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PLA2G6-Associated Neurodegeneration

Synonyms: NBIA2, PLA2G6-Related Disorders, PLAN. Includes: Atypical Neuroaxonal Dystrophy, Infantile Neuroaxonal Dystrophy, PLA2G6-Related Dystonia-Parkinsonism

, MS, CGC, , MA, MRCPCH, PhD, , MD, FRCP, FMedSci, , MD, and , MD.

Author Information
, MS, CGC
Molecular & Medical Genetics
Oregon Health & Science University
Portland, Oregon
, MA, MRCPCH, PhD
Pediatric Neurosciences/Pediatric Neurology
University College London
London, United Kingdom
, MD, FRCP, FMedSci
Medical and Molecular Genetics and Centre for Rare Diseases and Personalised Medicine
University of Birmingham
Birmingham, United Kingdom
, MD
Neurology and Molecular & Medical Genetics, Oregon Health & Science University
Portland, Oregon
, MD
Molecular & Medical Genetics, Pediatrics and Neurology
Oregon Health & Science University
Portland, Oregon

Initial Posting: ; Last Update: April 19, 2012.

Summary

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

  • Classic infantile neuroaxonal dystrophy (INAD)
  • Atypical neuroaxonal dystrophy (atypical NAD)
  • PLA2G6-related dystonia-parkinsonism

INAD usually begins between ages six months and three years with developmental regression, hypotonia, progressive psychomotor delay, and progressive spastic tetraparesis. Strabismus, nystagmus, and optic atrophy are common. Disease progression is rapid. Many affected children never learn to walk or lose the ability shortly after attaining it. Severe spasticity, progressive cognitive decline, and visual impairment typically result in death during the 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 or ataxia (as in the classic form) or speech delay and autistic features, which are sometimes the only evidence of disease for a year or more. 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 presents with subacute onset of dystonia-parkinsonism in late adolescence/early adulthood. Other findings are eye movement abnormalities, pyramidal tract signs, and marked cognitive decline.

Diagnosis/testing. Before 2006, the diagnosis of INAD was established by clinical and pathologic findings alone. Since the discovery of PLA2G6, the gene in which mutation causes PLA2G6-associated neurodegeneration, molecular genetic testing has been used to help confirm the diagnosis and, in many cases, eliminates the need for tissue biopsy.

Management. Treatment of manifestations: For 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.

For 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.

Prevention of secondary complications: Early physical therapy and orthopedic management to prevent contractures as the disease progresses.

Surveillance: Periodic assessment of vision and hearing.

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 and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in the family are known.

Diagnosis

Clinical Diagnosis

PLA2G6-associated neurodegeneration comprises a continuum of three phenotypes with overlapping clinical and radiologic features: infantile neuroaxonal dystrophy; atypical neuroaxonal dystrophy [Gregory et al 2008, Kurian et al 2008]; and PLA2G6-related dystonia-parkinsonism [Paisan-Ruiz et al 2009].

Infantile Neuroaxonal Dystrophy (INAD)

Predominant features

  • Onset before age three years
  • Psychomotor regression (most common presenting feature)
  • Cerebellar atrophy (see Figure 1)
  • Optic atrophy
  • Characteristic pattern of early truncal hypotonia followed by development of spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course)
  • Histopathologic evidence of dystrophic axons on biopsy from one or more of the following tissues: conjunctiva, skin, rectum, muscle, or other peripheral nerve (sural). Dystrophic axons viewed by electron microscopy (EM) exhibit:
    • Membranotubular profiles;
    • Mitochondrial aggregates;
    • Increased axonal diameter and thinned membrane.
Figure 1

Figure

Figure 1. Panel A. Left axial image shows high brain iron in the globus pallidus (see arrow) on T2-weighted MRI. Panel B. Right sagittal image shows cerebellar atrophy (see arrow).

Other common features

  • Symmetric pyramidal tract signs
  • Nystagmus
  • Strabismus
  • Bulbar dysfunction
  • Ataxia
  • EMG (electromyogram): evidence of denervation
  • EEG (electroencephalogram): fast rhythms
  • VEP (visual evoked potential): delayed with reduced amplitudes
  • NCV (nerve conduction velocity): distal axonal-type sensorimotor neuropathy
  • T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation), cortical cerebellar hyperintensities consistent with cerebellar gliosis, white matter abnormalities, thin vertically oriented corpus callosum (see Figure 1)
  • Seizures: may present early or late in the disease course [Wu et al 2009]

Note: MRI of the brain and ophthalmologic examination are keys to establishing strong clinical features of INAD.

