SCHZC
MCID: SCH018
MIFTS: 52

Schizencephaly (SCHZC)

Categories: Eye diseases, Fetal diseases, Genetic diseases, Muscle diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Schizencephaly

MalaCards integrated aliases for Schizencephaly:

Name: Schizencephaly 57 74 20 53 58 73 36 29 13 54 6 39 71
Familial Schizencephaly 58 71
Acquired Schizencephaly 58
Schzc 73

Characteristics:

Orphanet epidemiological data:

58
schizencephaly
Inheritance: Autosomal dominant,Autosomal recessive; Prevalence: 1-9/100000 (United Kingdom),1-9/100000 (United States); Age of onset: Antenatal,Neonatal; Age of death: any age;

Classifications:

Orphanet: 58  
Rare neurological diseases
Rare eye diseases
Developmental anomalies during embryogenesis


External Ids:

OMIM® 57 269160
KEGG 36 H01160
ICD10 via Orphanet 33 Q04.6
UMLS via Orphanet 72 C0266484
MedGen 41 C0266484
UMLS 71 C0266484 C2931870

Summaries for Schizencephaly

OMIM® : 57 Brunelli et al. (1996) described schizencephaly as an extremely rare congenital disorder characterized by a full-thickness cleft within the cerebral hemispheres. The clefts are lined with gray matter and most commonly involve the parasylvian regions (Wolpert and Barnes, 1992). Large portions of the cerebral hemispheres may be absent and replaced by cerebrospinal fluid. Two types of schizencephaly have been described, depending on the size of the area involved and the separation of the cleft lips (Wolpert and Barnes, 1992). Type I schizencephaly consists of a fused cleft. This fused pial-ependymal seam forms a furrow in the developing brain, and is lined by polymicrogyric gray matter. In type II schizencephaly, there is a large defect, a holohemispheric cleft in the cerebral cortex filled with fluid and lined by polymicrogyric gray matter. The clinical manifestations depend on the severity of the lesion. Patients with type I are often almost normal; they may have seizures and spasticity. In type II abnormalities, there is usually mental retardation, seizures, hypotonia, spasticity, inability to walk or speak, and blindness. Schizencephaly may be part of the larger phenotypic spectrum of holoprosencephaly (HPE; see 236100). (269160) (Updated 05-Mar-2021)

MalaCards based summary : Schizencephaly, also known as familial schizencephaly, is related to holoprosencephaly 1 and porencephaly. An important gene associated with Schizencephaly is SIX3 (SIX Homeobox 3), and among its related pathways/superpathways are Hedgehog signaling pathway and Ectoderm Differentiation. Affiliated tissues include brain, cortex and eye, and related phenotypes are eeg abnormality and strabismus

GARD : 20 Schizencephaly is a rare congenital (present from birth) brain malformation in which abnormal slits or clefts form in the cerebral hemispheres of the brain. The signs and symptoms of this condition may include developmental delay, seizures, and problems with brain-spinal cord communication. People with schizencephaly may also have an abnormally small head (microcephaly); hydrocephalus; intellectual disability; partial or complete paralysis; and/or poor muscle tone (hypotonia). Severity of symptoms depends on many factors including the extent of the clefting and whether or not other brain abnormalities are present. Although the exact cause of schizencephaly is unknown, it has been linked to a variety of genetic and non-genetic factors. Treatment generally consists of physical therapy and drugs to prevent seizures. In cases that are complicated by hydrocephalus, a surgically implanted tube, called a shunt, is often used to divert fluid to another area of the body where it can be absorbed.

NINDS : 53 Schizencephaly is an extremely rare developmental birth defect characterized by abnormal slits, or clefts, in the cerebral hemispheres of the brain.  Babies with clefts in both hemispheres (called bilateral clefts) commonly have developmental delays, delays in speech and language skills, and problems with brain-spinal cord communication.  Individuals with clefts in only one hemisphere (called unilateral clefts) are often paralyzed on one side of the body, but may have average to near-average intelligence.  Individuals with schizencephaly may also have an abnormally small head, cognitive delay and impairment, partial or complete paralysis, or poor muscle tone.  Most will experience seizures.  Some individuals may have an excessive accumulation of fluid in the brain called hydrocephalus.

