PCH6
MCID: PNT036
MIFTS: 44

Pontocerebellar Hypoplasia, Type 6 (PCH6)

Categories: Eye diseases, Fetal diseases, Genetic diseases, Mental diseases, Metabolic diseases, Muscle diseases, Neuronal diseases, Rare diseases, Respiratory diseases

Aliases & Classifications for Pontocerebellar Hypoplasia, Type 6

MalaCards integrated aliases for Pontocerebellar Hypoplasia, Type 6:

Name: Pontocerebellar Hypoplasia, Type 6 56 13
Pontocerebellar Hypoplasia Type 6 12 52 58 29 6 43 15 71
Pch6 56 58 73
Fatal Infantile Encephalopathy with Mitochondrial Respiratory Chain Defects 58 73
Encephalopathy, Fatal Infantile, with Mitochondrial Respiratory Chain Defects 56
Encephalopathy Fatal Infantile with Mitochondrial Respiratory Chain Defects 52
Hypoplasia, Pontocerebellar, Type 6 39
Pontocerebellar Hypoplasia 6 73

Characteristics:

Orphanet epidemiological data:

58
pontocerebellar hypoplasia type 6
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal; Age of death: early childhood;

OMIM:

56
Inheritance:
autosomal recessive

Miscellaneous:
variable severity
progressive disorder
death in childhood may occur
onset at birth or in first days or life


HPO:

31
pontocerebellar hypoplasia, type 6:
Inheritance autosomal recessive inheritance
Onset and clinical course variable expressivity progressive congenital onset
Clinical modifier death in childhood


Classifications:

Orphanet: 58  
Rare neurological diseases
Inborn errors of metabolism
Developmental anomalies during embryogenesis


External Ids:

Disease Ontology 12 DOID:0060275
OMIM 56 611523
OMIM Phenotypic Series 56 PS607596
MESH via Orphanet 44 C548074
ICD10 via Orphanet 33 Q04.3
UMLS via Orphanet 72 C1969084
Orphanet 58 ORPHA166073
MedGen 41 C1969084
UMLS 71 C1969084

Summaries for Pontocerebellar Hypoplasia, Type 6

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 166073 Definition Pontocerebellar hypoplasia type 6 (PCH6) is a rare form of pontocerebellar hypoplasia (see this term) characterized clinically at birth by hypotonia , clonus, epilepsy impaired swallowing and from infancy by progressive microencephaly, spasticity and lactic acidosis. Epidemiology PCH6 is reported in less than 10 cases to date Clinical description PCH6 is characterized clinically at birth by generalized hypotonia, lethargy and dysphagia . The clinical profile is characterized from infancy by a profound developmental delay , progressive microencephaly, hypotonia or spasticity treatment-resistant epilepsy. Etiology PCH6 is caused by missense and splice site mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2 ) gene located to 6q16.1. Diagnostic methods MRI demonstrates neocortical and more severe cerebral cortical atrophy (more severe than in other types of PCH), pontocerebellar hypoplasia with pons and cerebellum are equally affected. RARS2 mutation positive PCH6 patients can be screened by analysis of increased lactate in blood and cerebrospinal fluid. Biochemical analysis in muscle may demonstrate reduced activity of mitochondrial complexes I, III, and IV and normal activity of mitochondrial complex II. Prognosis Prognosis is poor, exact life expectancy is unknown but in most cases does not exceed infancy. Visit the Orphanet disease page for more resources.

MalaCards based summary : Pontocerebellar Hypoplasia, Type 6, also known as pontocerebellar hypoplasia type 6, is related to pontocerebellar hypoplasia and microcephaly, and has symptoms including seizures and apnea. An important gene associated with Pontocerebellar Hypoplasia, Type 6 is RARS2 (Arginyl-TRNA Synthetase 2, Mitochondrial), and among its related pathways/superpathways are Gene Expression and tRNA processing. Affiliated tissues include cerebellum, pons and eye, and related phenotypes are seizures and hyperreflexia

Disease Ontology : 12 A pontocerebellar hypoplasia that is characterized by olivopontocerebellar hypoplasia and developmental delay, has material basis in autosomal recessive inheritance of mutation in the RARS2 gene.

