 years.

Adult PLAN

To date, only a small number of individuals have been described with the shared common features of parkinsonism, neuropsychiatric features, and gait dysfunction among otherwise heterogenous findings [Karkheiran et al 2015, Magrinelli et al 2022]. Although the age at onset ranged from four to 37 years [Paisán-Ruiz et al 2009, Paisán-Ruiz et al 2010, Yoshino et al 2010, Bower et al 2011, Paisán-Ruiz et al 2012, Virmani et al 2014], most presented in early adulthood (late teens to 20s). Of those with childhood onset, one presented with foot drag and dystonia at age ten years and two others presented with an unsteady gait at ages six and eight years, respectively. The youngest individual presented with stuttering speech, clumsiness, and dyslexia at age four years (findings that may have been unrelated to PLAN) before developing psychiatric manifestations at age 17 years. In young adults, initial manifestations are frequently neurobehavioral/psychiatric disturbances, including depression, personality changes, aggression, delusions, or paranoia. Gait disturbance and extrapyramidal features are also common at presentation.

Regardless of the age at onset, affected individuals consistently developed dystonia and parkinsonism (typically bradykinesia, resting tremor, rigidity, and postural instability) that may be accompanied by rapid cognitive decline in their late teens to early twenties. There still remain outliers, such as an individual who developed tremor in his late teens but was then stable until his early 50s with onset of mild, slowly progressive parkinsonism [P Hogarth, unpublished data].

Neurobehavioral/psychiatric changes may precede the movement disorder or occur concomitantly.

Dystonia is most common in the hands and feet but may be more generalized.

Dysarthria also becomes progressive.

Although initially it is common to have a dramatic positive response to dopaminergic agents, this tends to be short-lived and quickly followed by development of motor fluctuations and dyskinesias.

Seizures and autonomic dysfunction may also occur in later stages of the disease.

Prognosis. In the individuals described to date, death usually occurs within about ten years of onset.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are limited to the observation of Xue et al [2023] that pathogenic loss-of-function and missense variants predicted to be more deleterious on in silico analysis are most often associated with infantile disease.

Nomenclature

Outdated Terms

Franz Seitelberger first described this condition [Seitelberger 1952], which was originally named "Seitelberger disease."

"Karak syndrome" was described in two sibs with early-onset cerebellar ataxia, dystonia, spasticity, and intellectual decline. Brain MRI findings included cerebellar atrophy and iron accumulation in the globus pallidus and substantia nigra [Mubaidin et al 2003]. Morgan et al [2006] identified pathogenic variants in PLA2G6 in individuals with Karak syndrome, which is now included in the phenotypic spectrum of PLAN and no longer considered a clinically distinct entity; what had been described as Karak syndrome is now referred to as juvenile PLAN.

Current Nomenclature

The authors propose the following usage:

  • PLAN to refer to the entire spectrum of disease associated with PLA2G6 variants
  • Infantile PLAN to refer to infantile neuroaxonal dystrophy (INAD). Infantile PLAN encompasses early-onset, rapidly progressive disease.
  • Juvenile PLAN to refer to atypical neuroaxonal dystrophy and Karak syndrome. Juvenile PLAN encompasses later childhood-onset disease with slower progression, spasticity, and predominant extrapyramidal findings (dystonia, dysarthria).
  • Adult PLAN to refer to PLA2G6-related dystonia-parkinsonism and PARK14. Adult PLAN encompasses adult-onset dystonia-parkinsonism accompanied by cognitive decline and neuropsychiatric changes. Adult PLAN is referred to as NBIA/DYT/PARK-PLA2G6 in the Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force [Marras et al 2016].

Prevalence

Disease prevalence is estimated to be between 1:987,267 and 1:1,570,079 pregnancies worldwide based on two independent models [Kurtovic-Kozaric et al 2024]. This suggests underdiagnosis of PLAN based on enrollment in the largest international NBIA registry [SJ Hayflick et al, personal observation].

A PLA2G6 founder variant, p.Val691del, has been described in a North African cohort [Romani et al 2015] and in the Bedouin (Israel) population [Khateeb et al 2006] (see Table 8).

