Scientists discover genetic defect responsible for microcephaly

September 30, 2002

BETHESDA, Md. - 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 "-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 2½ 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.

NIH/National Human Genome Research Institute

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