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Gordon Holmes syndrome

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Description

Gordon Holmes syndrome is a rare condition characterized by reproductive and neurological problems. One of the key features of the condition is reduced production of hormones that direct sexual development (hypogonadotropic hypogonadism). Many affected individuals have a delay in development of the typical signs of puberty, such as the growth of facial hair and deepening of the voice in males, and the start of monthly periods (menstruation) and breast development in females. Some never undergo puberty. While some people with Gordon Holmes syndrome seem to have normal puberty, they develop other problems with the reproductive system later in life.

In early adulthood, individuals with Gordon Holmes syndrome develop neurological problems, usually beginning with speech difficulties (dysarthria). As the condition worsens, affected individuals have problems with balance and coordination (cerebellar ataxia), often leading to difficulties with activities of daily living and a need for wheelchair assistance. Some affected individuals also develop memory problems and a decline in intellectual function (dementia).

Frequency

Gordon Holmes syndrome is a rare condition. Its prevalence is unknown.

Causes

Gordon Holmes syndrome can be caused by mutations in the RNF216 or PNPLA6 gene. Some people with the condition do not have mutations in these genes, indicating that mutations in other genes are likely involved in the condition.

The protein produced from the RNF216 gene is involved in a cellular process, called ubiquitination, by which unneeded proteins are tagged with a molecule called ubiquitin. The ubiquitin tag signals for the protein to be broken down. One of several proteins tagged by RNF216 is a protein found in nerve cells (neurons) that plays a role in a process called synaptic plasticity. Synaptic plasticity is the ability of the connections between neurons (synapses) to change and adapt over time in response to experience. This process is critical for learning and memory.

RNF216 gene mutations impair the ability of the RNF216 protein to tag unneeded proteins to be broken down. Impaired breakdown of the neuronal protein disrupts normal synaptic connections and plasticity, which likely contributes to dementia in people with Gordon Holmes syndrome. It is unclear how a lack of RNF216 protein function causes hypogonadotropic hypogonadism or cerebellar ataxia.

The PNPLA6 gene provides instructions for making a protein called neuropathy target esterase (NTE), which helps regulate the amount of certain fats (lipids) that make up the outer membrane surrounding cells. The correct levels of these lipids are critical to the stability and function of cell membranes. NTE is found most abundantly in the nervous system and is thought to help maintain the stability of membranes surrounding neurons. NTE is also thought to play a role in the release of hormones from the pituitary gland, a process that requires particular changes in the cell membrane. The pituitary gland is located at the base of the brain and produces several hormones, including those that help direct sexual development and growth.

PNPLA6 gene mutations are thought to impair NTE's function. Researchers speculate that such an impairment alters the balance of lipids in the cell membrane. This imbalance may damage neurons in the brain, causing cerebellar ataxia, and impair the pituitary gland's release of hormones involved in sexual development, leading to hypogonadotropic hypogonadism. Individuals with Gordon Holmes syndrome caused by PNPLA6 gene mutations do not appear to develop dementia.

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • cerebellar ataxia and hypogonadotropic hypogonadism
  • deficiency of luteinizing hormone-releasing hormone with ataxia
  • LHRH deficiency and ataxia

Additional Information & Resources

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Alqwaifly M, Bohlega S. Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation. Neurol Int. 2016 Jun 15;8(2):6444. doi: 10.4081/ni.2016.6444. eCollection 2016 Jun 15. Citation on PubMed or Free article on PubMed Central
  • Husain N, Yuan Q, Yen YC, Pletnikova O, Sally DQ, Worley P, Bichler Z, Shawn Je H. TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. Aging Cell. 2017 Apr;16(2):281-292. doi: 10.1111/acel.12551. Epub 2016 Dec 20. Citation on PubMed or Free article on PubMed Central
  • Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV, O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med. 2013 May 23;368(21):1992-2003. doi: 10.1056/NEJMoa1215993. Epub 2013 May 8. Citation on PubMed or Free article on PubMed Central
  • Topaloglu AK, Lomniczi A, Kretzschmar D, Dissen GA, Kotan LD, McArdle CA, Koc AF, Hamel BC, Guclu M, Papatya ED, Eren E, Mengen E, Gurbuz F, Cook M, Castellano JM, Kekil MB, Mungan NO, Yuksel B, Ojeda SR. Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. J Clin Endocrinol Metab. 2014 Oct;99(10):E2067-75. doi: 10.1210/jc.2014-1836. Epub 2014 Jul 17. Citation on PubMed
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