Differential Diagnosis

Infantile PLAN

Early diagnosis is challenging because the initial manifestations of global developmental delay or regression and disease progression are also observed in other genetic conditions including the following:

The observation of an elevated aspartate aminotransferase with normal alanine aminotransferase, elevated lactate dehydrogenase, and cerebellar atrophy in combination with these findings is suggestive of infantile PLAN [Kraoua et al 2016], particularly as evidence of brain iron accumulation may not be present if the brain MRI is performed when the child is young.

Selected genetic disorders of interest in the differential diagnosis of infantile PLAN are listed in Table 2.

Table 2.

Infantile PLAN: Genetic Differential Diagnosis

GeneDisorderMOIFeatures Similar to Infantile PLANFeatures Distinct from Infantile PLAN
ATM Classic ataxia-telangiectasiaARChildhood-onset cerebellar atrophy 1
  • Elevated serum AFP
  • Immunologic involvement (decreased serum concentration of Ig; decreased numbers of B & T cells; impairment of lymphocyte function)
  • Cerebellar atrophy is usually not present when first clinical manifestations occur.
  • ID is not common.
PANK2 Pantothenate kinase-associated neurodegeneration (PKAN)AR
  • Abnormal iron accumulation in basal ganglia (primarily globus pallidus) 2
  • DD (primarily motor but occasionally global)
  • "Eye of the tiger" sign (correlates very highly w/PKAN)
  • Increased muscle tone
ATXN2 Infantile-onset SCA2 3AD
  • DD
  • Hypotonia
  • Childhood-onset cerebellar atrophy
  • Infantile spasms w/hypsarrhythmia
  • Retinitis pigmentosa
ATXN7 Infantile- & juvenile-onset SCA7AD
  • Global DD
  • Hypotonia
  • Cerebellar atrophy
  • Retinal dystrophy
  • Prominent ataxia
KIF1A KIF1A-related neurodevelopmental disorder AD
(AR)
  • DD
  • Unsteady gait
  • Optic nerve atrophy
  • Disease progression is slower.
  • When present, cerebellar atrophy usually presents later in childhood. 1
MECP2 Rett syndrome (See MECP2 Disorders.)XL
  • Pattern of developmental plateau & regression
  • Unsteady gait
MRI appears relatively normal early in disease course & lacks specific pattern of findings assoc w/PLAN.
PLP1 Pelizaeus-Merzbacher disease (See PLP1-Related Disorders.)XL
  • Cerebellar atrophy
  • Nystagmus
  • Hypotonia
  • Progression to spasticity
MRI evidence of hypomyelination in cerebrum, cerebellum, & brain stem
PMM2 PMM2-CDG (CDG-Ia) (infantile form)AR
  • Cerebellar atrophy
  • Axial hypotonia
  • Hyporeflexia
  • Esotropia
  • DD
Involvement of other systems incl endocrine dysfunction, osteopenia, & cardiac, liver, & kidney manifestations
PPT1
(CLN1)		CLN1 disease (See Neuronal Ceroid Lipofuscinoses Overview.)ARNeurodegenerative courseWhen present, cerebellar atrophy usually presents later in childhood. 1
SMN1 Spinal muscular atrophy ARWeakness & hypotonia early in disease course
  • Tongue fasciculations
  • Absence of spasticity & cognitive decline
  • Not assoc w/cerebellar atrophy & abnormal iron accumulation

AD = autosomal dominant; AFP = alpha-fetoprotein; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; Ig = immunoglobulin; MOI = mode of inheritance; PLAN = PLA2G6-associated neurodegeneration; SCA = spinocerebellar ataxia; XL = X-linked

1.

Cerebellar atrophy can be detected by brain MRI before age two years in some children with PLAN [Farina et al 1999].

2.

An estimated 40%-50% of individuals with infantile PLAN have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T2-weighted MRI.

3.

