Advanced paternal age is associated with an increased risk of new mutations. Fragile X Hemophilia, Duchenne's, autism, schizophrenia

Advanced paternal age is associated with an increased risk of new mutations. All populations are at risk. The relative increased risk for these defects is related to advanced age of the father for autosomal dominant conditions and the maternal grandfather for X-linked conditions. Family histories will not provide clues as these types of mutations are sporadic. Examples of autosomal dominant conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan syndrome, Treacher Collins syndrome, Waardenberg syndrome, thanatophoric dysplasia, osteogenesis imperfecta, and Apert syndrome Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (Factor VIII deficiency), Hemophilia B (Factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigment), Hunter syndrome, Bruton agammaglobulinemia, and retinitis pigmentosa.



1 The FMR-1 gene is located on the X chromosome. This gene is responsible for instructing the cell to make FMRP, a protein assumed to be essential for normal brain functioning.
A Single Gene Disorder
Fragile X Syndrome is a single gene disorder located on the X chromosome. Understanding the basics of fragile X syndrome requires an understanding of how genes themselves are constructed and what they do.
Genes are made up of DNA, which provides the blueprint for life. This blueprint is a code containing four letters (C, G, A, T), abbreviations for four different nucleotides (cytosine, guanine, adenine, and thymine). Nucleotides are the essential building blocks that make DNA. The letters and the sequences in which they are arranged construct the messages that lead the body to produce key proteins.


Fragile X syndrome results from a mutation (a change in the typical DNA sequence) known as trinucleotide repeat expansion. This means that a series of three particular nucleotides (CGG) in the DNA is greatly expanded beyond its normal size, disrupting the normal messages that need to be sent. This fact was discovered in 1991 by several teams of researchers studying the X chromosome.


In the FMR-1 gene located on the X chromosome, most individuals have CGG repeat that occurs between 5 and 50 times, the average being around 30. These individuals are normal with respect to fragile X syndrome, and usually carry no risk of transmitting it, although the 40—60 repeat range is sometimes considered a "gray zone" which may or may not be unstable (have a risk of expanding). Some individuals have CGG sequences that are repeated in the range of about 50 to 200. These individuals are generally referred to as premutation carriers. This means that they carry the syndrome and can transmit it to their children. Premutation carriers, however, are not usually affected by fragile X syndrome. When the number of CGG repeats expands beyond 200, the individual usually has the full mutation. This means that they have fragile X syndrome and will experience the impairments and delays associated with the syndrome.

Detecting Fragile X Syndrome


Fragile X syndrome is detected through a DNA analysis that almost always requires drawing blood. The technique for identifying fragile X syndrome is a specialized process and not all genetic labs have this capability. For those that do have this capability, the procedure is virtually 100 percent reliable. Fragile X can be detected prenatally or in newborns through DNA testing. Also, the carrier status of parents can be accurately determined. However, these tests are not routinely done and must be specifically requested. It is impossible to determine how severely affected the child might be based on this procedure.


Inheriting Fragile X Syndrome


Fragile X syndrome is carried on the X chromosome. Since both males (XY) and females (XX) each have at least one X chromosome, both can be carriers or have the syndrome. If a father is a carrier, he can only pass the gene defect to his daughters, since he transmits a Y chromosome to his sons. All of his daughters will inherit the gene, and as far as is known, transmission from father to daughter only occurs in the premutation state. In other words, if a daughter inherits the gene from her father, she will have the premutation, not the full mutations. Interestingly, this happens even if the father has the full mutation, as the sperm cells of males with the full mutation have been shown to be in the premutation phase.


If a mother is the carrier, she can pass the gene defect to either sons or daughters, since she contributes an X chromosome to each. Children of carrier mothers have a 50 percent chance of inheriting the gene, since the mother has two Xs to give and only one is affected. It is through mothers that the gene can expand from the premutation to the full mutation. So, a carrier mother can have normal children, children with the premutation, or children with the full mutation.


The chances of expansion into the full mutation increase with successive generations. Thus the gene could be passed down in the premutation phase for several generations without anyone suspecting that the family has a genetic disorder that ultimately will lead to mental retardation or other developmental disabilities.

ARE ALL KINDS OF AUTISMS AND SCHIZOPHRENIAS ON THE RISE BECAUSE MEN ARE FATHERING BABIES IN THEIR MID 30s AND BEYOND, WAY BEYOND?

Minding Your Mind



New Key to Autism


September 25, 2006


By Michael Craig Miller, M.D.
Harvard Medical School




Convincing Evidence

What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older


This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program.



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"The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia."

The title is a quote from Dr. Dolores Malaspina


Poor, rural roots

Cho's parents have always struggled to make ends meet.

Sung-tae Cho, the killer's father, came from a poor rural area. He was a "country bumpkin" and considerably older than his wife, the daughter of a refugee, said Seung-hui Cho's great-aunt, Kim Yang-soon. "We practically forced her to get married."

Hyang-im's father had fled south during the Korean War that separated the south from its communist northern neighbor, according to Korean news reports.

Sung-tae and Hyang-im Cho were ambitious and apparently educated because after they settled on the still semi-rural outskirts of Seoul, they bought a used-book store. One could make a decent living selling secondhand books in the 1970s, before South Korea's economy began to boom. But one relative said the bookstore just eked out a profit.

To ease his family's plight, Sung-tae Cho left his wife behind to be a laborer in the Middle East, working on oil fields and construction sites in Saudi Arabia for most of the 1980s.

Back home, his wife gave birth March 22, 1982, to their daughter, Sun-kyung. On Jan. 18, 1984, Seung-hui was born.

For the first few years of Seung-hui Cho's life, the family lived in a dark, damp basement apartment on a busy commercial street in Shinchang, a suburb of Seoul. They lived at the bottom of a three-story, red-brick home, and paid $150 a month, a bargain even then.

Cho attended an elementary school a short walk from his home. About 950 students attend today, about half the number when Cho was there. The cluster of three-story buildings frames a large, U-shaped dirt courtyard.

The school files contain only a single sheet of paper on Cho, showing he left the school in August 1992, at age 8, after partially completing second grade.

"We don't know anything about that student," said the vice principal, who refused to identify himself. "And I'd like to point out that he did not graduate from here."