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SPG46
MCID: SPS109
MIFTS: 38

Spastic Paraplegia 46, Autosomal Recessive (SPG46)

Categories: Bone diseases, Ear diseases, Eye diseases, Gastrointestinal diseases, Genetic diseases, Mental diseases, Metabolic diseases, Nephrological diseases, Neuronal diseases, Rare diseases, Respiratory diseases, Skin diseases
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Aliases & Classifications for Spastic Paraplegia 46, Autosomal Recessive

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MalaCards integrated aliases for Spastic Paraplegia 46, Autosomal Recessive:

Name: Spastic Paraplegia 46, Autosomal Recessive 57 74 29 13 6 72
Spg46 57 12 59 74
Autosomal Recessive Spastic Paraplegia Type 46 12 59
Hereditary Spastic Paraplegia 46 12 15
Paraplegia, Spastic, Type 46, Autosomal Recessive 40
Autosomal Recessive Spastic Paraplegia 46 12

Characteristics:

Orphanet epidemiological data:

59
autosomal recessive spastic paraplegia type 46
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Childhood;

OMIM:

57
Inheritance:
autosomal recessive

Miscellaneous:
progressive disorder
onset in childhood (range 2 to 16 years)
some patients present with spasticity, whereas others present with cerebellar ataxia
some patients may have normal brain imaging


HPO:

32
spastic paraplegia 46, autosomal recessive:
Inheritance autosomal recessive inheritance
Onset and clinical course progressive slow progression


Classifications:

MalaCards categories:
Global: Genetic diseases Rare diseases Metabolic diseases
Anatomical: Neuronal diseases Eye diseases Gastrointestinal diseases Skin diseases Respiratory diseases Bone diseases Nephrological diseases Ear diseases Mental diseases
See all MalaCards categories (disease lists)
ICD10: 33 34
Orphanet: 59  
Rare neurological diseases


External Ids:

Disease Ontology 12 DOID:0110798
MeSH 44 D015419
ICD10 33 G11.4
ICD10 via Orphanet 34 G11.4
Orphanet 59 ORPHA320391
MedGen 42 C2828721
UMLS 72 C2828721
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Summaries for Spastic Paraplegia 46, Autosomal Recessive

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OMIM : 57 Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by Boukhris et al., 2010 and Martin et al., 2013). (614409)

MalaCards based summary : Spastic Paraplegia 46, Autosomal Recessive, also known as spg46, is related to paraplegia and spastic paraplegia 56, autosomal recessive, and has symptoms including cerebellar ataxia and abnormal pyramidal signs. An important gene associated with Spastic Paraplegia 46, Autosomal Recessive is GBA2 (Glucosylceramidase Beta 2). Affiliated tissues include brain, and related phenotypes are cataract and babinski sign

Disease Ontology : 12 A hereditary spastic paraplegia that has material basis in mutation in the GBA2 gene on chromosome 9p.

UniProtKB/Swiss-Prot : 74 Spastic paraplegia 46, autosomal recessive: A neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging.

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Related Diseases for Spastic Paraplegia 46, Autosomal Recessive

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Diseases in the Spastic Paraplegia 3a family:

Spastic Paraplegia 3, Autosomal Dominant Spastic Paraplegia 4, Autosomal Dominant
Spastic Paraplegia 17, Autosomal Dominant Spastic Paraplegia 15, Autosomal Recessive
Spastic Paraplegia 23, Autosomal Recessive Spastic Paraplegia 5a, Autosomal Recessive
Spastic Paraplegia 20, Autosomal Recessive Spastic Paraplegia 6, Autosomal Dominant
Spastic Paraplegia 9a, Autosomal Dominant Spastic Paraplegia 8, Autosomal Dominant
Spastic Paraplegia 10, Autosomal Dominant Spastic Paraplegia 11, Autosomal Recessive
Spastic Paraplegia 12, Autosomal Dominant Spastic Paraplegia 14, Autosomal Recessive
Spastic Paraplegia 13, Autosomal Dominant Spastic Paraplegia 19, Autosomal Dominant
Spastic Paraplegia 7, Autosomal Recessive Spastic Paraplegia 24, Autosomal Recessive
Spastic Paraplegia 25, Autosomal Recessive Spastic Paraplegia 27, Autosomal Recessive
Spastic Paraplegia 26, Autosomal Recessive Spastic Paraplegia 28, Autosomal Recessive
Spastic Paraplegia 29, Autosomal Dominant Spastic Paraplegia 33, Autosomal Dominant
Spastic Paraplegia 31, Autosomal Dominant Spastic Paraplegia 30, Autosomal Recessive
Spastic Paraplegia 18, Autosomal Recessive Spastic Paraplegia 32, Autosomal Recessive
Spastic Paraplegia 37, Autosomal Dominant Spastic Paraplegia 39, Autosomal Recessive
Spastic Paraplegia 35, Autosomal Recessive Spastic Paraplegia 38, Autosomal Dominant
Spastic Paraplegia 42, Autosomal Dominant Spastic Paraplegia 50, Autosomal Recessive
Spastic Paraplegia 36, Autosomal Dominant Spastic Paraplegia 45, Autosomal Recessive
Spastic Paraplegia 44, Autosomal Recessive Spastic Paraplegia 41, Autosomal Dominant
Spastic Paraplegia 48, Autosomal Recessive Spastic Paraplegia 51, Autosomal Recessive
Spastic Paraplegia 47, Autosomal Recessive Spastic Paraplegia 52, Autosomal Recessive
Spastic Paraplegia 46, Autosomal Recessive Spastic Paraplegia 53, Autosomal Recessive
Spastic Paraplegia 56, Autosomal Recessive Spastic Paraplegia 49, Autosomal Recessive
Spastic Paraplegia 54, Autosomal Recessive Spastic Paraplegia 55, Autosomal Recessive
Spastic Paraplegia 43, Autosomal Recessive Spastic Paraplegia 79, Autosomal Recessive
Spastic Paraplegia 72, Autosomal Recessive Spastic Paraplegia 57, Autosomal Recessive
Spastic Paraplegia 62, Autosomal Recessive Spastic Paraplegia 64, Autosomal Recessive
Spastic Paraplegia 61, Autosomal Recessive Spastic Paraplegia 63, Autosomal Recessive
Spastic Paraplegia 73, Autosomal Dominant Spastic Paraplegia 74, Autosomal Recessive
Spastic Paraplegia 9b, Autosomal Recessive Spastic Paraplegia 75, Autosomal Recessive
Spastic Paraplegia 76, Autosomal Recessive Spastic Paraplegia 77, Autosomal Recessive
Spastic Paraplegia 78, Autosomal Recessive Spastic Paraplegia 80, Autosomal Dominant
Hereditary Spastic Paraplegia 23 Hereditary Spastic Paraplegia 51
Hereditary Spastic Paraplegia 72 Hereditary Spastic Paraplegia
Spastic Paraplegia 4 Spastic Paraplegia 8
Spastic Paraplegia 11 Spastic Paraplegia 1
Spastic Paraplegia 10 Spastic Paraplegia 12
Spastic Paraplegia 13 Spastic Paraplegia 14
Spastic Paraplegia 15 Spastic Paraplegia 16
Spastic Paraplegia 17 Spastic Paraplegia 18
Spastic Paraplegia 19 Spastic Paraplegia 24
Spastic Paraplegia 25 Spastic Paraplegia 26
Spastic Paraplegia 29 Spastic Paraplegia 3
Spastic Paraplegia 31 Spastic Paraplegia 32
Spastic Paraplegia 39 Spastic Paraplegia 47
Spastic Paraplegia 51 Spastic Paraplegia 5a
Spastic Paraplegia 5b Spastic Paraplegia 6
Spastic Paraplegia 9 Spastic Paraplegia Type 49
Autosomal Recessive Spastic Paraplegia Type 60 Autosomal Recessive Spastic Paraplegia Type 59
Autosomal Recessive Spastic Paraplegia Type 69 Autosomal Recessive Spastic Paraplegia Type 70
Autosomal Recessive Spastic Paraplegia Type 71 Autosomal Recessive Spastic Paraplegia Type 66
Autosomal Recessive Spastic Paraplegia Type 67 Autosomal Dominant Spastic Paraplegia Type 9b

