Olivopontocerebellar Atrophy Clinical Presentation

Updated: Nov 11, 2014
  • Author: Christina J Azevedo, MD; Chief Editor: Selim R Benbadis, MD  more...
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Presentation

History

See the list below:

  • Dysphagia and dysarthria (and occasionally anarthria) are common manifestations of OPCA.

  • Respiratory stridor from vocal cord paralysis has been reported.

  • Dementia can appear at any age; it is especially common later in the disease.

  • Urinary incontinence occurs late in the course of the disease.

  • Sleep disturbances are common in persons with OPCA. [160]

Next:

Physical

Generally, cerebellar signs and extrapyramidal signs are the predominant signs of OPCA. In addition, peripheral neuropathy is common. Ophthalmoplegia, retinopathy, and parkinsonism may be present.

Typically, the clinical manifestations of OPCA consist of a slowly progressive pancerebellar syndrome that usually begins in the lower extremities and then progresses to the upper extremities and the bulbar musculature. Usually, the initial sign in OPCA is a broad-based cerebellar ataxic gait. A parkinsonian gait is a less common but recognized variant.

Cerebellar dysarthria is also common. The patient's speech has a poorly modulated and slurred quality, similar to that of a person intoxicated with alcohol. Other cerebellar findings include nystagmus, dysmetria on finger-to-nose testing, and ataxia on heel-to-shin testing.

The entire spectrum of cerebellar ocular motility disorders can occur in persons with OPCA. Nystagmus, slow saccades, and abnormal fundoscopic examination findings are present in varying degrees. Hyperactive vestibulo-ocular reflex also has been reported. In some cases, limitation of extraocular movements, particularly of upward gaze, is also present. This nuclear or supranuclear ophthalmoplegia occurs more frequently in familial OPCA than in sporadic OPCA. Retinal degeneration may be present.

Parkinsonian symptoms with cogwheel rigidity, bradykinesia, and tremor may be the predominant picture in some cases of OPCA. In these cases, distinguishing OPCA from Parkinson disease may be difficult.

The pyramidal finding that is most uniformly present is a bilateral extensor plantar response. Hyperactive deep tendon reflexes and spasticity due to pyramidal tract dysfunction are present early in the course of the disease. These are often lost later, especially the ankle jerks, as part of a concomitant peripheral neuropathy.

Position sense and vibratory function are reduced secondary to neuropathy.

The clinical presentation may vary among the subtypes of OPCA. It includes the following:

  • Abnormal movements are more frequent in familial OPCA. Abnormal movements may include myoclonus, spasmodic torticollis, chorea, and athetosis.

  • Nonpyramidal signs, such as amyotrophy, fasciculations, peripheral neuropathy, lightning pains, and pes cavus, are more common in sporadic OPCA than familial OPCA.

  • Autonomic failure is often seen, especially if sensitive methods of detection such as heart rate variability analysis are used. Severe autonomic impairment is more common in sporadic OPCA, which frequently evolves to a full-blown MSA.

Postural hypotension may predominate among the clinical features.

Previous
Next:

Causes

A unifying etiology of OPCA has not been established. [159] In the sporadic cases, abnormalities of alpha-synuclein (which is found as inclusion bodies in degenerating neurons) appear to play a significant role. In any of the inherited cases, specific genes have been identified, although in most cases the precise way in which the genes exert a pathological influence is not known. Many of the abnormal genes are of the expansion repeat variety. For example, in OPCA-I (or SCA-1), the SCA1 gene is on chromosome 6. It is a triple nucleotide repeat, with age of onset correlating with the length of repeat. The SCA2 gene is on chromosome 12.

To clarify the subtypes of the genetically determined OPCAs, the authors have placed them in tables. Table 1 below contains the most common types. Although the table is largely self-explanatory, a few points should be emphasized. The genetic OPCAs are now, at best, a subordinate category. Many neurogeneticists would say they are an obsolete category.

Where an OPCA represents a known mutation, it does do so because it is identified with a specific SCA (in the case of dominant mutations) or another specific genetically defined disease. For example, OPCA-IV was not previously genetically defined. However, OPCA-IV is now believed to be genetically the same as SCA-1. OPCA-I has also been found to be the same as SCA-1. Thus, no real distinction can now be made between OPCA-I, OPCA-IV, and SCA-1, except perhaps that in the historical cases of these syndromes, some differences existed in the phenotypic presentations of the same underlying disease.