Juvenile PLAN

Individuals with juvenile PLAN may first be diagnosed with a developmental disability such as autism spectrum disorder given communication/social deficits or cerebral palsy because of motor/gait abnormalities. Spasticity, dystonia, and dysarthria – findings similar to those of other forms of neurodegeneration with brain iron accumulation (NBIA) – eventually predominate.

Pantothenate kinase-associated neurodegeneration (PKAN) and mitochondrial membrane protein-associated neurodegeneration (MPAN) may present with similar features, but the MRI features distinguish them from PLAN.

Some complex hereditary spastic paraplegias, primary mitochondrial disorders, and cerebellar ataxias (see Hereditary Ataxia Overview) may also resemble juvenile PLAN.

Adult PLAN

Other genetic types of NBIA, monogenic causes of early-onset dystonia-parkinsonism, and primary mitochondrial disorders should be considered in the differential diagnosis of adult PLAN.

Selected genetic disorders of interest in the differential diagnosis of adult PLAN are listed in Table 4.

Table 4.

Adult PLAN: Genetic Differential Diagnosis

GeneDisorderMOIFeatures Distinct from Adult Plan
NBIA disorders (Note: Listed NBIA disorders can present with neuropsychiatric changes, gait changes, dystonia, & cognitive decline in late childhood or early adulthood.)
ATP13A2 Kufor-Rakeb syndrome (See NBIA Overview.)ARSupranuclear gaze palsy
C19orf12 Mitochondrial membrane protein-associated neurodegeneration (MPAN)AR
(AD)		Peripheral muscle atrophy & weakness
PANK2 Atypical pantothenate kinase-associated neurodegeneration (PKAN)AR"Eye of the tiger" sign on MRI & slow progression
Monogenic disorders assoc w/early-onset dystonia-parkinsonism 1 (Note: Listed disorders may be distinguished from PLAN by the absence of MRI findings specific to PLAN.)
ATP1A3 ATP1A3-related disorder ADOnset in adults is usually abrupt.
ATP7B Wilson disease ARAdults often present w/liver abnormalities.
FBXO7 PARK-FBXO7 (See Monogenic Parkinson Disease Overview.)AR
HTT Huntington disease AD
  • Prominent chorea
  • Regional atrophy of caudate & putamen early in disease course
PARK7
(DJ1)		PARK-DJ1 (See Monogenic Parkinson Disease Overview.)AR
PINK1 PINK1 type of young-onset Parkinson disease AR
PRKN Parkin type of early-onset Parkinson disease AR
PRKRA DYT-PRKRA (See Monogenic Isolated Dystonia Overview.)ARProminent oromandibular dystonia
SLC6A3 SLC6A3-related dopamine transporter deficiency syndrome (atypical form)AR
(AD)
  • To date, all persons evaluated w/DaTscan had very abnormal results w/absent or reduced tracer uptake in basal ganglia.
  • Distinct pattern on CSF neurotransmitter analysis
SNCA PARK-SNCA (See Monogenic Parkinson Disease Overview.)AD
SPG11 SPG11 1AR
  • Involves lower limb weakness/spasticity & peripheral neuropathy
  • "Ear of the lynx" sign on MRI
TAF1 X-linked dystonia-parkinsonism XLPrimarily afflicts Filipino men
TOR1A DYT-TOR1A ADAbsence of parkinsonism
VPS35 PARK-VPS35 AD~90% of affected persons have family history of Parkinson disease.

AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DaTscan = SPECT imaging using the ligand ioflupane; DYT = dystonia; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; PARK = Parkinson; SPG = spastic paraplegia

1.

Management

A consensus clinical management guideline has been published for PLA2G6-associated neurodegeneration (PLAN) [Wilson et al 2025] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PLAN, the evaluations summarized in Table 5a (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5a.