Atypical Neuronoaxonal Dystrophy (Atypical NAD)

Predominant features

  • Onset before age 20 years
  • Psychomotor regression
  • Prominent expressive language difficulties and autistic-like behavior
  • Disease progression slower than in classic disease
  • Cerebellar atrophy
  • Optic atrophy
  • Progressive dystonia and dysarthria
  • T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation)
  • Histopathologic evidence of dystrophic axons identical to that described for classic INAD

Other common features

  • Psychiatric/behavioral abnormalities
  • Spasticity (without preceding hypotonia)
  • Joint contractures
  • Seizures
  • Nystagmus
  • VEP: delayed with reduced amplitudes

Note: As with INAD, MRI of the brain and ophthalmologic examination are also keys to establishing strong clinical features of atypical NAD.

PLA2G6-Related Dystonia-Parkinsonism

Predominant features

  • Onset varies from childhood to young adulthood
  • Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses)
  • Dystonia
  • Cognitive decline
  • Neuropsychiatric changes
  • Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias

Note: Abnormal brain iron accumulation in the globus pallidus, substantia nigra and/or striatum is variable and may not be evident on MRI studies until late in the disease course for some individuals

Other common features

  • Dysarthria
  • Autonomic involvement
  • Mild cerebral atrophy
  • In some cases, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography (SPECT)

Testing

Tissue biopsy. Before the availability of molecular genetic testing, identification of dystrophic axons on electron microscopic examination of nerve ultrastructure in a tissue biopsy of conjunctiva, skin, muscle, sural nerve, or rectum was the finding necessary to establish the diagnosis of INAD. Because axonal spheroids accumulate with age and may not be evident in all tissues, individuals with INAD and atypical NAD may require multiple biopsies over time before axonal spheroids are identified. Furthermore, some individuals with convincing INAD phenotypes, including evidence of peripheral spheroids, do not have identifiable PLA2G6 mutations. Therefore, molecular genetic testing is now considered the most reliable method of identifying PLAN.

Note: Peripheral spheroids have not been described in pathologic specimens from persons with PLA2G6-associated dystonia-parkinsonism; however, limited pathologic material has been available thus far from this group.

Molecular Genetic Testing

Gene. PLA2G6 is the only gene in which mutations are known to cause PLA2G6-associated neurodegeneration. (See Table 1 and Molecular Genetics, Table A.)

Evidence for locus heterogeneity. Linkage data support the presence of at least one additional INAD locus [Morgan et al 2006].

Table 1. Summary of Molecular Genetic Testing Used in PLA2G6-Associated Neurodegeneration

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PLA2G6Sequence analysisSequence variants 4~85% 5
Deletion/duplication testing 6Exonic or whole-gene deletionsProposed ≤12.5% 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. For all individuals identified with PLA2G6 mutations, approximately 10% have only one mutant allele identified [NBIA International Mutation Database, unpublished data]. Large intragenic deletions have now been identified in several cases. Crompton et al [2010] describe the first reported use of MLPA in PLA2G6 analysis.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Morgan et al [2006] reported one large contiguous gene deletion (see Pathogenic allelic variants).

Testing Strategy

The steps to confirm the diagnosis in a proband have been altered by the advent of molecular genetic testing.

INAD or atypical NAD. When the clinician suspects a diagnosis of INAD or atypical NAD, an ophthalmologic examination and brain MRI are recommended first because optic atrophy and cerebellar atrophy are strong clinical features:

  • If suspicion remains high, molecular genetic testing by sequence analysis followed by deletion/duplication testing of PLA2G6 is recommended as the next step instead of an invasive biopsy.
  • If no PLA2G6 mutations are found but the evolving phenotype remains most consistent with INAD or atypical NAD, a biopsy to assess for axonal spheroids could be considered. Preferred tissues are, in order: conjunctiva, skin, rectum, other peripheral nerve.

PLA2G6-related dystonia-parkinsonism. When the clinician suspects a diagnosis of PLA2G6-related dystonia-parkinsonism, brain MRI is recommended if it has not already been performed. Note: Abnormal brain iron accumulation has been documented in some individuals with PLA2G6-related dystonia-parkinsonism, but not all [Paisan-Ruiz et al 2009, Yoshino et al 2010, Bower et al 2011].

