Olivopontocerebellar Atrophy Follow-up

  • Author: Christina J Azevedo MD; Chief Editor: Selim R Benbadis, MD   more...
 
Updated: May 27, 2010
 

Complications

  • Falls are the primary complications in the early stages of olivopontocerebellar atrophy (OPCA).
  • Aspiration pneumonia is more common in later stages of OPCA.
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Prognosis

Currently, no effective therapy is available for the neurodegenerative processes that constitute OPCA. Clinically, only supportive care can be given to patients with this progressive disease.

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Contributor Information and Disclosures
Author

Christina J Azevedo MD  Staff Physician, Department of Neurology, Dartmouth-Hitchcock Medical Center

Christina J Azevedo MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Coauthor(s)

Stephen A Berman, MD, PhD, MBA  Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Howard A Crystal, MD  Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center

Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Accera Pharmaceuticals Honoraria Consulting

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Nestor Galvez-Jimenez, MD, MSc, MHA  Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida

Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Ortho McNeil Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Speaking, consulting

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Table 1. Most Common OPCAs With Alternative Names
OMIM #OPCA NamesOther NamesGenetic PatternDescription
#164400OPCA-1,



OPCA-I,



Menzel type OPCA



SCA-1,



SCA-I,



ADCA-1,



ADCA-I



Gene map locus 6p23 expanded (CAG)n trinucleotide repeat in the ataxin-1 gene (ATXN1; 601556); autosomal dominant; genetic test availableOnset 30-40 years; ataxia, spasticity, dysarthria, ophthalmoplegia, slow saccades, nystagmus, optic atrophy, pyramidal tract signs; rare extrapyramidal signs; some have dementia; neuropathy occurs late[13]
#183090OPCA-2SCA-2, ADCA-IGene map locus 12q24 expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517); autosomal dominant; genetic test availableOnset in 30s; ataxia, dysarthria, muscle cramps; slow saccades; ophthalmoplegia; peripheral neuropathy; dementia (some); no pyramidal or extrapyramidal features[14]
%258300OPCA-II, Fickler-Winkler type OPCAFickler-Winkler SyndromeGene/biochemistry not known; autosomal recessiveAdult-onset; cerebellar ataxia, albinism, impaired intellect; neurological impairments similar to OPCA-I but no involuntary movements or sensory loss[9, 15, 16]
#164500OPCA-III, OPCA-3, OPCA with retinal degenerationADCA-II, SCA-7, OPCA with macular degeneration and external ophthalmoplegiaGene locus 3p21.1-p12; expanded trinucleotide repeat in the gene encoding ataxin-7 (ATXN7; 607640); autosomal dominant; genetic test availableOnset in mid 20s; initially pigmentary retinal degeneration then ataxia, dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signs[14]
^ 164600 Number now obsolete; considered the same as # 164400 (see first row above)OPCA-IV, Schut-Haymaker type OPCAGenetics unclear; glutamate dehydrogenase deficiency suspected in some; some cases may be linked to OPCA locus at chromosome 6p; may not be a pure genetic type; now thought to be same as OPCA-I (SCA-1) Adult-onset ataxia with involvement of cranial nerves IX, X, and XII[17]
