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Scientists discover genetic defect responsible for devastating brain disorder among Amish babiesOctober 1, 2002
BETHESDA, MARYLAND -- An international team, led by
researchers from the National Human Genome Research
Institute (NHGRI), has discovered the genetic cause for a
rare form of microcephaly, a devastating brain disorder
that has stricken infants among the Older Order Amish for
nine generations.
The study, published in the September issue of "Nature
Genetics," describes the gene mutation that underlies Amish
microcephaly (MCPHA), a birth defect marked by a profoundly
small head and brain size. Over the past 40 years, 61
babies with MCPHA have been born to 23 nuclear families in
the Old Order Amish community in Lancaster County, Pa. None
of the children has lived beyond the age of 14 months, and
most die between 4-6 months.
In their study in "Nature Genetics," the NHGRI team found
the gene defect causes developing cells to lose their
normal ability to transport the building blocks of DNA,
called base pairs, across the inner membrane walls of the
mitochondria, which are tiny structures that function as
the cells' metabolic power houses. Researchers believe that
without this carrying ability, called mitochondrial
deoxynucleotide transport, the cell's mitochondria cannot
make DNA properly, causing the brain of the unborn child to
develop abnormally. The NHGRI data also indicate that
mitochondrial deoxynucleotide transport may play a crucial
role in normal prenatal brain growth.
"It's a significant finding to all prenatal brain
development," says Dr. Leslie Biesecker, the study's lead
author and a senior investigator for the Genetic Disease
Research Branch at NHGRI. "It makes a tie between energy
metabolism and brain development."
Five other genes have been linked the brain-development
abnormalities, including one called ASPM that appears to
cause microcephaly in the children of a large family from
Pakistan. Microcephaly can also be caused by the
chromosomal disorder, trisomy 21 Down syndrome, and by
environmental factors, such as fetal alcohol syndrome and
fetal exposure to radiation before 15 weeks gestation.
"We'll have to look at how this abnormality ties into the
other genes that are known to cause microcephaly, figure
out how those genes interact with each other and then look
for other connections between energy metabolism and brain
development," Dr. Biesecker adds.
A diagnosis of microcephaly means a baby's head
circumference is significantly less than the average
newborn's head size of 33-38 cm (about 13-15 inches).
Specifically, the head circumference of a microcephalic
infant, measured by encircling the forehead and the
occiput, or back of the skull, is three standard deviations
or more below normal. Babies born with MCPHA have a
particularly severe form of the defect, with a head
circumference anywhere from six to 12 standard deviations
below the average for a normal newborn. Their skulls are
very small and their brains undeveloped and malformed.
"The brain (of MCPHA children) in some ways is quite
functional," said Dr. D. Holmes Morton, M.D., co-author of
the study and director of The Clinic for Special Children
in Strasburg, Pa., which cares for such children. "They
will present with normal brain stem function, cry, muscle
tone, suck and swallow. They have behaviors typical of the
normal newborn -- it can be quite amazing. But on MRI, it's
fairly obvious that there is an arrest in the development
of the brain that is quite profound, particularly in the
upper part of the brain, the cerebrum. It's an arrested
development that precludes any treatment."
In addition to brain and skull abnormalities, babies with
MCPHA have elevated levels of the biochemical alpha-
ketogluterate in their urine, a finding that is directly
related to MCPHA but still not clearly understood.
Scientists also are investigating the mystery of why the
children's other organs, such as the heart and liver,
seemingly are not affected, even though they rely on energy
production from mitochondria at a metabolic rate similar to
the brain during development.
MCPHA is inherited in an autosomal recessive pattern, which
means that it is necessary for a baby to inherit two copies
of the mutated gene to have the disorder. In affected
families, each parent contributes one changed copy of the
gene to the child who has the disorder. The parents are
called MCPHA carriers because they have one normal copy of
the gene and one changed copy of the gene, but do not show
symptoms of the disorder. When both parents are carriers
of the changed gene, each of their children has a 25
percent chance of having the disorder, a 50 percent chance
of being a carrier of the disorder (like their parents) and
a 25 percent chance of neither being a carrier nor having
the disorder. These risks are the same for each pregnancy.
Using the knowledge of the inherited nature of this form of
microcephaly, and the fact that it is only found in the Old
Order Amish who live in Lancaster County, scientists were
able to create an accurate genealogy, using pedigree
computer software. The genealogy, or family tree, revealed
that all 23 families who have children with MCPHA
apparently descended from a single Old Order Amish couple.
After Dr. Biesecker and his colleagues at the National
Center for Biotechnology Information (NCBI) created the
MCPHA family tree, they used a variety of methods -- whole
genome scan, fine-mapping and haplotype analysis -- to
identify a region on the long arm of chromosome 17 that
contained about 80 "candidate genes" for MCPHA. The
research team eventually pinpointed the affected gene,
called DeoxyNucleotide Carrier (DNC), in a region of 3cM,
or 2Mb, on chromosome 17q25.
The technique of haplotype mapping -- or finding blocks of
genes that are passed on together through generations --
not only helped the scientists find the MCPHA gene, but
also demonstrated exactly how the defect is inherited over
generations among the Old Order Amish.
After the NHGRI researchers identified the genetic defect
responsible for MCPHA, they turned to Ferdinando Palmieri's
laboratory at the University of Bari in Bari, Italy to
determine exactly how the mutation affects biological
functions. The Italian researchers injected normal and
mutant copies of the DNC gene into bacteria and then
examined the function of the proteins they produced. In
contrast to the protein generated by the normal gene, the
mutant protein completely lacked the ability to carry
deoxynucleotides.
Dr. Biesecker says that tools and techniques from the Human
Genome Project and the genome sequence -- published while
the study was being conducted -- helped cut years off his
team's 2 1/2 year project.
Dr. Biesecker also credited much of the project's success
to the close relationship between the Amish families and
Drs. D. Holmes Morton and Richard Kelley of The Clinic for
Special Children. Dr. Morton, who established the clinic as
both a pediatric practice and a genetics diagnostic
laboratory, saw the first case of Amish microcephaly in
1988 when a family asked him to come and see their child.
That family led Morton to dozens of other families who had
had children with the same syndrome. Thus, began Dr.
Morton's ongoing relationship with both the Amish and
Mennonite communities that has created study collaborations
with NHGRI on three other occasions and cultivated support
for the genetic research begun by Dr. Victor McKusick at
Johns Hopkins University and continued by Dr. Biesecker.
Dr. Morton, both a pediatrician and geneticist, has come to
know the Amish and Mennonite communities in a personal way.
About 50 percent of the Amish children are born at home
with the services of a midwife. Morton and his staff also
commonly make house calls in rural areas of Lancaster
County, Pa., providing compassionate medical care in
sometimes-difficult situations, such as babies with MCPHA.
"In the history of modern genetics, the Amish and Mennonite
people are incredibly important," explains Dr. Morton.
"They have made themselves available for studies in ways
that many populations either haven't or can't or don't.
"In the long run," he adds, "a lot of our success in being
able to do the kind of studies that we did with
microcephaly is due to the fact that the community knows
we'll help them with these difficult cases. A part of their
appreciation for that is helping out with these studies.
The familiarity is there."
NHGRI is one of the 27 institutes and centers at the
National Institute of Health (NIH), which is an agency of
the Department of Health and Human Services (DHHS). NHGRI
supports the NIH component of the Human Genome Project, a
worldwide research effort designed to analyze the structure
of human DNA and determine the location of the estimated
30,000 human genes. The NHGRI Intramural Research Program
develops and implements technology for understanding,
diagnosing, and treating genetic diseases.
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