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.

Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Infantile neuroaxonal dystrophy (INAD). Onset of INAD usually occurs between ages six months and three years. The disease presents with psychomotor regression (i.e., loss of previously acquired milestones) or delay, delayed walking, or gait disturbance.

Truncal hypotonia is observed early in disease course. Over time, affected persons develop a spastic tetraparesis, with symmetric pyramidal tract signs on clinical examination.

Visual signs and symptoms are common. Strabismus and nystagmus are early features of the disease. Later optic atrophy occurs in most cases. Optic atrophy 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 occur in a minority of individuals as a later symptom [Nardocci et al 1999, Wu et al 2009].

The progression of disease is usually rapid. Many affected children never learn to walk or lose this ability shortly after attaining it. During the end stages of disease, severe spasticity, progressive cognitive decline, and visual impairment result in a vegetative state. Death occurs as a result of secondary illnesses such as aspiration pneumonia, associated with bulbar dysfunction. Many affected children do not survive beyond their first decade, but some survive into their teens or later. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications.

Atypical NAD. Whereas the features of INAD are relatively homogeneous, atypical disease is quite varied.

In general, onset in atypical cases is in early childhood but can be as late as the late teens. In a series of 13 individuals, four had onset by age three years but a fairly stable course during early childhood resembling static encephalopathy, followed by neurologic deterioration between ages seven and 12 years [Nardocci et al 1999].

The presenting signs and symptoms may be similar to classic INAD, including gait instability or ataxia. Others may present with speech delay and autistic features, which may remain as the only evidence of disease for a year or more given the slow progression of atypical disease compared to classic disease [Gregory et al 2008].

Although spastic tetraparesis is evident late in the disease, it is rarely preceded by early truncal hypotonia. In contrast to classic disease, extrapyramidal findings (i.e., dystonia and dysarthria) predominate in atypical cases. Eye findings are similar to classic INAD. Neuropsychiatric disturbances including impulsivity, poor attention span, hyperactivity, and emotional lability are also common [Gregory et al 2008].

Atypical cases are rare, and the life span is not known; however, it is expected to be longer than that observed in classic disease.

PLA2G6-related dystonia-parkinsonism. To date, only a small number of affected individuals have been described. Although the age at onset varied from four to 30 years [Paisan-Ruiz et al 2009, Yoshino et al 2010, Bower et al 2011], the majority 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 another with stuttering speech, clumsiness, and dyslexia at age four years, findings which may not be related to the PLA2G6-associated neurodegeneration (PLAN). In young adults, initial symptoms are frequently neuropsychiatric, including depression, personality changes, aggression, delusions, or paranoia. Gait disturbance is also common at presentation.

Regardless of the age at onset, affected individuals consistently develop dystonia and parkinsonism in their late teens to early twenties, which may be accompanied by rapid cognitive decline. Neuropsychiatric changes may precede the movement disorder or occur concomitantly. 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. Of note, it is common to have an initially dramatic positive response to dopaminergic agents; however, this tends to be short-lived and followed quickly by the development of motor fluctuations and dyskinesias.

Genotype-Phenotype Correlations

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 exclusively by missense mutations.
  • Common mutations associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three mutations associated with PLA2G6-related dystonia-parkinsonism did not [Engel et al 2010].

Nomenclature

Outdated terms

  • Seitelberger [1952] first described this condition, 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 mutations in PLA2G6 in individuals with Karak syndrome, which is now included in the phenotypic spectrum of PLAN and no longer considered to be a clinically distinct entity; what had been described as Karak syndrome is now referred to as atypical NAD.

Current nomenclature. In addition to INAD, later-onset variants have been called late-infantile, juvenile, or atypical neuroaxonal dystrophy and neurodegeneration with brain iron accumulation (NBIA).

The authors propose the following usage:

  • INAD for early-onset, rapidly progressive disease
  • Atypical NAD for later childhood-onset disease with slower progression and predominant extrapyramidal findings (dystonia, dysarthria). The atypical NAD phenotype is expected to include a broad range of presentations including Karak syndrome.
  • PLA2G6-related dystonia-parkinsonism for adult-onset dystonia-parkinsonism accompanied by cognitive decline and neuropsychiatric changes.

