Last updated:
June 14, 2022
Years published: 1987, 1990, 1996, 1997, 1998, 2006, 2007, 2008, 2011, 2018
NORD gratefully acknowledges Alison Freed, BA, Allison Gregory, MS, CGC, and Susan J. Hayflick, MD, Hayflick Laboratory, Department of Molecular & Medical Genetics, Oregon Health & Science University, for the preparation of this report.
Summary
PLA2G6-associated neurodegeneration (PLAN) is an extremely rare, inherited degenerative disorder of the nervous system characterized by abnormalities of nerve endings within the brain, spinal cord and peripheral nerves. PLAN is inherited as an autosomal recessive genetic condition caused by changes (variants) in the PLA2G6 gene. PLA2G6 tells the body’s cells how to make the enzyme A2 phospholipase, an enzyme that breaks down certain fats known as lipids. Symptoms of PLAN may start as early as 3 months through 3 years. Based on an individual’s age of onset and symptoms, their disease may be classified as one of three types of PLAN: infantile neuroaxonal dystrophy (INAD), a juvenile onset form called atypical neuroaxonal dystrophy (aNAD) or an adult-onset type called PLA2G6-related dystonia-parkinsonism. However, there is a broad spectrum of symptoms with people falling between these three categories.
Introduction
PLAN is classified as a form of neurodegeneration with brain iron accumulation (NBIA), a group of disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and eye disease. These disorders usually show evidence of iron accumulation on brain MRI.
INAD
INAD is characterized by abnormalities of nerve endings (axons) within the brain and spinal cord (central nervous system) and outside the central nervous system (peripheral nerves), resulting in loss of proper nerve function.
The symptoms of INAD usually start to appear between the ages of 3 months and 3 years of age. The common pattern in young children with INAD is slowing of their development, followed by loss of skills and progression of the disorder over time.
Common symptoms include regression or delay:
-Loss of previously acquired milestones, such as the ability to sit, stand, or vocalize sounds and words
-Delayed walking or gait disturbance
-Loss of muscle control (ataxia)
-Low muscle tone in the trunk more than the limbs (truncal hypotonia)
-Later development of muscle tightness and weakness in both arms and legs (spastic tetraparesis)
-Abnormal reflexes
Common eye features include:
-Crossed eyes (strabismus) and rapid uncontrolled eye movements (nystagmus) seen early in disease
-Deterioration of the nerve that connects the eye to the brain (optic atrophy) seen later in disease
Common symptoms of cranial nerve dysfunction:
-Speech problems including poor articulation (dysarthria), poor use of voice (dysphonia) and poor understanding of words (dysphasia)
-Difficulty swallowing and chewing (dysphagia) causing nutritional problems
-Choking and nasal regurgitation
Later in the disease, seizures may develop and cognitive decline occurs with progression. Progression of INAD is usually rapid and many affected children never learn to walk or lose this ability shortly after learning it. During the last stages of disease, severe stiff muscles, progressive cognitive decline and vision loss have a large impact on daily life. Many children with INAD do not live beyond age 10, but some do survive into their teens and early twenties. Death usually occurs due to secondary problems, such as aspiration pneumonia or other infections.
aNAD
The symptoms of aNAD are more variable than those of INAD with symptoms developing usually by 4 years of age. Delayed speech and autistic features may be the first evidence of disease with regression or slowed development of milestones.
Common muscle symptoms:
-Involuntary muscle contractions (dystonia)
-Poor articulation and speech (dysarthria)
-Muscle tightness and weakness in both arms and legs
-Reduced joint mobility due to muscle tightness
-Overactive reflexes developing early disease
-Absent reflexes developing late in disease
Common neuropsychiatric symptoms:
-Poor attention span
-Impulsivity
-Hyperactivity
-Emotional lability
aNAD shares common eye symptoms with INAD. Seizures are rare but may occur later in the disease. Individuals with aNAD are fairly stable during their early childhood but start declining between the ages of 7 and 12. aNAD patients are very rare so the average life span is not known. However, the life span is expected to be longer than that of classic INAD since initial symptoms develop at a later age.
PLA2G6-related dystonia-parkinsonism
There have been only a small number of PLA2G6-related dystonia-parkinsonism cases reported. The age of onset of symptoms varies from 4 to 37 years.
Common symptoms include:
-Tremors
-Decreased muscle movement (hypokinesia)
-Stiffness
-Loss of balance
-Walking difficulties: shuffling, freezing or getting stuck while walking
-Involuntary muscles contractions and spasms (dystonia)
– Poor articulation and speech (dysarthria)
-Cold/blue hands and feet, difficulty regulating core body temperature
-Constipation
Common neuropsychiatric changes (often the first symptoms seen in young adults)
-Depression
-Personality changes
-Aggression
-Delusions
-Paranoia
As PLA2G6-related dystonia-parkinsonism is very rare, the long-term progression and average life span are difficult to predict. Once symptoms begin, the progression typically moves rapidly.
