ICRD
MCID: INF129
MIFTS: 44

Infantile Cerebellar-Retinal Degeneration (ICRD)

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

Aliases & Classifications for Infantile Cerebellar-Retinal Degeneration

MalaCards integrated aliases for Infantile Cerebellar-Retinal Degeneration:

Name: Infantile Cerebellar-Retinal Degeneration 57 12 20 58 72 36 29 13 6 15 70
Icrd 57 20 72
Degeneration, Cerebellar-Retinal, Infantile 39
Infantile Cerebellar Retinal Degeneration 20

Characteristics:

Orphanet epidemiological data:

58
infantile cerebellar-retinal degeneration
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM®:

57 (Updated 20-May-2021)
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy


HPO:

31
infantile cerebellar-retinal degeneration:
Inheritance autosomal recessive inheritance
Onset and clinical course infantile onset


Classifications:

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


Summaries for Infantile Cerebellar-Retinal Degeneration

GARD : 20 Infantile cerebellar retinal degeneration (ICRD) is a genetic condition present from birth ( congenital ) that involves the brain and eyes. Individuals with this condition usually develop symptoms around six months of age including developmental delays, low muscle tone ( hypotonia ), and seizures. Other symptoms may include head bobbing, abnormal muscle twitching and movement, and loss of brain cells in the main part of the brain called the cerebellum. Eye findings in individuals with this condition may include retinal degeneration (weakening of the layer of tissue in the back of the eye that senses light), strabismus (crossed eyes), and nystagmus (fast, uncontrollable movements of the eyes). ICRD is caused by mutations in the ACO2 gene and is inherited in an autosomal recessive manner. While there is still no cure for this condition, treatment options will depend on the type and severity of symptoms.

MalaCards based summary : Infantile Cerebellar-Retinal Degeneration, also known as icrd, is related to mitochondrial dna depletion syndrome, encephalomyopathic form and mitochondrial dna depletion syndrome 6, and has symptoms including seizures, ataxia and athetosis. An important gene associated with Infantile Cerebellar-Retinal Degeneration is ACO2 (Aconitase 2), and among its related pathways/superpathways are Citrate cycle (TCA cycle) and Glyoxylate and dicarboxylate metabolism. Affiliated tissues include eye, brain and cerebellum, and related phenotypes are sensorineural hearing impairment and failure to thrive

Disease Ontology : 12 A neurodegenerative disease that is characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration.

OMIM® : 57 Infantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012). A subset of patients may have a milder phenotype with variable features, including ataxia, developmental delay, and behavioral abnormalities (Blackburn et al., 2020). (614559) (Updated 20-May-2021)

KEGG : 36 Infantile cerebellar-retinal degeneration (ICRD) is a disorder characterized by profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Recently, missense mutations in a TCA enzyme, mitochondrial aconitase (ACO2), catalysing interconversion of citrate into isocitrate, have been reported in a sibship with infantile-onset encephalopathy, optic nerve involvement, and cerebellar atrophy.

UniProtKB/Swiss-Prot : 72 Infantile cerebellar-retinal degeneration: A severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration.