KEGG : 36 Schizencephaly is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. Gray matter-lined clefts in the cerebral cortex and a range of neurological presentations are characteristic. Mutations in SIX3, SHH, and EMX2 have been reported.

UniProtKB/Swiss-Prot : 73 Schizencephaly: Extremely rare human congenital disorder characterized by a full- thickness cleft within the cerebral hemispheres. These clefts are lined with gray matter and most commonly involve the parasylvian regions. Large portions of the cerebral hemispheres may be absent and replaced by cerebro-spinal fluid.

Wikipedia : 74 Schizencephaly (from Greek skhizein 'to split', and enkephalos 'brain') is a rare birth defect... more...

Related Diseases for Schizencephaly

Diseases related to Schizencephaly via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 195)
# Related Disease Score Top Affiliating Genes
1 holoprosencephaly 1 31.6 SIX3 SHH
2 porencephaly 30.0 MTHFR F5 EMX2 COL4A1
3 spastic cerebral palsy 29.9 F5 COL4A1
4 holoprosencephaly 2 29.9 SIX3 SHH
5 lobar holoprosencephaly 29.9 SIX3 SHH
6 spastic hemiplegia 29.8 MTHFR COL4A1
7 septooptic dysplasia 29.8 SOX2 SIX3 SHH HESX1
8 gastroschisis 29.7 MTHFR F5
9 cerebral palsy 29.4 MTHFR F5 COL4A1 BGLAP
10 periventricular nodular heterotopia 29.4 WDR62 HESX1 EMX2
11 gaucher's disease 29.1 MTHFR F5 BGLAP
12 holoprosencephaly 28.8 SOX2 SIX3 SHH LHX2 HESX1 EMX2
13 corpus callosum, agenesis of 11.1
14 silengo lerone pelizza syndrome 11.0
15 brain small vessel disease 1 with or without ocular anomalies 10.9
16 neuronal migration disorders 10.9
17 microcephaly 2, primary, autosomal recessive, with or without cortical malformations 10.9
18 polymicrogyria with or without vascular-type ehlers-danlos syndrome 10.4
19 polymicrogyria 10.4
20 hydrocephalus 10.2
21 seizure disorder 10.2
22 microcephaly 10.2
23 midline interhemispheric variant of holoprosencephaly 10.2 SIX3 SHH
24 septopreoptic holoprosencephaly 10.2 SIX3 SHH
25 holoprosencephaly 9 10.2 SIX3 SHH
26 corpus callosum lipoma 10.2 SIX3 SHH
27 cerebral hemisphere lipoma 10.2 SIX3 SHH
28 holoprosencephaly 4 10.2 SIX3 SHH
29 alobar holoprosencephaly 10.2 SIX3 SHH
30 culler-jones syndrome 10.2 SIX3 SHH
31 holoprosencephaly 11 10.2 SIX3 SHH
32 microform holoprosencephaly 10.2 SIX3 SHH
33 holoprosencephaly 3 10.2 SIX3 SHH
34 holoprosencephaly 7 10.2 SIX3 SHH
35 holoprosencephaly 5 10.1 SIX3 SHH
36 solitary median maxillary central incisor 10.1 SIX3 SHH
37 semilobar holoprosencephaly 10.1 SIX3 SHH
38 absence of septum pellucidum 10.1
39 pachygyria 10.1
40 patau syndrome 10.1 SIX3 SHH
41 pallister-hall syndrome 10.1 SIX3 SHH
42 optic nerve hypoplasia, bilateral 10.1
43 dystonia 10.1
44 encephalocele 10.1
45 human cytomegalovirus infection 10.0
46 hemiplegia 10.0
47 quadriplegia 10.0
48 fryns microphthalmia syndrome 10.0 SOX2 HESX1
49 spinal cord infarction 10.0 MTHFR F5
50 amaurosis fugax 10.0 MTHFR F5

