MCSZ
MCID: MCR064
MIFTS: 40

Microcephaly, Seizures, and Developmental Delay (MCSZ)

Categories: Genetic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Microcephaly, Seizures, and Developmental Delay

MalaCards integrated aliases for Microcephaly, Seizures, and Developmental Delay:

Name: Microcephaly, Seizures, and Developmental Delay 57 12 20 43 72 15 39 70
Epileptic Encephalopathy, Early Infantile, 10 57 20 43 13
Early Infantile Epileptic Encephalopathy 10 12 72 29 6
Eiee10 57 20 43 72
Mcsz 57 20 43 72
Developmental and Epileptic Encephalopathy 10 57 12
Epileptic Encephalopathy, Early Infantile, 10; Eiee10 57
Developmental and Epileptic Encephalopathy 10; Dee10 57
Microcephaly - Seizures - Developmental Delay 20
Early Infantile Epileptic Encephalopathy-10 20
Dee10 57

Characteristics:

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset prenatally or at birth
some patients may have a more protracted disorder with neurodegeneration


HPO:

31
microcephaly, seizures, and developmental delay:
Inheritance autosomal recessive inheritance


Classifications:



External Ids:

Disease Ontology 12 DOID:0080457
OMIM® 57 613402
OMIM Phenotypic Series 57 PS308350
MedGen 41 C3150667
UMLS 70 C3150667

Summaries for Microcephaly, Seizures, and Developmental Delay

MedlinePlus Genetics : 43 Microcephaly, seizures, and developmental delay (MCSZ) is a condition characterized by an abnormally small head size (microcephaly) and neurological problems related to impaired brain development before birth. Affected individuals typically have recurrent seizures (epilepsy) beginning in infancy and delayed development of motor skills, such as sitting and walking. Speech is also delayed, and some affected individuals are never able to speak. Intellectual disability and behavior problems, primarily hyperactivity, are also common features of MCSZ. Rarely, individuals with MCSZ also have poor balance and coordination (ataxia).

MalaCards based summary : Microcephaly, Seizures, and Developmental Delay, also known as epileptic encephalopathy, early infantile, 10, is related to microcephaly and seizure disorder. An important gene associated with Microcephaly, Seizures, and Developmental Delay is PNKP (Polynucleotide Kinase 3'-Phosphatase), and among its related pathways/superpathways are Cell junction organization and WNT Signaling. Affiliated tissues include skeletal muscle, and related phenotypes are hyporeflexia and ataxia

Disease Ontology : 12 A developmental and epileptic encephalopathy characterized by microcephaly, infantile onset of seizures and developmental delay that has material basis in homozygous or compound heterozygous mutation in the PNKP gene on chromosome 19q13.

OMIM® : 57 Microcephaly, seizures, and developmental delay is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients develop refractory seizures in infancy, consistent with a developmental and epileptic encephalopathy (DEE), whereas others have more well-controlled seizures and a more protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. (613402) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : 72 Microcephaly, seizures, and developmental delay: A disease characterized by infantile-onset seizures, microcephaly, severe intellectual disability and delayed motor milestones with absent speech or only achieving a few words. Most patients also have behavioral problems with hyperactivity. Microcephaly is progressive and without neuronal migration or structural abnormalities, consistent with primary microcephaly.

Related Diseases for Microcephaly, Seizures, and Developmental Delay

Diseases related to Microcephaly, Seizures, and Developmental Delay via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 microcephaly 10.3
2 seizure disorder 10.3
3 ataxia and polyneuropathy, adult-onset 10.1
4 developmental and epileptic encephalopathy 12 10.1
5 alacrima, achalasia, and mental retardation syndrome 10.1
6 ataxia-oculomotor apraxia 4 10.1
7 apraxia 10.1
8 speech disorder 10.1
9 oculomotor apraxia 10.1
10 craniofacial-deafness-hand syndrome 9.6 CDH9 CDH18

Graphical network of the top 20 diseases related to Microcephaly, Seizures, and Developmental Delay:



Diseases related to Microcephaly, Seizures, and Developmental Delay

Symptoms & Phenotypes for Microcephaly, Seizures, and Developmental Delay

Human phenotypes related to Microcephaly, Seizures, and Developmental Delay:

