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Pontocerebellar hypoplasia type 6(PCH6)

MedGen UID:
370596
Concept ID:
C1969084
Congenital Abnormality; Disease or Syndrome
Synonyms: Encephalopathy fatal infantile with mitochondrial respiratory chain defects; PCH6
SNOMED CT: Congenital pontocerebellar hypoplasia type 6 (718606005); Pontocerebellar hypoplasia type 6 (718606005); PCH6 - pontocerebellar hypoplasia type 6 (718606005); Fatal infantile encephalopathy with mitochondrial respiratory chain defect (718606005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): RARS2 (6q15)
 
Monarch Initiative: MONDO:0012683
OMIM®: 611523
Orphanet: ORPHA166073

Definition

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). [from OMIM]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Generalized-onset seizure
MedGen UID:
115963
Concept ID:
C0234533
Disease or Syndrome
A generalized-onset seizure is a type of seizure originating at some point within, and rapidly engaging, bilaterally distributed networks. The networks may include cortical and subcortical structures but not necessarily the entire cortex.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis
Upper limb spasticity
MedGen UID:
220882
Concept ID:
C1273957
Finding
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Profound global developmental delay
MedGen UID:
766364
Concept ID:
C3553450
Disease or Syndrome
A profound delay in the achievement of motor or mental milestones in the domains of development of a child.
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
Appendicular spasticity
MedGen UID:
937224
Concept ID:
C4313257
Finding
A type of spasticity that affects one or more limbs (arms or legs).
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Brain atrophy
MedGen UID:
1643639
Concept ID:
C4551584
Disease or Syndrome
Partial or complete wasting (loss) of brain tissue that was once present.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Elbow contracture
MedGen UID:
331445
Concept ID:
C1833142
Anatomical Abnormality
A limitation in the passive range of motion of the elbow resulting from loss of elasticity in the periarticular tissues owing to structural changes of non-bony tissues, such as muscles, tendons, ligaments, joint capsules or skin.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Narrow palate
MedGen UID:
278045
Concept ID:
C1398312
Finding
Width of the palate more than 2 SD below the mean (objective) or apparently decreased palatal width (subjective).
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Prominent nasal bridge
MedGen UID:
343051
Concept ID:
C1854113
Finding
Anterior positioning of the nasal root in comparison to the usual positioning for age.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex IV
MedGen UID:
866520
Concept ID:
C4020800
Finding
A reduction in the activity of the mitochondrial respiratory chain complex IV, which is part of the electron transport chain in mitochondria.

Professional guidelines

PubMed

Kahn-Kirby AH, Amagata A, Maeder CI, Mei JJ, Sideris S, Kosaka Y, Hinman A, Malone SA, Bruegger JJ, Wang L, Kim V, Shrader WD, Hoff KG, Latham JC, Ashley EA, Wheeler MT, Bertini E, Carrozzo R, Martinelli D, Dionisi-Vici C, Chapman KA, Enns GM, Gahl W, Wolfe L, Saneto RP, Johnson SC, Trimmer JK, Klein MB, Holst CR
PLoS One 2019;14(3):e0214250. Epub 2019 Mar 28 doi: 10.1371/journal.pone.0214250. PMID: 30921410Free PMC Article

Recent clinical studies

Etiology

Ngoh A, Bras J, Guerreiro R, Meyer E, McTague A, Dawson E, Mankad K, Gunny R, Clayton P, Mills PB, Thornton R, Lai M, Forsyth R, Kurian MA
Epilepsia 2016 May;57(5):e97-e102. Epub 2016 Apr 8 doi: 10.1111/epi.13358. PMID: 27061686Free PMC Article
Joseph JT, Innes AM, Smith AC, Vanstone MR, Schwartzentruber JA, Bulman DE, Majewski J, Daza RA, Hevner RF, Michaud J, Boycott KM; FORGE Canada Consortium
J Neuropathol Exp Neurol 2014 Nov;73(11):1009-25. doi: 10.1097/NEN.0000000000000123. PMID: 25289895
Cassandrini D, Cilio MR, Bianchi M, Doimo M, Balestri M, Tessa A, Rizza T, Sartori G, Meschini MC, Nesti C, Tozzi G, Petruzzella V, Piemonte F, Bisceglia L, Bruno C, Dionisi-Vici C, D'Amico A, Fattori F, Carrozzo R, Salviati L, Santorelli FM, Bertini E
J Inherit Metab Dis 2013 Jan;36(1):43-53. Epub 2012 May 8 doi: 10.1007/s10545-012-9487-9. PMID: 22569581
Namavar Y, Barth PG, Poll-The BT, Baas F
Orphanet J Rare Dis 2011 Jul 12;6:50. doi: 10.1186/1750-1172-6-50. PMID: 21749694Free PMC Article
Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, Writzl K, Ventura K, Cheng EY, Ferriero DM, Basel-Vanagaite L, Eggens VR, Krägeloh-Mann I, De Meirleir L, King M, Graham JM Jr, von Moers A, Knoers N, Sztriha L, Korinthenberg R; PCH Consortium, Dobyns WB, Baas F, Poll-The BT
Brain 2011 Jan;134(Pt 1):143-56. Epub 2010 Oct 15 doi: 10.1093/brain/awq287. PMID: 20952379Free PMC Article