Related Diseases for Infantile Cerebellar-Retinal Degeneration

Diseases related to Infantile Cerebellar-Retinal Degeneration via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 36)
# Related Disease Score Top Affiliating Genes
1 mitochondrial dna depletion syndrome, encephalomyopathic form 10.2 SUCLG1 SUCLA2
2 mitochondrial dna depletion syndrome 6 10.2 SUCLG1 SUCLA2
3 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 1 10.2 SUCLG1 SUCLA2
4 progressive external ophthalmoplegia with mitochondrial dna deletions, autosomal dominant 4 10.2 SUCLG1 SUCLA2
5 mitochondrial dna depletion syndrome 7 10.2 SUCLG1 SUCLA2
6 mitochondrial dna depletion syndrome 5 10.1 SUCLG1 SUCLA2
7 optic atrophy 9 10.1 SUCLA2 POLR3H ACO2
8 mitochondrial dna depletion syndrome 9 10.1 SUCLG1 SUCLA2
9 organic acidemia 10.1 SUCLG1 SUCLA2
10 neurodegeneration with brain iron accumulation 2a 10.0
11 hereditary ataxia 10.0
12 neuroaxonal dystrophy 10.0
13 retinal degeneration 10.0
14 athetosis 10.0
15 hypotonia 10.0
16 seizure disorder 10.0
17 kearns-sayre syndrome 10.0 SUCLG1 SUCLA2 SDHAF1
18 sensory ataxic neuropathy, dysarthria, and ophthalmoparesis 10.0 SUCLG1 SUCLA2
19 fumarase deficiency 9.9 SUCLA2 SDHAF1 L2HGDH ACO2
20 l-2-hydroxyglutaric aciduria 9.9 SLC25A1 MDH2 L2HGDH
21 d-2-hydroxyglutaric aciduria 1 9.9 SLC25A1 L2HGDH IDH3A
22 mitochondrial metabolism disease 9.9 TTC19 SUCLG1 SUCLA2
23 mitochondrial complex i deficiency, nuclear type 1 9.9 SUCLG1 IDH3A ACO2
24 combined d-2- and l-2-hydroxyglutaric aciduria 9.8 SLC25A1 SDHAF1 MDH2 L2HGDH
25 gracile syndrome 9.7 TTC19 LYRM7
26 2-hydroxyglutaric aciduria 9.7 SLC25A1 MDH2 L2HGDH IDH3A
27 leigh syndrome 9.7 TTC19 SUCLG1 SUCLA2 SDHAF1
28 3-methylglutaconic aciduria, type iii 9.6 SUCLG1 SUCLA2 MDH2
29 mitochondrial complex v deficiency, mitochondrial type 1 9.5 UQCC3 TTC19 LYRM7
30 isolated complex iii deficiency 9.5 UQCC3 TTC19 LYRM7
31 combined oxidative phosphorylation deficiency 22 9.5 UQCC3 TTC19 LYRM7
32 combined oxidative phosphorylation deficiency 4 9.5 UQCC3 TTC19 LYRM7
33 mitochondrial complex v deficiency, nuclear type 3 9.5 UQCC3 TTC19 LYRM7
34 mitochondrial complex iv deficiency, nuclear type 5 9.5 UQCC3 TTC19 LYRM7
35 mitochondrial complex iii deficiency 9.5 UQCC3 TTC19 LYRM7
36 lactic acidosis 9.4 UQCC3 SUCLG1 LYRM7

Graphical network of the top 20 diseases related to Infantile Cerebellar-Retinal Degeneration:



Diseases related to Infantile Cerebellar-Retinal Degeneration

Symptoms & Phenotypes for Infantile Cerebellar-Retinal Degeneration

Human phenotypes related to Infantile Cerebellar-Retinal Degeneration:

31 (show all 19)
# Description HPO Frequency HPO Source Accession
1 sensorineural hearing impairment 31 occasional (7.5%) HP:0000407
2 failure to thrive 31 HP:0001508
3 nystagmus 31 HP:0000639
4 ataxia 31 HP:0001251
5 optic atrophy 31 HP:0000648
6 intellectual disability, severe 31 HP:0010864
7 strabismus 31 HP:0000486
8 cerebral cortical atrophy 31 HP:0002120
9 areflexia 31 HP:0001284
10 hyporeflexia 31 HP:0001265
11 severe global developmental delay 31 HP:0011344
12 hypoplasia of the corpus callosum 31 HP:0002079
13 cerebellar atrophy 31 HP:0001272
14 retinal dystrophy 31 HP:0000556
15 athetosis 31 HP:0002305
16 generalized hypotonia 31 HP:0001290
17 demyelinating peripheral neuropathy 31 HP:0007108
18 progressive microcephaly 31 HP:0000253
19 seizure 31 HP:0001250

Symptoms via clinical synopsis from OMIM®:

57 (Updated 20-May-2021)
Neurologic Central Nervous System:
seizures
ataxia
athetosis
hypotonia
spastic quadriplegia
more
Head And Neck Eyes:
nystagmus
optic atrophy
strabismus
retinal dystrophy
abnormal pursuit

Muscle Soft Tissue:
hypotonia
decreased glutamate oxidation (about 63% of normal)

Head And Neck Head:
microcephaly, progressive

Neurologic Behavioral Psychiatric Manifestations:
adhd (rare)
anxiety (rare)
depressive symptoms (rare)

Growth Other:
failure to thrive

Neurologic Peripheral Nervous System:
areflexia
hyporeflexia
peripheral demyelinating neuropathy

Growth Weight:
low weight

Head And Neck Ears:
hearing loss, sensorineural (in 2 patients)

Clinical features from OMIM®:

614559 (Updated 20-May-2021)