Infantile and Juvenile PLA2G6-Associated Neurodegeneration: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Development Developmental assessment
  • Assess motor, adaptive, cognitive, social, & communication abilities.
  • Consider referral to SLP or AAC specialist.
  • Assess for autistic features & anxiety.
Neurologic Neurologic eval
  • Assess neuromotor abilities (tone, hyper- or hypokinetic movement disorder, balance, & gait).
  • Consider referral to PT, OT, orthopedics, &/or physiatry.
  • Assess quality of sleep; consider referral for sleep study.
  • Review videos of abnormal movements; consider EEG for clinical seizures &/or movements suspected to be seizures.
Feeding/
Gastrointestinal 		Gastroenterology / diet & nutrition / neurology eval
  • Assess for swallowing & nutritional status, GERD, & constipation.
  • Consider referral for swallow study or feeding specialist.
  • Supplementary feeding incl gastrotomy tube placement is commonly required to maintain good growth & nutrition.
Musculoskeletal Orthopedics / PM&R / PT & OT evalAssessment of:
  • Range of motion
  • Contractures, scoliosis, & hip abnormalities
  • Mobility, ADL, & need for adaptive devices
  • Need for PT &/or OT
Eyes/
Vision 		Baseline dilated ophthalmologic evalAssess for visual acuity, ocular motility, strabismus, optic atrophy, refractive errors, need for glasses, & need for low vision aids.
Neurobehavioral/psychiatric manifestations Psychiatric evalRefer for specific concerns such as anxiety, autistic features, depression, behavioral challenges, &/or other psychiatric issues.
Ears/
Hearing 		Hearing evalScreening eval for sensorineural hearing loss w/follow-up as indicated
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PLAN to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

AAC = augmentative and alternative communication; ADL = activities of daily living; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; PM&R = physical medicine and rehabilitation; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathology

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Table 5b.

Adult PLA2G6-Associated Neurodegeneration: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Neurologic Movement disorders neurologic eval
  • Neuromotor eval (tone, movement disorder, balance, & gait)
  • Consider referral to PT, OT, orthopedist, &/or PM&R specialist.
  • Assess swallowing & nutritional status & constipation; consider referral for swallow study or feeding specialist.
  • Assess communication (e.g., dysarthria); consider referral to SLP or AAC specialist.
  • Assess quality of sleep; consider referral for sleep study.
Cognitive Neuropsychiatric testing & evalTo establish a baseline, identify areas that may be amenable to treatment or other interventions, & assist in qualification for services
Eyes/
Vision 		Baseline dilated ophthalmologic evalAssess for visual acuity, ocular motility, optic atrophy, refractive errors, need for glasses, & low vision aids.
Neurobehavioral/psychiatric manifestations Psychiatric evalRefer for specific concerns such as anxiety, depression, aggression, delusions, paranoia, hallucinations, & other psychiatric issues.
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PLAN to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:
  • Community or online resources
  • Social work involvement for parental support
  • Home nursing referral

AAC = augmentative and alternative communication; MOI = mode of inheritance; OT = occupational therapist; PM&R = physical medicine and rehabilitation; PT = physical therapist; SLP = speech-language pathologist

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

There is no cure for PLAN. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Tables 6a and 6b).

Table 6a.

