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Hyperekplexia 4(HKPX4)

MedGen UID:
1642659
Concept ID:
C4693933
Disease or Syndrome
Synonyms: HKPX4; HYPEREKPLEXIA 4
 
Gene (location): ATAD1 (10q23.31)
 
Monarch Initiative: MONDO:0044330
OMIM®: 618011

Definition

Hyperekplexia-4 is an autosomal recessive severe neurologic disorder apparent at birth. Affected infants have extreme hypertonia and appear stiff and rigid. They have little if any development, poor or absent visual contact, and no spontaneous movement, consistent with an encephalopathy. Some patients have early-onset refractory seizures, and many have inguinal or umbilical hernia. Most patients die in the first months of life due to respiratory failure or other complications (summary by Piard et al., 2018). For a general description and a discussion of genetic heterogeneity of hyperekplexia, see HKPX1 (149400). [from OMIM]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Thumbs, congenital Clasped
MedGen UID:
98140
Concept ID:
C0431886
Congenital Abnormality
In the resting position, the tip of the thumb is on, or near, the palm, close to the base of the fourth or fifth finger.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Infantile spasms
MedGen UID:
854616
Concept ID:
C3887898
Disease or Syndrome
Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy).
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
Protrusion of the contents of the abdominal cavity through the inguinal canal.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
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.
Distal arthrogryposis
MedGen UID:
120512
Concept ID:
C0265213
Disease or Syndrome
An inherited primary limb malformation disorder characterized by congenital contractures of two or more different body areas and without primary neurologic and/or muscle disease that affects limb function.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Camptodactyly
MedGen UID:
195780
Concept ID:
C0685409
Congenital Abnormality
The distal interphalangeal joint and/or the proximal interphalangeal joint of the fingers or toes cannot be extended to 180 degrees by either active or passive extension.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Abnormal circulating acylcarnitine concentration
MedGen UID:
1684872
Concept ID:
C5139063
Finding
Any deviation from the normal concentration in the blood circulation of an acylcarnitine, which is produced by reversible esterification of the 3-hydroxyl group of carnitine.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).

Professional guidelines

PubMed

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
Cross JH
Semin Fetal Neonatal Med 2013 Aug;18(4):192-5. Epub 2013 Apr 30 doi: 10.1016/j.siny.2013.04.003. PMID: 23642846
Chokroverty S, Walczak T, Hening W
Electroencephalogr Clin Neurophysiol 1992 Aug;85(4):236-42. doi: 10.1016/0168-5597(92)90111-n. PMID: 1380910

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
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
Lanska DJ
Handb Clin Neurol 2010;95:501-46. doi: 10.1016/S0072-9752(08)02133-7. PMID: 19892136
Jacome DE
Epilepsia 1999 Apr;40(4):467-73. doi: 10.1111/j.1528-1157.1999.tb00742.x. PMID: 10219273
Fejerman N
Indian J Pediatr 1997 Sep-Oct;64(5):583-602. doi: 10.1007/BF02726110. PMID: 10771893

Diagnosis

Ben Mohamed D, Zouari R, Ketata J, Nabli F, Blel S, Ben Sassi S
Seizure 2023 Jan;104:12-14. Epub 2022 Nov 22 doi: 10.1016/j.seizure.2022.11.010. PMID: 36446232Free PMC Article
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
Cross JH
Semin Fetal Neonatal Med 2013 Aug;18(4):192-5. Epub 2013 Apr 30 doi: 10.1016/j.siny.2013.04.003. PMID: 23642846
Fejerman N
Indian J Pediatr 1997 Sep-Oct;64(5):583-602. doi: 10.1007/BF02726110. PMID: 10771893
Brown P
Curr Opin Neurol 1996 Aug;9(4):314-6. doi: 10.1097/00019052-199608000-00013. PMID: 8858191

