Rare Disease's Gene May Illuminate Major Disorders

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Rare Disease's Gene May Illuminate Major Disorders

http://www.medicalnewstoday.com/medicalnews.php?newsid=45442

Oregon Health and Science University researchers have identified the

gene behind a group of rare, progressive childhood disorders caused

by an abnormal buildup of iron in the brain.

Discovery of the PLA2G6 gene, whose mutated forms trigger several

genetic disorders categorized as neuroaxonal dystrophies, could shed

light on the nerve cell degeneration that leads to such neurological

maladies as Parkinson's and Alzheimer's diseases, both known to be

associated with brain iron accumulation.

" If you're a family with a kid with one of these diseases, the impact

is clear, specific and personal, " said J. Hayflick, M.D.,

professor of molecular and medical genetics, pediatrics and neurology

in the OHSU School of Medicine

(http://www.eurekalert.org/multimedia/pub/1206.php) But because it

may heighten understanding of other, better-known neurological

disorders, " To the general population, (the discovery) has a larger

impact, and that's a significant benefit. "

In a study published online June 18 in the journal Nature Genetics,

Hayflick and an international team of geneticists describe PLA2G6's

discovery using DNA from families with infantile neuroaxonal

dystrophy, or INAD, and a related disorder known as neurodegeneration

with brain iron accumulation, or NBIA.

In INAD, also known as Seitelberger disease, symptoms start by age 2

and worsen over time, and include loss of head control and the

ability to sit, crawl or walk, as well as deteriorating vision and

speech, according to the National Institute of Neurological Disorders

and Stroke, a branch of the National Institutes of Health. Children

with the disease die between ages 5 and 10.

NBIA, sometimes called Hallervorden-Spatz syndrome, manifests itself

between the teen years and adulthood. Symptoms include involuntary

muscle contractions, rigidity and spasms in the limbs, face and

torso, as well as confusion, disorientation, seizures, stupor and

dementia. Rapid deterioration, punctuated by stable periods, lasts

one to two months, with the rate of progression correlating with the

patient's age - the later the onset, the better the patient fares.

There is no cure nor standard treatment for either disease, which are

inherited in a recessive fashion, meaning that both parents must

contribute a defective gene to make both copies in the child

defective. Incidence is 1 in 500,000 to 1 million.

PLA2G6's discovery means a clinical test can be developed to help

families determine their chances of passing the disorders to their

children.

" That's a direct outcome of this work, " Hayflick said. " There are

families who literally are waiting to have this test. They've been

waiting for years. To have the option of bringing a child into this

world you know won't have to suffer like this is extraordinary for a

parent who's been through this. Some of them have had multiple

children with the disease. "

The disorders are caused by a build-up of iron in the basal ganglia,

a cluster of gray-matter tissue structures deep in the brain that

control motor function. The iron accumulation causes the branch-like

axons that transmit electrical impulses from the nerve cell body to

its terminal to swell, interrupting the signal sent to other nerve

cells nearby.

PLA2G6 is thought to encode an enzyme that breaks down lipids

involved in the reconstruction of a cell's membrane following damage

by light and other toxins. When the gene is mutated, lipid metabolism

is altered and iron builds up, triggering disease.

" I studied our entire INAD patient population for mutations in this

gene and found over 44 different changes in the gene which would lead

to disease, " said study co-author Westaway, Ph.D., research

assistant professor of molecular and medical genetics at OHSU.

Working with scientists at the University of Birmingham School of

Medicine, United Kingdom, Hayflick and Westaway collected DNA from 30

to 40 families affected by the diseases and narrowed the search for

the suspect gene to a 100-gene block of DNA on chromosome 22, the

second smallest chromosome in humans that contains 500 to 800 genes.

The team then looked for genes in the region whose function was

suggestive of the symptoms and parts of the body affected by the

diseases, and the search was further narrowed to 75 genes.

" You just start sequencing genes and compare healthy people to people

with the disease, " Hayflick said. " In people with the disease, you

see changes that are clearly disease causing. "

After scouring the 75 genes, " we finally found mutations in PLA2G6 in

a large kindred with multiple generations of affected individuals,

and in three other smaller families, " Westaway said.

The chromosomes containing the mutations are then compared to almost

200 control chromosomes not affected by the disease. " The severity of

the mutation is usually a very good clue that the gene has been

found, " she said. " That evidence is confirmed by continuing to find

different, but severe, mutations in the same gene in new patients

diagnosed with INAD, which we have done. "

PLA2G6 is among 18 lipid-metabolizing genes in a protein family known

as phospholipase A2 (PLA2), and INAD is the first inherited disorder

associated with mutations in one of these genes. Its

discovery " unequivocally " links PLA2 defects to neurodegeneration,

researchers say, which is significant because similar lipid

metabolism changes are seen in neurodegeneration associated with

ischemia from stroke, spinal cord trauma, head injury and Alzheimer's

disease, making this metabolic pathway a potential drug target.

In addition, iron is known to accumulate with age in brain regions

attacked by Alzheimer's and Parkinson's diseases. " This is a common

end effect of many neurodegenerative disorders, " Hayflick said.