Diseases related to Spastic Paraplegia 46, Autosomal Recessive via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 31)
# Related Disease Score Top Affiliating Genes
1 paraplegia 30.0 SPG21 SPG11
2 spastic paraplegia 56, autosomal recessive 29.6 GBA2 CYP2U1 COX6A1
3 spastic paraplegia 32, autosomal recessive 29.5 SPG21 SPG11
4 mast syndrome 29.0 SPG21 SPG11
5 spastic paraplegia 15, autosomal recessive 28.9 SPG21 SPG11 CYP2U1
6 spastic paraplegia 11, autosomal recessive 28.8 SPG21 SPG11
7 hereditary spastic paraplegia 28.6 SPG21 SPG11 GBA2 CYP2U1
8 ataxia and polyneuropathy, adult-onset 10.2
9 aceruloplasminemia 10.2
10 spastic paraplegia 5a 10.1 GBA2 CYP2U1
11 gaucher disease, type i 10.1
12 spastic paraplegia 7, autosomal recessive 10.1
13 spastic paraplegia 18, autosomal recessive 10.1
14 male infertility 10.1
15 gaucher's disease 10.1
16 spastic paraplegia 15 10.1
17 spastic paraplegia 18 10.1
18 spastic paraplegia 32 10.1
19 charcot-marie-tooth disease intermediate type 9.7 SPG21 COX6A1
20 charcot-marie-tooth disease, recessive intermediate d 9.7 SPG21 COX6A1
21 charcot-marie-tooth disease, axonal, type 2h 9.7 SPG21 COX6A1
22 charcot-marie-tooth disease, axonal, type 2r 9.7 SPG21 COX6A1
23 spastic paraplegia 55, autosomal recessive 9.6 SPG21 COX6A1
24 charcot-marie-tooth disease, axonal, type 2p 9.6 SPG21 COX6A1
25 charcot-marie-tooth disease, axonal, type 2b2 9.6 SPG21 COX6A1
26 charcot-marie-tooth disease, axonal, type 2b1 9.5 SPG21 COX6A1
27 spastic paraplegia 48, autosomal recessive 9.4 SPG21 SPG11
28 charcot-marie-tooth disease, axonal, type 2t 9.3 SPG21 CYP2U1 COX6A1
29 amyotrophic lateral sclerosis type 5 9.2 SPG21 SPG11 COX6A1
30 spastic paraplegia 35, autosomal recessive 9.2 SPG21 SPG11 CYP2U1
31 charcot-marie-tooth disease, axonal, type 2e 8.3 SPG21 SPG11 GBA2 CYP2U1 COX6A1

Graphical network of the top 20 diseases related to Spastic Paraplegia 46, Autosomal Recessive:



Diseases related to Spastic Paraplegia 46, Autosomal Recessive
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Symptoms & Phenotypes for Spastic Paraplegia 46, Autosomal Recessive

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Human phenotypes related to Spastic Paraplegia 46, Autosomal Recessive:

59 32 (show all 45)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 cataract 59 32 hallmark (90%) Very frequent (99-80%) HP:0000518
2 babinski sign 59 32 hallmark (90%) Very frequent (99-80%) HP:0003487
3 difficulty walking 59 32 hallmark (90%) Very frequent (99-80%) HP:0002355
4 lower limb spasticity 59 32 hallmark (90%) Very frequent (99-80%) HP:0002061
5 cerebral cortical atrophy 59 32 frequent (33%) Frequent (79-30%) HP:0002120
6 cerebellar atrophy 59 32 frequent (33%) Frequent (79-30%) HP:0001272
7 corpus callosum atrophy 59 32 frequent (33%) Frequent (79-30%) HP:0007371
8 nystagmus 59 32 occasional (7.5%) Occasional (29-5%) HP:0000639
9 hyperreflexia 59 32 occasional (7.5%) Occasional (29-5%) HP:0001347
10 scoliosis 59 32 occasional (7.5%) Occasional (29-5%) HP:0002650
11 hearing impairment 59 32 occasional (7.5%) Occasional (29-5%) HP:0000365
12 abnormal tendon morphology 59 32 occasional (7.5%) Occasional (29-5%) HP:0100261
13 pes cavus 59 32 occasional (7.5%) Occasional (29-5%) HP:0001761
14 decreased testicular size 59 32 occasional (7.5%) Occasional (29-5%) HP:0008734
15 dementia 59 32 occasional (7.5%) Occasional (29-5%) HP:0000726
16 truncal ataxia 59 32 occasional (7.5%) Occasional (29-5%) HP:0002078
17 infertility 59 32 occasional (7.5%) Occasional (29-5%) HP:0000789
18 urinary incontinence 59 32 occasional (7.5%) Occasional (29-5%) HP:0000020
19 head tremor 59 32 occasional (7.5%) Occasional (29-5%) HP:0002346
20 peripheral axonal neuropathy 59 32 occasional (7.5%) Occasional (29-5%) HP:0003477
21 reduced sperm motility 59 32 occasional (7.5%) Occasional (29-5%) HP:0012207
22 jerky ocular pursuit movements 59 32 occasional (7.5%) Occasional (29-5%) HP:0008003
23 spastic dysarthria 59 32 occasional (7.5%) Occasional (29-5%) HP:0002464
24 broad-based gait 59 32 occasional (7.5%) Occasional (29-5%) HP:0002136
25 impaired vibration sensation at ankles 59 32 occasional (7.5%) Occasional (29-5%) HP:0006938
26 upper limb spasticity 59 32 occasional (7.5%) Occasional (29-5%) HP:0006986
27 sperm head anomaly 59 32 occasional (7.5%) Occasional (29-5%) HP:0012865
28 intellectual disability 32 occasional (7.5%) HP:0001249
29 kyphosis 32 occasional (7.5%) HP:0002808
30 impaired vibration sensation in the lower limbs 32 occasional (7.5%) HP:0002166
31 cerebral atrophy 59 32 Frequent (79-30%) HP:0002059
32 ataxia 59 Very frequent (99-80%)
33 dysarthria 32 HP:0001260
34 abnormal pyramidal sign 59 Occasional (29-5%)
35 cognitive impairment 59 Frequent (79-30%)
36 spastic paraplegia 32 HP:0001258
37 lower limb muscle weakness 32 HP:0007340
38 ankle clonus 32 HP:0011448
39 spastic gait 32 HP:0002064
40 hypoplasia of the corpus callosum 32 HP:0002079
41 abnormality of the cerebral white matter 59 Frequent (79-30%)
42 limb dysmetria 32 HP:0002406
43 abnormal sperm morphology 59 Occasional (29-5%)
44 knee clonus 32 HP:0011449
45 upper limb dysmetria 32 HP:0020036