Infantile and Juvenile PLA2G6-Associated Neurodegeneration: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Tone abnormalities, movement abnormalities, & musculoskeletal issues Treatment by neurologist / PM&R specialist / orthopedist / PT, OT, speech therapist
  • Positioning & mobility devices (e.g., AFOs, trunk orthosis, walkers, wheelchairs, seating, lift)
  • Spasticity &/or dystonia mgmt may incl treatment w/trihexyphenidyl, gabapentin, clonidine, clonazepam, oral or intrathecal baclofen, & other medications. Re-evaluate need as disease progresses.
  • Botulinum toxin for focal dystonia or spasticity
  • Levodopa & other treatments for parkinsonism may be indicated in later stages of juvenile PLAN.
  • Standing activities & vitamin D supplementation for bone health
  • Targeted PT, OT, & speech therapy
Cognitive See Developmental Delay / Intellectual Disability Management Issues.
  • The progressive nature of the condition & motor deterioration that are often faster than cognitive decline should be taken into consideration w/regular interval assessments accounting for motor/vision difficulties.
  • Regular reviews of IEP to optimize function & potential in educational settings
Seizures Standard mgmt w/anti-seizure medications
Gastrointestinal issues
  • Swallowing/feeding eval as indicated & regular nutritional assessments
  • Manage constipation &/or reflux as needed
  • Once affected child can no longer maintain nutrition/hydration orally, or is unsafe to eat, placement of gastrostomy tube should be considered.
  • Increased fiber intake, stool softeners, &/or laxatives to treat constipation, which may be caused by autonomic dysfunction / poor motility, immobility, diet, &/or medications.
Eyes/
Vision
  • Glasses if indicated
  • Mgmt of strabismus
  • Low vision therapy
Hearing loss
  • Hearing aids or other supports as indicated
  • Treatment is more relevant for juvenile PLAN, as hearing loss is rarely treated in children w/severely progressed infantile disease.
Sleep Trial of medications related to potential underlying cause
  • Many children w/infantile PLAN go through an early phase of poor sleep of unknown cause, possibly due to GERD, increasing spasticity, or chronic irritability described below.
  • Consider individual trials of any of the following: melatonin, H2 blocker, gabapentin, baclofen.
Neurobehavioral/psychiatric manifestations
  • Psychiatric treatment as indicated for specific concerns
  • Chronic unexplained irritability is common in children w/severe neurologic impairment & particularly in early stages of infantile PLAN, for which gabapentin &/or melatonin can be helpful. 1
Autonomic manifestations Temperature monitoring & treatment as necessary w/warming or cooling strategies
  • Persons in late stages of infantile & juvenile PLAN may have sudden increases or decreases in body temperature.
  • At risk in hot or cold environments or w/medications that affect sweating
  • Some children w/infantile PLAN wear temperature monitors.
Pulmonary
  • Pulmonology exam
  • Airway clearance
  • Secretion mgmt
  • Non-invasive ventilation
  • Weakness, loss of mobility, dysphagia, & scoliosis put persons w/PLAN at risk for respiratory insufficiency & pneumonias.
  • Airway clearance strategies & devices are needed for acute mgmt & preventative care.
  • Routine & seasonal vaccinations & prophylactic antibiotics esp in winter months
  • Later in disease course, more intensive secretion mgmt, airway clearance, & sometimes non-invasive ventilation for respiratory insufficiency or sleep apnea are indicated.
Family/Community
  • Social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement, hospice care, &/or home nursing
  • Juvenile PLAN: consider involvement in adaptive sports or Special Olympics.

AFO = ankle-foot orthosis; GERD = gastroesophageal reflux disease; IED = individualized education plan; OT = occupational therapist; PLAN = PLA2G6-associated neurodegeneration; PT = physical therapist

1.

Table 6b.

Adult PLA2G6-Associated Neurodegeneration: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Tone abnormalities, movement abnormalities, & musculoskeletal issues Treatment by neurologist / PM&R specialist / orthopedist / OT, PT, & speech therapist
  • Botulinum toxin for focal dystonia or spasticity
  • Levodopa & other treatments for parkinsonism (Initial response to levodopa may be dramatic followed by early development of dyskinesias at lower doses than typically seen in idiopathic PD.)
  • Dystonia mgmt w/baclofen, clonazepam, trihexyphenidyl, clonidine
  • Consider need for positioning & mobility devices (e.g., AFOs, walkers, wheelchairs, lifts) & disability parking placard.
  • Deep brain stimulation has successfully treated parkinsonism & dystonia/dyskinesias in a small number of persons w/PLAN. 1
Cognitive Assess for cognitive decline & recommend resources/supports as appropriate (driver's test, disability benefits).
Seizures Standard mgmt w/anti-seizure medicationSeizures are rare in adult PLAN.
Gastrointestinal
  • Swallowing/feeding eval as indicated & regular nutritional assessments
  • Manage constipation as needed.
  • Constipation is a common problem best managed w/a daily regimen.
  • If excessive drooling is problematic, consider sublingual atropine drops (off-label) or scopolamine patch.
  • Gastrostomy tube placement should be considered as indicated & if desired by affected adult, starting discussions early.
Eyes/vision Exam w/visual acuity tests & visual field testing can monitor change over time.
Pulmonary Treatment by pulmonologist
  • Loss of mobility & dysphagia put adults w/PLAN at risk for pneumonias & other pulmonary complications.
  • Airway clearance strategies & devices can help support respiratory health.
  • In later disease, persons may need more intensive secretion mgmt, airway clearance, & sometimes non-invasive ventilation.
  • Routine & seasonal vaccinations
  • Tracheostomy may be indicated in some persons.
Neurobehavioral/psychiatric manifestations Treatment by psychiatrist
  • Psychiatric manifestations are common & often problematic.
  • Affected persons are at risk for extrapyramidal side effects from medication.
Family/Community
  • Social work involvement to connect families w/local resources, respite, & support
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care or hospice involvement &/or home nursing