UMLS symptoms related to Infantile Cerebellar-Retinal Degeneration:


seizures; ataxia; athetosis

Drugs & Therapeutics for Infantile Cerebellar-Retinal Degeneration

Search Clinical Trials , NIH Clinical Center for Infantile Cerebellar-Retinal Degeneration

Genetic Tests for Infantile Cerebellar-Retinal Degeneration

Genetic tests related to Infantile Cerebellar-Retinal Degeneration:

# Genetic test Affiliating Genes
1 Infantile Cerebellar-Retinal Degeneration 29 ACO2

Anatomical Context for Infantile Cerebellar-Retinal Degeneration

MalaCards organs/tissues related to Infantile Cerebellar-Retinal Degeneration:

40
Eye, Brain, Cerebellum

Publications for Infantile Cerebellar-Retinal Degeneration

Articles related to Infantile Cerebellar-Retinal Degeneration:

(show all 17)
# Title Authors PMID Year
1
Clinical, radiological, and genetic characteristics of 16 patients with ACO2 gene defects: Delineation of an emerging neurometabolic syndrome. 57 6 61
30689204 2019
2
Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2. 61 57 6
22405087 2012
3
Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2. 57 6
32519519 2020
4
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. 57 6
31130284 2019
5
Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy. 6 57
25351951 2014
6
Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency. 57 61
28463998 2017
7
First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. 6
32214227 2020
8
ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia. 57
29577077 2018
9
Complex hereditary spastic paraplegia associated with episodic visual loss caused by ACO2 variants. 61
33500398 2021
10
Novel compound heterozygous ACO2 mutations in an infant with progressive encephalopathy: A newly identified neurometabolic syndrome. 61
32713659 2020
11
The novel peptides ICRD and LCGEC screened from tuna roe show antioxidative activity via Keap1/Nrf2-ARE pathway regulation and gut microbiota modulation. 61
32454270 2020
12
Recessive ACO2 variants as a cause of isolated ophthalmologic phenotypes. 61
32449285 2020
13
Identification of a genome-specific repetitive element in the Gossypium D genome. 61
31915591 2020
14
Are older drivers' driving patterns during an on-road driving task representative of their real-world driving patterns? 61
30841798 2018
15
Functional cellular analyses reveal energy metabolism defect and mitochondrial DNA depletion in a case of mitochondrial aconitase deficiency. 61
26992325 2016
16
Effect of impulse control disorders on disability and quality of life in Parkinson's disease patients. 61
24035421 2014
17
Inactivation and mutagenesis of herpes virus by photodynamic treatment with therapeutic dyes. 61
2780827 1989

Variations for Infantile Cerebellar-Retinal Degeneration

ClinVar genetic disease variations for Infantile Cerebellar-Retinal Degeneration:

