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Hyperekplexia 3(HKPX3)

MedGen UID:
766202
Concept ID:
C3553288
Disease or Syndrome
Synonyms: HKPX3; HYPEREKPLEXIA 3, AUTOSOMAL DOMINANT; HYPEREKPLEXIA 3, AUTOSOMAL RECESSIVE; SLC6A5-Related Hyperekplexia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): SLC6A5 (11p15.1)
OMIM®: 614618

Definition

Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur. [from GTR]

Additional descriptions

From GeneReviews
Hereditary hyperekplexia (HPX) is characterized by generalized stiffness immediately after birth that normalizes during the first years of life; excessive startle reflex (eye blinking and a flexor spasm of the trunk) to unexpected (particularly auditory) stimuli; and a short period of generalized stiffness following the startle response during which voluntary movements are impossible. Exaggerated head-retraction reflex (HRR) consisting of extension of the head followed by violent flexor spasms of limbs and neck muscles elicited by tapping the tip of the nose is observed in most children. Other findings include periodic limb movements in sleep (PLMS) and hypnagogic (occurring when falling asleep) myoclonus. Sudden infant death (SIDS) has been reported. Intellect is usually normal; mild intellectual disability may occur.  https://www.ncbi.nlm.nih.gov/books/NBK1260
From GHR
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. This condition may explain some cases of sudden infant death syndrome (SIDS), which is a major cause of unexplained death in babies younger than 1 year. 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. Some individuals with this condition have a low tolerance for crowded places and loud noises. Some affected people have persistent limb movements during sleep. Affected individuals who have epilepsy have the disorder throughout their lives.  https://ghr.nlm.nih.gov/condition/hereditary-hyperekplexia

Clinical features

Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Exaggerated startle response
MedGen UID:
329357
Concept ID:
C1740801
Finding
An exaggerated startle reaction in response to a sudden unexpected visual or acoustic stimulus, or a quick movement near the face.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
A transient absence of spontaneous respiration.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Muscle stiffness
MedGen UID:
113151
Concept ID:
C0221170
Sign or Symptom
A condition in which muscles cannot be moved quickly without accompanying pain or spasm.

Recent clinical studies

Etiology

Masri A, Chung SK, Rees MI
Brain Dev 2017 Apr;39(4):306-311. Epub 2016 Nov 11 doi: 10.1016/j.braindev.2016.10.010. PMID: 27843043
Thomas RH, Drew CJ, Wood SE, Hammond CL, Chung SK, Rees MI
J Neurol Neurosurg Psychiatry 2015 Mar;86(3):341-3. Epub 2014 Jun 26 doi: 10.1136/jnnp-2014-307903. PMID: 24970905
Hmami F, Wood SE, Chaouki S, Oulmaati A, Hida M, Rees MI, Chung SK, Bouharrou A
Epileptic Disord 2014 Sep;16(3):354-7. doi: 10.1684/epd.2014.0663. PMID: 25036534
Chan KK, Cherk SW, Lee HH, Poon WT, Chan AY
J Child Neurol 2014 Jan;29(1):111-3. Epub 2012 Nov 8 doi: 10.1177/0883073812465338. PMID: 23143726
Lee CG, Kwon MJ, Yu HJ, Nam SH, Lee J, Ki CS, Lee M
J Child Neurol 2013 Jan;28(1):90-4. Epub 2012 Apr 24 doi: 10.1177/0883073812441058. PMID: 22532536

Diagnosis

Masri A, Chung SK, Rees MI
Brain Dev 2017 Apr;39(4):306-311. Epub 2016 Nov 11 doi: 10.1016/j.braindev.2016.10.010. PMID: 27843043
Schaefer N, Kluck CJ, Price KL, Meiselbach H, Vornberger N, Schwarzinger S, Hartmann S, Langlhofer G, Schulz S, Schlegel N, Brockmann K, Lynch B, Becker CM, Lummis SC, Villmann C
J Neurosci 2015 Jan 7;35(1):422-37. doi: 10.1523/JNEUROSCI.1509-14.2015. PMID: 25568133Free PMC Article
Hmami F, Wood SE, Chaouki S, Oulmaati A, Hida M, Rees MI, Chung SK, Bouharrou A
Epileptic Disord 2014 Sep;16(3):354-7. doi: 10.1684/epd.2014.0663. PMID: 25036534
Xiong W, Chen SR, He L, Cheng K, Zhao YL, Chen H, Li DP, Homanics GE, Peever J, Rice KC, Wu LG, Pan HL, Zhang L
Nat Neurosci 2014 Feb;17(2):232-9. Epub 2014 Jan 5 doi: 10.1038/nn.3615. PMID: 24390226Free PMC Article
Chan KK, Cherk SW, Lee HH, Poon WT, Chan AY
J Child Neurol 2014 Jan;29(1):111-3. Epub 2012 Nov 8 doi: 10.1177/0883073812465338. PMID: 23143726