Prevalence

Disease prevalence is not established; it is estimated at approximately 1:1,000,000.

Differential Diagnosis

Infantile Neuroaxonal Dystrophy (INAD)

Early diagnosis of infantile neuroaxonal dystrophy (INAD) is challenging because the initial symptoms of psychomotor regression and progression are also observed in other conditions.

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 [Farina et al 1999]. The differential diagnosis for childhood cerebellar atrophy includes infantile neuronal ceroid-lipofuscinosis (Santavuori-Haltia), ataxia-telangectasia, and hereditary ataxia; however, cerebellar atrophy usually presents later for these disorders.

An estimated 40%-50% of individuals with INAD have abnormal iron accumulation in the basal ganglia (primarily the globus pallidus), which is best detected on T2-weighted MRI. For this reason, conditions included in the neurodegeneration with brain iron accumulation (NBIA) category should also be considered in the differential diagnosis of INAD. Individuals with INAD have not been found to have an eye-of-the-tiger sign, which correlates very highly with pantothenate kinase-associated neurodegeneration (PKAN) [Hayflick et al 2003].

Since the identification of PLA2G6 mutations as causative of INAD, the need for invasive nerve biopsy to aid in diagnosis has decreased. While the presence of axonal spheroids in peripheral tissues remains specific to INAD, spheroids are found in the brain in a few other conditions, including PKAN, idiopathic NBIA, infantile GM2 gangliosidosis (see Hexosaminidase A Deficiency), Niemann-Pick disease type C, and Menkes disease (see ATP7A-Related Copper Transport Disorders).

Atypical Neuroaxonal Dystrophy (NAD)

Initial speech delay and limited social interaction may be consistent with autism (see Autism Overview).

Spasticity, dystonia, and dysarthria, findings similar to those of other forms of NBIA, eventually predominate; high brain iron in the globus pallidus and substantia nigra has been observed in nearly all cases, although ascertainment is likely to be biased [Gregory et al 2008]. Therefore, idiopathic NBIA should also be considered in the differential diagnosis of atypical NAD. PKAN may present with similar features.

PLA2G6-Related Dystonia-Parkinsonism

When high brain iron is present and mutations in PLA2G6 have been ruled out, other forms of NBIA should be considered in the differential diagnosis. Atypical PKAN, Kufor-Rakeb syndrome, and MPAN (mitochondrial membrane protein-associated neurodegeneration) can present with neuropsychiatric changes, parkinsonism, and dystonia in late childhood or early adulthood. As in PLA2G6-related dystonia-parkinsonism, individuals with MPAN and Kufor-Rakeb syndrome also exhibit cognitive decline.

Other forms of early-onset dystonia-parkinsonism must also be considered, including dopa-responsive dystonia, Wilson disease, Parkinson disease 2 (PARK2), PARK6, PARK7, PARK15, SLC6A3-related dystonia-parkinsonism, dystonia 3 (DYT3), DYT12, DYT16, and spastascin-related hereditary spastic paraplegia (SPG11) [Schneider & Bhatia 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with PLAN, the following evaluations are recommended:

  • Thorough ophthalmologic examination (if not performed during the diagnostic evaluation) to assess for optic atrophy
  • EEG for the possibility of unrecognized seizure activity
  • Genetics consultation

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

Treatment of Manifestations

The following treatments for 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)
  • Treatment by a psychiatrist for those with a later-onset, more protracted course accompanied by neuropsychiatric symptoms
  • Over-the-counter fiber supplements and/or stool softeners to treat constipation that is likely caused by a combination of immobility, diet, and medications
  • Transdermal scopolamine patch to reduce the volume of secretions in those with excessive drooling or difficulty controlling secretions
  • Measures such as a gastric feeding tube or tracheostomy as needed to prevent aspiration pneumonia

Treatments for PLA2G6-related dystonia-parkinsonism are also palliative but differ somewhat:

  • Treatment with dopaminergic agents is likely to be beneficial for the motor symptoms of parkinsonism and dystonia and may initially produce a dramatic response. In cases to date, this response diminished over time, and affected individuals often developed prominent early dyskinesias, complicating medical management. Despite the dyskinesias, treatment with dopaminergic agents may still be indicated, as affected individuals typically experience benefit for a period of time and the dyskinesias are expected to decline after discontinuation of treatment. The use of deep brain stimulation for PLA2G6-associated dystonia-parkinsonism has not been reported.
  • Treatment by a psychiatrist for neuropsychiatric symptoms is indicated.
  • Evaluation by physical therapy may guide the management of postural instability and gait difficulties. Occupational therapy may offer tools to assist with activities of daily living.
  • Interventions such as a gastric feeding tube or tracheostomy may be needed to reduce the risk of aspiration pneumonia.