AFO = ankle-foot orthosis; GERD = gastroesophageal reflux disease; IED = individualized education plan; OT = occupational therapist; PD = Parkinson disease; PLAN = PLA2G6-associated neurodegeneration; PT = physical therapist

1.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) with regular review as the needs change as the disease progresses.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, placement of an NG-tube or G-tube may be necessary.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid speech and language development.

Neurobehavioral/Psychiatric Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 7 are recommended.

Table 7.

PLA2G6-Associated Neurodegeneration: Recommended Surveillance

System/ConcernEvaluationFrequency
Tone abnormalities, movement abnormalities, & musculoskeletal issues Exam by neurologist / PM&R specialist
  • Annually or sooner if indicated
  • May become more frequent w/disease progression
Cognitive Developmental pediatrics / neurology exam
  • Annually early in disease course
  • Typically not needed in later stages
Seizures EEGWhen indicated as determined by treating neurologist
Eyes/
Vision 		Ophthalmology examAnnually early in disease course
As needed in later stages
Hearing Audiology exam
Neurobehavioral/psychiatric manifestations Psychiatry evalOnly as indicated
Pulmonary Pulmonology examAt least annually in later stages of disease
Gastrointestinal Exam by feeding specialists / dieticians
  • Annually once gastrostomy tube is placed
  • Swallow study as indicated
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

Agents/Circumstances to Avoid

Individuals with adult PLAN. Neuroleptic treatment for delusions, paranoia, hallucinations, or other issues may exacerbate parkinsonism as first-generation and most second-generation antipsychotic drugs block dopamine receptors. Safer alternatives that may be considered are quetiapine, clozapine, or primavanserin [Pirker et al 2026].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Two women with adult PLAN were reported to reproduce [Paisán-Ruiz et al 2010, Virmani et al 2014]. Since onset of manifestations of adult PLAN has been reported as late as age 30 years, some women may become pregnant before onset of manifestations and/or early in the disease course. For pregnant women who may be symptomatic, the main issue is the potential for teratogenic effects of medications taken during pregnancy. Also, it is not known if pregnancy itself may have short-term or long-term effects on the course of adult PLAN for the affected pregnant woman. The authors are aware of one woman who had onset of motor manifestations immediately following the significantly difficult delivery of her first child [S Hayflick, personal observation].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Chelation therapy. Because some individuals with PLAN have high brain iron and PLAN is a neurodegeneration with brain iron accumulation (NBIA) disorder, the option of chelation therapy is sometimes raised. The chelator deferiprone has been investigated for pantothenate kinase-associated neurodegeneration, a form of NBIA [Klopstock et al 2019], but has not yet been studied in a clinical trial setting for PLAN.

Gene therapy. Two gene therapy strategies are currently under investigation in murine disease models of PLAN (see Gene Therapy for INAD and Fundraising for the pioneering gene therapy program at University College London).

Docosahexaenoic acid (DHA) is selectively hydrolyzed from phospholipids by the action of the 85/88 kDa calcium-independent phospholipase A2 enzyme, the protein encoded by PLA2G6. Although not yet tested as an intervention in individuals with PLAN, a Pla2g6-mutated mouse model showed reduced DHA metabolism and signaling [Basselin et al 2010]; evidence from a more recent study showed that DHA can reverse selective 85/88 kDa calcium-independent phospholipase A2 inhibition [Mazzocchi-Jones 2015]. Given the low risk of harm from DHA supplementation, the authors recommend its administration at a dose that is age appropriate.

