Which spinocerebellar ataxias (SCAs) are considered olivopontocerebellar atrophies (OPCAs)?

Updated: Dec 17, 2018
  • Author: Sombat Muengtaweepongsa, MD, MSc; Chief Editor: Selim R Benbadis, MD  more...
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In 1974, Skre studied the hereditary ataxia diseases in western Norway and chose to consider all these disorders as members of a comprehensive group of diseases termed spinocerebellar ataxias. [9] This classification then evolved in the classification of SCAs. According to Paulson and Ammache in 2001, SCAs include all well-understood types of dominant OPCA and many other dominant ataxias. [10] Geneticists sometimes state that the OPCA classification has been replaced by the SCA classification. This does not mean that every currently defined SCA is also an OPCA. The SCAs that could typically be considered to be an OPCA are SCA types 1, 2, 3, 7, and possibly 17.

In addition to these major forms, which might be called the traditional or classic OPCAs, some extremely rare diseases also involve degeneration of the same, or very similar, anatomical regions. These are mainly infantile or childhood diseases. They are not what neurologists (even pediatric neurologists) usually call OPCAs. However, occasionally in the literature they are called infantile OPCAs and thus they are included in Table 2 in Causes.

Table 3 in Causes lists a large number of the known SCAs (no table of such diseases is ever totally up-to-date for long), and those that can be reasonably identified as OPCAs are noted.

Table 2. Extremely Rare Types of OPCAs (Open Table in a new window)

OMIM #

OPCA Names

Other Names

Genetic Pattern

Description

%607596

Pontocerebellar hypoplasia type 1, PCH-1

Pontocerebellar hypoplasia with infantile spinal muscular atrophy, pontocerebellar hypoplasia with anterior horn cell disease

Autosomal recessive

Cerebellar hypoplasia plus motor neuron loss; sometimes called a combination of olivopontocerebellar degeneration plus spinal muscular atrophy; present from birth; patients usually die in infancy [27, 28]

%277470

Pontocerebellar hypoplasia type 2, PCH-2

Pontocerebellar hypoplasia with progressive cerebral atrophy, Volendam neurodegenerative disease

Autosomal recessive

Congenital microcephaly, extrapyramidal findings, epilepsy; autopsy in one case showed that the olivopontocerebellar system was the most heavily involved in degeneration

%608027

Pontocerebellar hypoplasia type, PCH-3, Pontocerebellar hypoplasia with optic atrophy

Cerebellar atrophy with progressive microcephaly, CLAM

Autosomal recessive; gene map locus 7q11-q21Gene map locus 7q11-q21

Onset 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 [29]

225753

Pontocerebellar hypoplasia type 4, PCH-4

Fatal infantile encephalopathy with olivopontocerebellar hypoplasia

Probably autosomal recessive, possibly autosomal dominant or maternal transmission; biochemical defect and gene locus not known

Patients die in infancy; severe olivopontocerebellar hypoplasia on autopsy [30, 31]

610204

Pontocerebellar hypoplasia type 5, PCH-5

Olivopontocerebellar hypoplasia, fetal onset

Genetics not clear

Pontocerebellar 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 [31]

#278800

De Sanctis-Cacchione syndrome

 

Gene 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 [32, 33, 34]

#212065

Congenital disorder of glycosylation, type Ia

 

Phosphomannomutase-2 (PMM2; 601785); autosomal recessive

Severe 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 [35, 36]

Table 3. Dominant SCAs with OPCAs Identified (Open Table in a new window)

Disease OMIM #

Disease Names

Locus

GeneProduct (OMIM #)

Description

References

#164400

SCA-1, OPCA-I, OPCA-IV (OPCA-IV same as OPCA-I), ADCA-1

ATXN1, 6p23

CAG expansion repeat in N-terminal coding region of Ataxin-1 (*601556);

Onset 30-40 years; ataxia, spasticity, dysarthria, ophthalmoplegia, slow saccades, nystagmus, optic atrophy, pyramidal tract signs; rare extrapyramidal; signs; some have dementia; neuropathy occurs late. Expansion repeat causes toxic gain of function via abnormally long ataxin-1. This worsens in subsequent generations.