164700OPCA-V, OPCA-5, OPCA with dementia and extrapyramidal signsThis may be the same as SCA-17Autosomal dominant; genetic test available for SCA-17, but unclear if this is the sameCerebellar ataxia, rigidity, dementia; neuronal loss in cerebellum, basal ganglia, substantia nigra, olivary nuclei, cerebral cortex[18, 8]
%302500OPCA-X, OPCA X-linked-1SCA-X1 (do not confuse this with SAX-1, the locus for hereditary (autosomal dominant) spastic ataxia [%108600])X-linked, some cases linked to Xp11.21-q21.3; not homogenous; gene(s) not knownOnset in first or second decade and often bedbound by 20s; loss of cerebellar Purkinje cells, inferior olivary cells, myelin loss in spinocerebellar tracts, posterior columns, and corticospinal tracts; gait and limb ataxia, intention tremor, dysmetria, dysdiadochokinesia, dysarthria, and nystagmus; some have peripheral neuropathy[19, 20]
Table 2. Extremely Rare Types of OPCAs
OMIM #OPCA NamesOther NamesGenetic PatternDescription
%607596Pontocerebellar hypoplasia type 1, PCH-1Pontocerebellar hypoplasia with infantile spinal muscular atrophy, pontocerebellar hypoplasia with anterior horn cell diseaseAutosomal recessiveCerebellar hypoplasia plus motor neuron loss; sometimes called a combination of olivopontocerebellar degeneration plus spinal muscular atrophy; present from birth; patients usually die in infancy[21, 22]
%277470Pontocerebellar hypoplasia type 2, PCH-2Pontocerebellar hypoplasia with progressive cerebral atrophy, Volendam neurodegenerative diseaseAutosomal recessiveCongenital microcephaly, extrapyramidal findings, epilepsy; autopsy in one case showed that the olivopontocerebellar system was the most heavily involved in degeneration
%608027Pontocerebellar hypoplasia type, PCH-3, Pontocerebellar hypoplasia with optic atrophyCerebellar atrophy with progressive microcephaly, CLAMAutosomal recessive; gene map locus 7q11-q21Gene map locus 7q11-q21Onset in infancy or childhood, cerebellar atrophy with progressive microcephaly; on MRI of small brainstem, small cerebellar vermis and atrophy of the cerebellum and cerebrum; ataxia, truncal hypotonia, and exaggerated deep tendon reflexes; one patient had optic atrophy; seizures common[23]
225753Pontocerebellar hypoplasia type 4, PCH-4Fatal infantile encephalopathy with olivopontocerebellar hypoplasiaProbably autosomal recessive, possibly autosomal dominant or maternal transmission; biochemical defect and gene locus not known Patients die in infancy; severe olivopontocerebellar hypoplasia on autopsy[24, 25]
610204Pontocerebellar hypoplasia type 5, PCH-5Olivopontocerebellar hypoplasia, fetal onsetGenetics not clearPontocerebellar hypoplasia is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem with significant hypoplasia of the olivae, the pons, and the cerebellum; patients typically die in infancy[25]
#278800De Sanctis-Cacchione syndromeGene map locus 10q11; an excision repair gene named variously ERCC6, CKN2, COFS, and CSB causing Cockayne syndrome type B (CSB; 133540) or genes of xeroderma pigmentosum, usually XPA (ie, complementation group A); 278700 9q22.3 or more rarely, other genes associated with xeroderma pigmentosum; autosomal recessive Xeroderma pigmentosum (severe sun sensitivity), mental retardation, dwarfism, and progressive neurological deterioration; overlaps with known types of xeroderma pigmentosum and Cockayne syndrome, especially XPA and CSB, apparently as allelic variants but other unknown factors may bring out the olivopontocerebellar (and cerebral) atrophy[26, 27, 28]