31 (show all 14)
# Description HPO Frequency HPO Source Accession
1 hyporeflexia 31 occasional (7.5%) HP:0001265
2 ataxia 31 very rare (1%) HP:0001251
3 global developmental delay 31 very rare (1%) HP:0001263
4 ventriculomegaly 31 very rare (1%) HP:0002119
5 cerebellar atrophy 31 very rare (1%) HP:0001272
6 hyperactivity 31 very rare (1%) HP:0000752
7 seizure 31 very rare (1%) HP:0001250
8 intellectual disability, severe 31 HP:0010864
9 skeletal muscle atrophy 31 HP:0003202
10 motor delay 31 HP:0001270
11 hypoplasia of the corpus callosum 31 HP:0002079
12 progressive microcephaly 31 HP:0000253
13 simplified gyral pattern 31 HP:0009879
14 hypotonia 31 HP:0001252

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Neurologic Behavioral Psychiatric Manifestations:
hyperactivity

Muscle Soft Tissue:
hypotonia
muscular atrophy

Head And Neck Head:
microcephaly, progressive

Neurologic Central Nervous System:
simplified gyral pattern
enlarged ventricles
delayed motor development
mental retardation, severe
cerebellar ataxia (in some patients)
more
Neurologic Peripheral Nervous System:
hyporeflexia (in some patients)
sensorimotor polyneuropathy (in some patients)

Laboratory Abnormalities:
patient cells show defective dna repair in response to irradiation and free radical damage

Clinical features from OMIM®:

613402 (Updated 05-Apr-2021)

Drugs & Therapeutics for Microcephaly, Seizures, and Developmental Delay

Search Clinical Trials , NIH Clinical Center for Microcephaly, Seizures, and Developmental Delay

Genetic Tests for Microcephaly, Seizures, and Developmental Delay

Genetic tests related to Microcephaly, Seizures, and Developmental Delay:

# Genetic test Affiliating Genes
1 Early Infantile Epileptic Encephalopathy 10 29 PNKP

Anatomical Context for Microcephaly, Seizures, and Developmental Delay

MalaCards organs/tissues related to Microcephaly, Seizures, and Developmental Delay:

40
Skeletal Muscle

Publications for Microcephaly, Seizures, and Developmental Delay

Articles related to Microcephaly, Seizures, and Developmental Delay:

(show all 24)
# Title Authors PMID Year
1
Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. 61 57 6
23224214 2013
2
Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. 57 6 61
20118933 2010
3
Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. 6 61
25728773 2015
4
The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort. 61
32980744 2020
5
Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair. 61
32504494 2020
6
Linker region is required for efficient nuclear localization of polynucleotide kinase phosphatase. 61
32970693 2020
7
Compound Heterozygous Mutations in PNKP Gene in an Iranian Child with Microcephaly, Seizures, and Developmental Delay. 61
31707899 2019
8
From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations. 61
31436889 2019
9
Ataxia with Oculomotor Apraxia Type 4 with PNKP Common "Portuguese" and Novel Mutations in Two Belarusian Families. 61
31061747 2019
10
Novel PNKP mutations causing defective DNA strand break repair and PARP1 hyperactivity in MCSZ. 61
31041400 2019
11
Multi affected pedigree with congenital microcephaly: WES revealed PNKP gene mutation. 61
30195441 2019
12
The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. 61
30039206 2018
13
The Rev1 interacting region (RIR) motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair. 61
28821613 2017
14
Lingering single-strand breaks trigger Rad51-independent homology-directed repair of collapsed replication forks in the polynucleotide kinase/phosphatase mutant of fission yeast. 61
28922417 2017
15
Structural and functional characterization of the PNKP-XRCC4-LigIV DNA repair complex. 61
28453785 2017
16
Polynucleotide kinase-phosphatase (PNKP) mutations and neurologic disease. 61
27125728 2017
17
Neurological disorders associated with DNA strand-break processing enzymes. 61
27470939 2017
18
Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. 61
27769281 2016
19
Microcephalic primordial dwarfism in an Emirati patient with PNKP mutation. 61
27232581 2016
20
Expanding the ataxia with oculomotor apraxia type 4 phenotype. 61
27066586 2016
21
Nicolaides-Baraitser Syndrome 61
26468571 2015
22
Polynucleotide kinase-phosphatase enables neurogenesis via multiple DNA repair pathways to maintain genome stability. 61
26290337 2015
23
Impact of PNKP mutations associated with microcephaly, seizures and developmental delay on enzyme activity and DNA strand break repair. 61
22508754 2012
24
Congenital axonal neuropathy and encephalopathy. 61
18358405 2008

Variations for Microcephaly, Seizures, and Developmental Delay

ClinVar genetic disease variations for Microcephaly, Seizures, and Developmental Delay:

6 (show top 50) (show all 102)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 PNKP NM_007254.4(PNKP):c.526C>T (p.Leu176Phe) SNV Pathogenic 4848 rs267606957 GRCh37: 19:50367633-50367633
GRCh38: 19:49864376-49864376
2 PNKP NM_007254.4(PNKP):c.1295_1298+6del Deletion Pathogenic 159788 rs587784366 GRCh37: 19:50365023-50365032
GRCh38: 19:49861766-49861775
3 PNKP NM_007254.4(PNKP):c.1386+49_1387-33del Deletion Pathogenic 211919 rs752902474 GRCh37: 19:50364800-50364816
GRCh38: 19:49861543-49861559
4 PNKP NM_007254.4(PNKP):c.1261_1262insGGGTCGCCATCGACAAC (p.Ile421fs) Insertion Pathogenic 807469 rs1600416052 GRCh37: 19:50365065-50365066
GRCh38: 19:49861808-49861809
5 PNKP NM_007254.4(PNKP):c.1253_1269dup (p.Thr424fs) Duplication Pathogenic 4847 rs587784365 GRCh37: 19:50365057-50365058
GRCh38: 19:49861800-49861801
6 PNKP NM_007254.4(PNKP):c.976G>A (p.Glu326Lys) SNV Pathogenic 4846 rs267606956 GRCh37: 19:50365681-50365681
GRCh38: 19:49862424-49862424
7 PNKP NM_007254.4(PNKP):c.636+1G>T SNV Pathogenic 436354 rs1247055716 GRCh37: 19:50367435-50367435
GRCh38: 19:49864178-49864178
8 PNKP NM_007254.4(PNKP):c.968C>T (p.Thr323Met) SNV Likely pathogenic 159803 rs372148913 GRCh37: 19:50365689-50365689
GRCh38: 19:49862432-49862432
9 PNKP NM_007254.4(PNKP):c.1256T>A (p.Val419Asp) SNV Likely pathogenic 206408 rs748365843 GRCh37: 19:50365071-50365071
GRCh38: 19:49861814-49861814
10 PNKP NM_007254.4(PNKP):c.1221_1223del (p.Thr408del) Deletion Likely pathogenic 190219 rs786205207 GRCh37: 19:50365104-50365106
GRCh38: 19:49861847-49861849
11 PNKP NM_007254.4(PNKP):c.103A>G (p.Arg35Gly) SNV Likely pathogenic 977854 GRCh37: 19:50370359-50370359
GRCh38: 19:49867102-49867102
12 PNKP NM_007254.4(PNKP):c.286G>C (p.Val96Leu) SNV Likely pathogenic 977855 GRCh37: 19:50368596-50368596
GRCh38: 19:49865339-49865339
13 PNKP NM_007254.4(PNKP):c.829dup (p.Thr277fs) Duplication Likely pathogenic 977906 GRCh37: 19:50365982-50365983
GRCh38: 19:49862725-49862726
14 PNKP NM_007254.4(PNKP):c.188C>T (p.Ala63Val) SNV Conflicting interpretations of pathogenicity 159792 rs3739173 GRCh37: 19:50369666-50369666
GRCh38: 19:49866409-49866409
15 PNKP NM_007254.4(PNKP):c.302C>T (p.Pro101Leu) SNV Conflicting interpretations of pathogenicity 159793 rs587784367 GRCh37: 19:50368580-50368580
GRCh38: 19:49865323-49865323
16 PNKP NM_007254.4(PNKP):c.*15C>T SNV Conflicting interpretations of pathogenicity 138727 rs1050332 GRCh37: 19:50364490-50364490
GRCh38: 19:49861233-49861233
17 PNKP NM_007254.4(PNKP):c.1029+2T>C SNV Conflicting interpretations of pathogenicity 206401 rs199919568 GRCh37: 19:50365626-50365626
GRCh38: 19:49862369-49862369
18 PNKP NM_007254.4(PNKP):c.416G>A (p.Arg139His) SNV Conflicting interpretations of pathogenicity 159794 rs34472250 GRCh37: 19:50368466-50368466
GRCh38: 19:49865209-49865209
19 PNKP NM_007254.4(PNKP):c.901C>T (p.Arg301Trp) SNV Uncertain significance 95491 rs201503405 GRCh37: 19:50365830-50365830
GRCh38: 19:49862573-49862573
20 PNKP NM_007254.4(PNKP):c.1360C>A (p.Leu454Met) SNV Uncertain significance 95478 rs200611702 GRCh37: 19:50364891-50364891
GRCh38: 19:49861634-49861634
21 PNKP NM_007254.4(PNKP):c.1133A>C (p.Lys378Thr) SNV Uncertain significance 813902 rs1600416892 GRCh37: 19:50365356-50365356
GRCh38: 19:49862099-49862099
22 PNKP NM_007254.4(PNKP):c.416G>A (p.Arg139His) SNV Uncertain significance 159794 rs34472250 GRCh37: 19:50368466-50368466
GRCh38: 19:49865209-49865209
23 PNKP NM_007254.4(PNKP):c.901C>T (p.Arg301Trp) SNV Uncertain significance 95491 rs201503405 GRCh37: 19:50365830-50365830
GRCh38: 19:49862573-49862573
24 PNKP NM_007254.4(PNKP):c.107G>A (p.Gly36Glu) SNV Uncertain significance 569918 rs756589726 GRCh37: 19:50370355-50370355
GRCh38: 19:49867098-49867098
25 PNKP NM_007254.4(PNKP):c.1430T>C (p.Met477Thr) SNV Uncertain significance 565845 rs766655539 GRCh37: 19:50364724-50364724
GRCh38: 19:49861467-49861467
26 PNKP NM_007254.4(PNKP):c.1381A>G (p.Asn461Asp) SNV Uncertain significance 409614 rs775762473 GRCh37: 19:50364870-50364870
GRCh38: 19:49861613-49861613
27 PNKP NM_007254.4(PNKP):c.1510C>G (p.Arg504Gly) SNV Uncertain significance 206419 rs148669160 GRCh37: 19:50364561-50364561
GRCh38: 19:49861304-49861304
28 PNKP NM_007254.4(PNKP):c.264G>T (p.Gly88=) SNV Uncertain significance 844974 GRCh37: 19:50368618-50368618
GRCh38: 19:49865361-49865361
29 PNKP NM_007254.4(PNKP):c.1385G>A (p.Arg462Gln) SNV Uncertain significance 95479 rs376854895 GRCh37: 19:50364866-50364866
GRCh38: 19:49861609-49861609
30 PNKP NM_007254.4(PNKP):c.831G>A (p.Thr277=) SNV Uncertain significance 95489 rs148491228 GRCh37: 19:50365981-50365981
GRCh38: 19:49862724-49862724
31 PNKP NM_007254.4(PNKP):c.519C>T (p.Asp173=) SNV Uncertain significance 138708 rs144284975 GRCh37: 19:50367640-50367640
GRCh38: 19:49864383-49864383
32 PNKP NM_007254.4(PNKP):c.199-15C>T SNV Uncertain significance 384389 rs201254691 GRCh37: 19:50368698-50368698
GRCh38: 19:49865441-49865441
33 PNKP NM_007254.4(PNKP):c.671G>A (p.Arg224His) SNV Uncertain significance 159799 rs199705876 GRCh37: 19:50367294-50367294
GRCh38: 19:49864037-49864037
34 PNKP NM_007254.4(PNKP):c.994C>T (p.Pro332Ser) SNV Uncertain significance 159804 rs373922574 GRCh37: 19:50365663-50365663
GRCh38: 19:49862406-49862406
35 PNKP NM_007254.4(PNKP):c.1385G>C (p.Arg462Pro) SNV Uncertain significance 206414 rs376854895 GRCh37: 19:50364866-50364866
GRCh38: 19:49861609-49861609
36 PNKP NM_007254.4(PNKP):c.19C>T (p.Pro7Ser) SNV Uncertain significance 206421 rs201221600 GRCh37: 19:50370443-50370443
GRCh38: 19:49867186-49867186
37 PNKP NM_007254.4(PNKP):c.290A>G (p.Asn97Ser) SNV Uncertain significance 197287 rs140290151 GRCh37: 19:50368592-50368592
GRCh38: 19:49865335-49865335
38 PNKP NM_007254.4(PNKP):c.1559A>G (p.Glu520Gly) SNV Uncertain significance 285527 rs886043128 GRCh37: 19:50364512-50364512
GRCh38: 19:49861255-49861255
39 PNKP NM_007254.4(PNKP):c.1003G>A (p.Gly335Ser) SNV Uncertain significance 582794 rs768567927 GRCh37: 19:50365654-50365654
GRCh38: 19:49862397-49862397
40 PNKP NM_007254.4(PNKP):c.1559A>G (p.Glu520Gly) SNV Uncertain significance 285527 rs886043128 GRCh37: 19:50364512-50364512
GRCh38: 19:49861255-49861255
41 PNKP NM_007254.4(PNKP):c.627G>A (p.Glu209=) SNV Uncertain significance 211922 rs532550120 GRCh37: 19:50367445-50367445
GRCh38: 19:49864188-49864188
42 PNKP NM_007254.4(PNKP):c.579-5C>T SNV Uncertain significance 329895 rs767753048 GRCh37: 19:50367498-50367498
GRCh38: 19:49864241-49864241
43 PNKP NM_007254.4(PNKP):c.579-4G>A SNV Uncertain significance 159797 rs371834726 GRCh37: 19:50367497-50367497
GRCh38: 19:49864240-49864240
44 PNKP NM_007254.4(PNKP):c.1003G>T (p.Gly335Cys) SNV Uncertain significance 206399 rs768567927 GRCh37: 19:50365654-50365654
GRCh38: 19:49862397-49862397
45 PNKP NM_007254.4(PNKP):c.-35T>C SNV Uncertain significance 206372 rs550311179 GRCh37: 19:50370747-50370747
GRCh38: 19:49867490-49867490
46 PNKP NM_007254.4(PNKP):c.1158C>G (p.Leu386=) SNV Uncertain significance 384948 rs373766090 GRCh37: 19:50365331-50365331
GRCh38: 19:49862074-49862074
47 PNKP NM_007254.4(PNKP):c.678G>A (p.Lys226=) SNV Uncertain significance 378397 rs141969535 GRCh37: 19:50367287-50367287
GRCh38: 19:49864030-49864030
48 PNKP NM_007254.4(PNKP):c.673G>A (p.Gly225Arg) SNV Uncertain significance 206392 rs144257114 GRCh37: 19:50367292-50367292
GRCh38: 19:49864035-49864035
49 PNKP NM_007254.4(PNKP):c.1126+9C>T SNV Uncertain significance 138719 rs3739202 GRCh37: 19:50365433-50365433
GRCh38: 19:49862176-49862176
50 PNKP NM_007254.4(PNKP):c.131G>A (p.Arg44Gln) SNV Uncertain significance 568677 rs1568663138 GRCh37: 19:50370331-50370331
GRCh38: 19:49867074-49867074

UniProtKB/Swiss-Prot genetic disease variations for Microcephaly, Seizures, and Developmental Delay:

72
# Symbol AA change Variation ID SNP ID
1 PNKP p.Leu176Phe VAR_063835 rs267606957
2 PNKP p.Glu326Lys VAR_063836 rs267606956
3 PNKP p.Arg462Pro VAR_076537 rs376854895

Expression for Microcephaly, Seizures, and Developmental Delay

Search GEO for disease gene expression data for Microcephaly, Seizures, and Developmental Delay.

Pathways for Microcephaly, Seizures, and Developmental Delay

GO Terms for Microcephaly, Seizures, and Developmental Delay

Cellular components related to Microcephaly, Seizures, and Developmental Delay according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 adherens junction GO:0005912 9.13 CDH9 CDH18 CDH12
2 catenin complex GO:0016342 8.8 CDH9 CDH18 CDH12

Biological processes related to Microcephaly, Seizures, and Developmental Delay according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cell adhesion GO:0007155 9.61 CDH9 CDH18 CDH12
2 cell-cell adhesion GO:0098609 9.58 CDH9 CDH18 CDH12
3 homophilic cell adhesion via plasma membrane adhesion molecules GO:0007156 9.54 CDH9 CDH18 CDH12
4 cell morphogenesis GO:0000902 9.5 CDH9 CDH18 CDH12
5 adherens junction organization GO:0034332 9.43 CDH9 CDH18 CDH12
6 calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules GO:0016339 9.33 CDH9 CDH18 CDH12
7 cell-cell junction assembly GO:0007043 9.13 CDH9 CDH18 CDH12
8 cell-cell adhesion via plasma-membrane adhesion molecules GO:0098742 8.8 CDH9 CDH18 CDH12

Molecular functions related to Microcephaly, Seizures, and Developmental Delay according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 cadherin binding GO:0045296 9.13 CDH9 CDH18 CDH12
2 calcium ion binding GO:0005509 8.92 GCA CDH9 CDH18 CDH12

Sources for Microcephaly, Seizures, and Developmental Delay

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-Apr-2021)
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 Tocris
70 UMLS
71 UMLS via Orphanet
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