6 (show all 28)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 POLR3H , ACO2 NM_001098.3(ACO2):c.2338_2339del (p.Gln780fs) Deletion Pathogenic 242873 rs1114167284 GRCh37: 22:41924611-41924612
GRCh38: 22:41528607-41528608
2 ACO2 NM_001098.3(ACO2):c.336C>G (p.Ser112Arg) SNV Pathogenic 29584 rs786200924 GRCh37: 22:41903957-41903957
GRCh38: 22:41507953-41507953
3 ACO2 NM_001098.3(ACO2):c.776G>A (p.Gly259Asp) SNV Pathogenic 189312 rs786204828 GRCh37: 22:41911862-41911862
GRCh38: 22:41515858-41515858
4 POLR3H , ACO2 NM_001098.3(ACO2):c.2208G>C (p.Lys736Asn) SNV Pathogenic 189313 rs786204829 GRCh37: 22:41924026-41924026
GRCh38: 22:41528022-41528022
5 POLR3H , ACO2 NM_001098.3(ACO2):c.2328_2331del (p.Lys776fs) Deletion Pathogenic 189314 rs786204830 GRCh37: 22:41924599-41924602
GRCh38: 22:41528595-41528598
6 ACO2 NM_001098.3(ACO2):c.1240T>G (p.Phe414Val) SNV Pathogenic 978053 GRCh37: 22:41918935-41918935
GRCh38: 22:41522931-41522931
7 POLR3H , ACO2 NM_001098.3(ACO2):c.1966_1969del (p.Arg656fs) Deletion Pathogenic 803706 rs1601936467 GRCh37: 22:41923304-41923307
GRCh38: 22:41527300-41527303
8 ACO2 NM_001098.3(ACO2):c.433-2_433-1inv Inversion Pathogenic 978056 GRCh37: 22:41907878-41907879
GRCh38: 22:41511874-41511875
9 ACO2 NM_001098.3(ACO2):c.719G>A (p.Gly240Asp) SNV Pathogenic 424533 rs141878785 GRCh37: 22:41911805-41911805
GRCh38: 22:41515801-41515801
10 POLR3H , ACO2 NM_001098.3(ACO2):c.1787A>G (p.His596Arg) SNV Pathogenic 978054 GRCh37: 22:41922291-41922291
GRCh38: 22:41526287-41526287
11 ACO2 NM_001098.3(ACO2):c.1390G>T (p.Glu464Ter) SNV Likely pathogenic 803705 rs1601927180 GRCh37: 22:41919853-41919853
GRCh38: 22:41523849-41523849
12 POLR3H , ACO2 NM_001098.3(ACO2):c.1819C>T (p.Arg607Cys) SNV Likely pathogenic 218316 rs864309499 GRCh37: 22:41922323-41922323
GRCh38: 22:41526319-41526319
13 POLR3H , ACO2 NM_001098.3(ACO2):c.2135C>T (p.Pro712Leu) SNV Likely pathogenic 218317 rs375761361 GRCh37: 22:41923953-41923953
GRCh38: 22:41527949-41527949
14 ACO2 NM_001098.3(ACO2):c.1744C>G (p.Leu582Val) SNV Uncertain significance 982607 GRCh37: 22:41921335-41921335
GRCh38: 22:41525331-41525331
15 POLR3H , ACO2 NM_001098.3(ACO2):c.2051G>A (p.Arg684Gln) SNV Uncertain significance 214022 rs200345386 GRCh37: 22:41923389-41923389
GRCh38: 22:41527385-41527385
16 POLR3H , ACO2 NM_001098.3(ACO2):c.2302G>A (p.Ala768Thr) SNV Uncertain significance 1031072 GRCh37: 22:41924576-41924576
GRCh38: 22:41528572-41528572
17 ACO2 NM_001098.3(ACO2):c.245T>C (p.Ile82Thr) SNV Uncertain significance 844771 GRCh37: 22:41903866-41903866
GRCh38: 22:41507862-41507862
18 ACO2 NM_001098.3(ACO2):c.719G>C (p.Gly240Ala) SNV Uncertain significance 214018 rs141878785 GRCh37: 22:41911805-41911805
GRCh38: 22:41515801-41515801
19 POLR3H , ACO2 NM_001098.3(ACO2):c.2050C>T (p.Arg684Trp) SNV Uncertain significance 562210 rs768950391 GRCh37: 22:41923388-41923388
GRCh38: 22:41527384-41527384
20 ACO2 NM_001098.3(ACO2):c.1550C>T (p.Thr517Met) SNV Uncertain significance 522983 rs540169523 GRCh37: 22:41920917-41920917
GRCh38: 22:41524913-41524913
21 POLR3H , ACO2 NM_001098.3(ACO2):c.2153T>C (p.Ile718Thr) SNV Uncertain significance 562211 rs1569026431 GRCh37: 22:41923971-41923971
GRCh38: 22:41527967-41527967
22 POLR3H , ACO2 NM_001098.3(ACO2):c.2026C>G (p.Leu676Val) SNV Uncertain significance 587436 rs1569025557 GRCh37: 22:41923364-41923364
GRCh38: 22:41527360-41527360
23 ACO2 NM_001098.3(ACO2):c.1285C>T (p.Arg429Trp) SNV Uncertain significance 592149 rs757438868 GRCh37: 22:41918980-41918980
GRCh38: 22:41522976-41522976
24 ACO2 NM_001098.3(ACO2):c.220C>G (p.Leu74Val) SNV Uncertain significance 189310 rs141772938 GRCh37: 22:41903841-41903841
GRCh38: 22:41507837-41507837
25 ACO2 NM_001098.3(ACO2):c.719G>C (p.Gly240Ala) SNV Uncertain significance 214018 rs141878785 GRCh37: 22:41911805-41911805
GRCh38: 22:41515801-41515801
26 POLR3H , ACO2 NM_001098.3(ACO2):c.2051G>A (p.Arg684Gln) SNV Uncertain significance 214022 rs200345386 GRCh37: 22:41923389-41923389
GRCh38: 22:41527385-41527385
27 POLR3H , ACO2 NM_001098.3(ACO2):c.1942C>T (p.Arg648Cys) SNV Uncertain significance 816929 rs369064868 GRCh37: 22:41922446-41922446
GRCh38: 22:41526442-41526442
28 ACO2 NM_001098.3(ACO2):c.220C>G (p.Leu74Val) SNV Likely benign 189310 rs141772938 GRCh37: 22:41903841-41903841
GRCh38: 22:41507837-41507837