#212065Congenital disorder of glycosylation, type IaPhosphomannomutase-2 (PMM2; 601785); autosomal recessiveSevere congenital psychomotor retardation, generalized hypotonia, hyporeflexia, and trunk ataxia, neonatal-onset OPCA, peripheral neuropathy, retinitis pigmentosa; defects in other systems include heart and musculoskeletal systems; severe neonatal neurodegenerative disease; some patients have olivopontocerebellar phenotype; usually death in infancy or childhood[29, 30]
Table 3. Dominant SCAs with OPCAs Identified
Disease OMIM #Disease NamesLocusGeneProduct (OMIM #)DescriptionReferences
#164400SCA-1, OPCA-I, OPCA-IV (OPCA-IV same as OPCA-I), ADCA-1ATXN1, 6p23Ataxin-1 (*601556); genetic test availableOnset 30-40 years; ataxia, spasticity, dysarthria, ophthalmoplegia, slow saccades, nystagmus, optic atrophy, pyramidal tract signs; rare extrapyramidal; signs; some have dementia; neuropathy occurs late Menzel, 1891[31] ; Waggoner et al, 1938[32] ; Schut, 1950[33] ; Schut and Haymaker, 1951[17] ; Orr et al, 1993[34]
#183090SCA-2, OPCA-2, ADCA-1ATXN2, 12q24Ataxin-2 (601517); genetic test availableOnset in 30s; ataxia, dysarthria, muscle cramps; slow saccades/ophthalmoplegia; peripheral neuropathy, hyporeflexia, dementia in some; no pyramidal or extrapyramidal features Boller and Segarra, 1969[35] ; Wadia and Swami, 1971[36] ; Ueyama et al, 1998[37]
#109150SCA-3 or Machado-Joseph disease, ADCA-1ATXN3, 14q24.3-q31Machado-Joseph disease protein 1(ATXN3). (607047); genetic test availableAll have ataxia, dysarthria, ophthalmoplegia; type I onset in mid 20s with facial-lingual myokymia, pyramidal and extrapyramidal features; type II onset in 40s; type III onset in mid 40s with peripheral neuropathy (weakness and atrophy) Nakano et al, 1972[38] ; Kawaguchi et al, 1994[39]
%600223SCA-4, ADCA-1Gene unknown, 16q22.1 (same region as #117210 below)Onset average approximately 40 years (range, 19-72 y); pure ataxia in some cases, most have sensory axonal neuropathy; deafness in some Gardner et al, 1994[40] ; Hellenbroich et al, 2003[41]
#117210SCA, 16q22-linked ADCA-3PLEKHG4, 16q22.1Puratrophin-1 (609526)Typically pure cerebellar ataxia with gait ataxia, cerebellar dysarthria, limb ataxia, decreased muscle tone, horizontal-gaze nystagmus; lacks other feature seen in SCA-4, ADCA-1 (but sometimes called SCA-4) Ishikawa et al, 2005[42]
#600224SCA-5, ADCA-3SPTBN2, 11p13Spectrin beta chain, brain 2 (604985)Onset mid 30s; downbeat nystagmus; ataxia, dysarthria, impaired smooth pursuit, and gaze-evoked nystagmus; slow progression; both vermal and hemispheric cerebellar atrophy, normal life expectancy Ikeda et al, 2006[43]
#183086SCA-6, ADCA-1 ADCA-3CACNA1A, 19p13Voltage-dependent P/Q-type Ca+2 channel alpha-1a subunit (601011); genetic test availableOnset 20-40 years; ataxia, dysarthria, nystagmus, distal sensory loss, normal life expectancySubramony et al, 1996[44] ; Zhuchenko et al, 1997[45]
#164500SCA-7, OPCA-3 ADCA-2ATXN7, 3p21.1-p12Ataxin-7 (607640); genetic test availableOnset mid 20s; pigmentary retinal degeneration, ataxia, dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signsDavid et al, 1997[46] ; Harding, 1982[7]
