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PLAN

PLAN, or 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 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.

This disorder is made up of three distinct forms with differing characteristics that include INAD, or Infantile Neuroaxonal Dystrophy; NAD, or atypical neuroaxonal dystrophy, which starts a few years later in life than INAD; and an adult form of dystonia-parkinsonism in which onset occurs in the second to third decade of life.

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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 later turns into stiffness (spasticity) as they get older, 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 occur.

A loss of cognitive abilities occurs, and many affected children never learn to walk or lose the ability early on. 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.

Clinical Diagnosis

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.

Management

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

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. 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 becoming depressed, which may require treatment by a doctor.

Clinical Diagnosis

Certain MRI views (T2-weighted images) that show a hypointense globus pallidus indicating iron accumulation and an 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 (difficulty pronouncing words). 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 (rapid involuntary eye movements).

Management

Drug therapy is provided for spasticity and seizures. For dystonia associated with atypical INAD, oral or intrathecal baclofen may be tried. Treatment by a psychiatrist is indicated for those with later-onset neuropsychiatric (mental disorder due to disease of the nervous system) 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.

 

PLA2G6-related dystonia-parkinsonism

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

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, rigidty, and impaired postural responses); dystonia; cognitive decline; neuropsychiatric (mental disorder due to disease of the nervous system) 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 (difficulty pronouncing words), autonomic involvement and mild cerebral atrophy.

Management

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 as the disease progresses.

Genetics

PLAN is inherited in an autosomal recessive manner. 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. Statistically, there is a one in four chance that two carriers would have an affected child. 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.

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 that found that the PLA2G6 gene produces an enzyme that controls fatty acid levels in the brain. 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.

 

Please see the link in the right hand column on this page for more detailed clinical information on PLAN at Gene Reviews, which was used as a source for some of the above information. Gene Reviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.

Gene Review Authors: Allison Gregory, MS, CGC, Manju A Kurian, MA, MRCPCH, PhD, Eamonn R Maher, MD, FRCP, FMedSci, Penelope Hogarth, MD, and Susan J Hayflick, MD.