Prevention of Secondary Complications

A rehabilitation program including physical therapy and orthopedic management should be initiated early in the disease course to prevent contractures when the individual is permanently nonambulatory.

Surveillance

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

Evaluation of Relatives at Risk

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

Pregnancy Management

Women with the INAD and atypical NAD forms of PLAN have not been known to reproduce due to the relatively early onset and severity of disease.

One woman with PLA2G6-related dystonia-parkinsonism has been reported to reproduce [Paisan-Ruiz et al 2010]. Since onset of manifestations of PLAN has been reported as late as age 30 years, some women may become pregnant before onset of symptoms or early in the disease course. For those who may be symptomatic, the main issue is potential teratogenic effects of medications taken during pregnancy. It is not known whether pregnancy itself may have short or long-term effects on the disease course for the affected pregnant woman.

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.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • 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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • Individuals with INAD and atypical NAD have not been known to reproduce.
  • All offspring of individuals with later-onset PLA2G6-related dystonia-parkinsonism will be obligate (unaffected) carriers.
  • If the reproductive partner of a person with PLA2G6-related dystonia-parkinsonism is a carrier, the risk to their offspring of being homozygous is 50% and of being heterozygous (unaffected carriers) is 50%. The phenotype of the homozygous offspring within the PLAN spectrum will be influenced by the type of mutation present in the carrier partner; current data are not sufficient to predict which PLAN phenotype the homozygous offspring will display.

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

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family are known. The following situations may arise when carrier detection is pursued by at-risk individuals and their reproductive partners:

  • Two PLA2G6 pathogenic variants are identified in the proband. In this case, the at-risk family members can be offered testing for the family-specific mutations to clarify his/her carrier status.
  • Only one PLA2G6 pathogenic variant is identified in the proband. Molecular genetic testing will be informative for relatives related to the parent with the identifiable mutation. Molecular genetic testing will not be informative for relatives related to the carrier parent in whom no mutation has been identified.
  • Neither pathogenic variant is identified in the proband. Molecular genetic testing of relatives will not be informative.
  • The proband is deceased, and no DNA-based testing was performed. It is appropriate to attempt to obtain any available tissue samples for DNA extraction for PLA2G6 molecular genetic testing. If DNA cannot be obtained, it is appropriate to test at-risk family members following genetic counseling in which the limitations of testing are explained. For those family members in whom a PLA2G6 pathogenic variant is not identified, a revised carrier risk can be calculated.
  • A person has a reproductive partner who is a known carrier or is at risk of being a carrier. The reproductive partners of carriers or those at risk of being carriers can be offered molecular genetic testing with the understanding that a negative result can reduce but does not eliminate their risk of being a carrier.

Related Genetic Counseling Issues

Testing of at-risk sibs. The proband may have younger or similarly-aged sibs who could be affected. Although early diagnosis is not likely to significantly reduce morbidity or mortality, testing of at-risk sibs may be desired:

  • If both PLA2G6 pathogenic variants have been identified in the proband, the sibs may be tested to determine if they have inherited both PLA2G6 pathogenic variants.
  • If the PLA2G6 pathogenic variants have not been identified in the proband, a plan for assessing at-risk sibs should be designed based on the primary findings in the proband and the established clinical criteria for INAD/atypical NAD/PLA2G6-related dystonia-darkinsonism. Evaluations are likely to include brain MRI, ophthalmologic assessment, and possibly biopsy for histologic examination of peripheral nerves (see Diagnosis).

