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Cortical dysplasia-focal epilepsy syndrome(PTHSL1)

MedGen UID:
413258
Concept ID:
C2750246
Disease or Syndrome
Synonyms: Pitt-Hopkins-like syndrome 1; PTHSL1
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CNTNAP2 (7q35-36.1)
 
Monarch Initiative: MONDO:0012400
OMIM®: 610042
Orphanet: ORPHA163681

Definition

Pitt-Hopkins-like syndrome-1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by Smogavec et al., 2016). [from OMIM]

Clinical features

From HPO
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Language disorder
MedGen UID:
44069
Concept ID:
C0023015
Mental or Behavioral Dysfunction
Language impairment is a deficit in comprehension or production of language that includes reduced vocabulary, limited sentence structure, or impairments in written or spoken communication. Language abilities are substantially and quantifiably below age expectations.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Focal aware seizure
MedGen UID:
65895
Concept ID:
C0234974
Disease or Syndrome
A type of focal-onset seizure in which awareness is preserved. Awareness during a seizure is defined as the patient being fully aware of themself and their environment throughout the seizure, even if immobile.
Focal impaired awareness seizure
MedGen UID:
543022
Concept ID:
C0270834
Disease or Syndrome
Focal impaired awareness seizure (or focal seizure with impaired or lost awareness) is a type of focal-onset seizure characterized by some degree (which may be partial) of impairment of the person's awareness of themselves or their surroundings at any point during the seizure.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Cortical dysplasia
MedGen UID:
98129
Concept ID:
C0431380
Congenital Abnormality
The presence of developmental dysplasia of the cerebral cortex.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Bilateral tonic-clonic seizure with focal onset
MedGen UID:
164077
Concept ID:
C0877017
Disease or Syndrome
A bilateral tonic-clonic seizure with focal onset is a focal-onset seizure which progresses into a bilateral tonic-clonic phase.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.
Delayed gross motor development
MedGen UID:
332508
Concept ID:
C1837658
Finding
A type of motor delay characterized by a delay in acquiring the ability to control the large muscles of the body for walking, running, sitting, and crawling.
Progressive language deterioration
MedGen UID:
334494
Concept ID:
C1843793
Finding
Progressive loss of previously present language abilities.
Poor speech
MedGen UID:
341172
Concept ID:
C1848207
Finding
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Reduced tendon reflexes
MedGen UID:
356648
Concept ID:
C1866934
Finding
Diminution of tendon reflexes, which is an invariable sign of peripheral nerve disease.
Focal cortical dysplasia
MedGen UID:
853938
Concept ID:
C2938983
Congenital Abnormality
A type of malformation of cortical development that primarily affects areas of neocortex. It can be identified on conventional magnetic resonance imaging as focal cortical thickening, abnormal gyration, and blurring between gray and white matter, often associated with clusters of heterotopic neurons.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Reduced social responsiveness
MedGen UID:
868342
Concept ID:
C4022736
Finding
A reduced ability to participate in the back-and-forth flow of social interaction appropriate to culture and developmental level, which is normally characterized by an influence of the behavior of one person on the behavior of another person. This results in difficulty interacting with others through emotional, physical, or verbal communication.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hyperventilation
MedGen UID:
9377
Concept ID:
C0020578
Finding
Hyperventilation refers to an increased pulmonary ventilation rate that is faster than necessary for the exchange of gases. Hyperventilation can result from increased frequency of breathing, an increased tidal volume, or both, and leads to an excess intake of oxygen and the blowing off of carbon dioxide.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCortical dysplasia-focal epilepsy syndrome

Recent clinical studies

Etiology

Veersema TJ, van Schooneveld MMJ, Ferrier CH, van Eijsden P, Gosselaar PH, van Rijen PC, Spliet WGM, Mühlebner A, Aronica E, Braun KPJ
Epilepsy Behav 2019 May;94:209-215. Epub 2019 Apr 8 doi: 10.1016/j.yebeh.2019.03.009. PMID: 30974349
Toma C, Pierce KD, Shaw AD, Heath A, Mitchell PB, Schofield PR, Fullerton JM
PLoS Genet 2018 Dec;14(12):e1007535. Epub 2018 Dec 26 doi: 10.1371/journal.pgen.1007535. PMID: 30586385Free PMC Article
Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, Zweier C
J Med Genet 2016 Dec;53(12):820-827. Epub 2016 Jul 20 doi: 10.1136/jmedgenet-2016-103880. PMID: 27439707
Fauser S, Essang C, Altenmüller DM, Staack AM, Steinhoff BJ, Strobl K, Bast T, Schubert-Bast S, Stephani U, Wiegand G, Prinz M, Brandt A, Zentner J, Schulze-Bonhage A
Epilepsia 2015 Jan;56(1):66-76. Epub 2014 Dec 13 doi: 10.1111/epi.12876. PMID: 25495786