Symptoms via clinical synopsis from OMIM:

57
Head And Neck Eyes:
nystagmus
jerky smooth pursuit
cataracts, congenital (in some patients)

Muscle Soft Tissue:
limb muscle weakness
increased muscle tone

Head And Neck Ears:
hearing loss (in some patients)

Genitourinary Internal Genitalia Male:
small testicles (in some patients)
abnormal sperm head (in some patients)
low sperm velocity (in some patients)
infertility (in some male patients)

Neurologic Peripheral Nervous System:
decreased vibratory sense in the lower limbs (in some patients)
axonal sensory polyneuropathy (in some patients)

Neurologic Central Nervous System:
dysarthria
hyperreflexia
cerebellar atrophy
lower limb spasticity
spastic gait
more
Skeletal Spine:
scoliosis (in some patients)
kyphosis (in some patients)

Skeletal Feet:
pes cavus (in some patients)

Genitourinary Bladder:
urinary incontinence (variable)

Clinical features from OMIM:

614409

UMLS symptoms related to Spastic Paraplegia 46, Autosomal Recessive:


cerebellar ataxia, abnormal pyramidal signs

GenomeRNAi Phenotypes related to Spastic Paraplegia 46, Autosomal Recessive according to GeneCards Suite gene sharing:

26
# Description GenomeRNAi Source Accession Score Top Affiliating Genes
1 Mildly decreased CFP-tsO45G cell surface transport GR00360-A-1 9.02 CREB3 CYP2U1 GBA2 SPG11 SPG21
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Drugs & Therapeutics for Spastic Paraplegia 46, Autosomal Recessive

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Search Clinical Trials , NIH Clinical Center for Spastic Paraplegia 46, Autosomal Recessive

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Genetic Tests for Spastic Paraplegia 46, Autosomal Recessive

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Genetic tests related to Spastic Paraplegia 46, Autosomal Recessive:

# Genetic test Affiliating Genes
1 Spastic Paraplegia 46, Autosomal Recessive 29 GBA2
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Anatomical Context for Spastic Paraplegia 46, Autosomal Recessive

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MalaCards organs/tissues related to Spastic Paraplegia 46, Autosomal Recessive:

41
Brain
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Publications for Spastic Paraplegia 46, Autosomal Recessive

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Articles related to Spastic Paraplegia 46, Autosomal Recessive:

(show all 15)
# Title Authors PMID Year
1
A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum. 38 8 71
20593214 2010
2
A novel GBA2 gene missense mutation in spastic ataxia. 8 71
24252062 2014
3
Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. 8 71
23332916 2013
4
Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. 8 71
23332917 2013
5
Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity. 8
18332254 2008
6
Distinct phenotypes within autosomal recessive ataxias not linked to already known loci. 8
16550933 2005
7
Hereditary Spastic Paraplegia Overview 71
20301682 2000
8
Assay of β-glucosidase 2 (GBA2) activity using lithocholic acid β-3-O-glucoside substrate for cultured fibroblasts and glucosylceramide for brain tissue. 38
30864417 2019
9
Species-specific differences in nonlysosomal glucosylceramidase GBA2 function underlie locomotor dysfunction arising from loss-of-function mutations. 38
30662006 2019
10
Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. 38
29980238 2018
11
Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia. 38
29524657 2018
12
SPG46 and SPG56 are rare causes of hereditary spastic paraplegia in China. 38
27553021 2016
13
ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. 38
26556829 2016
14
Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46). 38
26220345 2015
15
Mutations in CYP2U1, DDHD2 and GBA2 genes are rare causes of complicated forms of hereditary spastic paraparesis. 38
24337409 2014
Sources

Variations for Spastic Paraplegia 46, Autosomal Recessive

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ClinVar genetic disease variations for Spastic Paraplegia 46, Autosomal Recessive:

6 (show all 12)
# Gene Variation Type Significance SNP ID GRCh37 Pos GRCh38 Pos
1 GBA2 GBA2, TYR121TER single nucleotide variant Pathogenic
2 GBA2 NM_020944.3(GBA2): c.518G> A (p.Trp173Ter) single nucleotide variant Pathogenic 9:35744343-35744343 9:35744346-35744346
3 GBA2 NM_020944.3(GBA2): c.363C> A (p.Tyr121Ter) single nucleotide variant Pathogenic 9:35744700-35744700 9:35744703-35744703
4 GBA2 NM_020944.3(GBA2): c.1018C> T (p.Arg340Ter) single nucleotide variant Pathogenic rs398123014 9:35740830-35740830 9:35740833-35740833
5 GBA2 GBA2, 4-BP DUP, 1471GGCA duplication Pathogenic
6 GBA2 GBA2, TRP173TER undetermined variant Pathogenic
7 GBA2 NM_020944.3(GBA2): c.700C> T (p.Arg234Ter) single nucleotide variant Pathogenic rs398123013 9:35741755-35741755 9:35741758-35741758
8 GBA2 NM_020944.3(GBA2): c.1888C> T (p.Arg630Trp) single nucleotide variant Pathogenic/Likely pathogenic rs398123012 9:35738808-35738808 9:35738811-35738811
9 GBA2 NM_020944.3(GBA2): c.2618G> A (p.Arg873His) single nucleotide variant Pathogenic/Likely pathogenic rs398123015 9:35737332-35737332 9:35737335-35737335
10 GBA2 NM_020944.3(GBA2): c.1780G> C (p.Asp594His) single nucleotide variant Likely pathogenic rs398123064 9:35739014-35739014 9:35739017-35739017
11 GBA2 NM_020944.3(GBA2): c.1285C> T (p.Arg429Trp) single nucleotide variant Uncertain significance 9:35740119-35740119 9:35740122-35740122
12 GBA2 NM_020944.3(GBA2): c.1030G> C (p.Ala344Pro) single nucleotide variant not provided rs750984776 9:35740622-35740622 9:35740625-35740625

UniProtKB/Swiss-Prot genetic disease variations for Spastic Paraplegia 46, Autosomal Recessive:

74
# Symbol AA change Variation ID SNP ID
1 GBA2 p.Arg630Trp VAR_069634 rs398123012
2 GBA2 p.Arg873His VAR_069635 rs398123015
3 GBA2 p.Asp594His VAR_081410 rs398123064

Sources

Expression for Spastic Paraplegia 46, Autosomal Recessive

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Search GEO for disease gene expression data for Spastic Paraplegia 46, Autosomal Recessive.
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Pathways for Spastic Paraplegia 46, Autosomal Recessive

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GO Terms for Spastic Paraplegia 46, Autosomal Recessive

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Cellular components related to Spastic Paraplegia 46, Autosomal Recessive according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 endoplasmic reticulum membrane GO:0005789 8.8 GBA2 CYP2U1 CREB3
Sources

Sources for Spastic Paraplegia 46, Autosomal Recessive

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3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 TGDB
71 Tocris
72 UMLS
73 UMLS via Orphanet
The MalaCards human disease database index: 1-9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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