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Genetics Revealed in Amish Brain Disorder
Genetics Revealed in Amish Brain Disorder
T
he genetic cause for a rare form of microcephaly, a devastating brain disorder that has stricken infants among the Older Order Amish for nine generations, has been discovered by an international team, led by researchers from the National Human Genome Research Institute (NHGRI). 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 and 6 months. In their work, 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 cells’ 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 to 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 6 to 12 standard deviations below the average for a normal newborn. Their skulls are very small and their brains undeveloped and malformed.
December 2002 | January 2003
miscarriage risk and blood folate levels, such as maternal age, education, maternal smoking, obesity, number of previous pregnancies and country of origin. They found that folate deficiency was associated with a 50 percent increase in risk of early miscarriage. They also found that high folate levels were not associated with miscarriage risk. The researchers defined folate deficiency as a blood folate level below 4.9 nmol/L, which is the cutoff for recommending folic acid supplements in Sweden. Women with blood folate levels between 5.0 and 8.9 nmol/L were considered to have adequate folate intakes, while women with folate levels greater than 9.0 nmol/L were considered to have high folate intakes. The authors noted, however, that American women have higher folate levels than do Swedish women. According to the 1999 CDC’s National Health and Nutrition Examination Study, the average blood folate level for American women is 16.2 nmol/L.
New Recommendations on SERMS
T
he American College of Obstetricians and Gynecologists (ACOG) has issued new recommendations on the use of selective estrogen receptor modulators (SERMS), which are a relatively new class of synthetic estrogens that act like estrogen in certain parts of the body (such as the bones) while leaving other parts of the body unaffected. The use of SERMS as alternative treatment to hormone replacement therapy in postmenopausal women has received increased public attention in the wake of the recent Women’s Health Study results, which revealed small but significant increased risks for certain diseases in women using hormone replacement therapy. Although SERMS are referred to collectively, their effects on different parts of the body can vary. ACOG’s
AWHONN Lifelines
495
T
he genetic cause for a rare form of microcephaly, a devastating brain disorder that has stricken infants among the Older Order Amish for nine generations, has been discovered by an international team, led by researchers from the National Human Genome Research Institute (NHGRI). 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 and 6 months. In their work, 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 cells’ 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 to 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 6 to 12 standard deviations below the average for a normal newborn. Their skulls are very small and their brains undeveloped and malformed.
December 2002 | January 2003
miscarriage risk and blood folate levels, such as maternal age, education, maternal smoking, obesity, number of previous pregnancies and country of origin. They found that folate deficiency was associated with a 50 percent increase in risk of early miscarriage. They also found that high folate levels were not associated with miscarriage risk. The researchers defined folate deficiency as a blood folate level below 4.9 nmol/L, which is the cutoff for recommending folic acid supplements in Sweden. Women with blood folate levels between 5.0 and 8.9 nmol/L were considered to have adequate folate intakes, while women with folate levels greater than 9.0 nmol/L were considered to have high folate intakes. The authors noted, however, that American women have higher folate levels than do Swedish women. According to the 1999 CDC’s National Health and Nutrition Examination Study, the average blood folate level for American women is 16.2 nmol/L.
New Recommendations on SERMS
T
he American College of Obstetricians and Gynecologists (ACOG) has issued new recommendations on the use of selective estrogen receptor modulators (SERMS), which are a relatively new class of synthetic estrogens that act like estrogen in certain parts of the body (such as the bones) while leaving other parts of the body unaffected. The use of SERMS as alternative treatment to hormone replacement therapy in postmenopausal women has received increased public attention in the wake of the recent Women’s Health Study results, which revealed small but significant increased risks for certain diseases in women using hormone replacement therapy. Although SERMS are referred to collectively, their effects on different parts of the body can vary. ACOG’s
AWHONN Lifelines
495