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Pontocerebellar hypoplasia type 1A(PCH1A)

MedGen UID:
335969
Concept ID:
C1843504
Disease or Syndrome
Synonyms: PCH1A; Pontocerebellar hypoplasia with anterior horn cell disease; Pontocerebellar hypoplasia with infantile spinal muscular atrophy
 
Gene (location): VRK1 (14q32.2)
 
Monarch Initiative: MONDO:0011866
OMIM®: 607596

Definition

Pontocerebellar hypoplasia (PCH) refers to a group of severe neurodegenerative disorders affecting growth and function of the brainstem and cerebellum, resulting in little or no development. Different types were classified based on the clinical picture and the spectrum of pathologic changes. PCH type 1 is characterized by central and peripheral motor dysfunction associated with anterior horn cell degeneration resembling infantile spinal muscular atrophy (SMA; see SMA1, 253300); death usually occurs early. Genetic Heterogeneity of Pontocerebellar Hypoplasia Also see PCH1B (614678), caused by mutation in the EXOSC3 gene (606489); PCH1C (616081), caused by mutation in the EXOSC8 gene (606019); PCH1D (618065), caused by mutation in the EXOSC9 gene (606180); PCH1E (619303), caused by mutation in the SLC25A46 gene (610826); PCH1F (619304), caused by mutation in the EXOSC1 gene (606493); PCH2A (277470), caused by mutation in the TSEN54 gene (608755); PCH2B (612389), caused by mutation in the TSEN2 gene (608753); PCH2C (612390), caused by mutation in the TSEN34 gene (608754); PCH2D (613811), caused by mutation in the SEPSECS gene (613009); PCH3 (608027), caused by mutation in the PCLO gene (604918); PCH4 (225753), caused by mutation in the TSEN54 gene; PCH5 (610204), caused by mutation in the TSEN54 gene; PCH6 (611523), caused by mutation in the RARS2 gene (611524); PCH7 (614969), caused by mutation in the TOE1 gene (613931); PCH8 (614961), caused by mutation in the CHMP1A gene (164010); PCH9 (615809), caused by mutation in the AMPD2 gene (102771); PCH10 (615803), caused by mutation in the CLP1 gene (608757); PCH11 (617695), caused by mutation in the TBC1D23 gene (617687); PCH12 (618266), caused by mutation in the COASY gene (609855); PCH13 (618606), caused by mutation in the VPS51 gene (615738); PCH14 (619301), caused by mutation in the PPIL1 gene (601301); PCH15 (619302), caused by mutation in the CDC40 gene (605585); PCH16 (619527), caused by mutation in the MINPP1 gene (605391); and PCH17 (619909), caused by mutation in the PRDM13 gene (616741) on chromosome 6q16. [from OMIM]