#608768SCA-8, ADCA-2KLHL1AS, 13q21Genetic test availableOnset 20s to 70s; ataxia, dysarthria, nystagmus, impaired smooth pursuitKoob et al, 1999[47] ; Ikeda et al, 2000[48] ; Factor et al, 2005[49] (Factor et al case was actually consistent with MSA)
SCA-9Unassigned categoryUnassigned categoryUnassigned category
+603516SCA-10 ADCA-3ATXN10, 22q13Ataxin-10; genetic test availableOnset in 20s; ataxia, dysarthria, nystagmus, epileptic seizures; to date only found in Mexican familiesGrewal et al, 1998[50] ; Zu et al, 1999[51] ; Grewal et al, 2002[52]
%604432SCA-11SCA11, 15q14-q21.3Tau-tubulin kinase 2Onset at 20-40 years; ataxia, dysarthria, nystagmusWorth et al, 1999[53]
#604326SCA-12PPP2R2B, 5q31-q33Serine/threonine protein phosphatase 2A, 55-kd regulatory subunit B, beta isoform; genetic test availableOnset at 8-55 years, commonly 30s; upper extremity and head tremor, gait ataxia, ophthalmoplegia, hyperreflexia, bradykinesia, dementia Holmes et al, 1999[54] ; Fujigasaki et al, 2001[55]
#605259SCA-13KCNC3, 19q13.3-q13.4Voltage-gated K+ channel, subfamily C member 3Onset in childhood; ataxia, dysarthria, mental retardation; slow progressionWaters et al, 2006[56]
#605361SCA-14PRKCG, 19q13.4Kinase C, gamma type; genetic test availableOnset mostly in most those older than 39 years; ataxia, dysarthria, nystagmus; younger patients (< 27 y) also had intermittent axial myoclonus prior to ataxia Yamashita et al 2000[57] ; Brkanac, Bylenok et al 2002[58] ; Chen, Brkanac et al 2003[59] ; Yabe et al 2003[60]
%606658SCA-15Gene unknown, 3p26.1-p25.3Inositol 1,4,5-triphosphate receptor type 1Similar to SCA-6 and SCA-8; MRI-proven cerebellar atrophy; onset at 10-50 years; slowly progressive pure cerebellar ataxia, ataxic dysarthria, tremor; may have head titubation, nystagmus, oculovestibular reflex abnormalities, mild hyperreflexia (no spasticity or Babinski signs) Storey et al, 2001[61] ; Knight et al, 2003[62] ; Hara et al, 2004[63]
%606364SCA-16SCA16, 8q22.1-q24.1Contactin-4MRI-proven cerebellar atrophy without brainstem involvement; onset at 20-66 years; pure cerebellar ataxia, some with head tremor, slow progression Miyoshi et al, 2001[64]
#607136SCA-17, may be OPCA-5TBP, 6q27TATA-box–binding protein; genetic test availableOnset at 3-55 years; ataxia and involvement of pyramidal, extrapyramidal, and, possibly autonomic system; intellectual impairment, dementia, psychosis, chorea; presentation similar to Huntington disease; degeneration of caudate, putamen, thalamus, frontal cortex, temporal cortex, and cerebellum Nakamura et al, 2001[65] ; Rolfs et al, 2003[66] ; Maltecca et al, 2003[67]
%607458SCA-18SCA18 7q22-q32Onset in teens, 20s, and 30s; sensorimotor neuropathy with ataxia; gait abnormality, dysmetria, hyporeflexia, muscle weakness and atrophy, axonal neuropathy, decreased vibratory and proprioceptive sense Brkanac et al, 2002[68]
%607346SCA-191p21-q21Onset at 12-40 years; gait and limb ataxia, hyporeflexia, dysphagia, dysarthria, and gaze-evoked horizontal nystagmus; cerebellar atrophy on MRIs Schelhaas et al, 2001[69] ; Verbeek et al, 2002[70] ; Chung et al, 2003[71] ; Schelhaas et al, 2004[72]
%608687SCA-20SCA20, 11p13-q11Onset at 19-64 years; dysarthria, gait ataxia, upper limb, slow progression; more variable features are mild pyramidal signs, hypermetric saccades, nystagmus, palatal tremor, slow cognitive decline; CT scan shows dentate calcification Knight et al, 2004[73]