INAD and other forms of PLAN are inherited in an autosomal recessive pattern. Variants of the PLA2G6 gene cause PLAN.
Researchers believe that the PLA2G6 gene carries instructions to create (encode) an enzyme that breaks down certain fats known as lipids. When the PLA2G6 gene is changed, the breakdown of lipids is affected, which may result in the excess accumulation of membranes in the nerve axons.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one working gene and one non-working gene, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive working genes from both parents is 25 percent. The risk is the same for males and females.
All individuals carry a few recessive genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
PLAN is an extremely rare genetic disorder, and the incidence and prevalence are not known with any certainty. It is estimated to occur in about 1-2/million children.
PLAN is diagnosed by means of a thorough clinical evaluation, brain MRI, a detailed history, and a variety of specialized tests including molecular genetic testing to sequence the PLA2G6 gene. A diagnosis of PLAN is confirmed by finding two changes in the PLA2G6 gene that are predicted to affect how it works or have been documented in other patients with PLAN. If no gene variant or only one gene variant is found through sequencing analysis of the PLA2G6 gene, then genetic testing may proceed to deletion/duplication analysis. This looks for large pieces of the gene that may be extra or missing, which sequencing can miss. Among individuals who go forward with deletion/duplication analysis, a gene change may be found in ~ 12.5 % of patients.
Brain imaging techniques may also be used to detect, confirm, and/or characterize specific abnormalities of the central nervous system that may be associated with PLAN. Magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to create cross-sectional images of the brain, often reveals progressive, generalized degeneration (diffuse atrophy) of tissue of the outer portion of the cerebellum (cerebellar cortex). Images may reveal areas of iron accumulation, although this is only observed about half the time and usually occurs later in disease.
In addition, microscopic examination (i.e., light and electron microscopy) of samples (biopsies) of peripheral nerve tissue from the skin or the transparent membrane covering the whites of the eyes (conjunctivae) may reveal swelling and degeneration of nerve endings (dystrophic axonal swellings or “spheroids”).
In infants and children with INAD, specialized testing may also be conducted to evaluate electrical activity (electrophysiological studies) of certain areas of the body. For example, electromyograms (EMG), tests that record electrical activity in skeletal muscles at rest and during muscle contraction, may indicate that, although nerve signals may be transmitted at normal speed to muscles (normal nerve conduction velocities [NCV]), there is failed communication of such signals to the muscles (denervation). Electroencephalography (EEG), which records the brain’s electrical impulses, may reveal abnormally high amplitude and fast activity within brain wave patterns. INAD may result in a decreased or absent response when the eye is stimulated by light (visually evoked potential [VEP]), confirming degeneration in optic pathways in the brain.
Treatment
The treatment of PLAN is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who diagnose and treat neurological disorders (neurologists), eye specialists (ophthalmologists), and/or other health care professionals may need to systematically and comprehensively plan an affected child’s treatment. Treatment will likely eventually include a combination of medications and other therapies, like physical or occupational therapy. With progression, treatments like a feeding tube or pulmonary hygiene to help prevent infections may be added.
Because some individuals with PLAN have high brain iron and this disorder falls into the category of NBIA, the option of therapies to remove iron (chelation) 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.
A proof-of-concept gene therapy strategy is currently under investigation in mouse disease models of PLAN.
Development of small molecule therapies is also under investigation in cell and mouse disease models.
Docosahexaenoic acid (DHA) is hydrolyzed from phospholipids by the action of the protein encoded by the PLA2G6 gene. Although not yet tested as an intervention in individuals with INAD, early experiments suggest that DHA may reverse the inhibition of the PLA2G6 protein.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., neurological abnormalities, neuromuscular impairment, optic atrophy, etc.].)
JOURNAL ARTICLES
Gregory A, Westaway SK, Holm IE, Kotzbauer PT, Hogarth P, Sonek S, Coryell JC, Nguyen TM, Nardocci N, Zorzi G, Rodriguez D, Desguerre I, Bertini E, Simonati A, Levinson B, Dias C, Barbot C, Carrilho I, Santos M, Malik I, Gitschier J, Hayflick SJ. Neurodegeneration associated with genetic defects in phospholipase A2. Neurology. 2008;71:1402–9.
Morgan NV, Westaway SK, Morton JE, et al., PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet. 2006;38:752-4.
Egan RA, Weleber RG, Hogarth P, et al. Neuro-ophthalmologic and electroretinographic findings in pantothenate kinase-associated neurodegeneration (formerly Hallervorden-Spatz syndrome). Am J Ophthalmol. 2005;140:267-74.
INTERNET
Gregory A, Kurian MA, Maher ER, et al. PLA2G6-Associated Neurodegeneration. 2008 Jun 19 [Updated 2017 Mar 23]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1675/ Accessed January 23, 2018.
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