Lesch-nyhan syndrome

Inheritance

How is Lesch-Nyhan Syndrome inherited?

Lesch-Nyhan syndrome is inherited in an X-linked recessive pattern. The “X” chromosome is a sex chromosome. The “Y” chromosome is the other sex chromosome. Males usually have one X chromosome and one Y chromosome. Females usually have two X chromosomes. The HPRT1 gene for Lesch-Nyhan Syndrome is located on the X chromosome. Because males only have one X chromosome, and therefore one HPRT1 gene, if this gene has a change (mutation) causing the gene to not work correctly, the male is affected with Lesch-Nyhan syndrome. Because females have two X chromosomes, if one of their HPRT1 genes has a change (mutation) and the other does not have a change, they are known as “carriers.” Most female carriers have no symptoms of Lesch-Nyhan syndrome. There have been a few very rare reports of females who have severe symptoms of Lesch-Nyhan syndrome.

A change in the HPRT1 gene can be inherited from a "carrier" mother or it can occur for the first time in the child (de novo mutation). When a male child has a HPRT1 gene mutation, it is predicted that about 2/3 (66%) of the time the mother is found to be a carrier and 1/3 (33%) of the time the HPRT1 gene mutation happens brand new in the child and is not inherited from the mother (de novo). There is some suspicion for a higher chance than 2/3 (66%) for the mother to be carrier in Lesch-Nyhan syndrome.

The chance of having another child with Lesch-Nyhan syndrome will depend on whether the mother is a carrier or not. If the mother is not a carrier, the chance of having another child with Lesch-Nyhan syndrome is small although not impossible due to the chance that more than one of her eggs may contain the gene change (germline mosaicism).

If a female is a carrier of Lesch-Nyhan syndrome (LNS), there is 50% chance that each male child will have Lesch-Nyhan syndrome, and a 50% chance of a male child NOT having Lesch-Nyhan syndrome. For a female child of a carrier there is a 50% chance that she will be a carrier of Lesch-Nyhan syndrome. Overall, in each pregnancy there is a 25% chance to have a boy with LNS, 25% chance to have a boy who does not have LNS, 25% chance to have a girl who is a carrier, 25% chance to have a girl who is not a carrier.

Genetic testing of the HPRT1 gene is available.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

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If a male child has a HPRT1 gene mutation, what percentage of the time is this inherited from his mother?

Can female carriers of Lesch-Nyhan Syndrome be severely affected like males?

What percentage of males with Lesch-Nyhan Syndrome are found to have a HPRT1 gene mutation?

Do all people with a HPRT1 gene mutation have Lesch-Nyhan Syndrome?

What does it mean to have inherited a “variant” in the gene for Lesch-Nyhan Syndrome?

If a woman is a carrier of Lesch-Nyhan Syndrome and has a known HPRT1 gene mutation, what is the chance that her children will be affected?

If a male is affected with Lesch-Nyhan Syndrome, what is the chance that his children will be affected?

If a male child has a HPRT1 gene mutation, what percentage of the time is this inherited from his mother?

A change in the HPRT1 gene causing Lesch-Nyhan syndrome can be inherited from a "carrier" mother or it can occur for the first time in the child (de novo mutation). When a boy has a HPRT1 gene mutation, it is predicted that about 2/3 (66%) of the time the mother will be a carrier, and 1/3 (33%) of the time the HPRT1 gene mutation happens for the first time in the child and is not inherited from the mother (de novo). Some studies show that there may be a higher chance than 2/3 (66%) for the mother to be carrier in Lesch-Nyhan syndrome.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

References
  • Francke U, Winter RM, Lin D, Bakay B, Seegmiller JE, Nyhan WL. Use of carrier detection tests to estimate male to female ratio of mutation rates in Lesch-Nyhan disease. In: Hook EB, Porter IH, eds. Population Aspects of Human Mutation. New York, NY: Academic Press. 1981:117-27.
  • http://www.ncbi.nlm.nih.gov/books/NBK1149/
Can female carriers of Lesch-Nyhan Syndrome be severely affected like males?

Female carriers of Lesch-Nyhan syndrome generally do not have symptoms. However, they may have increased uric acid in their urine that can lead to symptoms of gout and/or kidney stones when they are older.

Lesch-Nyhan syndrome (LNS) almost always occurs in boys. It is inherited in an X-linked recessive manner. The HPRT1 gene is located on the X chromosome. Because boys only have one X chromosome (the other is the Y chromosome), if their HPRT1 gene has a change and is not working correctly, they have (LNS). Because females usually have two X chromosomes, and therefore two copies of the HPRT1 gene, if one copy has a change and is not working correctly, their other copy can usually compensate and make enough of the gene product for there to not be symptoms.