Graphical network of the top 20 diseases related to Schizencephaly:



Diseases related to Schizencephaly

Symptoms & Phenotypes for Schizencephaly

Human phenotypes related to Schizencephaly:

58 31 (show all 15)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 eeg abnormality 58 31 hallmark (90%) Very frequent (99-80%) HP:0002353
2 strabismus 58 31 hallmark (90%) Very frequent (99-80%) HP:0000486
3 aplasia/hypoplasia of the corpus callosum 58 31 hallmark (90%) Very frequent (99-80%) HP:0007370
4 porencephalic cyst 31 hallmark (90%) HP:0002132
5 intellectual disability 58 31 frequent (33%) Frequent (79-30%) HP:0001249
6 global developmental delay 58 31 frequent (33%) Frequent (79-30%) HP:0001263
7 spastic tetraplegia 58 31 frequent (33%) Frequent (79-30%) HP:0002510
8 hemiparesis 58 31 frequent (33%) Frequent (79-30%) HP:0001269
9 seizure 31 frequent (33%) HP:0001250
10 seizures 58 Frequent (79-30%)
11 spasticity 58 Very frequent (99-80%)
12 agenesis of corpus callosum 31 HP:0001274
13 cerebral cortical atrophy 31 HP:0002120
14 porencephaly 58 Very frequent (99-80%)
15 schizencephaly 31 HP:0010636

Clinical features from OMIM®:

269160 (Updated 05-Mar-2021)

MGI Mouse Phenotypes related to Schizencephaly:

46
# Description MGI Source Accession Score Top Affiliating Genes
1 growth/size/body region MP:0005378 10.1 COL4A1 EMX2 F5 HESX1 LHX2 MTHFR
2 mortality/aging MP:0010768 10.02 COL4A1 EMX2 F5 HESX1 LHX2 MTHFR
3 nervous system MP:0003631 10.02 COL4A1 EMX2 F5 HESX1 LHX2 MTHFR
4 embryo MP:0005380 9.98 COL4A1 EMX2 F5 HESX1 SHH SIX3
5 craniofacial MP:0005382 9.93 EMX2 HESX1 LHX2 SHH SIX3 SOX2
6 reproductive system MP:0005389 9.8 BGLAP COL4A1 EMX2 MTHFR SHH SOX2
7 respiratory system MP:0005388 9.76 COL4A1 EMX2 HESX1 LHX2 SHH SIX3
8 taste/olfaction MP:0005394 9.43 EMX2 HESX1 LHX2 SHH SIX3 SOX2
9 vision/eye MP:0005391 9.28 COL4A1 EMX2 HESX1 LHX2 MTHFR SHH

Drugs & Therapeutics for Schizencephaly

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Human Epilepsy Genetics--Neuronal Migration Disorders Study Unknown status NCT00041600

Search NIH Clinical Center for Schizencephaly

Genetic Tests for Schizencephaly

Genetic tests related to Schizencephaly:

# Genetic test Affiliating Genes
1 Schizencephaly 29 EMX2 SHH SIX3

Anatomical Context for Schizencephaly

MalaCards organs/tissues related to Schizencephaly:

40
Brain, Cortex, Eye, Spinal Cord, Temporal Lobe, Fetal Brain, Bone

Publications for Schizencephaly

Articles related to Schizencephaly:

(show top 50) (show all 472)
# Title Authors PMID Year
1
A number of schizencephaly patients including 2 brothers are heterozygous for germline mutations in the homeobox gene EMX2. 57 6 54 61
9359037 1997
2
Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly. 6 57 61
20157829 2010
3
Germline mutations in the homeobox gene EMX2 in patients with severe schizencephaly. 57 61 6
8528262 1996
4
No major role for the EMX2 gene in schizencephaly. 54 57 61
18409201 2008
5
Comprehensive EMX2 genotyping of a large schizencephaly case series. 57 54 61
17506092 2007
6
Maternally inherited heterozygous sequence change in the sonic hedgehog gene in a male patient with bilateral closed-lip schizencephaly and partial absence of the corpus callosum. 57 61
19533790 2009
7
Schizencephaly: heterogeneous etiologies in a population of 4 million California births. 57 61
16059942 2005
8
Familial schizencephaly. 61 57
8214352 1993
9
Schizencephaly: case report of familial incidence. 61 57
1580960 1992
10
Familial schizencephaly. 57 61
1743422 1991
11
Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. 6
20425842 2010
12
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function. 6
19346217 2009
13
Mutations in the human SIX3 gene in holoprosencephaly are loss of function. 6
18791198 2008
14
Mutational analysis of SHH and GLI3 in anorectal malformations. 6
18655123 2008
15
SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. 6
12709790 2003
16
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. 6
10556296 1999
17
Schizencephalies; a study of the congenital clefts in the cerebral mantle; clefts with fused lips. 57
21026933 1946
18
EMX2-independent familial schizencephaly: clinical and genetic analyses. 61 54
15887302 2005
19
Schizencephaly: clinical spectrum, epilepsy, and pathogenesis. 61 54
15921232 2005
20
Developmental anomalies of the scapula-the "omo"st forgotten bone. 54 61
12884444 2003
21
Familial schizencephaly associated with EMX2 mutation. 54 61
9153481 1997
22
Fetal brain small vessel disease 1 caused by a novel mutation in the COL4A1 gene. 61
33057775 2021
23
Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients. 61
33199158 2021
24
Review of the MRI brain findings of septo-optic dysplasia. 61
33019967 2021
25
Novel COL4A2 mutation causing familial malformations of cortical development. 61
33577044 2021
26
Brain and Placental Pathology in Fetal COL4A1 Related Disease. 61
33475042 2021
27
Intermittent photic stimulation triggering a temporal lobe seizure in a patient with schizencephaly and pachygyria. 61
33458644 2021
28
Prenatal cranial MR findings in fetuses with suspected CMV infection: Correlation with postnatal outcome and differential diagnostic considerations. 61
32741149 2020
29
The spectrum of brain malformations and disruptions in twins. 61
33205886 2020
30
Novel COL4A1 mutations identified in infants with congenital hemolytic anemia in association with brain malformations. 61
33298904 2020
31
Excitatory/Inhibitory Synaptic Ratios in Polymicrogyria and Down Syndrome Help Explain Epileptogenesis in Malformations. 61
33450624 2020
32
Pseudo-Roberts Syndrome: An Entity or Not? 61
33026893 2020
33
Unilateral right closed-lip schizencephaly. 61
32928828 2020
34
Prenatal clinical manifestations in individuals with COL4A1/2 variants. 61
32732225 2020
35
COL4A1 and COL4A2 mutations: when to test a fetus? 61
32515830 2020
36
Epilepsy in paediatric patients with schizencephaly. 61
32588606 2020
37
Neuroimaging of septo-optic dysplasia-plus with midbrain hypoplasia and ophthalmoplegia. 61
32195380 2020
38
Persistent falcine sinus with temporo-occipital schizencephaly: case report with a review of literature in relation to the undeveloped vein of Galen and/or straight sinus. 61
31154486 2020
39
Adult-Onset Seizure Disorder Secondary to Schizencephaly. 61
32181192 2020
40
An Unusual, Intermediate-Sized Lesion Affecting Motor Organization in a Patient With Schizencephaly: A Case Report. 61
32765236 2020
41
A Rare Case of an Infant with Left Hemiparesis: A Case Report of Bilateral Open-lip Schizencephaly. 61
33329869 2020
42
Dissociative Language Representation in a Patient with Schizencephaly. 61
33032283 2020
43
Trio-Based Whole-Exome Sequencing Identifies a De novo EFNB1 Mutation as a Genetic Cause in Female Infant With Brain Anomaly and Developmental Delay. 61
32984200 2020
44
A journey through formation and malformations of the neo-cortex. 61
31776716 2020
45
Inborn errors of metabolism leading to neuronal migration defects. 61
31747049 2020
46
Schizencephaly accompanied by occipital encephalocele and deletion of chromosome 22q13.32: a case report. 61
31130048 2019
47
Unilateral Open-lip Schizencephaly with Tonsillar Herniation in a Preterm Infant. 61
31908665 2019
48
Septo-optic Dysplasia : Assessment of Associated Findings with Special Attention to the Olfactory Sulci and Tracts. 61
29663010 2019
49
Increased Sylvian fissure angle as early sonographic sign of malformation of cortical development. 61
30381845 2019
50
Malignant Hyperthermia and Cerebral Venous Sinus Thrombosis After Ventriculoperitoneal Shunt in Infant with Schizencephaly and COL4A1 Mutation. 61
31029817 2019