Clinical features

From HPO
Clubfoot
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Abnormal foot morphology
MedGen UID:
1762829
Concept ID:
C5399834
Anatomical Abnormality
An abnormality of the skeleton of foot.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Poor suck
MedGen UID:
324693
Concept ID:
C1837142
Finding
An inadequate sucking reflex, resulting in the difficult of newborns to be breast-fed.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Fasciculations
MedGen UID:
5124
Concept ID:
C0015644
Sign or Symptom
Fasciculations are observed as small, local, involuntary muscle contractions (twitching) visible under the skin. Fasciculations result from increased irritability of an axon (which in turn is often a manifestation of disease of a motor neuron). This leads to sporadic discharges of all the muscle fibers controlled by the axon in isolation from other motor units.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Hand tremor
MedGen UID:
68689
Concept ID:
C0239842
Finding
An unintentional, oscillating to-and-fro muscle movement affecting the hand.
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.
Demyelinating peripheral neuropathy
MedGen UID:
82859
Concept ID:
C0270922
Disease or Syndrome
Demyelinating neuropathy is characterized by slow nerve conduction velocities with reduced amplitudes of sensory/motor nerve conduction and prolonged distal latencies.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Limb ataxia
MedGen UID:
196692
Concept ID:
C0750937
Finding
A kind of ataxia that affects movements of the extremities.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Degeneration of anterior horn cells
MedGen UID:
375215
Concept ID:
C1843505
Finding
Hypoplasia of the ventral pons
MedGen UID:
334768
Concept ID:
C1843507
Finding
Underdevelopment of the ventral portion of the pons.
Hypoplasia of the pons
MedGen UID:
341246
Concept ID:
C1848529
Finding
Underdevelopment of the pons.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Lateral ventricle dilatation
MedGen UID:
383904
Concept ID:
C1856409
Pathologic Function
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
Neuronal loss in basal ganglia
MedGen UID:
413431
Concept ID:
C2750913
Finding
A reduction in the number of nerve cells in the basal ganglia.
Basal ganglia gliosis
MedGen UID:
416417
Concept ID:
C2750915
Finding
Focal proliferation of glial cells in the basal ganglia.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
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.
Spinal muscular atrophy
MedGen UID:
7755
Concept ID:
C0026847
Disease or Syndrome
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Congenital contracture
MedGen UID:
83066
Concept ID:
C0332878
Congenital Abnormality
One or more flexion contractures (a bent joint that cannot be straightened actively or passively) that are present at birth.
Distal amyotrophy
MedGen UID:
338530
Concept ID:
C1848736
Disease or Syndrome
Muscular atrophy affecting muscles in the distal portions of the extremities.
Enlarged cisterna magna
MedGen UID:
344031
Concept ID:
C1853377
Finding
Increase in size of the cisterna magna, one of three principal openings in the subarachnoid space between the arachnoid and pia mater, located between the cerebellum and the dorsal surface of the medulla oblongata.
EMG: neuropathic changes
MedGen UID:
867363
Concept ID:
C4021727
Finding
The presence of characteristic findings of denervation on electromyography (fibrillations, positive sharp waves, and giant motor unit potentials).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Intercostal muscle weakness
MedGen UID:
786098
Concept ID:
C0240017
Finding
Lack of strength of the intercostal muscles, i.e., of the muscle groups running along the ribs that create and move the chest wall.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.

Professional guidelines

PubMed

Ivanov I, Atkinson D, Litvinenko I, Angelova L, Andonova S, Mumdjiev H, Pacheva I, Panova M, Yordanova R, Belovejdov V, Petrova A, Bosheva M, Shmilev T, Savov A, Jordanova A
Eur J Paediatr Neurol 2018 Jul;22(4):674-681. Epub 2018 Apr 3 doi: 10.1016/j.ejpn.2018.03.011. PMID: 29656927
Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F
Orphanet J Rare Dis 2014 Feb 13;9:23. doi: 10.1186/1750-1172-9-23. PMID: 24524299Free PMC Article

Recent clinical studies

Etiology

Damseh NS, Obeidat AN, Ahammed KS, Al-Ashhab M, Awad MA, van Hoof A
Am J Med Genet A 2023 Jul;191(7):1923-1928. Epub 2023 Apr 6 doi: 10.1002/ajmg.a.63198. PMID: 37024942
Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F
Orphanet J Rare Dis 2014 Feb 13;9:23. doi: 10.1186/1750-1172-9-23. PMID: 24524299Free PMC Article
Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, Graul-Neumann L, Seidel U, Korinthenberg R, Kirschner J, Seeger J, Ryan MM, Muntoni F, Steinlin M, Sztriha L, Colomer J, Hübner C, Brockmann K, Van Maldergem L, Schiff M, Holzinger A, Barth P, Reardon W, Yourshaw M, Nelson SF, Eggermann T, Zerres K
Neurology 2013 Jan 29;80(5):438-46. Epub 2013 Jan 2 doi: 10.1212/WNL.0b013e31827f0f66. PMID: 23284067Free PMC Article
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

Radvanska E, Pos Z, Zatkova A, Hyblova M, Bauer F, Szemes T, Kadasi L, Radvanszky J
Bratisl Lek Listy 2022;123(8):568-572. doi: 10.4149/BLL_2022_090. PMID: 35852507
Ivanov I, Atkinson D, Litvinenko I, Angelova L, Andonova S, Mumdjiev H, Pacheva I, Panova M, Yordanova R, Belovejdov V, Petrova A, Bosheva M, Shmilev T, Savov A, Jordanova A
Eur J Paediatr Neurol 2018 Jul;22(4):674-681. Epub 2018 Apr 3 doi: 10.1016/j.ejpn.2018.03.011. PMID: 29656927
Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F
Orphanet J Rare Dis 2014 Feb 13;9:23. doi: 10.1186/1750-1172-9-23. PMID: 24524299Free PMC Article
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
Szabó N, Szabó H, Hortobágyi T, Túri S, Sztriha L
Pediatr Neurol 2008 Oct;39(4):286-8. doi: 10.1016/j.pediatrneurol.2008.06.017. PMID: 18805371

