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Cerebellar atrophy with seizures and variable developmental delay(CASVDD)

MedGen UID:
1683734
Concept ID:
C5193132
Disease or Syndrome
Synonyms: CASVDD; CEREBELLAR ATROPHY WITH SEIZURES AND VARIABLE DEVELOPMENTAL DELAY
 
Gene (location): CACNA2D2 (3p21.31)
 
Monarch Initiative: MONDO:0032788
OMIM®: 618501

Definition

Cerebellar atrophy with seizures and variable developmental delay (CASVDD) is an autosomal recessive neurologic disorder characterized by cerebellar ataxia associated with atrophy of the cerebellar vermis on brain imaging. Most patients also have onset of severe refractory seizures in the first year of life and show global developmental delay, compatible with epileptic encephalopathy (summary by Edvardson et al., 2013). However, at least 1 patient with normal cognitive development and only 1 febrile seizure has been reported (Valence et al., 2019), suggesting significant clinical variability of this disorder. [from OMIM]

Clinical features

From HPO
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).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Cerebellar vermis atrophy
MedGen UID:
149271
Concept ID:
C0742028
Disease or Syndrome
Wasting (atrophy) of the vermis of cerebellum.
Gait ataxia
MedGen UID:
155642
Concept ID:
C0751837
Sign or Symptom
A type of ataxia characterized by the impairment of the ability to coordinate the movements required for normal walking. Gait ataxia is characteirzed by a wide-based staggering gait with a tendency to fall.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
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.
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).
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Abnormality of eye movement
MedGen UID:
99227
Concept ID:
C0497202
Finding
An abnormality in voluntary or involuntary eye movements or their control.

Professional guidelines

PubMed

Muthaffar OY, Alqarni A, Shafei JA, Bahowarth SY, Alyazidi AS, Naseer MI
Genes Genomics 2024 Apr;46(4):475-487. Epub 2024 Jan 19 doi: 10.1007/s13258-023-01481-8. PMID: 38243045
Kjaergaard S, Schwartz M, Skovby F
Arch Dis Child 2001 Sep;85(3):236-9. doi: 10.1136/adc.85.3.236. PMID: 11517108Free PMC Article

Recent clinical studies

Etiology

Giacomini T, Nuovo S, Zanni G, Mancardi MM, Cusmai R, Pepi C, Bertini E, Valente EM, Battini R, Ferrari A, Romaniello R, Zucca C, Borgatti R, Uccella S, Severino M, Striano P, Pistorio A, Prato G, De Grandis E, Nobili L, Pisciotta L
Eur J Paediatr Neurol 2021 Mar;31:61-69. Epub 2021 Feb 19 doi: 10.1016/j.ejpn.2021.02.006. PMID: 33640666
Kortüm F, Jamra RA, Alawi M, Berry SA, Borck G, Helbig KL, Tang S, Huhle D, Korenke GC, Hebbar M, Shukla A, Girisha KM, Steinlin M, Waldmeier-Wilhelm S, Montomoli M, Guerrini R, Lemke JR, Kutsche K
Eur J Hum Genet 2018 May;26(5):695-708. Epub 2018 Feb 20 doi: 10.1038/s41431-018-0098-2. PMID: 29463858Free PMC Article
Salman MS, Marles SL, Booth FA, Del Bigio MR
Pediatr Neurol 2009 May;40(5):365-70. doi: 10.1016/j.pediatrneurol.2008.11.020. PMID: 19380073