%607454SCA-21SCA21, 7p21-15Onset at 6-30 years; cerebellar ataxia, limb ataxia and akinesia, dysarthria, dysgraphia, hyporeflexia, postural tremor, resting tremor, rigidity, cognitive impairment, cerebellar atrophy Devos et al, 2001[74] ; Vuillaume et al, 2002[75]
%607346SCA-221p21-q21Now believed to be identical to SCA-19 (Schelhaas et al, 2004[72] ) though Chung et al (2004)[71] dispute this Schelhaas et al, 2001[69] ; Verbeek et al, 2002[70] ; Chung et al, 2004[71] ; Schelhaas et al, 2004[72]
%610245SCA-2320p13-12.3Onset at 40s and 50s; slow progression; gait and limb ataxia, dysarthria (varies), slow saccades and ocular dysmetria, decreased vibratory sense; severe cerebellar atrophy Verbeek, et al, 2004[76]
%608703SCA-25SCA25, 2p21-p13Onset in childhood; invariable features are cerebellar ataxia; variable features are lower limb areflexia, peripheral sensory neuropathy, nystagmus, decreased visual acuity, facial tics, extensor plantar responses, urinary urgency, and gastrointestinal symptoms Stevanin et al, 2004[77]
%609306SCA-2619p13.3Onset t 25-60 years; pure cerebellar signs, including ataxia of the trunk and limbs, dysarthria, and irregular visual pursuit movements; intelligence normal; MRI shows atrophy of cerebellum, sparing pons and medulla Yu et al, 2005[78]
#609307SCA-27FGF14, 13q34Fibroblast growth factor 14 (601515)Onset in childhood; cerebellar ataxia, tremor, low IQ, aggressive behavior, eye movement abnormalities are nystagmus, cerebellar dysarthria, head tremor, orofacial dyskinesias, cerebellar atrophy, pes cavus, axonal sensory neuropathy, neuronal loss in cerebral cortex, amygdala, and basal ganglia van Swieten et al, 2003[79]
%610246SCA-2818p11.22-q11.2AFG3-like protein 2Onset at 19.5 years (range, 12-36 y); imbalance and mild gait incoordination; gaze-evoked nystagmus, slow saccades, ophthalmoparesis, and, often, ptosis; frequently lower limb hyporeflexia Cagnoli et al, 2006[80]
#125370Dentatorubral-pallidoluysian atrophy (DRPLA)DRPLA, 12p13.31Atropin-1–related protein (607462); genetic test availableOnset in 20s to 30s; myoclonic epilepsy, dementia, ataxia, choreoathetosis, degeneration of dentatorubral and pallidoluysian systems Naito and Oyanagi, 1982[81] ; Koide et al, 1994[82]
#160120Episodic ataxia type 1, EA-1KCNA1, 12p13K+1 voltage-gated channel (A1) (600111); genetic test available on research basisOnset usually in childhood; continuous muscle movement (myokymia) and periodic ataxiaVan Dyke et al, 1975[83] ; Hanson et al, 1977[84] ; Gancher and Nutt, 1986[85] ; Browne et al, 1994[86] ; Brandt and Strupp, 1997[87] ; Eunson et al, 2000[88]
#108500Episodic ataxia type 2, EA-2CACNA 1A, 19p13Voltage-dependent P/Q-type Ca+2 channel alpha-1A subunit (601011); genetic test available on research basisOnset in childhood; ataxia, downbeating nystagmus dizziness treated with acetazolamide; no progression after childhood; cerebellar atrophy Parker, 1946[89] ; White, 1969[90] ; Subramony et al, 2003[91] ; Spacey et al, 2005[92] ; Imbrici et al, 2005[93]
%606554Episodic ataxia type 3, EA-31q42UnknownOnset at 1-42 years; vestibular ataxia, vertigo, tinnitus, interictal myokymiaSteckley et al, 2001[94] ; Cader et al, 2005[95]
%606552Episodic ataxia type 4, EA-4UnknownUnknownOnset in third to sixth decade; recurrent attacks of vertigo, diplopia, and ataxia; slowly progressive cerebellar ataxia in some; periodic vestibulocerebellar ataxia in an autosomal dominant pedigree pattern, defective smooth pursuit, gaze-evoked nystagmus, ataxia, vertigo Farmer and Mustian, 1963[96] ; Vance et al, 1984[97] ; Damji et al, 1996[98]