Variations for Schizencephaly

ClinVar genetic disease variations for Schizencephaly:

6 (show all 15)
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 SHH NM_000193.4(SHH):c.869G>A (p.Gly290Asp) SNV Pathogenic 8887 rs104894047 7:155596114-155596114 7:155803420-155803420
2 SIX3 NM_005413.4(SIX3):c.385G>T (p.Glu129Ter) SNV Pathogenic 30380 rs387906867 2:45169628-45169628 2:44942489-44942489
3 SIX3 NM_005413.4(SIX3):c.109G>T (p.Gly37Cys) SNV Pathogenic 30381 rs199823175 2:45169352-45169352 2:44942213-44942213
4 EMX2 EMX2, 1-BP INS Insertion Pathogenic 9519
5 EMX2 NM_004098.4(EMX2):c.407-1G>A SNV Pathogenic 9520 rs1564751655 10:119305142-119305142 10:117545631-117545631
6 EMX2 NM_004098.4(EMX2):c.407-4G>T SNV Pathogenic 9521 rs1411887961 10:119305139-119305139 10:117545628-117545628
7 EMX2 EMX2, G-T, EXON 2, NT1 SNV Pathogenic 9522
8 SIX3 NM_005413.4(SIX3):c.499G>T (p.Ala167Ser) SNV Pathogenic 30382 rs387906868 2:45169742-45169742 2:44942603-44942603
9 SHH NM_000193.4(SHH):c.593G>A (p.Cys198Tyr) SNV Pathogenic 931342 7:155596390-155596390 7:155803696-155803696
10 SIX3 NM_005413.4(SIX3):c.208T>C (p.Ser70Pro) SNV Uncertain significance 931003 2:45169451-45169451 2:44942312-44942312
11 SHH NM_000193.4(SHH):c.1147G>A (p.Ala383Thr) SNV Uncertain significance 8886 rs137853341 7:155595836-155595836 7:155803142-155803142
12 COL4A1 NM_001845.6(COL4A1):c.2093A>G (p.Lys698Arg) SNV Uncertain significance 447160 rs375318302 13:110835342-110835342 13:110182995-110182995
13 COL4A1 NM_001845.6(COL4A1):c.1588C>T (p.Pro530Ser) SNV Uncertain significance 195868 rs145172612 13:110839625-110839625 13:110187278-110187278
14 COL4A1 NM_001845.6(COL4A1):c.7C>A (p.Pro3Thr) SNV Uncertain significance 289628 rs751749989 13:110959368-110959368 13:110307021-110307021
15 SIX3 NM_005413.4(SIX3):c.127G>T (p.Gly43Cys) SNV Uncertain significance 498633 rs1436891421 2:45169370-45169370 2:44942231-44942231