Therapy

Giménez C, Pérez-Siles G, Martínez-Villarreal J, Arribas-González E, Jiménez E, Núñez E, de Juan-Sanz J, Fernández-Sánchez E, García-Tardón N, Ibáñez I, Romanelli V, Nevado J, James VM, Topf M, Chung SK, Thomas RH, Desviat LR, Aragón C, Zafra F, Rees MI, Lapunzina P, Harvey RJ, López-Corcuera B
J Biol Chem 2012 Aug 17;287(34):28986-9002. Epub 2012 Jun 29 doi: 10.1074/jbc.M111.319244. PMID: 22753417Free PMC Article
Mineyko A, Whiting S, Graham GE
Can J Neurol Sci 2011 May;38(3):411-6. PMID: 21515498
Schlapbach LJ, Sozzo A, Ramelli G, Bianchetti MG
J Inherit Metab Dis 2006 Feb;29(1):238-9. doi: 10.1007/s10545-006-0082-9. PMID: 16601904
Shahar E, Raviv R
Pediatr Neurol 2004 Jul;31(1):30-4. doi: 10.1016/j.pediatrneurol.2003.12.007. PMID: 15246489
Stewart WA, Wood EP, Gordon KE, Camfield PR
J Child Neurol 2002 Feb;17(2):154-6. doi: 10.1177/088307380201700216. PMID: 11952081

Prognosis

Masri A, Chung SK, Rees MI
Brain Dev 2017 Apr;39(4):306-311. Epub 2016 Nov 11 doi: 10.1016/j.braindev.2016.10.010. PMID: 27843043
Thomas RH, Drew CJ, Wood SE, Hammond CL, Chung SK, Rees MI
J Neurol Neurosurg Psychiatry 2015 Mar;86(3):341-3. Epub 2014 Jun 26 doi: 10.1136/jnnp-2014-307903. PMID: 24970905
Mineyko A, Whiting S, Graham GE
Can J Neurol Sci 2011 May;38(3):411-6. PMID: 21515498
Shahar E, Raviv R
Pediatr Neurol 2004 Jul;31(1):30-4. doi: 10.1016/j.pediatrneurol.2003.12.007. PMID: 15246489
Stewart WA, Wood EP, Gordon KE, Camfield PR
J Child Neurol 2002 Feb;17(2):154-6. doi: 10.1177/088307380201700216. PMID: 11952081

Clinical prediction guides

Winczewska-Wiktor A, Badura-Stronka M, Monies-Nowicka A, Nowicki MM, Steinborn B, Latos-Bieleńska A, Monies D
BMC Neurol 2016 Mar 12;16:35. doi: 10.1186/s12883-016-0554-y. PMID: 26968164Free PMC Article
Thomas RH, Drew CJ, Wood SE, Hammond CL, Chung SK, Rees MI
J Neurol Neurosurg Psychiatry 2015 Mar;86(3):341-3. Epub 2014 Jun 26 doi: 10.1136/jnnp-2014-307903. PMID: 24970905
Villmann C, Oertel J, Melzer N, Becker CM
J Neurochem 2009 Nov;111(3):837-47. Epub 2009 Sep 1 doi: 10.1111/j.1471-4159.2009.06372.x. PMID: 19732286
Kang HC, Jeong You S, Jae Chey M, Sam Baik J, Kim JW, Ki CS
Mov Disord 2008 Mar 15;23(4):610-3. doi: 10.1002/mds.21909. PMID: 18175347
Gilbert SL, Ozdag F, Ulas UH, Dobyns WB, Lahn BT
Mol Diagn 2004;8(3):151-5. PMID: 15771552

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