PLA2G6-Associated Neurodegeneration, is named for the responsible gene: PLA2G6. This gene is thought to be important in helping cells maintain a healthy membrane (outer layer). It also is involved in lipid (fat) metabolism. It is not yet known how changes in this gene cause the symptoms of PLAN or the excess accumulation of iron in the brain in some affected individuals.
PLAN is made up of three distinct forms with differing characteristics:
- INAD, or Infantile Neuroaxonal Dystrophy: early onset, rapidly progressive disease
- Atypical NAD, or atypical neuroaxonal dystrophy: later childhood onset with slower progression and predominant extrapyramidal (nerves that regulate motor control) findings, such as dystonia (involuntary muscle contractions that cause repetitive or twisting movements) and dysarthria (difficulty pronouncing words). It includes a broad range of presentations
- PLA2G6-related dystonia-parkinsonism: adult-onset dystonia-parkinsonism accompanied by cognitive decline and neuropsychiatric changes (mental disorder due to disease of the nervous system)
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Infantile Neuroaxonal Dystrophy (INAD)
Classic INAD starts early in life and progresses rapidly. It usually develops between 6 months and 3 years of age. The first signs are often delays in developing skills, such as walking and talking. Children may be floppy or have low muscle tone early on (hypotonia), but this turns into stiffness (spasticity) as they age, especially in the arms and legs. Eye disease caused by the degeneration of the optic nerve (optic atrophy) is common later on and can cause poor vision and eventual blindness. Seizures and fast rhythms on an EEG may also result.
A loss of cognitive abilities occurs, and many affected children never learn to walk or lose that ability. Many affected children do not survive beyond their first decade, but some survive into their teens and beyond. Supportive care can contribute to a longer life span by reducing the risk of infection and other complications.
Clinical Diagnosis - INAD
An MRI of the brain and an eye exam are keys to diagnosing INAD. In addition to a loss of motor skills, affected individuals also experience cerebellar atrophy, strabismus (crossed eyes) and nystagmus (rapid involuntary eye movements). Abnormal axons (a part of nerve cells), called spheroid bodies, can be seen on biopsies but may not appear until later in the disease as they accumulate with age. Abnormal brain iron accumulation varies among affected individuals and may not be evident on MRI studies.
Management - INAD
Drugs are given to treat spasticity and seizures. Fiber supplements and/or stool softeners are used to treat constipation. A transdermal scopolamine patch may help with mouth secretions. Feeding modifications such as softer foods or a feeding tube may be required to prevent aspiration pneumonia and achieve adequate nutrition.
NAD usually starts in early childhood but can occur as late as the end of the second decade. It has a slower progression and a different variety of movement problems than INAD. At first, the individual may have delays in speaking or exhibit features similar to autism. Eventually, difficulty with movement develops, and these individuals usually have dystonia. Behavior changes are common, such as acting impulsively, not being able to pay attention for long periods of time or depression, which may require treatment by a doctor.
Clinical Diagnosis - Atypical NAD
Certain MRI views (T2-weighted images) of the brain show an abnormality in the globus pallidus, a part of the brain that controls movement. The abnormality, called hypointensity, indicates iron accumulation. Consequently, an MRI and eye exam are keys to establishing strong clinical features of NAD.
Predominant features of NAD are onset before age 20, psychomotor regression (i.e. loss of previously acquired skills), language difficulties, autistic-like behavior, cerebellar atrophy, optic atrophy, progressive dystonia and dysarthria. As with INAD, biopsies show evidence of abnormal axons called spheroid bodies. Other common features are psychiatric and behavior abnormalities, spasticity, joint contractures, seizures and nystagmus.
Management - Atypical NAD
Drug therapy is provided for spasticity and seizures. For dystonia associated with atypical NAD, oral or intrathecal baclofen may be tried. Treatment by a psychiatrist is indicated for those with later-onset neuropsychiatric symptoms. Fiber supplements and/or stool softeners are used to treat constipation. A transdermal scopolamine patch may help with mouth secretions. Feeding modifications such as softer foods or a feeding tube may be required to prevent aspiration pneumonia and achieve adequate nutrition.
