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Hereditary hyperekplexia

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Description

Hereditary hyperekplexia is a condition in which affected infants have increased muscle tone (hypertonia) and an exaggerated startle reaction to unexpected stimuli, especially loud noises. Following the startle reaction, infants experience a brief period in which they are very rigid and unable to move. During these rigid periods, some infants stop breathing, which, if prolonged, can be fatal. Infants with hereditary hyperekplexia have hypertonia at all times, except when they are sleeping.

Other signs and symptoms of hereditary hyperekplexia can include muscle twitches when falling asleep (hypnagogic myoclonus) and movements of the arms or legs while asleep. Some infants, when tapped on the nose, extend their head forward and have spasms of the limb and neck muscles. Rarely, infants with hereditary hyperekplexia experience recurrent seizures (epilepsy).

The signs and symptoms of hereditary hyperekplexia typically fade by age 1. However, older individuals with hereditary hyperekplexia may still startle easily and have periods of rigidity, which can cause them to fall down. They may also continue to have hypnagogic myoclonus or movements during sleep. As they get older, individuals with this condition may have a low tolerance for crowded places and loud noises. People with hereditary hyperekplexia who have epilepsy have the seizure disorder throughout their lives.

Hereditary hyperekplexia may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year.

Frequency

The exact prevalence of hereditary hyperekplexia is unknown. This condition has been identified in more than 150 individuals worldwide.

Causes

Mutations in multiple genes have been found to cause hereditary hyperekplexia. Most of these genes provide instructions for producing proteins that are found in nerve cells (neurons). These proteins are involved in the response of neurons to a molecule called glycine. This molecule is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the nervous system. Gene mutations that cause hereditary hyperekplexia disrupt normal glycine signaling in neurons in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Abnormal signaling in neurons in the brain and neurons that send signals to muscles throughout the body result in abnormal muscle movements, exaggerated startle reaction, and other symptoms characteristic of this disorder.

Most cases of hereditary hyperekplexia are caused by mutations in the GLRA1 gene. The GLRA1 gene provides instructions for making one part, the alpha (α)1 subunit, of the glycine receptor protein. When this protein attaches (binds) to glycine, signaling between cells is stopped. GLRA1 gene mutations lead to the production of a receptor that cannot properly respond to glycine. As a result, glycine is less able to regulate signaling in the spinal cord and brainstem leading to increased cells signaling and the signs and symptoms of hereditary hyperekplexia. Mutations in other genes account for the remaining cases of hereditary hyperekplexia.

Inheritance

Hereditary hyperekplexia has different inheritance patterns.

This condition can be inherited in an autosomal dominant pattern, which means a mutation in one copy of any of the associated genes in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

Hereditary hyperekplexia can also be inherited in an autosomal recessive pattern, which means one of the associated genes has mutations in both copies of the gene in each cell. The parents of an individual with an autosomal recessive disorder typically each carry one copy of the altered gene, but do not show signs and symptoms of the disorder.

Other Names for This Condition

  • congenital stiff-man syndrome
  • congenital stiff-person syndrome
  • familial hyperekplexia
  • hyperekplexia
  • startle syndrome
  • STHE
  • stiff-baby syndrome

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

  • Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol. 2006 Jun;5(6):513-24. Review. Citation on PubMed
  • Bode A, Wood SE, Mullins JG, Keramidas A, Cushion TD, Thomas RH, Pickrell WO, Drew CJ, Masri A, Jones EA, Vassallo G, Born AP, Alehan F, Aharoni S, Bannasch G, Bartsch M, Kara B, Krause A, Karam EG, Matta S, Jain V, Mandel H, Freilinger M, Graham GE, Hobson E, Chatfield S, Vincent-Delorme C, Rahme JE, Afawi Z, Berkovic SF, Howell OW, Vanbellinghen JF, Rees MI, Chung SK, Lynch JW. New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms. J Biol Chem. 2013 Nov 22;288(47):33745-59. doi: 10.1074/jbc.M113.509240. Epub 2013 Oct 9. Citation on PubMed or Free article on PubMed Central
  • Harvey RJ, Topf M, Harvey K, Rees MI. The genetics of hyperekplexia: more than startle! Trends Genet. 2008 Sep;24(9):439-47. doi: 10.1016/j.tig.2008.06.005. Epub 2008 Aug 15. Review. Citation on PubMed
  • Masri A, Chung SK, Rees MI. Hyperekplexia: Report on phenotype and genotype of 16 Jordanian patients. Brain Dev. 2017 Apr;39(4):306-311. doi: 10.1016/j.braindev.2016.10.010. Epub 2016 Nov 11. Citation on PubMed
  • Rees MI, Harvey K, Pearce BR, Chung SK, Duguid IC, Thomas P, Beatty S, Graham GE, Armstrong L, Shiang R, Abbott KJ, Zuberi SM, Stephenson JB, Owen MJ, Tijssen MA, van den Maagdenberg AM, Smart TG, Supplisson S, Harvey RJ. Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease. Nat Genet. 2006 Jul;38(7):801-6. Epub 2006 Jun 4. Citation on PubMed or Free article on PubMed Central
  • Villmann C, Oertel J, Melzer N, Becker CM. Recessive hyperekplexia mutations of the glycine receptor alpha1 subunit affect cell surface integration and stability. J Neurochem. 2009 Nov;111(3):837-47. doi: 10.1111/j.1471-4159.2009.06372.x. Epub 2009 Sep 1. Citation on PubMed
  • Zhang Y, Bode A, Nguyen B, Keramidas A, Lynch JW. Investigating the Mechanism by Which Gain-of-function Mutations to the α1 Glycine Receptor Cause Hyperekplexia. J Biol Chem. 2016 Jul 15;291(29):15332-41. doi: 10.1074/jbc.M116.728592. Epub 2016 May 18. Citation on PubMed or Free article on PubMed Central
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