OMIM : 56 Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596). (611523)

UniProtKB/Swiss-Prot : 73 Pontocerebellar hypoplasia 6: A disorder characterized by an abnormally small cerebellum and brainstem, infantile encephalopathy, generalized hypotonia, lethargy and poor feeding. Recurrent apnea, intractable seizures occur early in the course of this condition.

Related Diseases for Pontocerebellar Hypoplasia, Type 6

Diseases in the Pontocerebellar Hypoplasia family:

Pontocerebellar Hypoplasia, Type 4 Pontocerebellar Hypoplasia, Type 2a
Pontocerebellar Hypoplasia, Type 1a Pontocerebellar Hypoplasia, Type 3
Pontocerebellar Hypoplasia, Type 5 Pontocerebellar Hypoplasia, Type 6
Pontocerebellar Hypoplasia, Type 2b Pontocerebellar Hypoplasia, Type 2c
Pontocerebellar Hypoplasia, Type 2d Pontocerebellar Hypoplasia, Type 1b
Pontocerebellar Hypoplasia, Type 8 Pontocerebellar Hypoplasia, Type 7
Pontocerebellar Hypoplasia, Type 10 Pontocerebellar Hypoplasia, Type 9
Pontocerebellar Hypoplasia, Type 2e Pontocerebellar Hypoplasia, Type 1c
Pontocerebellar Hypoplasia, Type 2f Pontocerebellar Hypoplasia, Type 11
Pontocerebellar Hypoplasia, Type 1d Pontocerebellar Hypoplasia, Type 12
Pontocerebellar Hypoplasia, Type 13 Exosc3-Related Pontocerebellar Hypoplasia
Tsen54-Related Pontocerebellar Hypoplasia Pontocerebellar Hypoplasia Type 1

Diseases related to Pontocerebellar Hypoplasia, Type 6 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 31)
# Related Disease Score Top Affiliating Genes
1 pontocerebellar hypoplasia 30.4 TSEN54 TSEN34 TSEN2 RARS2
2 microcephaly 28.6 TSEN54 TSEN34 TSEN2 KARS1 AARS1
3 3-methylglutaconic aciduria, type iii 10.3
4 cerebellar hypoplasia 10.2
5 cerebral atrophy 10.2
6 encephalopathy 10.2
7 pontocerebellar hypoplasia type 1 10.2 TSEN54 RARS2
8 pontocerebellar hypoplasia, type 2d 10.2 TSEN54 RARS2
9 mitochondrial complex iv deficiency 10.1
10 hydrops fetalis, nonimmune 10.1
11 peho syndrome 10.1
12 alacrima, achalasia, and mental retardation syndrome 10.1
13 early infantile epileptic encephalopathy 10.1
14 lactic acidosis 10.1
15 dystonia 10.1
16 hypotonia 10.1
17 tsen54-related pontocerebellar hypoplasia 10.0 TSEN54 TSEN34 TSEN2
18 pontocerebellar hypoplasia, type 2a 9.9 TSEN54 TSEN34 TSEN2
19 pontocerebellar hypoplasia, type 2e 9.9 TSEN54 TSEN34 TSEN2
20 hemoglobin h disease 9.9 TSEN54 TSEN34 TSEN2
21 spastic ataxia 9.8 MARS2 DARS2
22 46 xx gonadal dysgenesis 9.8 LARS2 DARS2
23 charcot-marie-tooth disease, recessive intermediate b 9.6 KARS1 AARS1
24 charcot-marie-tooth disease, axonal, type 2n 9.6 KARS1 AARS1
25 charcot-marie-tooth disease intermediate type 9.6 KARS1 AARS1
26 charcot-marie-tooth disease, axonal, type 2d 9.5 KARS1 AARS1
27 deafness, autosomal recessive 89 9.5 RARS2 LARS2 KARS1
28 robinow syndrome, autosomal recessive 1 9.5 RARS2 LARS2 KARS1
29 charcot-marie-tooth disease, dominant intermediate c 9.4 KARS1 DARS2 AARS1
30 charcot-marie-tooth disease 9.0 RARS2 MARS2 KARS1 DARS2 AARS1
31 perrault syndrome 8.6 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1

Graphical network of the top 20 diseases related to Pontocerebellar Hypoplasia, Type 6:



Diseases related to Pontocerebellar Hypoplasia, Type 6

Symptoms & Phenotypes for Pontocerebellar Hypoplasia, Type 6

Human phenotypes related to Pontocerebellar Hypoplasia, Type 6:

31 (show all 22)
# Description HPO Frequency HPO Source Accession
1 seizures 31 HP:0001250
2 hyperreflexia 31 HP:0001347
3 failure to thrive 31 HP:0001508
4 global developmental delay 31 HP:0001263
5 narrow palate 31 HP:0000189
6 narrow forehead 31 HP:0000341
7 generalized hypotonia 31 HP:0001290
8 absent speech 31 HP:0001344
9 apnea 31 HP:0002104
10 increased serum lactate 31 HP:0002151
11 prominent nasal bridge 31 HP:0000426
12 cerebellar hypoplasia 31 HP:0001321
13 deeply set eye 31 HP:0000490
14 poor suck 31 HP:0002033
15 cerebellar atrophy 31 HP:0001272
16 lower limb spasticity 31 HP:0002061
17 atrophy/degeneration affecting the brainstem 31 HP:0007366
18 poor head control 31 HP:0002421
19 increased csf lactate 31 HP:0002490
20 cerebral atrophy 31 HP:0002059
21 progressive microcephaly 31 HP:0000253
22 upper limb spasticity 31 HP:0006986

Symptoms via clinical synopsis from OMIM:

56
Neurologic Central Nervous System:
seizures
hyperreflexia
cerebellar atrophy
poor head control
cerebral atrophy
more
Head And Neck Mouth:
narrow palate

Laboratory Abnormalities:
increased serum lactate
increased csf lactate

Muscle Soft Tissue:
hypotonia
edematous hands and feet (1 patient)
reduced activity of mitochondrial respiratory chains (1 family)

Head And Neck Face:
bitemporal narrowing
dysmorphic features described in 1 patient

Respiratory:
apneic episodes

Growth Other:
failure to thrive

Abdomen Gastrointestinal:
feeding difficulties
poor sucking

Head And Neck Nose:
prominent nasal bridge

Head And Neck Eyes:
deep-set eyes
dysconjugate eye movements

Head And Neck Head:
microcephaly, progressive

Clinical features from OMIM:

611523

UMLS symptoms related to Pontocerebellar Hypoplasia, Type 6:


seizures, apnea

Drugs & Therapeutics for Pontocerebellar Hypoplasia, Type 6

Search Clinical Trials , NIH Clinical Center for Pontocerebellar Hypoplasia, Type 6

Cochrane evidence based reviews: pontocerebellar hypoplasia type 6

Genetic Tests for Pontocerebellar Hypoplasia, Type 6

Genetic tests related to Pontocerebellar Hypoplasia, Type 6:

# Genetic test Affiliating Genes
1 Pontocerebellar Hypoplasia Type 6 29 RARS2

Anatomical Context for Pontocerebellar Hypoplasia, Type 6

MalaCards organs/tissues related to Pontocerebellar Hypoplasia, Type 6:

40
Cerebellum, Pons, Eye, Brain

Publications for Pontocerebellar Hypoplasia, Type 6

Articles related to Pontocerebellar Hypoplasia, Type 6:

(show all 18)
# Title Authors PMID Year
1
Pontocerebellar hypoplasia type 6: A British case with PEHO-like features. 61 56 6
20635367 2010
2
A novel mutation in the promoter of RARS2 causes pontocerebellar hypoplasia in two siblings. 56 6
25809939 2015
3
Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. 56 6
17847012 2007
4
[Clinical and genetic characteristics of 62 children with mitochondrial epilepsy]. 61
31665838 2019
5
A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome. 61
31536827 2019
6
Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy. 61
30921410 2019
7
Three human aminoacyl-tRNA synthetases have distinct sub-mitochondrial localizations that are unaffected by disease-associated mutations. 61
30006346 2018
8
Expanding spectrum of RARS2 gene disorders: Myoclonic epilepsy, mental retardation, spasticity, and extrapyramidal features. 61
29881806 2018
9
Distinct magnetic resonance imaging features in a patient with novel RARS2 mutations: A case report and review of the literature. 61
29434700 2018
10
RARS2 Mutations: Is Pontocerebellar Hypoplasia Type 6 a Mitochondrial Encephalopathy? 61
27683254 2017
11
Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. 61
27769281 2016
12
RARS2 mutations cause early onset epileptic encephalopathy without ponto-cerebellar hypoplasia. 61
26970947 2016
13
Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations. 61
26083569 2015
14
Neuropathologic features of pontocerebellar hypoplasia type 6. 61
25289895 2014
15
Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations. 61
24047924 2013
16
Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients. 61
22569581 2013
17
Further delineation of pontocerebellar hypoplasia type 6 due to mutations in the gene encoding mitochondrial arginyl-tRNA synthetase, RARS2. 61
22086604 2012
18
Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. 61
20952379 2011

