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Genetic Services

What is Huntington Disease?

Having Healthy Babies without Revealing Parental Disease Risk:

Disclosing and Non-Disclosing PGD Programs for Couples at Risk for Huntington Disease

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Dr. George Huntington in 1872 described the type of movement disorder that went on to bear his name.
Huntington disease (HD) is a slowly progressive neurodegenerative disorder that affects approximately 1 in 10,000 individuals.  The disease usually becomes manifest around age 40, although behavioral changes may be apparent a decade or so before.  Progressive physical disturbance including uncontrolled movements, abnormal swallowing and muscle stiffness is seen along with a progressive dementia which runs a course of about 15 years and ends in a vegetative state.  Imagining of the brain reveals loss of cells in the basal ganglia (an area that controls coordination of movement) which is progressive over time.

HD is inherited as a dominant genetic disorder which means that each affected individual inherited the condition from one of their parents and then has a 50% chance of passing the gene onto their own children.  Everyone who inherits the gene will eventually develop HD.

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The genetics of Huntington disease: An affected parent will pass the gene onto 1/2 of his or her children of either sex who will also develop the disease as an adult.
The gene for HD was identified in 1993 after finding its location on chromosome 4 in 1983. A gene called Huntingtin was discovered which contained a so called trinucleotide repeat.  This is an area of the DNA where the same three DNA bases are repeated multiple times.  In the case of HD, the repeat is a (CAG) triplet which normally is present 11-31 times, but when passed to an individual who will develop HD is expanded to over 36 (CAG) repeats.  The repeat is known to be unstable and can expand further when it is passed on from an male affected with HD.

In many families, the diagnosis of HD is made in a parent when their children are of reproductive age.  This places a tremendous amount of stress in at-risk children to make decision regarding their own families.  At-risk individuals can get tested to know if they carry the HD gene, however many individuals do not wish to be made aware of the information at this point in their life.  Reproductive choices for these families include testing of an ongoing pregnancy by chorionic villous sampling or amniocentesis.  Unfortunately, if the pregnancy is affected with HD, the status of the at-risk parent is then known.  Adoption, or use of gamete donors is also possible but most people would prefer to use their own genes in making children.  Preimplantation Genetic Diagnosis (PGD) is another alternative form of prenatal diagnosis which is performed on embryos created from the parents gametes by IVF by testing the embryos prior to implantation in the uterus.  Using this technology, only embryos known to be free of the HD gene would be used to attempt pregnancy.

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Illustration of the CAG repeat in a normal and HD gene.
In 1996, our group described a strategy for testing couples at risk for serious late-onset dominant genetic disorders such as HD (Schulman et al. Preimplantation Genetic testing for Huntington Disease and Certain Other Dominantly Inherited Disorders, 1996, Clinical Genetics 49;57-8)  Couples would undergo IVF with PGD and molecular testing for the HD mutation without disclosure of the genetic status of the at-risk partner.  Couples receive no information regarding the outcome of the IVF cycle or the genetic testing and are told only that HD-free embryos would be transferred to the uterus.  This would occur if the at-risk individual is not affected (which we would find out ahead of time) or after testing of embryos reveals that it does not carry an HD expansion. The couple is not informed of their particular circumstance and the physician, after consultation with the couple, acts as their medical agent and makes decisions regarding the embryo transfer.  This approach allows for exclusion of the HD gene from the family line in future generations.  In 2002, we (Stern et al. Non-disclosing preimplantation Genetic Diagnosis for Huntington Disease 2002, Prenatal Diagnosis 22:503-507) published our experience with this non-disclosing testing for couples at-risk for HD. The article can be read by clicking here.

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Folk singer and political activist Woody Guthrie was a well know person who died from Huntington disease.  The condition has also been called Woody Guthrie disease.  After his death in 1967, his wife Marjorie established the Huntington Disease Society of America.
Since the 1990s, the Diagnostics Laboratory of the Genetics and IVF Institute (GIVF) has assisted many couples at-risk for HD by using cutting edge, advancing tests detecting HD in early embryos, with most of the improvements coming the last few years.   Initially, the test was comprised of a single marker PCR test using highly radioactive gel electrophoresis requiring 2 or more days of continuous bench work to detect the presence or absence of expanded HD alleles in each embryo.  Today, the assay has evolved to include several linked markers plus detection of the expanded allele using fluorescent PCR and capillary electrophoresis, with a 24-hour time-to-results protocol.  Not only has the laboratory vastly improved the performance and accuracy of the HD assay, but we recently have coupled the mutational component of the assay to a 24-chromosome microarray screen, run in parallel from the same starting material, such that HD unaffected embryos are selected that are also free of chromosomal aneuploidy.  Retooling the GIVF HD PCR assay to incorporate the microarray component in a 24-hour protocol for the first time allows for a day 5 embryo biopsy and a day 6 fresh transfer.   The sensitivity of PCR combined with the comprehensive nature of microarray screening advances the GIVF HD assay to a level of sophistication that has not been reported by any other testing laboratories nationwide.

 

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