Menzel, 1891 [37] ; Waggoner et al, 1938 [38] ; Schut, 1950 [39] ; Schut and Haymaker, 1951 [23] ; Orr et al, 1993 [40]

Donato et al. 2012 [41]

#183090

SCA-2, OPCA-2, ADCA-1

ATXN2, 12q24

Ataxin-2 (601517); genetic test available

Onset in 30s; ataxia, dysarthria, muscle cramps; slow saccades/ophthalmoplegia; peripheral neuropathy, hyporeflexia, dementia in some; no pyramidal or extrapyramidal features

Boller and Segarra, 1969 [42] ; Wadia and Swami, 1971 [43] ; Ueyama et al, 1998 [44]

#109150

SCA-3 or Machado-Joseph disease, ADCA-1

ATXN3, 14q24.3-q31

Machado-Joseph disease protein 1(ATXN3). (607047); genetic test available

All 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 [45] ; Kawaguchi et al, 1994 [46]

%600223

SCA-4, ADCA-1

Gene 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 [47] ; Hellenbroich et al, 2003 [48]

#117210

SCA, 16q22-linked ADCA-3

PLEKHG4, 16q22.1

Puratrophin-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 [49]

#600224

SCA-5, ADCA-3

SPTBN2, 11p13

Spectrin 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 [50]

#183086

SCA-6, ADCA-1 ADCA-3

CACNA1A, 19p13

Voltage-dependent P/Q-type Ca+2 channel alpha-1a subunit (601011); genetic test available

Onset 20-40 years; ataxia, dysarthria, nystagmus, distal sensory loss, normal life expectancy

Subramony et al, 1996 [51] ; Zhuchenko et al, 1997 [52]

#164500

SCA-7, OPCA-3 ADCA-2

ATXN7, 3p21.1-p12

Ataxin-7 (607640); genetic test available

Onset mid 20s; pigmentary retinal degeneration, ataxia, dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signs

David et al, 1997 [53] ; Harding, 1982 [7]

#608768

SCA-8, ADCA-2

KLHL1AS, 13q21

Genetic test available

Onset 20s to 70s; ataxia, dysarthria, nystagmus, impaired smooth pursuit

Koob et al, 1999 [54] ; Ikeda et al, 2000 [55] ; Factor et al, 2005 [56] (Factor et al case was actually consistent with MSA)

 

SCA-9

Unassigned category

 

Unassigned category

Unassigned category

+603516

SCA-10 ADCA-3

ATXN10, 22q13

Ataxin-10; genetic test available

Onset in 20s; ataxia, dysarthria, nystagmus, epileptic seizures; to date only found in Mexican families

Grewal et al, 1998 [57] ; Zu et al, 1999 [58] ; Grewal et al, 2002 [59]

%604432

SCA-11

SCA11, 15q14-q21.3

Tau-tubulin kinase 2

Onset at 20-40 years; ataxia, dysarthria, nystagmus

Worth et al, 1999 [60]

#604326

SCA-12

PPP2R2B, 5q31-q33

Serine/threonine protein phosphatase 2A, 55-kd regulatory subunit B, beta isoform; genetic test available

Onset at 8-55 years, commonly 30s; upper extremity and head tremor, gait ataxia, ophthalmoplegia, hyperreflexia, bradykinesia, dementia

Holmes et al, 1999 [61] ; Fujigasaki et al, 2001 [62]

#605259

SCA-13

KCNC3, 19q13.3-q13.4

Voltage-gated K+ channel, subfamily C member 3

Onset in childhood; ataxia, dysarthria, mental retardation; slow progression

Waters et al, 2006 [63]

#605361

SCA-14

PRKCG, 19q13.4

Kinase C, gamma type; genetic test available

Onset 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 [64] ; Brkanac, Bylenok et al 2002 [65] ; Chen, Brkanac et al 2003 [66] ; Yabe et al 2003 [67]

%606658

SCA-15

Gene unknown, 3p26.1-p25.3

Inositol 1,4,5-triphosphate receptor type 1

Similar 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 [68] ; Knight et al, 2003 [69] ; Hara et al, 2004 [70]

%606364

SCA-16

SCA16, 8q22.1-q24.1

Contactin-4

MRI-proven cerebellar atrophy without brainstem involvement; onset at 20-66 years; pure cerebellar ataxia, some with head tremor, slow progression

Miyoshi et al, 2001 [71]