Diagnosis

Magyar CL, Murdock DR, Burrage LC, Dai H, Lalani SR, Lewis RA, Lin Y, Astudillo MF, Rosenfeld JA, Tran AA, Gibson JB; Undiagnosed Diseases Network, Bacino CA, Lee BH, Chao HT
Am J Med Genet A 2022 Jun;188(6):1868-1874. Epub 2022 Feb 23 doi: 10.1002/ajmg.a.62704. PMID: 35194938Free PMC Article
Schneeberger PE, Nampoothiri S, Holling T, Yesodharan D, Alawi M, Knisely AS, Müller T, Plecko B, Janecke AR, Kutsche K
Brain 2021 Nov 29;144(10):3036-3049. doi: 10.1093/brain/awab206. PMID: 34037727
Giacomini T, Nuovo S, Zanni G, Mancardi MM, Cusmai R, Pepi C, Bertini E, Valente EM, Battini R, Ferrari A, Romaniello R, Zucca C, Borgatti R, Uccella S, Severino M, Striano P, Pistorio A, Prato G, De Grandis E, Nobili L, Pisciotta L
Eur J Paediatr Neurol 2021 Mar;31:61-69. Epub 2021 Feb 19 doi: 10.1016/j.ejpn.2021.02.006. PMID: 33640666
Agostini A, Marchetti D, Izzi C, Cocco I, Pinelli L, Accorsi P, Iascone Maria R, Giordano L
Am J Med Genet B Neuropsychiatr Genet 2018 Dec;177(8):687-690. Epub 2018 Oct 22 doi: 10.1002/ajmg.b.32677. PMID: 30345598
Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, Kubota M, Kawawaki H, Matsufuji M, Kojima Y, Tateno A, Goldberg-Stern H, Straussberg R, Marom D, Leshinsky-Silver E, Nakashima M, Nishiyama K, Tsurusaki Y, Miyake N, Tanaka F, Matsumoto N, Saitsu H
Epilepsia 2014 Jul;55(7):994-1000. Epub 2014 Jun 2 doi: 10.1111/epi.12668. PMID: 24888894

Prognosis

Giacomini T, Nuovo S, Zanni G, Mancardi MM, Cusmai R, Pepi C, Bertini E, Valente EM, Battini R, Ferrari A, Romaniello R, Zucca C, Borgatti R, Uccella S, Severino M, Striano P, Pistorio A, Prato G, De Grandis E, Nobili L, Pisciotta L
Eur J Paediatr Neurol 2021 Mar;31:61-69. Epub 2021 Feb 19 doi: 10.1016/j.ejpn.2021.02.006. PMID: 33640666
Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J
Neuropediatrics 2018 Oct;49(5):330-338. Epub 2018 Jun 25 doi: 10.1055/s-0038-1661396. PMID: 29940663
Latimer CS, Flanagan ME, Cimino PJ, Jayadev S, Davis M, Hoffer ZS, Montine TJ, Gonzalez-Cuyar LF, Bird TD, Keene CD
J Huntingtons Dis 2017;6(4):337-348. doi: 10.3233/JHD-170261. PMID: 29036832Free PMC Article
Schroer RJ, Holden KR, Tarpey PS, Matheus MG, Griesemer DA, Friez MJ, Fan JZ, Simensen RJ, Strømme P, Stevenson RE, Stratton MR, Schwartz CE
Am J Med Genet A 2010 Nov;152A(11):2775-83. doi: 10.1002/ajmg.a.33093. PMID: 20949524Free PMC Article
Kjaergaard S, Schwartz M, Skovby F
Arch Dis Child 2001 Sep;85(3):236-9. doi: 10.1136/adc.85.3.236. PMID: 11517108Free PMC Article

Clinical prediction guides

Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J
Neuropediatrics 2018 Oct;49(5):330-338. Epub 2018 Jun 25 doi: 10.1055/s-0038-1661396. PMID: 29940663
Dunn P, Prigatano GP, Szelinger S, Roth J, Siniard AL, Claasen AM, Richholt RF, De Both M, Corneveaux JJ, Moskowitz AM, Balak C, Piras IS, Russell M, Courtright AL, Belnap N, Rangasamy S, Ramsey K, Opitz JM, Craig DW, Narayanan V, Huentelman MJ, Schrauwen I
Am J Med Genet A 2017 Mar;173(3):611-617. Epub 2017 Jan 31 doi: 10.1002/ajmg.a.38069. PMID: 28139025
Kjaergaard S, Schwartz M, Skovby F
Arch Dis Child 2001 Sep;85(3):236-9. doi: 10.1136/adc.85.3.236. PMID: 11517108Free PMC Article

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