The onset of PLA2G6-related dystonia-parkinsonism varies from childhood to second and third decade of life. These individuals experience dystonia, eye movement abnormalities, slowness, poor balance, rigidity and marked cognitive decline.
Clinical Diagnosis - PLA2G6-related dystonia-parkinsonism
Abnormal brain iron accumulation in the globus pallidus, substantia nigra and/or striatum varies among affected individuals and may not be evident on MRI studies until late in the disease.
The main features are variable onset from childhood to young adulthood; parkinsonism (tremor, bradykinesia [slow movements], rigidity and impaired postural responses); dystonia; cognitive decline; neuropsychiatric changes; and an initial dramatic response to dopaminergic (levodopa) treatment followed by the early development of dyskinesias (diminished voluntary movements and the presence of involuntary movements). Other common features are dysarthria, autonomic involvement and mild cerebral atrophy.
Management - PLA2G6-related dystonia-parkinsonism
Consider treating with dopaminergic agents. Consult a psychiatrist to treat neuropsychiatric symptoms. A physical therapy evaluation may help problems with posture and walking. Occupational therapy can help the person perform activities of daily living. Periodic assessment of vision and hearing may be needed. To prevent secondary complications: Start physical therapy early and orthopedic management to help prevent contractures (tightening of the muscles, tendons, skin and nearby tissues, which cause joints to stiffen) as the disease progresses.
PLAN is inherited in an autosomal recessive manner, meaning the affected individual receives two mutated genes, one from each parent. This is how it works:
- Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change (mutation) in it, the person should still have normal health. That person is called a carrier.
- Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes on to their child. There is a one in four chance that two carriers would have a child with the disorder. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation.
Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.
If the disease-causing mutations have been identified in the family, prenatal testing for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.
Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.
A main resource for the clinical information provided here is PLA2G6-Associated Neurodegeneration - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult to understand for the general public.
The following discussion of research to better understand PLAN is for informational purposes only. We do not endorse specific studies or clinical trials, experimental drugs, procedures, biotech or pharmaceutical companies.
Research has been vital to understanding the role of PLA2G6 and how the loss of function affects nerve health. Understanding the role of this gene is an important step in finding ways to treat the disease. The function of the gene has been investigated in various animal models such as fruit flies and mice, as well as in induced pluripotent stem cell cultures (iPSCs). iPSCs are derived from skin (fibroblasts) or blood cells of healthy or affected individuals and converted to stem cells through overexpression of a group of genes known as Yamanaka factors. These cells can then be converted to any type of cell in the body. The relevant cell type that is used for PLAN research are dopamine neurons. The function of the protein produced by the gene, called iPLA2β, is not fully understood. According to preliminary research, it is thought to be a phospholipase enzyme that controls fatty acid levels in the brain. PLA2G6 mutations appear to cause a loss of catalytic activity and mislocalization of the protein, meaning the protein is not found where it normally is located, in the distal axons and dendrites.
Studies in patient cells show that the loss of PLAG26 function causes an expansion of lysosomes (membrane-covered cell structures that break down cellular waste), aberrant morphology (abnormal shapes) and changes in the mitochondria, and accumulation of glucosylceramide (a basic component of the cell membrane). This is very similar to what is observed in fruit fly models, which suggests that drugs that work in the flies may work in humans. This opens up an avenue for screening drugs that alleviate neurodegeneration.
Researchers have been seeking therapeutic approaches to restore PLA2G6 enzyme function in INAD. Potential therapeutic strategies may include gene therapy, enzyme replacement therapy through modification of the PLA2G6 protein so it can be delivered to the brain, use of pharmacological chaperones to improve the function of mutant PLA2G6 proteins, or stimulation of other enzymes to compensate for the loss of PLA2G6 function such as Acyl CoenzymeA or other phospholipase enzymes. Challenges exist for each of these potential treatments, and all require extensive research before they can be tried in human subjects.