Variations for Pontocerebellar Hypoplasia, Type 6

ClinVar genetic disease variations for Pontocerebellar Hypoplasia, Type 6:

6 (show all 26) ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 RARS2 RARS2, -2A-GSNV Pathogenic 208208
2 RARS2 NM_020320.5(RARS2):c.110+5A>GSNV Pathogenic 891 6:88279230-88279230 6:87569512-87569512
3 RARS2 NM_020320.5(RARS2):c.1024A>G (p.Met342Val)SNV Pathogenic 30911 rs387907048 6:88231193-88231193 6:87521475-87521475
4 RARS2 NM_020320.5(RARS2):c.1A>G (p.Met1Val)SNV Pathogenic 225026 rs774923951 6:88299675-88299675 6:87589957-87589957
5 RARS2 NM_020320.5(RARS2):c.1237+1G>ASNV Pathogenic 488586 rs759922477 6:88229300-88229300 6:87519582-87519582
6 RARS2 NM_020320.5(RARS2):c.1612del (p.Thr538fs)deletion Pathogenic 522857 rs781417096 6:88224713-88224713 6:87514995-87514995
7 RARS2 NM_020320.5(RARS2):c.-2A>GSNV Pathogenic 802251 6:88299677-88299677 6:87589959-87589959
8 RARS2 NM_020320.5(RARS2):c.943C>T (p.Arg315Ter)SNV Pathogenic/Likely pathogenic 215061 rs199835443 6:88234306-88234306 6:87524588-87524588
9 RARS2 NM_020320.5(RARS2):c.419T>G (p.Phe140Cys)SNV Pathogenic/Likely pathogenic 215055 rs772887102 6:88258341-88258341 6:87548623-87548623
10 RARS2 NM_020320.5(RARS2):c.1054_1055del (p.Lys352fs)deletion Likely pathogenic 212016 rs756696262 6:88229955-88229956 6:87520237-87520238
11 RARS2 NM_020320.5(RARS2):c.370del (p.Gln124fs)deletion Likely pathogenic 436508 rs1554203400 6:88265151-88265151 6:87555433-87555433
12 RARS2 NM_020320.5(RARS2):c.1544A>G (p.Asp515Gly)SNV Likely pathogenic 488585 rs765088174 6:88226566-88226566 6:87516848-87516848
13 RARS2 NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)SNV Likely pathogenic 632596 rs1258569046 6:88239290-88239290 6:87529572-87529572
14 RARS2 NM_020320.5(RARS2):c.1650+5G>ASNV Likely pathogenic 632595 rs750433723 6:88224670-88224670 6:87514952-87514952
15 RARS2 NM_020320.5(RARS2):c.1282G>A (p.Gly428Arg)SNV Likely pathogenic 802249 6:88228565-88228565 6:87518847-87518847
16 RARS2 NM_020320.5(RARS2):c.449T>C (p.Ile150Thr)SNV Likely pathogenic 802250 6:88258311-88258311 6:87548593-87548593
17 RARS2 NM_020320.5(RARS2):c.35A>G (p.Gln12Arg)SNV Conflicting interpretations of pathogenicity 30912 rs147391618 6:88299641-88299641 6:87589923-87589923
18 RARS2 NM_020320.5(RARS2):c.442A>G (p.Thr148Ala)SNV Conflicting interpretations of pathogenicity 358237 rs143389605 6:88258318-88258318 6:87548600-87548600
19 RARS2 NM_020320.5(RARS2):c.1679G>A (p.Arg560His)SNV Conflicting interpretations of pathogenicity 215071 rs756502974 6:88224189-88224189 6:87514471-87514471
20 RARS2 NM_020320.5(RARS2):c.1026G>A (p.Met342Ile)SNV Conflicting interpretations of pathogenicity 215064 rs34647222 6:88231191-88231191 6:87521473-87521473
21 RARS2 NM_020320.5(RARS2):c.472_474del (p.Lys158del)deletion Conflicting interpretations of pathogenicity 215072 rs757743894 6:88255395-88255397 6:87545677-87545679
22 RARS2 NM_020320.5(RARS2):c.818G>T (p.Arg273Leu)SNV Uncertain significance 215059 rs139721632 6:88239320-88239320 6:87529602-87529602
23 RARS2 NM_020320.5(RARS2):c.773G>A (p.Arg258His)SNV Uncertain significance 215080 rs145297855 6:88239365-88239365 6:87529647-87529647
24 RARS2 NM_020320.5(RARS2):c.189del (p.Gln64fs)deletion Uncertain significance 225452 rs1085307089 6:88273872-88273872 6:87564154-87564154
25 RARS2 NM_020320.5(RARS2):c.1405C>T (p.Arg469Cys)SNV Uncertain significance 548557 rs767150990 6:88228358-88228358 6:87518640-87518640
26 RARS2 NM_020320.5(RARS2):c.214C>G (p.Leu72Val)SNV Uncertain significance 561096 rs1562212838 6:88272503-88272503 6:87562785-87562785