    Note: Neither the absence of axonal spheroids nor a normal brain MRI rules out INAD or atypical NAD, as these findings develop over time and spheroids vary by location. Diagnostic tests may need to be repeated at a later age for at-risk sibs in families without PLA2G6 mutations. A normal MRI and absence of other symptoms (including regression) in a sib who is older than the affected sibling was when cerebellar atrophy and/or other symptoms were present is reassuring.
  • Predictions of clinical course and age of onset are more challenging in asymptomatic individuals diagnosed with PLA2G6-related dystonia-parkinsonism than in individuals with INAD or atypical NAD. Age of onset can vary widely in individuals from the same family; additionally, some of the neuropsychiatric changes that may be present early in disease course (e.g., anxiety or depression) are also common in the general population and thus may not be attributable to the onset of PLA2G6-related dystonia-parkinsonism.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing for pregnancies at increased risk is possible by molecular genetic testing of DNA extracted from fetal cells obtained by amniocentesis at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The pathogenic variants in PLA2G6 must be identified in the affected sib or both parents before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dystrophie Neuro Axonale Infantile Association
    France
  • NBIA Disorders Association
    2082 Monaco Court
    El Cajon CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: info@NBIAdisorders.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov
  • NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) Registry
    CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
    Email: pwood@nbiadisorders.org
  • Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Phone: 503-494-4344
    Fax: 503-494-6886
    Email: gregorya@ohsu.edu

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
PLA2G622q13​.185 kDa calcium-independent phospholipase A2PLA2G6 @ LOVDPLA2G6

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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 Genetic Pathogenesis

PLA2G6 encodes 85-kd calcium-independent phospholipase A2 (iPLA2-VIA). The iPLA2 family of phospholipase A2 enzymes catalyzes the hydrolysis of glycerophospholipids, generating a free fatty acid (usually arachidonic acid) and a lysophospholipid. The iPLA2-VIA protein has proposed roles in phospholipid remodeling, arachidonic acid release, leukotriene and prostaglandin synthesis, and apoptosis [Balsinde & Balboa 2005]. The iPLA2 enzymes play a critical role in cell membrane homeostasis by helping to regulate levels of phospholipids [Baburina & Jackowski 1999]. Defects in iPLA2-VIA 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 INAD [Morgan et al 2006].

Gene structure. The longest characterized PLA2G6 transcript (NM_003560.2) has 17 exons that are alternatively spliced to create several transcript variants encoding multiple protein isoforms [Larsson et al 1998]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. No commonly occurring PLA2G6 benign variants have been identified to date.

Pathogenic allelic variants. The original report of pathogenic variants in PLA2G6 described 44 unique mutations: 32 missense mutations, five small deletions leading to a frameshift, three nonsense mutations, two leading to amino-acid deletions without a frameshift, one splice site mutation, and one large deletion [Morgan et al 2006]. Some pathogenic variants have been identified in multiple families reported to be unrelated, although several share ethnic backgrounds [NBIA International Mutation Database, unpublished data]. The large deletion was a contiguous gene deletion involving PLA2G6 intron 13, the remainder of PLA2G6, and extending into exons 1 and 2 of the adjacent putative transcript FLJ22582, now identified as the gene BAIAP2L2 [Morgan et al 2006].

Normal gene product. The longest transcript (NM_003560.2) encodes a protein of 806 amino acids (NP_003551.2). iPLA2-VIA is one of several calcium-independent phospholipases. The protein is active as a tetramer.

Abnormal gene product. The two enzymatically active isoforms of the protein are predicted to be affected by all of the mutations reported to date [Morgan et al 2006]. A subset of mutations would also alter the shorter enzymatically inactive isoforms, which seem to act as dominant-negative inhibitors when incorporated in the tetramer [Larsson et al 1998, Balsinde & Balboa 2005].

References

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Suggested Reading

  1. Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, Roeber S, Tarabin V, Dusi S, Krajewska-Walasek M, Jozwiak S, Hempel M, Winkelmann J, Elstr M, Oexle K, Klopstock T, Mueller-Felber W, Gasser T, Trenkwalder C, Tiranti V, Kretzschmar H, Schmitz G, Strom TM, Meitinger T, Prokisch H. Absense of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet. 2011;89:543–50. [PMC free article: PMC3188837] [PubMed: 21981780]
  2. Tonelli A, Romaniello R, Grasso R, Cavallini A, Righini A, Bresolin N. Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy. Clin Genet. 2010;78:432–40. [PubMed: 20584031]

Chapter Notes

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, 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.

Revision History

  • 19 April 2012 (me) Comprehensive update posted live
  • 1 September 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 19 June 2008 (me) Review posted live
  • 14 June 2007 (ag) Original submission
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