LCCS1
MCID: LTH007
MIFTS: 51

Lethal Congenital Contracture Syndrome 1 (LCCS1)

Categories: Bone diseases, Fetal diseases, Genetic diseases, Nephrological diseases, Neuronal diseases, Rare diseases, Respiratory diseases

Aliases & Classifications for Lethal Congenital Contracture Syndrome 1

MalaCards integrated aliases for Lethal Congenital Contracture Syndrome 1:

Name: Lethal Congenital Contracture Syndrome 1 56 12 52 73 29 13 6 43 15 71
Multiple Contracture Syndrome, Finnish Type 56 12 52 58
Lccs1 56 12 58 73
Lethal Autosomal Recessive Syndrome of Multiple Congenital Contractures 52
Contracture Syndrome, Lethal, Congenital, Type 1 39
Lethal Congenital Contracture Syndrome Type 1 58
Multiple Contracture Syndrome Finnish Type 73
Herva Disease 58
Lccs 56

Characteristics:

Orphanet epidemiological data:

58
lethal congenital contracture syndrome type 1
Inheritance: Autosomal recessive; Age of onset: Neonatal; Age of death: infantile;

OMIM:

56
Miscellaneous:
neonatal death

Inheritance:
autosomal recessive


HPO:

31
lethal congenital contracture syndrome 1:
Clinical modifier neonatal death
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare respiratory diseases
Developmental anomalies during embryogenesis


External Ids:

Disease Ontology 12 DOID:0060559
OMIM 56 253310
OMIM Phenotypic Series 56 PS253310
MESH via Orphanet 44 C537194
ICD10 via Orphanet 33 Q68.8
UMLS via Orphanet 72 C1854664
Orphanet 58 ORPHA1486
MedGen 41 C1854664
UMLS 71 C1854664

Summaries for Lethal Congenital Contracture Syndrome 1

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 1486 Definition Lethal congenital contracture syndrome type 1 is a rare, genetic arthrogryposis syndrome characterized by total fetal akinesia (detectable since the 13th week of gestation) accompanied by hydrops, micrognathia , pulmonary hypoplasia, pterygia and multiple joint contractures (usually flexion contractures in the elbows and extension in the knees), leading invariably to death before the 32nd week of gestation. Lack of anterior horn motoneurons, severe atrophy of the ventral spinal cord and severe skeletal muscle hypoplasia are characteristic neuropathological findings, with no evidence of other organ structural anomalies. Visit the Orphanet disease page for more resources.

MalaCards based summary : Lethal Congenital Contracture Syndrome 1, also known as multiple contracture syndrome, finnish type, is related to lethal congenital contracture syndrome and anterior horn cell disease. An important gene associated with Lethal Congenital Contracture Syndrome 1 is GLE1 (GLE1 RNA Export Mediator), and among its related pathways/superpathways are Metabolism and Innate Immune System. The drugs Calcium carbonate and Calcium have been mentioned in the context of this disorder. Affiliated tissues include skeletal muscle, bone and spinal cord, and related phenotypes are hypertelorism and short stature

Disease Ontology : 12 A lethal congenital contracture syndrome that has material basis in homozygous or compound heterozygous mutation in the mRNA export mediator GLE1 on chromosome 9q34.

OMIM : 56 Autosomal recessive lethal congenital contracture syndrome (LCCS) is the most severe, neonatally lethal, form of arthrogryposis (see 108120), a disorder characterized by congenital nonprogressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth (summary by Markus et al., 2012). (253310)

UniProtKB/Swiss-Prot : 73 Lethal congenital contracture syndrome 1: A form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non- progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS1 patients manifest early fetal hydrops and akinesia, micrognathia, pulmonary hypoplasia, pterygia, and multiple joint contractures. It leads to prenatal death.

Related Diseases for Lethal Congenital Contracture Syndrome 1

Diseases in the Lethal Congenital Contracture Syndrome family:

Lethal Congenital Contracture Syndrome 1 Lethal Congenital Contracture Syndrome 2
Lethal Congenital Contracture Syndrome 3 Lethal Congenital Contracture Syndrome 4
Lethal Congenital Contracture Syndrome 5 Lethal Congenital Contracture Syndrome 6
Lethal Congenital Contracture Syndrome 7 Lethal Congenital Contracture Syndrome 8
Lethal Congenital Contracture Syndrome 9 Lethal Congenital Contracture Syndrome 10
Lethal Congenital Contracture Syndrome 11

Diseases related to Lethal Congenital Contracture Syndrome 1 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 31)
# Related Disease Score Top Affiliating Genes
1 lethal congenital contracture syndrome 32.3 RAE1 NUP155 IPPK GLE1 ERBB3 DDX19B
2 anterior horn cell disease 28.5 RAE1 NUP88 NUP85 NUP155 GLE1 DDX19B
3 leukoencephalopathy, brain calcifications, and cysts 12.0
4 cerebroretinal microangiopathy with calcifications and cysts 1 11.5
5 hepatocellular carcinoma 11.4
6 congenital arthrogryposis with anterior horn cell disease 11.4
7 lung large cell carcinoma 11.4
8 leukoencephalopathy, cerebral calcifications, and cysts 11.2
9 lethal congenital contracture syndrome 3 11.2
10 lethal congenital contracture syndrome 7 11.2
11 lethal congenital contracture syndrome 8 11.2
12 lung cancer 10.2
13 ataxia and polyneuropathy, adult-onset 10.1
14 branchiootic syndrome 1 10.1
15 lung cancer susceptibility 3 10.1
16 alkuraya-kucinskas syndrome 10.1
17 distal arthrogryposis 10.1
18 spinal muscular atrophy 10.1
19 squamous cell carcinoma 10.1
20 lung benign neoplasm 10.1
21 dystonia 10.1
22 compartment syndrome 10.1
23 muscular atrophy 10.1
24 intracranial hypertension 10.1
25 spasticity 10.1
26 congenital amyoplasia 10.1
27 lethal congenital contracture syndrome 2 10.0 GLE1 ERBB3
28 congenital contractures 10.0
29 achalasia-addisonianism-alacrima syndrome 9.5 NUP35 NUP160
30 genetic steroid-resistant nephrotic syndrome 9.2 NUP93 NUP85 NUP160
31 nephrotic syndrome 9.2 NUP93 NUP85 NUP160

Graphical network of the top 20 diseases related to Lethal Congenital Contracture Syndrome 1:



Diseases related to Lethal Congenital Contracture Syndrome 1

Symptoms & Phenotypes for Lethal Congenital Contracture Syndrome 1

Human phenotypes related to Lethal Congenital Contracture Syndrome 1:

58 31 (show all 25)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hypertelorism 58 31 hallmark (90%) Very frequent (99-80%) HP:0000316
2 short stature 58 31 hallmark (90%) Very frequent (99-80%) HP:0004322
3 micrognathia 58 31 hallmark (90%) Very frequent (99-80%) HP:0000347
4 skeletal muscle atrophy 58 31 hallmark (90%) Very frequent (99-80%) HP:0003202
5 abnormality of the hip bone 58 31 hallmark (90%) Very frequent (99-80%) HP:0003272
6 pulmonary hypoplasia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002089
7 short neck 58 31 frequent (33%) Frequent (79-30%) HP:0000470
8 abnormal cortical bone morphology 58 31 frequent (33%) Frequent (79-30%) HP:0003103
9 polyhydramnios 58 31 frequent (33%) Frequent (79-30%) HP:0001561
10 limitation of joint mobility 58 31 frequent (33%) Frequent (79-30%) HP:0001376
11 webbed neck 58 31 frequent (33%) Frequent (79-30%) HP:0000465
12 slender long bone 58 31 frequent (33%) Frequent (79-30%) HP:0003100
13 low-set, posteriorly rotated ears 58 31 frequent (33%) Frequent (79-30%) HP:0000368
14 abnormality of the ribs 58 31 frequent (33%) Frequent (79-30%) HP:0000772
15 recurrent fractures 58 31 frequent (33%) Frequent (79-30%) HP:0002757
16 abnormality of the elbow 58 31 frequent (33%) Frequent (79-30%) HP:0009811
17 amniotic constriction ring 58 31 frequent (33%) Frequent (79-30%) HP:0009775
18 abnormal form of the vertebral bodies 58 31 occasional (7.5%) Occasional (29-5%) HP:0003312
19 arthrogryposis multiplex congenita 31 HP:0002804
20 edema 31 HP:0000969
21 abnormality of the thorax 31 HP:0000765
22 hypoplasia of the musculature 31 HP:0009004
23 abnormality of the amniotic fluid 31 HP:0001560
24 widening of cervical spinal canal 31 HP:0004571
25 paucity of anterior horn motor neurons 31 HP:0007277

Symptoms via clinical synopsis from OMIM:

56
Head And Neck Face:
micrognathia

Neurologic Central Nervous System:
paucity of anterior horn motor neurons

Chest Ribs Sternum Clavicles And Scapulae:
thin fishbone-like ribs

Prenatal Manifestations Amniotic Fluid:
marked fetal hydrops

Respiratory Lung:
pulmonary hypoplasia

Muscle Soft Tissue:
muscle atrophy
muscle hypoplasia

Skeletal Limbs:
multiple congenital contractures
generalized thinning of tubular bones

Clinical features from OMIM:

253310

GenomeRNAi Phenotypes related to Lethal Congenital Contracture Syndrome 1 according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased viability of wild-type and TP53 knockout cells, decreased TP53 protein expression ratio (wild-type / TP53 knockout cells) GR00196-A-1 9.8 DDX19B GLE1 NUP214 NUP88 NUP93 NXF1
2 Increased caspase activity GR00400-S-1 9.73 NUP42 NUP85
3 Increased caspase activity GR00400-S-2 9.73 DDX19B NUP42 NUP85 NUP93
4 Decreased p24 protein expression GR00163-A-1 9.58 NUP155 NUP160 NUP85
5 Nuclear 40S maturation defects GR00209-A-2 9.55 NUP160 NUP214 NUP88 NUP93 RAE1
6 Decreased TP53 protein expression ratio (wild-type / TP53 knockout cells) GR00196-A-2 9.54 DDX19B NUP214 NUP88
7 Nuclear 60S biogenesis defects GR00209-A-3 9.43 GLE1 NUP160 NUP214 NUP88 NUP93 RAE1
8 Nucleoplasmic pre-40S maturation defects GR00209-A-1 9.23 GLE1 NUP155 NUP160 NUP214 NUP85 NUP88

Drugs & Therapeutics for Lethal Congenital Contracture Syndrome 1

Drugs for Lethal Congenital Contracture Syndrome 1 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 11)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1
Calcium carbonate Approved, Investigational Phase 1 471-34-1
2
Calcium Approved, Nutraceutical Phase 1 7440-70-2 271
3 Gastrointestinal Agents Phase 1
4 Anti-Ulcer Agents Phase 1
5 Calcium, Dietary Phase 1
6 Antacids Phase 1
7 Hormones Phase 1
8 Calcium Supplement Phase 1
9
Menthol Approved 2216-51-5 16666
10 Dermatologic Agents
11 Antipruritics

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 A Human Crossover Study to Compare the Bioavailability of Calcium From AlgaeCal® Versus a Proprietary Calcium Dietary Supplement Completed NCT01609413 Phase 1
2 Addictive Potential of Little Cigars/Cigarillos in Dual Users: Effect by Flavor and Gender Recruiting NCT03496077
3 Assessing Tobacco Product Choice When the Cost of Menthol Cigarettes Increases Recruiting NCT03612349

Search NIH Clinical Center for Lethal Congenital Contracture Syndrome 1

Cochrane evidence based reviews: lethal congenital contracture syndrome 1

Genetic Tests for Lethal Congenital Contracture Syndrome 1

Genetic tests related to Lethal Congenital Contracture Syndrome 1:

# Genetic test Affiliating Genes
1 Lethal Congenital Contracture Syndrome 1 29 GLE1

Anatomical Context for Lethal Congenital Contracture Syndrome 1

MalaCards organs/tissues related to Lethal Congenital Contracture Syndrome 1:

40
Skeletal Muscle, Bone, Spinal Cord, Lung, Brain

Publications for Lethal Congenital Contracture Syndrome 1

Articles related to Lethal Congenital Contracture Syndrome 1:

(show all 17)
# Title Authors PMID Year
1
Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. 61 56 6
18204449 2008
2
Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. 61 6
24243016 2013
3
Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1. 6
28884921 2017
4
Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1. 56
22610851 2012
5
Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in Finland--an epidemiological study. 56
16892327 2006
6
Assignment of the disease locus for lethal congenital contracture syndrome to a restricted region of chromosome 9q34, by genome scan using five affected individuals. 56
9683599 1998
7
Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus. 56
7897624 1995
8
Lethal congenital contracture syndrome: further delineation and genetic aspects. 56
7966188 1994
9
A syndrome of multiple congenital contractures: neuropathological analysis on five fetal cases. 56
3344776 1988
10
A lethal autosomal recessive syndrome of multiple congenital contractures. 56
3993672 1985
11
Multiple ankyloses, facial anomalies, and pulmonary hypoplasia associated with severe antenatal spinal muscular atrophy. 56
6875715 1983
12
A homozygous I684T in GLE1 as a novel cause of arthrogryposis and motor neuron loss. 61
28657126 2018
13
Expansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrum. 61
27684565 2017
14
Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo. 61
26921650 2016
15
Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. 61
25343993 2015
16
Insights into mRNA export-linked molecular mechanisms of human disease through a Gle1 structure-function analysis. 61
24275432 2014
17
A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in spinal neural precursor survival and motor axon arborization. 61
22357925 2012

Variations for Lethal Congenital Contracture Syndrome 1

ClinVar genetic disease variations for Lethal Congenital Contracture Syndrome 1:

6 ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 GLE1 NM_001499.2(GLE1):c.433-10A>GSNV Pathogenic 6462 rs386833693 9:131284937-131284937 9:128522658-128522658
2 GLE1 NM_001499.2(GLE1):c.1706G>A (p.Arg569His)SNV Likely pathogenic 6463 rs121434407 9:131298693-131298693 9:128536414-128536414
3 GLE1 NM_001499.2(GLE1):c.5C>G (p.Pro2Arg)SNV Uncertain significance 285426 rs150246404 9:131267089-131267089 9:128504810-128504810
4 ERBB3 NM_001982.3(ERBB3):c.3567_3569AGA[2] (p.Glu1191del)short repeat Uncertain significance 522965 rs780883720 12:56495375-56495377 12:56101591-56101593

UniProtKB/Swiss-Prot genetic disease variations for Lethal Congenital Contracture Syndrome 1:

73
# Symbol AA change Variation ID SNP ID
1 GLE1 p.Arg569His VAR_043875 rs121434407

Expression for Lethal Congenital Contracture Syndrome 1

Search GEO for disease gene expression data for Lethal Congenital Contracture Syndrome 1.

Pathways for Lethal Congenital Contracture Syndrome 1

Pathways related to Lethal Congenital Contracture Syndrome 1 according to GeneCards Suite gene sharing:

(show all 21)
# Super pathways Score Top Affiliating Genes
1
Show member pathways
13.95 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
2
Show member pathways
13.88 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
3
Show member pathways
13.71 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
4
Show member pathways
13.66 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
5
Show member pathways
13.63 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
6
Show member pathways
13.37 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
7
Show member pathways
13.33 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
8
Show member pathways
13.33 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
9
Show member pathways
13.23 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
10
Show member pathways
13.15 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
11
Show member pathways
13.14 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
12
Show member pathways
12.88 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
13
Show member pathways
12.76 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
14
Show member pathways
12.71 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
15
Show member pathways
12.59 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
16
Show member pathways
12.51 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
17
Show member pathways
12.35 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
18
Show member pathways
12.04 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
19
Show member pathways
11.91 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
20
Show member pathways
11.87 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
21 11.54 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42

GO Terms for Lethal Congenital Contracture Syndrome 1

Cellular components related to Lethal Congenital Contracture Syndrome 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 nucleus GO:0005634 10.13 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
2 nuclear envelope GO:0005635 9.81 RAE1 NXF1 NUP93 NUP85 NUP42 NUP35
3 nuclear membrane GO:0031965 9.8 NUP93 NUP85 NUP42 NUP35 NUP155 GLE1
4 host cell GO:0043657 9.61 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
5 nuclear pore outer ring GO:0031080 9.4 NUP85 NUP160
6 nuclear pore GO:0005643 9.4 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
7 nuclear pore cytoplasmic filaments GO:0044614 9.37 NUP214 GLE1

Biological processes related to Lethal Congenital Contracture Syndrome 1 according to GeneCards Suite gene sharing:

(show all 19)
# Name GO ID Score Top Affiliating Genes
1 protein transport GO:0015031 10.22 NXF1 NUP93 NUP88 NUP85 NUP42 NUP35
2 viral process GO:0016032 10.19 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
3 regulation of cellular response to heat GO:1900034 10.11 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
4 intracellular transport of virus GO:0075733 10.09 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
5 regulation of gene silencing by miRNA GO:0060964 10.06 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
6 viral transcription GO:0019083 10.02 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
7 protein sumoylation GO:0016925 9.97 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
8 protein import into nucleus GO:0006606 9.93 NUP93 NUP88 NUP85 NUP214 NUP155
9 nucleocytoplasmic transport GO:0006913 9.92 NUP93 NUP88 NUP85 NUP35 NUP155
10 poly(A)+ mRNA export from nucleus GO:0016973 9.91 NXF1 NUP93 NUP214 GLE1 DDX19B
11 tRNA export from nucleus GO:0006409 9.91 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
12 regulation of glycolytic process GO:0006110 9.81 RAE1 NUP93 NUP88 NUP85 NUP42 NUP35
13 protein export from nucleus GO:0006611 9.72 NUP88 NUP42 NUP214
14 mRNA transport GO:0051028 9.7 NXF1 NUP93 NUP88 NUP85 NUP42 NUP35
15 nuclear envelope organization GO:0006998 9.58 NUP93 NUP155
16 nephron development GO:0072006 9.58 NUP85 NUP160
17 ribosomal small subunit export from nucleus GO:0000056 9.57 NUP88 NUP214
18 transcription-dependent tethering of RNA polymerase II gene DNA at nuclear periphery GO:0000972 9.56 RAE1 NUP155
19 mRNA export from nucleus GO:0006406 9.4 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42

Molecular functions related to Lethal Congenital Contracture Syndrome 1 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein binding GO:0005515 9.8 RAE1 NXF1 NUP93 NUP88 NUP85 NUP42
2 structural constituent of nuclear pore GO:0017056 9.17 NUP93 NUP88 NUP85 NUP35 NUP214 NUP160
3 nuclear export signal receptor activity GO:0005049 9.16 NUP42 NUP214

Sources for Lethal Congenital Contracture Syndrome 1

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
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
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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