#607136

SCA-17, may be OPCA-5

TBP, 6q27

TATA-box–binding protein; genetic test available

Onset 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 [72] ; Rolfs et al, 2003 [73] ; Maltecca et al, 2003 [74]

%607458

SCA-18

SCA18 7q22-q32

 

Onset 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 [75]

%607346

SCA-19

1p21-q21

 

Onset at 12-40 years; gait and limb ataxia, hyporeflexia, dysphagia, dysarthria, and gaze-evoked horizontal nystagmus; cerebellar atrophy on MRIs

Schelhaas et al, 2001 [76] ; Verbeek et al, 2002 [77] ; Chung et al, 2003 [78] ; Schelhaas et al, 2004 [79]

%608687

SCA-20

SCA20, 11p13-q11

 

Onset 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 [80]

%607454

SCA-21

SCA21, 7p21-15

 

Onset 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 [81] ; Vuillaume et al, 2002 [82]

%607346

SCA-22

1p21-q21

 

Now believed to be identical to SCA-19 (Schelhaas et al, 2004 [79] ) though Chung et al (2004) [78] dispute this

Schelhaas et al, 2001 [76] ; Verbeek et al, 2002 [77] ; Chung et al, 2004 [78] ; Schelhaas et al, 2004 [79]

%610245

SCA-23

20p13-12.3

 

Onset 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 [83]

%608703

SCA-25

SCA25, 2p21-p13

 

Onset 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 [84]

%609306

SCA-26

19p13.3

 

Onset 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 [85]

#609307

SCA-27

FGF14, 13q34

Fibroblast 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 [86]

%610246

SCA-28

18p11.22-q11.2

AFG3-like protein 2

Onset 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 [87]

#125370

Dentatorubral-pallidoluysian atrophy (DRPLA)

DRPLA, 12p13.31

Atropin-1–related protein (607462); genetic test available

Onset in 20s to 30s; myoclonic epilepsy, dementia, ataxia, choreoathetosis, degeneration of dentatorubral and pallidoluysian systems

Naito and Oyanagi, 1982 [88] ; Koide et al, 1994 [89]

#160120

Episodic ataxia type 1, EA-1

KCNA1, 12p13

K+1 voltage-gated channel (A1) (600111); genetic test available on research basis

Onset usually in childhood; continuous muscle movement (myokymia) and periodic ataxia

Van Dyke et al, 1975 [90] ; Hanson et al, 1977 [91] ; Gancher and Nutt, 1986 [92] ; Browne et al, 1994 [93] ; Brandt and Strupp, 1997 [94] ; Eunson et al, 2000 [95]

#108500

Episodic ataxia type 2, EA-2

CACNA 1A, 19p13

Voltage-dependent P/Q-type Ca+2 channel alpha-1A subunit (601011); genetic test available on research basis

Onset in childhood; ataxia, downbeating nystagmus dizziness treated with acetazolamide; no progression after childhood; cerebellar atrophy

Parker, 1946 [96] ; White, 1969 [97] ; Subramony et al, 2003 [98] ; Spacey et al, 2005 [99] ; Imbrici et al, 2005 [100]

%606554

Episodic ataxia type 3, EA-3

1q42

Unknown

Onset at 1-42 years; vestibular ataxia, vertigo, tinnitus, interictal myokymia

Steckley et al, 2001 [101] ; Cader et al, 2005 [102]

%606552

Episodic ataxia type 4, EA-4

Unknown

Unknown

Onset 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 [103] ; Vance et al, 1984 [104] ; Damji et al, 1996 [105]

+601949

Episodic ataxia type 5, EA-5

CACNB 4, 2q22-q23

Voltage-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 [106] ; Escayg et al, 2000 [107] ; Herrmann et al, 2005 [108]

%601042

Choreoathetosis spasticity, episodic, CSE

12p13 (close to potassium channel gene KCNA1 but not the same)

Unknown

Onset at 2-15 years; paroxysmal choreoathetosis with episodic ataxia and spasticity

Auburger et al, 1996 [109] ; Müller et al, 1998 [110]

%108600

Hereditary (autosomal dominant) spastic ataxia

SAX1, 12p13

Unknown

Onset 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 [111] ; Gayle and Williams, 1933 [112] ; Mahloudji, 1963 [113] ; Meijer et al, 2002 [114] ; Grewal et al, 2004 [115]


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