Diagnosis

Zhang Y, Yu Y, Zhao X, Xu Y, Chen L, Li N, Yao R, Wang J, Yu T
Pediatr Neurol 2022 Jun;131:30-41. Epub 2022 Apr 15 doi: 10.1016/j.pediatrneurol.2022.04.002. PMID: 35468344
Nagafuji M, Hitaka D, Iwabuchi A, Miyazono Y, Takada H
Am J Case Rep 2021 Dec 21;22:e934417. doi: 10.12659/AJCR.934417. PMID: 34930889Free PMC Article
Joseph JT, Innes AM, Smith AC, Vanstone MR, Schwartzentruber JA, Bulman DE, Majewski J, Daza RA, Hevner RF, Michaud J, Boycott KM; FORGE Canada Consortium
J Neuropathol Exp Neurol 2014 Nov;73(11):1009-25. doi: 10.1097/NEN.0000000000000123. PMID: 25289895
Cassandrini D, Cilio MR, Bianchi M, Doimo M, Balestri M, Tessa A, Rizza T, Sartori G, Meschini MC, Nesti C, Tozzi G, Petruzzella V, Piemonte F, Bisceglia L, Bruno C, Dionisi-Vici C, D'Amico A, Fattori F, Carrozzo R, Salviati L, Santorelli FM, Bertini E
J Inherit Metab Dis 2013 Jan;36(1):43-53. Epub 2012 May 8 doi: 10.1007/s10545-012-9487-9. PMID: 22569581
Namavar Y, Barth PG, Poll-The BT, Baas F
Orphanet J Rare Dis 2011 Jul 12;6:50. doi: 10.1186/1750-1172-6-50. PMID: 21749694Free PMC Article

Prognosis

Nicolle R, Altin N, Siquier-Pernet K, Salignac S, Blanc P, Munnich A, Bole-Feysot C, Malan V, Caron B, Nitschké P, Desguerre I, Boddaert N, Rio M, Rausell A, Cantagrel V
BMC Med Genomics 2023 Jun 21;16(1):143. doi: 10.1186/s12920-023-01582-z. PMID: 37344844Free PMC Article
Zhang Y, Yu Y, Zhao X, Xu Y, Chen L, Li N, Yao R, Wang J, Yu T
Pediatr Neurol 2022 Jun;131:30-41. Epub 2022 Apr 15 doi: 10.1016/j.pediatrneurol.2022.04.002. PMID: 35468344
Lax NZ, Alston CL, Schon K, Park SM, Krishnakumar D, He L, Falkous G, Ogilvy-Stuart A, Lees C, King RH, Hargreaves IP, Brown GK, McFarland R, Dean AF, Taylor RW
J Neuropathol Exp Neurol 2015 Jul;74(7):688-703. doi: 10.1097/NEN.0000000000000209. PMID: 26083569Free PMC Article
Cassandrini D, Cilio MR, Bianchi M, Doimo M, Balestri M, Tessa A, Rizza T, Sartori G, Meschini MC, Nesti C, Tozzi G, Petruzzella V, Piemonte F, Bisceglia L, Bruno C, Dionisi-Vici C, D'Amico A, Fattori F, Carrozzo R, Salviati L, Santorelli FM, Bertini E
J Inherit Metab Dis 2013 Jan;36(1):43-53. Epub 2012 May 8 doi: 10.1007/s10545-012-9487-9. PMID: 22569581
Namavar Y, Barth PG, Poll-The BT, Baas F
Orphanet J Rare Dis 2011 Jul 12;6:50. doi: 10.1186/1750-1172-6-50. PMID: 21749694Free PMC Article

Clinical prediction guides

Nicolle R, Altin N, Siquier-Pernet K, Salignac S, Blanc P, Munnich A, Bole-Feysot C, Malan V, Caron B, Nitschké P, Desguerre I, Boddaert N, Rio M, Rausell A, Cantagrel V
BMC Med Genomics 2023 Jun 21;16(1):143. doi: 10.1186/s12920-023-01582-z. PMID: 37344844Free PMC Article
Zhang Y, Yu Y, Zhao X, Xu Y, Chen L, Li N, Yao R, Wang J, Yu T
Pediatr Neurol 2022 Jun;131:30-41. Epub 2022 Apr 15 doi: 10.1016/j.pediatrneurol.2022.04.002. PMID: 35468344
Lax NZ, Alston CL, Schon K, Park SM, Krishnakumar D, He L, Falkous G, Ogilvy-Stuart A, Lees C, King RH, Hargreaves IP, Brown GK, McFarland R, Dean AF, Taylor RW
J Neuropathol Exp Neurol 2015 Jul;74(7):688-703. doi: 10.1097/NEN.0000000000000209. PMID: 26083569Free PMC Article
Kastrissianakis K, Anand G, Quaghebeur G, Price S, Prabhakar P, Marinova J, Brown G, McShane T
Arch Dis Child 2013 Dec;98(12):1004-7. Epub 2013 Sep 18 doi: 10.1136/archdischild-2013-304308. PMID: 24047924

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