UniProtKB/Swiss-Prot genetic disease variations for Infantile Cerebellar-Retinal Degeneration:

72
# Symbol AA change Variation ID SNP ID
1 ACO2 p.Ser112Arg VAR_067543 rs786200924
2 ACO2 p.Gly259Asp VAR_073436 rs786204828
3 ACO2 p.Lys736Asn VAR_073438 rs786204829

Expression for Infantile Cerebellar-Retinal Degeneration

Search GEO for disease gene expression data for Infantile Cerebellar-Retinal Degeneration.

Pathways for Infantile Cerebellar-Retinal Degeneration

Pathways related to Infantile Cerebellar-Retinal Degeneration according to KEGG:

36
# Name Kegg Source Accession
1 Citrate cycle (TCA cycle) hsa00020
2 Glyoxylate and dicarboxylate metabolism hsa00630

Pathways related to Infantile Cerebellar-Retinal Degeneration according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1
Show member pathways
13.76 SUCLG1 SUCLA2 SLC25A19 SLC25A1 MDH2 L2HGDH
2
Show member pathways
13.01 SUCLG1 SUCLA2 MDH2 L2HGDH IDH3A ACO2
3 12.16 SUCLG1 MDH2 ACO2 ACO1
4
Show member pathways
11.96 SUCLG1 SUCLA2 MDH2 IDH3A ACO2 ACO1
5
Show member pathways
11.55 SUCLG1 SUCLA2 MDH2 L2HGDH IDH3A ACO2
6 11.46 SUCLG1 MDH2 ACO2
7
Show member pathways
11.11 SUCLG1 SUCLA2 MDH2 IDH3A ACO2 ACO1
8 11.01 SUCLG1 SUCLA2
9 10.91 MDH2 ACO2 ACO1
10 10.71 SUCLG1 SUCLA2

GO Terms for Infantile Cerebellar-Retinal Degeneration

Cellular components related to Infantile Cerebellar-Retinal Degeneration according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrial inner membrane GO:0005743 9.65 UQCC3 TTC19 SLC25A19 SLC25A1 L2HGDH
2 mitochondrial matrix GO:0005759 9.5 SUCLG1 SUCLA2 SDHAF1 MDH2 LYRM7 IDH3A
3 mitochondrion GO:0005739 9.44 UQCC3 TTC19 SUCLG1 SUCLA2 SLC25A19 SLC25A1
4 integral component of mitochondrial inner membrane GO:0031305 9.33 UQCC3 SLC25A19 L2HGDH

Biological processes related to Infantile Cerebellar-Retinal Degeneration according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 gluconeogenesis GO:0006094 9.32 SLC25A1 MDH2
2 isocitrate metabolic process GO:0006102 9.26 IDH3A ACO2
3 citrate metabolic process GO:0006101 9.16 ACO2 ACO1
4 mitochondrial respiratory chain complex III assembly GO:0034551 9.13 UQCC3 TTC19 LYRM7
5 tricarboxylic acid cycle GO:0006099 9.1 SUCLG1 SUCLA2 MDH2 IDH3A ACO2 ACO1

Molecular functions related to Infantile Cerebellar-Retinal Degeneration according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 4 iron, 4 sulfur cluster binding GO:0051539 9.43 ACO2 ACO1
2 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor GO:0016616 9.4 MDH2 IDH3A
3 ATP transmembrane transporter activity GO:0005347 9.37 SLC25A19 SLC25A1
4 3 iron, 4 sulfur cluster binding GO:0051538 9.32 ACO2 ACO1
5 succinate-CoA ligase (GDP-forming) activity GO:0004776 9.26 SUCLG1 SUCLA2
6 succinate-CoA ligase (ADP-forming) activity GO:0004775 9.16 SUCLG1 SUCLA2
7 aconitate hydratase activity GO:0003994 8.96 ACO2 ACO1
8 citrate dehydratase activity GO:0047780 8.62 ACO2 ACO1

Sources for Infantile Cerebellar-Retinal Degeneration

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