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.

Genetic Counseling

Mode of Inheritance

PLA2G6-associated neurodegeneration (PLAN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a PLA2G6 pathogenic variant, each sib of an affected individual has at conception 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.
  • If the proband has PLAN as the result of uniparental isodisomy and only one parent is heterozygous for a PLA2G6 pathogenic variant, each sib of an affected individual has at conception a 50% chance of being an asymptomatic carrier and a 50% chance of being unaffected and not a carrier (the risk to the sibs of being affected with PLAN is not increased over that of the general population).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • Individuals with infantile PLAN and juvenile PLAN have not been known to reproduce due to the relatively early onset and severity of disease.
  • Unless the reproductive partner of an individual with adult PLAN also has PLAN or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in PLA2G6. If the reproductive partner of a person with adult PLAN is a carrier, offspring have a 50% chance of inheriting biallelic PLA2G6 pathogenic variants and being affected and a 50% chance of being an asymptomatic carrier.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a PLA2G6 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the PLA2G6 pathogenic variants in the family.

Related Genetic Counseling Issues

Predictive testing of asymptomatic at-risk sibs. A proband may have sibs younger or close in age who could be affected. Although early diagnosis is not likely to significantly reduce morbidity or mortality, testing of at-risk sibs may be desired. For adult PLAN, at-risk sibs may desire predictive testing as part of their reproductive planning. This should be done in the setting of genetic counseling; individuals considering testing should be provided with appropriate psychosocial support.

  • Predictive testing for at-risk sibs is possible if both PLA2G6 pathogenic variants have been identified in the proband.
  • Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with adult PLAN than in individuals with infantile PLAN or juvenile PLAN. Age of onset can vary widely in individuals from the same family; additionally, some of the neuropsychiatric changes that may be present early in the disease course (e.g., anxiety or depression) are also common in the general population and thus may not be attributable to the onset of adult PLAN.

In a family with an established diagnosis of PLAN, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PLAN, particularly if consanguinity is likely and/or both partners are of the same ancestry. A founder variant has been described in a North African cohort and in the Bedouin (Israel) population (see Table 8).

Prenatal Testing and Preimplantation Genetic Testing

Once both PLA2G6 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for PLAN are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

  • INADcure Foundation
    Email: info@INADcure.org
  • NBIA Disorders Association
    Email: info@NBIAdisorders.org
  • NBIAcure
    Center of Excellence for NBIA Clinical Care and Research
    International Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Email: info@nbiacure.org
  • Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON)
    Email: TIRCON@med.uni-muenchen.de

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PLA2G6-Associated Neurodegeneration: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
PLA2G622q13​.185/88 kDa calcium-independent phospholipase A2PLA2G6 @ LOVDPLA2G6PLA2G6

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PLA2G6-Associated Neurodegeneration (View All in OMIM)

256600NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; NBIA2A
603604PHOSPHOLIPASE A2, GROUP VI; PLA2G6
610217NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2B; NBIA2B

Molecular Pathogenesis

PLA2G6 encodes 85/88 kDa calcium-independent phospholipase A2 (CaI-PLA2). The PLA2 family of phospholipase A2 enzymes catalyzes the hydrolysis of glycerophospholipids, generating a free fatty acid (usually arachidonic acid) and a lysophospholipid. CaI-PLA2 has proposed roles in phospholipid remodeling, arachidonic acid release, leukotriene and prostaglandin synthesis, and apoptosis [Balsinde & Balboa 2005]. The PLA2 enzymes play a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids [Baburina & Jackowski 1999]. Defects in CaI-PLA2 could lead to a relative abundance of membrane phospholipids or skewing of the proportions of specific species and secondary structural abnormalities, which may contribute to the axonal pathology observed in infantile PLA2G6-associated neurodegeneration (PLAN) [Morgan et al 2006].