Expression for Pontocerebellar Hypoplasia, Type 6

Search GEO for disease gene expression data for Pontocerebellar Hypoplasia, Type 6.

Pathways for Pontocerebellar Hypoplasia, Type 6

GO Terms for Pontocerebellar Hypoplasia, Type 6

Cellular components related to Pontocerebellar Hypoplasia, Type 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 mitochondrion GO:0005739 9.63 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1
2 mitochondrial matrix GO:0005759 9.35 RARS2 MARS2 LARS2 KARS1 DARS2
3 tRNA-intron endonuclease complex GO:0000214 8.8 TSEN54 TSEN34 TSEN2

Biological processes related to Pontocerebellar Hypoplasia, Type 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 translation GO:0006412 9.73 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1
2 RNA phosphodiester bond hydrolysis, endonucleolytic GO:0090502 9.58 TSEN54 TSEN34 TSEN2
3 tRNA processing GO:0008033 9.55 TSEN54 TSEN34 TSEN2 KARS1 AARS1
4 RNA phosphodiester bond hydrolysis GO:0090501 9.54 TSEN54 TSEN34 TSEN2
5 tRNA splicing, via endonucleolytic cleavage and ligation GO:0006388 9.5 TSEN54 TSEN34 TSEN2
6 mitochondrial translation GO:0032543 9.48 RARS2 LARS2
7 aminoacyl-tRNA metabolism involved in translational fidelity GO:0106074 9.46 LARS2 AARS1
8 tRNA aminoacylation GO:0043039 9.43 DARS2 AARS1
9 tRNA-type intron splice site recognition and cleavage GO:0000379 9.13 TSEN54 TSEN34 TSEN2
10 tRNA aminoacylation for protein translation GO:0006418 9.1 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1

Molecular functions related to Pontocerebellar Hypoplasia, Type 6 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 ATP binding GO:0005524 9.88 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1
2 nucleic acid binding GO:0003676 9.77 TSEN34 TSEN2 KARS1 DARS2 AARS1
3 amino acid binding GO:0016597 9.43 KARS1 AARS1
4 tRNA binding GO:0000049 9.43 KARS1 DARS2 AARS1
5 ligase activity GO:0016874 9.43 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1
6 tRNA-intron endonuclease activity GO:0000213 9.33 TSEN54 TSEN34 TSEN2
7 aminoacyl-tRNA editing activity GO:0002161 9.32 LARS2 AARS1
8 aminoacyl-tRNA ligase activity GO:0004812 9.1 RARS2 MARS2 LARS2 KARS1 DARS2 AARS1

Sources for Pontocerebellar Hypoplasia, Type 6

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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