PLAN, or PLA2G6-Associated Neurodegeneration, one of the NBIA (Neurodegeneration with Brain Iron Accumulation) disorders is caused by mutation in PLA2G6 Gene. This gene helps cells maintain a healthy membrane (outer layer). It is involved in fat (lipid) metabolism.
It is not yet known how changes in this gene cause the symptoms of PLAN or high brain iron in some affected individuals.
Based on an individual’s age of onset and symptoms, this disorder is classified in three distinct forms of PLAN with different characteristics
- INAD, or Infantile Neuroaxonal Dystrophy, the symptoms usually start to appear between the ages of 6 months and 1 year…
- aNAD, or atypical neuroaxonal dystrophy, the symptoms are more variable than INAD. Individuals typically start showing symptoms in early childhood, usually by 4 years of age…
- adult form of dystonia-parkinsonism or PLA2G6-related dystonies-parkinsonism in which onset occurs in the second to third decade of life.
There are also individuals between these categories representing a broad spectrum of symptoms that is really a continuum of overlapping clinical and radiologic features.
INAD
Classic INAD starts early in life, between ages 6 months and 3 years with psychomotor regression or delay, progresses rapidly. The first signs are often delays in developing skills, many affected children never learn to walk or lose the ability shortly after attaining it. Children may be floppy or have low muscle tone but this later turns into severe spasticity (stiffness) as they get older, especially in the arms and legs. Disease progression is rapid.
Symptoms of INAD
Loss of motor skills
- Hypotonia low muscle tonus and progressive spastic tetraparesis
- Spasticity stiffness on a later stage
cerebellar atrophy progressive cognitive decline
visual impairment strabismus (crossed eyes), nystagmus (rapid involuntary eye movements) and optic atrophy are common
Visual abnormalities is common later on and can cause poor vision and eventual blindness.
Seizures
EEG fast rhythms may also occur.
Many affected children do not survive beyond their first decade, but some survive into their teens or later thanks to supportive care to a longer life span by reducing the risk of infection and other complications.
Diagnosis and testing for INAD
Onset before age three years
Clinical tests
- Psychomotor regression (most common presenting feature)
- Early truncal hypotonia followed by spastic tetraparesis (usually with hyperreflexia in the early disease stages with progression to areflexia later in the disease course)
- Visual impairment, strabismus, nystagmus, optic atrophy
Laboratory tests
- Elevated aspartate aminotransferase / alanine aminotransferase ratio
- Elevated lactate dehydrogenase
Radiographic tests
- Seizures that may present early or late in the disease course
MRI
- Cerebellum atrophy
- 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 and hypertrophy of the clava
- 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
- Eye exam are keys to diagnosing INAD and aNAD
Molecular genetic testing of PLA2G6 to identify mutation in PLA2G6.
Electron microscopic examination of nerve biopsies for dystrophic axons Abnormal axons (a part of nerve cells), called spheroid bodies or axonal spheroids can be seen on biopsies but may not appear until later in the disease as they accumulate with age.
aNAD
Atypical NAD usually starts in early childhood but can be 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, children may have delays in speaking or exhibit features similar to autism. The course is fairly stable during early childhood and resembles static encephalopathy but is followed by neurologic deterioration between ages seven and 12 years.
Symptoms of aNAD
Movement difficulties
- progressive dystonia, gait instability, Ataxia
- Progressive dysarthria difficulty pronouncing words and speech delay
Neuropsychiatric Disturbances, autistic features, impulsivity, poor attention span, hyperactivity, and emotional lability
Visual impairment Strabismus, nystagmus (rapid involuntary eye movements), optic atrophy
Diagnosis of aNAD
Symptoms onset before age 20
Clinical
- Psychomotor regression, loss of previously acquired skills), psychiatric and behavior abnormalities
- Gait abnormalities
- Prominent expressive language difficulties
- Psychiatric/behavioral abnormalities including autistic-like behavior
- Visual abnormalities: nystagmus, optic atrophy
- Spasticity (without preceding hypotonia)
- Joint contractures
- Progressive dystonia and dysarthria
- Disease progression slower than in INAD
Radiographic
- Cerebellar atrophy
- T2-weighted MRI of the brain: hypointense globus pallidus (indicating iron accumulation)
Neurophysiologic
- Delayed with reduced amplitudes
- Seizures
Molecular genetic testing of PLA2G6 to identify mutation in PLA2G6.
Electron microscopic examination of nerve biopsies for dystrophic axons as with INAD, biopsies show evidence of abnormal axons (a part of nerve cells), called spheroid bodies or axonal spheroids can be seen on biopsies but may not appear until later in the disease as they accumulate with age.