One of the potential therapeutic strategies, pharmacological chaperones, has shown potential in early research. As proteins are produced from DNA, they are folded into configurations that are required for proper function in the cell by small molecules called chaperones. Further research in this area would involve screening many drugs for the potential to act as a chaperone and to stabilize PLA2G6 protein folding.
Another potential therapeutic strategy is stimulation of other enzymes. Scientists have hypothesized that other enzymes called acyl CoA synthetases could compensate when the PLA2G6 enzyme is impaired by mutations. They have observed that a protein that stimulates the activity of acyl CoA synthetases has a beneficial effect on mice with a PLA2G6 mutation.
Research into gene therapy for INAD is in the early stages of development. The goal of gene therapy is to deliver healthy copies of the gene, in this case PLA2G6, into a patient’s cells to treat the disease. Genes can be delivered through a viral vector, which is a virus that is scientifically engineered to carry the functional gene into the cell. Before a treatment can be tested in humans, it must first be used in animal models that are genetically engineered to have a PLA2G6 mutation. Scientists have developed a mouse model that is genetically engineered to have a PLA2G6 mutation. These mice develop movement and coordination problems similar to individuals with INAD. Researchers have found that when the mice receive the gene therapy, they have improved outcomes in length of life and mobility.
Researchers are now in a position to publish their findings and seek major grant funding to potentially investigate the therapy in human subjects. The researchers hope this strategy paves the way for future clinical trials in patients with PLAN.
PLAN Natural History Studies and Biobanks
PLANReady Natural History Study
The NBIA Research Group at Oregon Health & Science University has developed a study called PLANready. Its purpose is to help better understand the natural history of PLAN, meaning how symptoms appear and change over time. By studying individuals with PLAN, they also hope to identify disease markers that can be used in future clinical trials. A disease marker is any symptom or measurement that happens reliably in a disease, changes predictably with disease progression and becomes “better” with successful treatment. A disease marker could be an MRI finding, a protein level in the blood, or a rating scale to measure symptoms or function. Natural history studies provide data that serve as the foundation for future drug trials.
To find out more about this natural history study and to contribute to data collection go to: PLANready | NBIA.
TIRCON International NBIA Registry
The TIRCON International NBIA Registry was created under an EU grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries currently take part in the registry by entering their patient data. There are over 700 entries consisting of NBIA patients and controls as of July 2020. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de for more information on this registry.
Retrotope Natural History Study
Retrotope, Inc., is a biopharmaceutical company that began a natural history study in June 2019 with an estimated completion date of December 2021. It is looking at various outcome measures such as INAD mortality and morbidity. The study is not recruiting more participants at this time. For more information, go to A Natural History Study of Infantile Neuroaxonal Dystrophy.
The New York Stem Cell Foundation Research Institute (NYSCF)
The NYSCF’s mission is to accelerate cures for major diseases through stem cell research. The institute is collecting skin cell samples from patients and their families in addition to obtaining medical and family histories. The skin cells are then converted into induced pluripotent stem cells, which are cells that have the ability to differentiate into different types of cells such as neurons. This enables researchers to understand more about the disease and accelerate the rate in which treatments can be discovered. To learn more about this biobank, contact Geoff McGrane at gmcgrane@NYSCF.org
PLAN Clinical Trials
A clinical trial by Retrotope sets out to test a potential drug treatment called RT001 for individuals with INAD. This trial has 19 participants who all received the compound and are being followed over time to observe their response. It began in November 2018 and is expected to be completed by June 2021.
More information can be found at A Study to Assess the Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy.
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies.
PLAN Research Publications and Articles
Following is a list of some recent research articles. Others can be found at Pub Med Central.
2021 - Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy
2020 - Lack of Association Between PLA2G6 Genetic Variation and Parkinson's Disease: A Systematic Review
2018 - PLA2G6-Associated Neurodegeneration (PLAN): Review of Clinical Phenotypes and Genotypes
2018 - Pantothenate Kinase-Associated Neurodegeneration (PKAN) and PLA2G6-Associated Neurodegeneration (PLAN): Review of Two Major Neurodegeneration with Brain Iron Accumulation (NBIA) Phenotypes
2017 - Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration