CLN4A
MCID: CRD226
MIFTS: 46

Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive (CLN4A)

Categories: Eye diseases, Genetic diseases, Mental diseases, Metabolic diseases, Neuronal diseases, Rare diseases

Aliases & Classifications for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

MalaCards integrated aliases for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

Name: Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive 56
Ceroid Lipofuscinosis, Neuronal, Kufs Type, Adult Onset 56 29 13
Cln4a 56 12 73
Autosomal Recessive Neuronal Ceroid Lipofuscinosis 4a 12 52
Adult Neuronal Ceroid Lipofuscinosis 73 71
Neuronal Ceroid Lipofuscinosis 4a 12 15
Kufs Disease 73 36
Ceroid Lipofuscinosis, Neuronal, 4a 73
Kufs Disease Autosomal Recessive 73
Cln6 Disease Kufs Type a 73
Cln4a Disease 58

Characteristics:

Orphanet epidemiological data:

58
cln4a disease
Inheritance: Autosomal recessive; Age of onset: Adult;

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
onset in adulthood (third to fourth decade)
type a characterized by progressive myoclonic epilepsy
type b characterized by dementia, motor disturbances, and facial dyskinesia
for similar autosomal dominant form, see


HPO:

31
ceroid lipofuscinosis, neuronal, 4a, autosomal recessive:
Inheritance autosomal recessive inheritance
Onset and clinical course adult onset


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare eye diseases
Inborn errors of metabolism


External Ids:

Disease Ontology 12 DOID:0110730
OMIM 56 204300
OMIM Phenotypic Series 56 PS256730
KEGG 36 H02276
MeSH 43 D009472
ICD10 32 E75.4
ICD10 via Orphanet 33 E75.4
Orphanet 58 ORPHA228340
UMLS 71 C0022797

Summaries for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

OMIM : 56 Adult-onset neuronal ceroid lipofuscinosis, also known as Kufs disease, is a neurodegenerative disorder without retinal involvement. There are 2 overlapping phenotypes: type A, characterized by progressive myoclonic epilepsy, and type B, characterized by dementia and a variety of motor-system signs (summary by Arsov et al., 2011). In general, the neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The clinical course includes progressive dementia, seizures, and progressive visual failure. The ultrastructural pattern of lipopigment in CLN4 comprises a mixed pattern of 'granular,' 'curvilinear,' and 'fingerprint' profiles (Mole et al., 2005). For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730). (204300)

MalaCards based summary : Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive, also known as ceroid lipofuscinosis, neuronal, kufs type, adult onset, is related to adult neuronal ceroid lipofuscinosis and ceroid lipofuscinosis, neuronal, 13, and has symptoms including seizures, myoclonus and abnormality of extrapyramidal motor function. An important gene associated with Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive is CLN6 (CLN6 Transmembrane ER Protein), and among its related pathways/superpathways are Protein processing in endoplasmic reticulum and Lysosome. Affiliated tissues include retina, eye and brain, and related phenotypes are seizures and depressivity

Disease Ontology : 12 A neuronal ceroid lipofuscinosis that is characterized by adult-onset of progressive dementia, seizures, and progressive visual failure and lipopigment patterns with mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles and has material basis in homozygous or compound heterozygous mutation in the CLN6 gene on chromosome 15q23.

KEGG : 36 Kufs disease, an adult-onset neuronal ceroid lipofuscinosis (NCL), differs from most other forms of NCL because the retina is not involved, and vision is preserved. The clinical presentation has been divided into two types. Type A presents with progressive myoclonus epilepsy, whereas type B presents with dementia and a variety of motor disturbances. It has been reported that mutations in CLN6 cause recessive type A Kufs disease. Mutations in DNAJC5 have been found in some cases of dominant Kufs disease, also presenting with progressive myoclonus epilepsy. Mutations in CTSF were recently identified in recessive type B Kufs disease.

UniProtKB/Swiss-Prot : 73 Ceroid lipofuscinosis, neuronal, 4A: An adult-onset neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. CLN4A has no visual involvement and is characterized by progressive myoclonic epilepsy.

Related Diseases for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Diseases in the Neuronal Ceroid Lipofuscinosis family:

Ceroid Lipofuscinosis, Neuronal, 4b, Autosomal Dominant Ceroid Lipofuscinosis, Neuronal, 3
Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive Ceroid Lipofuscinosis, Neuronal, 2
Ceroid Lipofuscinosis, Neuronal, 1 Ceroid Lipofuscinosis, Neuronal, 5
Ceroid Lipofuscinosis, Neuronal, 8 Ceroid Lipofuscinosis, Neuronal, 6
Ceroid Lipofuscinosis, Neuronal, 9 Ceroid Lipofuscinosis, Neuronal, 10
Ceroid Lipofuscinosis, Neuronal, 7 Ceroid Lipofuscinosis, Neuronal, 11
Ceroid Lipofuscinosis, Neuronal, 13 Adult Neuronal Ceroid Lipofuscinosis

Diseases related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive via text searches within MalaCards or GeneCards Suite gene sharing:

(show top 50) (show all 85)
# Related Disease Score Top Affiliating Genes
1 adult neuronal ceroid lipofuscinosis 34.6 TPP1 PPT1 DNAJC5 CLN6
2 ceroid lipofuscinosis, neuronal, 13 31.4 TPP1 PPT1 DNAJC5 CTSD CLN6 CLN3
3 cerebral atrophy 30.8 CLN6 CLN3
4 neuronal ceroid-lipofuscinoses 30.6 PPT1 CLN6 CLN3
5 progressive myoclonus epilepsy 30.5 TPP1 CLN6 CLN3
6 neuronal ceroid lipofuscinosis 30.1 TPP1 PPT1 DNAJC5 CTSD CLN6 CLN3
7 ceroid storage disease 29.9 TPP1 PPT1 DNAJC5 CLN6 CLN3
8 ceroid lipofuscinosis, neuronal, 1 29.7 TPP1 PPT1 DNAJC5 CTSD CLN6 CLN3
9 visual epilepsy 29.4 TPP1 PPT1 DNM1 DNAJC5 CLN6 CLN3
10 ceroid lipofuscinosis, neuronal, 2 29.3 TPP1 PPT1 DNAJC5 CTSD CLN6 CLN3
11 aceruloplasminemia 29.1 SOD1 KCNC3 GRM1 DNM1 CALB1
12 ceroid lipofuscinosis, neuronal, 4b, autosomal dominant 12.4
13 cln4 disease 12.2
14 ceroid lipofuscinosis, neuronal, 6 11.9
15 epilepsy, progressive myoclonic, 4, with or without renal failure 10.4
16 ataxia and polyneuropathy, adult-onset 10.4
17 myoclonus 10.4
18 dementia 10.3
19 ceroid lipofuscinosis, neuronal, 11 10.2 DNAJC5 CLN6 CLN3
20 spinocerebellar ataxia, autosomal recessive 7 10.2 TPP1 CLN6
21 alzheimer disease 10.2
22 huntington disease 10.2
23 ceroid lipofuscinosis, neuronal, 5 10.2
24 ceroid lipofuscinosis, neuronal, 8 10.2
25 yemenite deaf-blind hypopigmentation syndrome 10.2
26 neurodegeneration with brain iron accumulation 10.2
27 niemann-pick disease 10.2
28 glioblastoma multiforme 10.2
29 movement disease 10.2
30 dystonia 10.2
31 prion disease 10.2
32 muscular atrophy 10.2
33 retinal degeneration 10.2
34 47,xyy 10.2
35 glioma 10.2
36 myoclonus epilepsy 10.2
37 dysphagia 10.2
38 glial tumor 10.2
39 aphasia 10.1
40 early myoclonic encephalopathy 10.1
41 seizure disorder 10.1
42 mucopolysaccharidosis-plus syndrome 10.1 TPP1 IDUA ARSG
43 nerve compression syndrome 10.1 IDUA ARHGEF10
44 ceroid lipofuscinosis, neuronal, 9 10.1 TPP1 DNAJC5 CLN6 CLN3
45 spinocerebellar ataxia, autosomal recessive 13 10.0 KCNC3 GRM1
46 amyotrophic lateral sclerosis 1 10.0
47 creutzfeldt-jakob disease 10.0
48 pick disease of brain 10.0
49 myoclonic epilepsy of unverricht and lundborg 10.0
50 3-methylglutaconic aciduria, type iii 10.0

Graphical network of the top 20 diseases related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:



Diseases related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Symptoms & Phenotypes for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Human phenotypes related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

31 (show all 15)
# Description HPO Frequency HPO Source Accession
1 seizures 31 HP:0001250
2 depressivity 31 HP:0000716
3 ataxia 31 HP:0001251
4 myoclonus 31 HP:0001336
5 dementia 31 HP:0000726
6 visual hallucinations 31 HP:0002367
7 abnormality of extrapyramidal motor function 31 HP:0002071
8 leukoencephalopathy 31 HP:0002352
9 cerebral atrophy 31 HP:0002059
10 auditory hallucinations 31 HP:0008765
11 increased neuronal autofluorescent lipopigment 31 HP:0002074
12 curvilinear intracellular accumulation of autofluorescent lipopigment storage material 31 HP:0003205
13 fingerprint intracellular accumulation of autofluorescent lipopigment storage material 31 HP:0003208
14 rectilinear intracellular accumulation of autofluorescent lipopigment storage material 31 HP:0003226
15 granular osmiophilic deposits (grod) in cells 31 HP:0003657

Symptoms via clinical synopsis from OMIM:

56
Neurologic Central Nervous System:
seizures
myoclonus
dementia
cerebral atrophy
cerebellar ataxia
more
Laboratory Abnormalities:
granular osmiophilic deposits (grod) in cells resulting in 'fingerprint' profiles ultrastructurally
granular osmiophilic deposits (grod) in cells resulting in 'curvilinear' profiles ultrastructurally
granular osmiophilic deposits (grod) in cells resulting in 'rectilinear' profiles ultrastructurally

Neurologic Behavioral Psychiatric Manifestations:
depression
behavioral changes
auditory and visual hallucinations

Clinical features from OMIM:

204300

UMLS symptoms related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:


seizures, myoclonus, abnormality of extrapyramidal motor function, cerebellar ataxia

GenomeRNAi Phenotypes related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Decreased viability GR00221-A-2 10.03 SOD1
2 Decreased viability GR00221-A-3 10.03 SOD1
3 Decreased viability GR00221-A-4 10.03 SOD1
4 Decreased viability GR00240-S-1 10.03 KCNC3
5 Decreased viability GR00381-A-1 10.03 IDUA
6 Decreased viability GR00402-S-2 10.03 ARHGEF10 ARSG CALB1 CAPN1 CLN3 CLN6
7 no effect GR00402-S-1 9.6 ARHGEF10 ARSG CALB1 CAPN1 CLN3 CLN6

MGI Mouse Phenotypes related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

45
# Description MGI Source Accession Score Top Affiliating Genes
1 behavior/neurological MP:0005386 10.34 ARHGEF10 ARSG CALB1 CLN3 CLN6 CTSD
2 homeostasis/metabolism MP:0005376 10.22 ARHGEF10 ARSG CAPN1 CLN3 CTSD DNAJC5
3 mortality/aging MP:0010768 10.13 CAPN1 CLN3 CLN6 CTSD DNAJC5 DNM1
4 cellular MP:0005384 10.1 ARSG CAPN1 CLN3 CTSD DNM1 FBN2
5 hearing/vestibular/ear MP:0005377 9.97 CALB1 CTSD DNAJC5 DNM1 FBN2 IDUA
6 nervous system MP:0003631 9.83 ARHGEF10 ARSG CALB1 CLN3 CLN6 CTSD
7 muscle MP:0005369 9.81 DNAJC5 FBN2 GRM1 HACD1 IDUA KCNC3
8 vision/eye MP:0005391 9.44 ARSG CLN3 CLN6 CTSD DNAJC5 DNM1

Drugs & Therapeutics for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Search Clinical Trials , NIH Clinical Center for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Genetic Tests for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Genetic tests related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

# Genetic test Affiliating Genes
1 Ceroid Lipofuscinosis, Neuronal, Kufs Type, Adult Onset 29

Anatomical Context for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

MalaCards organs/tissues related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

40
Retina, Eye, Brain

Publications for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Articles related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

(show all 14)
# Title Authors PMID Year
1
Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. 56 6
21549341 2011
2
Kufs' disease: a critical reappraisal. 56 6
3284607 1988
3
Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features. 56
30561534 2019
4
Neuronal ceroid lipofuscinoses. 6
19084560 2009
5
Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. 56
15965709 2005
6
Neuronal Ceroid-Lipofuscinoses 6
20301601 2001
7
Familial Kufs' disease presenting as a progressive myoclonic epilepsy. 56
10929274 2000
8
Neuronal ceroid-lipofuscinosis: a clinical and morphological study of 19 patients. 56
7668317 1995
9
Adult neuronal ceroid-lipofuscinosis. 56
2663281 1989
10
Familial occurrence of adult-type neuronal ceroid lipofuscinosis. 56
6477218 1984
11
Adult ceroid-lipofuscinosis (Kufs' disease) in two brothers. Retinal and visceral storage in one; diagnostic muscle biopsy in the other. 56
760366 1979
12
Electron microscopy of storage cytosomes in Kufs' disease. 56
5478271 1970
13
Juvenile and late forms of amaurotic idiocy in one family. 56
14003453 1962
14
The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. 61
24069350 2013

Variations for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

ClinVar genetic disease variations for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

6 ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 CLN6 NM_017882.3(CLN6):c.200T>C (p.Leu67Pro)SNV Pathogenic 30599 rs154774633 15:68506725-68506725 15:68214387-68214387
2 CLN6 NM_017882.3(CLN6):c.17G>C (p.Arg6Thr)SNV Pathogenic 30602 rs154774636 15:68521906-68521906 15:68229568-68229568
3 CLN6 NM_017882.3(CLN6):c.53C>T (p.Ala18Val)SNV Conflicting interpretations of pathogenicity 193389 rs547125345 15:68521870-68521870 15:68229532-68229532
4 CLN6 NM_017882.3(CLN6):c.923G>C (p.Ser308Thr)SNV Conflicting interpretations of pathogenicity 198573 rs143578698 15:68500491-68500491 15:68208153-68208153
5 CLN6 NM_017882.3(CLN6):c.728C>T (p.Ala243Val)SNV Uncertain significance 205174 rs767164948 15:68500686-68500686 15:68208348-68208348
6 CLN6 NM_017882.3(CLN6):c.308G>A (p.Arg103Gln)SNV Uncertain significance 30600 rs154774634 15:68504191-68504191 15:68211853-68211853
7 CLN6 NM_017882.3(CLN6):c.139C>T (p.Leu47Phe)SNV Uncertain significance 30601 rs154774635 15:68510933-68510933 15:68218595-68218595
8 CLN6 NM_017882.3(CLN6):c.482C>T (p.Thr161Met)SNV Uncertain significance 452272 rs757734645 15:68504017-68504017 15:68211679-68211679
9 CLN6 NM_017882.3(CLN6):c.41G>A (p.Gly14Asp)SNV Uncertain significance 579778 rs994590268 15:68521882-68521882 15:68229544-68229544

UniProtKB/Swiss-Prot genetic disease variations for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive:

73
# Symbol AA change Variation ID SNP ID
1 CLN6 p.Arg6Thr VAR_065834 rs154774636
2 CLN6 p.Leu47Phe VAR_065836 rs154774635
3 CLN6 p.Leu67Pro VAR_065837 rs154774633
4 CLN6 p.Asn77Lys VAR_065838 rs154774641
5 CLN6 p.Arg103Gln VAR_065839 rs154774634
6 CLN6 p.Arg149His VAR_065840 rs154774638
7 CLN6 p.Phe238Thr VAR_065841

Expression for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Search GEO for disease gene expression data for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive.

Pathways for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Pathways related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to KEGG:

36
# Name Kegg Source Accession
1 Protein processing in endoplasmic reticulum hsa04141
2 Lysosome hsa04142

Pathways related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 11.89 SOD1 NCS1 GRM1 CAPN1 CALB1
2 11.19 TPP1 PPT1 IDUA CTSD CLN3 ARSG

GO Terms for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

Cellular components related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to GeneCards Suite gene sharing:

(show all 15)
# Name GO ID Score Top Affiliating Genes
1 extracellular exosome GO:0070062 10.1 TPP1 SOD1 PPT1 IDUA DNM1 CTSD
2 synapse GO:0045202 9.93 PPT1 NCS1 KCNC3 DNM1 CALB1
3 neuronal cell body GO:0043025 9.85 SOD1 PPT1 KCNC3 CALB1
4 glutamatergic synapse GO:0098978 9.81 NCS1 GRM1 DNM1 CALB1
5 dendrite GO:0030425 9.77 PPT1 NCS1 KCNC3 GRM1 CALB1
6 neuron projection GO:0043005 9.72 SOD1 PPT1 GRM1 CLN3 CALB1
7 axon GO:0030424 9.65 PPT1 NCS1 KCNC3 DNM1 CALB1
8 melanosome GO:0042470 9.61 TPP1 DNAJC5 CTSD
9 calyx of Held GO:0044305 9.52 NCS1 CALB1
10 postsynaptic cytosol GO:0099524 9.48 NCS1 CALB1
11 dense core granule GO:0031045 9.46 SOD1 NCS1
12 synaptic vesicle GO:0008021 9.46 PPT1 DNM1 DNAJC5 CLN3
13 presynaptic cytosol GO:0099523 9.4 NCS1 CALB1
14 lysosomal lumen GO:0043202 9.26 TPP1 PPT1 IDUA CTSD
15 lysosome GO:0005764 9.23 TPP1 SOD1 PPT1 IDUA CTSD CLN3

Biological processes related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 negative regulation of neuron apoptotic process GO:0043524 9.62 SOD1 PPT1 DNAJC5 CLN3
2 locomotory behavior GO:0007626 9.61 SOD1 GRM1 CALB1
3 regulation of presynaptic cytosolic calcium ion concentration GO:0099509 9.46 NCS1 CALB1
4 protein catabolic process GO:0030163 9.46 TPP1 PPT1 CTSD CLN6
5 regulation of postsynaptic cytosolic calcium ion concentration GO:0099566 9.4 GRM1 CALB1
6 regulation of synapse structure or activity GO:0050803 9.37 PPT1 DNM1
7 cellular macromolecule catabolic process GO:0044265 9.26 PPT1 CLN6
8 lysosomal lumen acidification GO:0007042 9.13 PPT1 CLN6 CLN3
9 lysosome organization GO:0007040 8.92 TPP1 PPT1 CLN6 CLN3

Molecular functions related to Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein binding GO:0005515 9.86 TPP1 SOD1 PPT1 NCS1 KCNJ10 KCNC3
2 hydrolase activity GO:0016787 9.17 TPP1 PPT1 IDUA DNM1 CTSD CAPN1

Sources for Ceroid Lipofuscinosis, Neuronal, 4a, Autosomal Recessive

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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