As of January 11, 2016, there have been less than ten females reported to be actually affected with Lesch-Nyhan syndrome. These females all had something called “skewed inactivation of the X-chromosome.” A female has two X chromosomes in every cell. One X chromosome (and therefore one HPRT1 gene) is randomly inactivated in every cell. In these affected females, one of their X chromosomes in every cell has a HPRT1 gene mutation. In skewed inactivation of the X-chromosome, more cells have the “normal” X chromosomes inactivated, and more cells have the X chromosomes with the HPRT1 gene mutation activated. Because these females have more X chromosomes with the HPRT1 gene mutation that are active, they are actually affected with Lesch-Nyhan syndrome. Again, this is very rare.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

References
  • De Gregorio L, Nyhan WL, Serafin E, Chamoles NA. An unexpected affected female patient in a classical Lesch-Nyhan family. Mol Genet Metab. 2000;69:263–8. PMID: 10767182.
  • Jinnah HA, De Gregorio L, Harris JC, Nyhan WL, O'Neill JP. The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases. Mutat Res. 2000;463:309–26. PMID: 11018746.
  • http://www.ncbi.nlm.nih.gov/books/NBK1149/
What percentage of males with Lesch-Nyhan Syndrome are found to have a HPRT1 gene mutation?

Greater than 90-95% of males with Lesch-Nyhan syndrome are found to have a change (mutation) in the HPRT1 gene located on the X chromosome. A person can still have Lesch-Nyhan syndrome even if a gene change is not found on genetic testing.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

Do all people with a HPRT1 gene mutation have Lesch-Nyhan Syndrome?

Lesch-Nyhan syndrome is caused when there is a change in the HPRT1 gene on the X chromosome. The protein produced from the HPRT1 gene is an enzyme called hypoxanthine-guanine phosphoribosyltransferase (HPRT). Some changes (mutations) in the HPRT1 gene, cause the HPRT enzyme to not work properly, work at very low levels, or not work at all. Typically all people with a “severe” HPRT1 gene mutation have Lesch-Nyhan syndrome.

Sometimes there are mutations in HPRT1 that allow more of the enzyme to be made and work better, although still not to normal levels. These mutations can cause HPRT-related hyperuricemia and HPRT-related gout. Both of these conditions are caused by partial HPRT enzyme deficiency. The specific HPRT1 gene mutations are less severe and people have lower than normal levels of the needed protein (HPRT enzyme), but not as low as people with Lesch-Nyhan syndrome.

HPRT-related hyperuricemia may cause pain and swelling in joints (gout), crystals in the urine (this can be seen on urine test), and kidney stones. Sometimes kidney disease may occur. Males affected with this condition usually show symptoms in childhood. People with this do not show the neurological or behavioral issues seen in Lesch-Nyhan syndrome.

HPRT-related gout (also known as Kelley-Seegmiller syndrome) explains less than 2% of adult males with gout.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

References
What does it mean to have inherited a “variant” in the gene for Lesch-Nyhan Syndrome?

When a person inherits a “variant” in the HPRT1 gene for Lesch-Nyhan syndrome, it means they have a change in the gene, but it is currently not known if this change actually causes Lesch-Nyhan syndrome. These are often called variants of uncertain significance (VUS). Sometimes the interpretation of variants change as more people are tested and more data is received by the laboratory. Your genetics doctor can also help to decide whether or not they think the variant of uncertain significance is significant for you or not.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

If a woman is a carrier of Lesch-Nyhan Syndrome and has a known HPRT1 gene mutation, what is the chance that her children will be affected?

Lesch-Nyhan syndrome (LNS) is inherited in an X-linked recessive pattern. The “X” chromosome is a sex chromosome. The “Y” chromosome is the other sex chromosome. Males usually have one X chromosome and one Y chromosome. Females usually have two X chromosomes. The HPRT1 gene for Lesch-Nyhan Syndrome is located on the X chromosome. When a female has a change (mutation) in one of her two HPRT1 genes, she is called a carrier for LNS.

If a woman is a carrier of Lesch-Nyhan syndrome (LNS), there is 50% chance that each male child will have LNS, and a 50% chance of a male child NOT having LNS. For a female child of a carrier, there is a 50% chance that she will be a carrier of Lesch-Nyhan syndrome.

Overall, in each pregnancy there is a 25% chance to have a boy with LNS, 25% chance to have a boy who does not have LNS, 25% chance to have a girl who is a carrier, 25% chance to have a girl who is not a carrier.

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

If a male is affected with Lesch-Nyhan Syndrome, what is the chance that his children will be affected?

Most males with Lesch-Nyhan syndrome cannot have children. If a male is affected with Lesch-Nyhan syndrome, his ability to have children will depend on the severity of his condition.

Lesch-Nyhan syndrome is inherited in an X-linked recessive pattern. The “X” chromosome is a sex chromosome. The “Y” chromosome is the other sex chromosome. Males usually have one X chromosome and one Y chromosome. Females usually have two X chromosomes. The HPRT1 gene for Lesch-Nyhan Syndrome is located on the X chromosome.

If a male is mildly affected and decides to have children, there is a 0% chance that his male children will be affected (because males pass on their Y sex chromosome to their male children), and a 100% chance that his female children will be carriers (because males pass on their X chromosome to their female children).

To learn more about the genetics of Lesch Nyhan syndrome, speak with a geneticist or genetic counselor. You can find a genetics clinic near you by searching the American College of Medical Genetics. To find a genetic counselor search on the National Society of Genetic Counselors under "Find a Counselor".

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