Therapy

Seale J, Murphy J, Mantle A, Chan B
Adv Neonatal Care 2020 Feb;20(1):33-37. doi: 10.1097/ANC.0000000000000674. PMID: 31567315
Damásio J, Leite MI, Coutinho E, Waters P, Woodhall M, Santos MA, Carrilho I, Vincent A
JAMA Neurol 2013 Apr;70(4):498-501. doi: 10.1001/jamaneurol.2013.1872. PMID: 23380884
de la Roche J, Leuwer M, Krampfl K, Haeseler G, Dengler R, Buchholz V, Ahrens J
BMC Neurol 2012 Sep 24;12:104. doi: 10.1186/1471-2377-12-104. PMID: 23006332Free PMC Article
Tijssen MA, Schoemaker HC, Edelbroek PJ, Roos RA, Cohen AF, van Dijk JG
J Neurol Sci 1997 Jul;149(1):63-7. doi: 10.1016/s0022-510x(97)05378-1. PMID: 9168167
Hayashi T, Tachibana H, Kajii T
Am J Med Genet 1991 Aug 1;40(2):138-43. doi: 10.1002/ajmg.1320400203. PMID: 1897565

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
Mine J, Taketani T, Yoshida K, Yokochi F, Kobayashi J, Maruyama K, Nanishi E, Ono M, Yokoyama A, Arai H, Tamaura S, Suzuki Y, Otsubo S, Hayashi T, Kimura M, Kishi K, Yamaguchi S
Dev Med Child Neurol 2015 Apr;57(4):372-7. Epub 2014 Oct 30 doi: 10.1111/dmcn.12617. PMID: 25356525
Cross JH
Semin Fetal Neonatal Med 2013 Aug;18(4):192-5. Epub 2013 Apr 30 doi: 10.1016/j.siny.2013.04.003. PMID: 23642846
Jacome DE
Epilepsia 1999 Apr;40(4):467-73. doi: 10.1111/j.1528-1157.1999.tb00742.x. PMID: 10219273
Fejerman N
Indian J Pediatr 1997 Sep-Oct;64(5):583-602. doi: 10.1007/BF02726110. PMID: 10771893

Clinical prediction guides

Ben Mohamed D, Zouari R, Ketata J, Nabli F, Blel S, Ben Sassi S
Seizure 2023 Jan;104:12-14. Epub 2022 Nov 22 doi: 10.1016/j.seizure.2022.11.010. PMID: 36446232Free PMC Article
Aboheimed GI, AlRasheed MM, Almudimeegh S, Peña-Guerra KA, Cardona-Londoño KJ, Salih MA, Seidahmed MZ, Al-Mohanna F, Colak D, Harvey RJ, Harvey K, Arold ST, Kaya N, Ruiz AJ
J Biol Chem 2022 Jul;298(7):102018. Epub 2022 May 6 doi: 10.1016/j.jbc.2022.102018. PMID: 35526563Free PMC Article
Langlhofer G, Schaefer N, Maric HM, Keramidas A, Zhang Y, Baumann P, Blum R, Breitinger U, Strømgaard K, Schlosser A, Kessels MM, Koch D, Qualmann B, Breitinger HG, Lynch JW, Villmann C
J Neurosci 2020 Jun 17;40(25):4954-4969. Epub 2020 Apr 30 doi: 10.1523/JNEUROSCI.2490-19.2020. PMID: 32354853Free PMC Article
Simard C, Vogrig A, Joubert B, Muñiz-Castrillo S, Picard G, Rogemond V, Ducray F, Berzero G, Psimaras D, Antoine JC, Desestret V, Honnorat J
Neurol Neuroimmunol Neuroinflamm 2020 May;7(3) Epub 2020 Mar 13 doi: 10.1212/NXI.0000000000000699. PMID: 32170042Free PMC Article
Tijssen MA, Schoemaker HC, Edelbroek PJ, Roos RA, Cohen AF, van Dijk JG
J Neurol Sci 1997 Jul;149(1):63-7. doi: 10.1016/s0022-510x(97)05378-1. PMID: 9168167

Recent systematic reviews

Simard C, Vogrig A, Joubert B, Muñiz-Castrillo S, Picard G, Rogemond V, Ducray F, Berzero G, Psimaras D, Antoine JC, Desestret V, Honnorat J
Neurol Neuroimmunol Neuroinflamm 2020 May;7(3) Epub 2020 Mar 13 doi: 10.1212/NXI.0000000000000699. PMID: 32170042Free PMC Article

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