Mechanism of disease causation. Loss of function

Evaluation of PLA2G6 variants of uncertain significance. For this ultrarare disorder, it is common to identify novel variants or variants of uncertain significance (VUS), partly because of the limited number of reported individuals worldwide. While there are no clinical biomarkers or functional tests to confirm a diagnosis of PLAN, a combination of clinical features, brain MRI findings, elevated aspartate aminotransferase or lactate dehydrogenase (LDH) with otherwise normal liver function tests, abnormal electromyography or nerve conduction studies, and/or fast waves on interictal EEG can help determine the likely pathogenicity of variants. This can be especially useful in consanguineous individuals in whom a homozygous VUS has been identified.

Tissue biopsy. If no PLA2G6 pathogenic variants are identified but the evolving phenotype remains most consistent with infantile or juvenile PLAN, a biopsy for identification of dystrophic axons (axonal spheroids) can be considered from one of the following preferred tissues: conjunctiva, skin, rectum, muscle, or other peripheral nerve (sural). Histopathologic evidence of dystrophic axons on biopsy, viewed by electron microscopic examination, includes the following:

  • Membranotubular profiles
  • Mitochondrial aggregates
  • Increased axonal diameter and thinned membrane

Note: (1) Because axonal spheroids accumulate with age and may not be evident in all tissues, a biopsy cannot rule out the diagnosis of PLAN but can help confirm a diagnosis. (2) Peripheral spheroids have not been described in pathologic specimens from persons with adult PLAN; however, to date pathologic material available from this group has been limited.

Missing variants. If molecular genetic testing has identified only one PLA2G6 pathogenic variant in the proband, additional possibilities to consider include the following:

  • The proband does not have PLAN.
  • The proband has a variant on the other allele that has not yet been detected or is undetectable by current methods.

Table 8.

PLA2G6 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_003560​.2
NP_003551​.2 		c.2070_2072delp.Val691delFounder variant in a North African cohort [Romani et al 2015] & in Bedouin (Israel) population [Khateeb et al 2006]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Susan Hayflick (ude.usho@kcilfyah), Jenny Wilson (ude.usho@nejsliw), Penny Hogarth (ude.usho@phtragoh), and Allison Gregory (ude.usho@ayrogerg) are actively involved at Oregon Health & Science University in clinical care and natural history research regarding individuals with PLA2G6-associated neurodegeneration (PLAN). They would be happy to communicate with persons who have any questions regarding diagnosis of PLAN, and they frequently review MRIs and genetic testing reports from other centers.

Manju Kurian and Audrey Soo are actively involved at UCL/Great Ormond Street Hospital (London) in PLAN research and clinical care, and would be happy to be contacted for any PLAN-related queries.

Cure INAD UK
Email: gro.danieruc@ofni
Web page: https://www.cureinaduk.org/

The INAD Foundation
Web page: https://theinadfoundation.org.au/

Acknowledgments

This work was supported in part by grants from the National Institute of Child Health and Human Development, the National Eye Institute, L'Association Internationale de Dystrophie Neuro Axonale Infantile, INADcure, INAD Warriors, and the NBIA Disorders Association. This work was made possible by support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 01 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Susan Hayflick receives endowed professorship support as the William A Whitsell Dean's Leadership Professor. MAK has received funding from an NIHR Professorship and the Sir Jules Thorn Award for Biomedical Research.

Author History

Allison Gregory, MS, CGC (2008-present)
Susan J Hayflick, MD (2008-present)
Penelope Hogarth, MD (2008-present)
Manju A Kurian, MA, MRCPCH, PhD (2008-present)
Eamonn R Maher, MD, FRCP, FMedSci; University of Cambridge (2008-2026)
Audrey KS Soo, BSc, MBBS, MRCPCH, PhD (2026-present)
Jenny L Wilson, MD (2026-present)

Revision History

  • 14 April 2026 (bp) Comprehensive update posted live
  • 23 March 2017 (sw) Comprehensive update posted live
  • 21 August 2014 (me) Comprehensive update posted live
  • 19 April 2012 (me) Comprehensive update posted live
  • 19 June 2008 (me) Review posted live
  • 14 June 2007 (ag) Original submission

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