+601949Episodic ataxia type 5, EA-5CACNB 4, 2q22-q23Voltage-dependent L-type calcium beta-4 subunit (+601949)Onset in third or fourth decade; mutation at C104F in French-Canadian family; ataxia similar to EA-2; severe episodic lasting hours to weeks; treatment with acetazolamide; interictal ataxia includes gait and truncal, mild dysarthria; nystagmus (downbeat, spontaneous, gaze evoked); seizures Escayg et al, 1998[99] ; Escayg et al, 2000[100] ; Herrmann et al, 2005[101]
%601042Choreoathetosis spasticity, episodic, CSE12p13 (close to potassium channel gene KCNA1 but not the same)UnknownOnset at 2-15 years; paroxysmal choreoathetosis with episodic ataxia and spasticityAuburger et al, 1996[102] ; Müller et al, 1998[103]
%108600Hereditary (autosomal dominant) spastic ataxiaSAX1, 12p13UnknownOnset at 10-20 years; lower limb spasticity, generalized ataxia with dysarthria, dysphagia, impaired ocular movements, gait abnormalities; brain and cord MRIs normal; neuropathology shows midbrain neuronal loss Ferguson and Critchley, 1929[104] ; Gayle and Williams, 1933[105] ; Mahloudji, 1963[106] ; Meijer et al, 2002[107] ; Grewal et al, 2004[108]
Table 4. Dominant Ataxia Nomenclature
SCAsSCA-1SCA-2SCA-3SCA types 8, 12, 17, 25, 27, 28, (13)SCA-7SCAs 4, 5, 6, 10, 11, 14, 15, 22, 26, (13)
OPCAsOPCA-1†, OPCA-IV†OPCA-2No OPCA matching SCA-3No OPCA matching above SCAsOPCA-IIINo OPCA matching above SCAs
ADCAsADCA-1ADCA-1ADCA-1ADCA-1ADCA-2ADCA-3
EponymsMenzel type OPCA (or Menzel ataxia)‡, Schut- Haymaker type OPCA†, Dejerine-Thomas ataxiaHolguin type ataxia, Wadia-Swami syndrome, Dejerine-Thomas ataxiaMachado-Joseph disease, Dejerine-Thomas ataxiaDejerine-Thomas ataxiaSanger-Brown ataxia§, Dejerine-Thomas ataxiaHolmes ataxiall, ataxia of Marie, Foix, and Alajouanine, Marie ataxia, Nonne syndrome#
*SCA-13 is often said to not be part of ADCA classification. It is mainly a childhood mental retardation/ataxia syndrome. The ataxia is not accompanied by significant brainstem pathology, similar to ADCA-3. The mental retardation can be interpreted as a dementia, putting it in ADCA-1.



† OPCA-IV (Schut-Haymaker OPCA) is now thought to be an SCA-1, which makes it OPCA-I (ie, strictly speaking, OPCA-IV no longer exists).



‡ Menzel OPCA is sometimes taken much more broadly as virtually any OPCA except perhaps OPCA-III. Alternatively, it is taken as essentially the same as ADCA-1. In addition, it is sometimes applied to sporadic OPCAs that have similar presentations to any of the syndromes under ADCA-1.



§ Sanger-Brown ataxia is sometimes taken more broadly. As expansively defined, the term could be used for virtually any of these.



ll Holmes ataxia is sometimes applied to pure sporadic cerebellar ataxia of late onset.



This is sometimes used for most any of these syndromes, which seems to be the sense in which it was used in the original 1893 paper by Marie.



# This is a very obscure term. It is most commonly used for conditions fitting ADCA-3.



**The authors found no papers calling SCA-3 Dejerine-Thomas ataxia, but Dejerine-Thomas ataxia is so broadly defined, the term could possibly be applied to SCA-3.



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