UniProtKB/Swiss-Prot genetic disease variations for Schizencephaly:

73
# Symbol AA change Variation ID SNP ID
1 COL4A1 p.Gly655Arg VAR_073812
2 COL4A1 p.Gly870Arg VAR_073815
3 COL4A1 p.Gly897Ser VAR_073817
4 COL4A1 p.Gly948Ser VAR_073818 rs155530307
5 COL4A1 p.Gly1041Glu VAR_073819
6 COL4A1 p.Gly1082Glu VAR_073820
7 COL4A1 p.Gly1326Arg VAR_073822 rs587777379
8 COL4A1 p.Gly1332Asp VAR_073823
9 COL4A1 p.Glu1615Lys VAR_073825
10 SIX3 p.Ala167Ser VAR_071343 rs387906868

Expression for Schizencephaly

Search GEO for disease gene expression data for Schizencephaly.

Pathways for Schizencephaly

Pathways related to Schizencephaly according to KEGG:

36
# Name Kegg Source Accession
1 Hedgehog signaling pathway hsa04340

Pathways related to Schizencephaly according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.29 SOX2 SHH HESX1
2 10.85 SHH BGLAP
3 10.63 SOX2 SHH
4 10.42 SOX2 SIX3 HESX1

GO Terms for Schizencephaly

Cellular components related to Schizencephaly according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 chromatin GO:0000785 9.35 SOX2 SIX3 LHX2 HESX1 EMX2
2 endoplasmic reticulum lumen GO:0005788 8.92 SHH F5 COL4A1 BGLAP

Biological processes related to Schizencephaly according to GeneCards Suite gene sharing:

(show all 18)
# Name GO ID Score Top Affiliating Genes
1 multicellular organism development GO:0007275 9.89 SOX2 SIX3 SHH HESX1 EMX2
2 regulation of transcription, DNA-templated GO:0006355 9.88 SOX2 SIX3 SHH LHX2 HESX1 EMX2
3 positive regulation of cell differentiation GO:0045597 9.58 SOX2 SHH
4 eye development GO:0001654 9.57 SOX2 SIX3
5 hair follicle development GO:0001942 9.56 SHH LHX2
6 dorsal/ventral pattern formation GO:0009953 9.55 SHH LHX2
7 brain development GO:0007420 9.55 SIX3 LHX2 HESX1 EMX2 COL4A1
8 odontogenesis GO:0042476 9.54 SHH BGLAP
9 branching involved in blood vessel morphogenesis GO:0001569 9.52 SHH COL4A1
10 telencephalon development GO:0021537 9.51 SIX3 LHX2
11 cerebral cortex development GO:0021987 9.5 WDR62 LHX2 EMX2
12 thyroid gland development GO:0030878 9.48 SHH HESX1
13 anatomical structure formation involved in morphogenesis GO:0048646 9.46 SHH LHX2
14 osteoblast development GO:0002076 9.43 SHH BGLAP
15 pituitary gland development GO:0021983 9.43 SOX2 SIX3 HESX1
16 cell proliferation in forebrain GO:0021846 9.37 SIX3 EMX2
17 forebrain development GO:0030900 9.26 SOX2 SHH HESX1 EMX2
18 telencephalon regionalization GO:0021978 8.8 SIX3 SHH LHX2

Molecular functions related to Schizencephaly according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 DNA-binding transcription factor activity, RNA polymerase II-specific GO:0000981 9.35 SOX2 SIX3 LHX2 HESX1 EMX2
2 RNA polymerase II proximal promoter sequence-specific DNA binding GO:0000978 9.02 SOX2 SIX3 LHX2 HESX1 EMX2

Sources for Schizencephaly

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
20 GARD
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
53 NINDS
54 Novoseek
56 OMIM via Orphanet
57 OMIM® (Updated 05-Mar-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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