PLA2G6-related dystonia-parkinsonism
PLA2G6-related dystonia-parkinsonism has a variable age of onset, from childhood to second and third decade of life. Most individuals present in early adulthood gait disturbance or neuropsychiatric changes.
In their late teens to early twenties, the patients experience Dystonia, most common in the hands and feet but may be more generalized, Eye movement abnormalities and parkinsonism, bradykinesia slowness, postural instability (poor balance), resting tremor, rigidity, which may be accompanied by rapid cognitive decline.
Diagnosis of PLA2G6-Related Dystonia-Parkinsonism
Clinical
The main features are variable onset from childhood to young adulthood
- Onset varying from childhood to young adulthood
- Parkinsonism (tremor, bradykinesia, rigidity, and markedly impaired postural responses)
- Dystonia
- Dysarthria
- Autonomic involvement (e.g., cold/blue hands and feet, difficulty regulating core body temperature, constipation)
- Cognitive decline
- Neuropsychiatric (mental disorder) changes due to disease of the nervous system and cognitive decline, neuropsychiatric (mental disorder)
- Initial dramatic response to dopaminergic treatment followed by the early development of dyskinesias (diminished voluntary movements and the presence of involuntary movements).
- Reduced dopamine transporter labeling similar to that seen in idiopatic Parkinson disease
- dysarthria (difficulty pronouncing words), autonomic involvement and mild cerebral atrophy.
Radiographic
- Cerebral atrophy
- Abnormal brain iron accumulation in the globus pallidus, substantia nigra, and/or striatum are variable and may not be evident on MRI studies until late in the disease course for some individuals.
- In some individuals, frontotemporal atrophy/hypoperfusion on single-photon emission computed tomography
Molecular genetic testing of PLA2G6 to identify mutation in PLA2G6.
Treatment of manifestations for Individuals with INAD, aNAD and PLA2G6-Related Dystonia-Parkinsonism
Routine pharmacologic treatment of spasticity and seizures;
- Baclofen oral or intrathecal for dystonia associated with aNAD
- Fiber supplements and/or stool softeners are used to treat constipation
- Transdermal scopolamine patch may help with mouth secretions.
- Dopaminergic agents for Individuals with PLA2G6-related dystonia-parkinsonism
- Psychotherapy for those with later-onset neuropsychiatric symptoms;
- Physical therapy for management of postural instability and gait difficulties
- Occupational therapy to assist with activities of daily living
- Orthopedic treatment to prevent contractures as the disease progresses
- Body temperature monitoring may be required for individuals with progressive autonomic involvement to identify dangerous fluctuations in core body temperature
- feeding modifications as needed softer foods or a feeding tube to prevent aspiration pneumonia and achieve adequate nutrition
Surveillance
Periodic assessment of vision and hearing of nonverbal children is indicated as needed to determine the level of sensory deficits.
Genetics
PLA2G6-associated neurodegeneration is inherited in autosomal recessive manner. Recessive diseases only occur when both parents are carriers for the same condition and then pass their changed genes on to their child. Statistically, there is 25% chance that two carriers would have an affected child, 50% chance the parents will have a child who is also a carrier and 25% chances that the child will not have the gene mutation.
Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are suggested if the disease-causing mutations in the family are known.
Molecular genetic testing approaches can include single-gene testing, use of a multi-gene panel and more comprehensive genomic testing
Prenatal Testing
If the disease-causing mutations have been identified in the family, prenatal diagnosis 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.
Research
In a seed grant provided by the NBIA Disorders Association, Dr. Paul Kotzbauer of Washington University in St. Louis, Mo., is researching “Therapeutic Approaches to Increase Acyl Coenzyme A Production in NBIA.” His hope is to develop a therapy for NBIA caused by PLA2G6 mutations.
That work builds on earlier research in Kotzbauer’s lab.The scientists hypothesize 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.
The lab is testing several experimental drugs that can stimulate the production of acyl CoA synthetase enzymes in the brain. Because several of these drugs have been found to increase acyl CoA production in other tissues, there is a reasonable chance they will have a similar effect on brain cells.
If the project succeeds in identifying one or more drugs that are helpful, Kotzbauer hopes to get more funding to test whether the approach improves neurological impairment in mice with a PLA2G6 gene mutation.
In a 2014 three year $150,000 grant provided by NBIA Disorders Association to Dr. Manju Kurian of University College London, she is researching a gene therapy approach for PLAN. The team has expertise in gene therapy and will use a “viral vector” as a delivery system to replace the faulty gene with a working gene. The researchers hope this strategy paves the way for future clinical trials in patients with PLAN.