Prognosis

Braunisch MC, Gallwitz H, Abicht A, Diebold I, Holinski-Feder E, Van Maldergem L, Lammens M, Kovács-Nagy R, Alhaddad B, Strom TM, Meitinger T, Senderek J, Rudnik-Schöneborn S, Haack TB
Clin Genet 2018 Feb;93(2):255-265. Epub 2017 Nov 8 doi: 10.1111/cge.13084. PMID: 28653766
Eggens VR, Barth PG, Niermeijer JM, Berg JN, Darin N, Dixit A, Fluss J, Foulds N, Fowler D, Hortobágyi T, Jacques T, King MD, Makrythanasis P, Máté A, Nicoll JA, O'Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CB, Marquering HA, Poll-Thé BT, Baas F
Orphanet J Rare Dis 2014 Feb 13;9:23. doi: 10.1186/1750-1172-9-23. PMID: 24524299Free PMC Article
Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, Graul-Neumann L, Seidel U, Korinthenberg R, Kirschner J, Seeger J, Ryan MM, Muntoni F, Steinlin M, Sztriha L, Colomer J, Hübner C, Brockmann K, Van Maldergem L, Schiff M, Holzinger A, Barth P, Reardon W, Yourshaw M, Nelson SF, Eggermann T, Zerres K
Neurology 2013 Jan 29;80(5):438-46. Epub 2013 Jan 2 doi: 10.1212/WNL.0b013e31827f0f66. PMID: 23284067Free PMC Article
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
Sanefuji M, Kira R, Matsumoto K, Gondo K, Torisu H, Kawakami H, Iwaki T, Hara T
J Child Neurol 2010 Nov;25(11):1429-34. Epub 2010 Jun 17 doi: 10.1177/0883073810372991. PMID: 20558670

Clinical prediction guides

Sheffer R, Gur M, Brooks R, Salah S, Daana M, Fraenkel N, Eisenstein E, Rabie M, Nevo Y, Jalas C, Elpeleg O, Edvardson S, Harel T
Eur J Hum Genet 2019 Sep;27(9):1419-1426. Epub 2019 Apr 11 doi: 10.1038/s41431-019-0400-y. PMID: 30976113Free PMC Article
François-Moutal L, Jahanbakhsh S, Nelson ADL, Ray D, Scott DD, Hennefarth MR, Moutal A, Perez-Miller S, Ambrose AJ, Al-Shamari A, Coursodon P, Meechoovet B, Reiman R, Lyons E, Beilstein M, Chapman E, Morris QD, Van Keuren-Jensen K, Hughes TR, Khanna R, Koehler C, Jen J, Gokhale V, Khanna M
ACS Chem Biol 2018 Oct 19;13(10):3000-3010. Epub 2018 Sep 6 doi: 10.1021/acschembio.8b00745. PMID: 30141626Free PMC Article
Rudnik-Schöneborn S, Senderek J, Jen JC, Houge G, Seeman P, Puchmajerová A, Graul-Neumann L, Seidel U, Korinthenberg R, Kirschner J, Seeger J, Ryan MM, Muntoni F, Steinlin M, Sztriha L, Colomer J, Hübner C, Brockmann K, Van Maldergem L, Schiff M, Holzinger A, Barth P, Reardon W, Yourshaw M, Nelson SF, Eggermann T, Zerres K
Neurology 2013 Jan 29;80(5):438-46. Epub 2013 Jan 2 doi: 10.1212/WNL.0b013e31827f0f66. PMID: 23284067Free PMC Article
Burglen L, Chantot-Bastaraud S, Garel C, Milh M, Touraine R, Zanni G, Petit F, Afenjar A, Goizet C, Barresi S, Coussement A, Ioos C, Lazaro L, Joriot S, Desguerre I, Lacombe D, des Portes V, Bertini E, Siffroi JP, de Villemeur TB, Rodriguez D
Orphanet J Rare Dis 2012 Mar 27;7:18. doi: 10.1186/1750-1172-7-18. PMID: 22452838Free PMC Article
Szabó N, Szabó H, Hortobágyi T, Túri S, Sztriha L
Pediatr Neurol 2008 Oct;39(4):286-8. doi: 10.1016/j.pediatrneurol.2008.06.017. PMID: 18805371

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