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

 

 

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

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

Laboratory tests

 

Radiographic tests

 

MRI

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

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

Radiographic

Neurophysiologic

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

 

Radiographic

Molecular genetic testing of PLA2G6 to identify mutation in PLA2G6.

 

Treatment of manifestations for Individuals with INAD, aNAD and PLA2G6-Related Dystonia-Parkinsonism

 

 

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.