Diagnosis

Veersema TJ, van Schooneveld MMJ, Ferrier CH, van Eijsden P, Gosselaar PH, van Rijen PC, Spliet WGM, Mühlebner A, Aronica E, Braun KPJ
Epilepsy Behav 2019 May;94:209-215. Epub 2019 Apr 8 doi: 10.1016/j.yebeh.2019.03.009. PMID: 30974349
Ito Y, Yamamoto H, Okanishi T, Maesawa S, Natsume J
Pediatr Int 2019 Mar;61(3):319-321. Epub 2019 Mar 4 doi: 10.1111/ped.13793. PMID: 30834636
Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, Zweier C
J Med Genet 2016 Dec;53(12):820-827. Epub 2016 Jul 20 doi: 10.1136/jmedgenet-2016-103880. PMID: 27439707
Bagić A
Clin Neurophysiol 2016 Jan;127(1):60-66. Epub 2015 May 15 doi: 10.1016/j.clinph.2015.05.009. PMID: 26055337
Lacuey N, Davila JC, Zonjy B, Amina S, Couce M, Turnbull J, Miller J, Lüders H, Lhatoo SD
Epileptic Disord 2015 Jun;17(2):134-42. doi: 10.1684/epd.2015.0749. PMID: 26056053

Therapy

Hadouiri N, Darmency V, Guibaud L, Arzimanoglou A, Sorlin A, Carmignac V, Rivière JB, Huet F, Luu M, Bardou M, Thauvin-Robinet C, Vabres P, Faivre L
Eur J Med Genet 2020 Nov;63(11):104036. Epub 2020 Aug 14 doi: 10.1016/j.ejmg.2020.104036. PMID: 32805448
Matsushita Y, Sakai Y, Shimmura M, Shigeto H, Nishio M, Akamine S, Sanefuji M, Ishizaki Y, Torisu H, Nakabeppu Y, Suzuki A, Takada H, Hara T
Sci Rep 2016 Mar 10;6:22991. doi: 10.1038/srep22991. PMID: 26961412Free PMC Article
Rozanski VE, Peraud A, Noachtar S
Epileptic Disord 2015 Jun;17(2):184-7. doi: 10.1684/epd.2015.0750. PMID: 26030473
Fauser S, Essang C, Altenmüller DM, Staack AM, Steinhoff BJ, Strobl K, Bast T, Schubert-Bast S, Stephani U, Wiegand G, Prinz M, Brandt A, Zentner J, Schulze-Bonhage A
Epilepsia 2015 Jan;56(1):66-76. Epub 2014 Dec 13 doi: 10.1111/epi.12876. PMID: 25495786

Prognosis

Veersema TJ, van Schooneveld MMJ, Ferrier CH, van Eijsden P, Gosselaar PH, van Rijen PC, Spliet WGM, Mühlebner A, Aronica E, Braun KPJ
Epilepsy Behav 2019 May;94:209-215. Epub 2019 Apr 8 doi: 10.1016/j.yebeh.2019.03.009. PMID: 30974349
Toma C, Pierce KD, Shaw AD, Heath A, Mitchell PB, Schofield PR, Fullerton JM
PLoS Genet 2018 Dec;14(12):e1007535. Epub 2018 Dec 26 doi: 10.1371/journal.pgen.1007535. PMID: 30586385Free PMC Article
Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, Zweier C
J Med Genet 2016 Dec;53(12):820-827. Epub 2016 Jul 20 doi: 10.1136/jmedgenet-2016-103880. PMID: 27439707
Fauser S, Essang C, Altenmüller DM, Staack AM, Steinhoff BJ, Strobl K, Bast T, Schubert-Bast S, Stephani U, Wiegand G, Prinz M, Brandt A, Zentner J, Schulze-Bonhage A
Epilepsia 2015 Jan;56(1):66-76. Epub 2014 Dec 13 doi: 10.1111/epi.12876. PMID: 25495786

Clinical prediction guides

Hu WH, Zhao BT, Zhang C, Wang X, Sang L, Shao XQ, Qiao H, Zhang JG, Zhang K
Clin Neurophysiol 2019 Sep;130(9):1596-1603. Epub 2019 Jun 22 doi: 10.1016/j.clinph.2019.05.029. PMID: 31319288
Toma C, Pierce KD, Shaw AD, Heath A, Mitchell PB, Schofield PR, Fullerton JM
PLoS Genet 2018 Dec;14(12):e1007535. Epub 2018 Dec 26 doi: 10.1371/journal.pgen.1007535. PMID: 30586385Free PMC Article
Smogavec M, Cleall A, Hoyer J, Lederer D, Nassogne MC, Palmer EE, Deprez M, Benoit V, Maystadt I, Noakes C, Leal A, Shaw M, Gecz J, Raymond L, Reis A, Shears D, Brockmann K, Zweier C
J Med Genet 2016 Dec;53(12):820-827. Epub 2016 Jul 20 doi: 10.1136/jmedgenet-2016-103880. PMID: 27439707
Fauser S, Essang C, Altenmüller DM, Staack AM, Steinhoff BJ, Strobl K, Bast T, Schubert-Bast S, Stephani U, Wiegand G, Prinz M, Brandt A, Zentner J, Schulze-Bonhage A
Epilepsia 2015 Jan;56(1):66-76. Epub 2014 Dec 13 doi: 10.1111/epi.12876. PMID: 25495786
Najm IM, Tassi L, Sarnat HB, Holthausen H, Russo GL
Acta Neuropathol 2014 Jul;128(1):5-19. Epub 2014 Jun 12 doi: 10.1007/s00401-014-1304-0. PMID: 24916270

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