Note also in the table that OPCA-2 and OPCA-II are not the same. This is unusual because for the other numbered OPCAs, the Arabic and Roman numbers can be used interchangeably. OPCA-2 is identical to SCA-2 and is autosomal dominant. OPCA-II, sometimes called Fickler-Winkler syndrome, is autosomal recessive and its gene is unknown. Separating the 2 types by using an Arabic 2 and a Roman II is not fully standard, and some books speak of the dominant versus recessive OPCA-2 (OPCA-II). Despite their similar names, the phenotypes are not very similar. In this text, Roman numerals are used for the OPCA types, with the exception of OPCA-X, which means X-linked OPCA, not OPCA type 10.

In the organization of the table, the first column contains the Online Mendelian Inheritance in Man number (OMIM#). The OMIM catalog was developed by Dr Victor McKusick and his colleagues at Johns Hopkins University, and the OMIM Web site is hosted by the US National Center for Biotechnology Information (NCBI) on what is essentially the same Web site as PubMed.

In the table, both the OPCA specific names and other names for each condition are listed; also listed is the genetic pattern, including the mode of Inheritance, the locus (including the chromosomal region and the names of the gene and protein if available), and a concise description of the condition.

Table 1. Most Common OPCAs With Alternative Names (Open Table in a new window)

OMIM #

OPCA Names

Other Names

Genetic Pattern

Description

#164400

OPCA-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 available

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 [15]

#183090

OPCA-2

SCA-2, ADCA-I

Gene map locus 12q24 expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517); autosomal dominant; genetic test available

Onset in 30s; ataxia, dysarthria, muscle cramps; slow saccades; ophthalmoplegia; peripheral neuropathy; dementia (some); no pyramidal or extrapyramidal features [16]

%258300

OPCA-II, Fickler-Winkler type OPCA

Fickler-Winkler Syndrome

Gene/biochemistry not known; autosomal recessive

Adult-onset; cerebellar ataxia, albinism, impaired intellect; neurological impairments similar to OPCA-I but no involuntary movements or sensory loss [9, 17, 18]

#164500

OPCA-III, OPCA-3, OPCA with retinal degeneration

ADCA-II, SCA-7, OPCA with macular degeneration and external ophthalmoplegia

Gene locus 3p21.1-p12; expanded trinucleotide repeat in the gene encoding ataxin-7 (ATXN7; 607640); autosomal dominant; genetic test available

Onset in mid 20s; initially pigmentary retinal degeneration then ataxia, dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signs [16]

^ 164600 Number now obsolete; considered the same as # 164400 (see first row above)

OPCA-IV, Schut-Haymaker type OPCA

 

Genetics 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 [19]

164700

OPCA-V, OPCA-5, OPCA with dementia and extrapyramidal signs

This may be the same as SCA-17

Autosomal dominant; genetic test available for SCA-17, but unclear if this is the same

Cerebellar ataxia, rigidity, dementia; neuronal loss in cerebellum, basal ganglia, substantia nigra, olivary nuclei, cerebral cortex [20, 8]

%302500

OPCA-X, OPCA X-linked-1

SCA-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 known

Onset 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 [21, 22]

In addition to what are considered the standard types of OPCA, some types are even rarer and more obscure. These are pediatric disease in which involvement of the cerebellum, pons, and the region of the inferior oliva is noted. They are not what most neurologists think of when they use the term OPCA. The only reason they are listed here is because the reader may encounter these and see them referred to as infantile OPCA or some variant thereof.

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 [23, 24]

%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 [25]

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 [26, 27]

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 [27]

#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 [28, 29, 30]

#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 [31, 32]

Although Table 1 gives the SCA equivalent for the OPCAs, many neurology residents have asked to see a table showing how the OPCAs fit into the larger SCA category. Table 3 gives that framework and the OPCAs are identified in the larger context.

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 [33] ; Waggoner et al, 1938 [34] ; Schut, 1950 [35] ; Schut and Haymaker, 1951 [19] ; Orr et al, 1993 [36]

Donato et al. 2012 [37]

#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 [38] ; Wadia and Swami, 1971 [39] ; Ueyama et al, 1998 [40]

#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 [41] ; Kawaguchi et al, 1994 [42]

%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 [43] ; Hellenbroich et al, 2003 [44]

#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 [45]

#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 [46]

#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 [47] ; Zhuchenko et al, 1997 [48]

#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 [49] ; 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 [50] ; Ikeda et al, 2000 [51] ; Factor et al, 2005 [52] (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 [53] ; Zu et al, 1999 [54] ; Grewal et al, 2002 [55]

%604432

SCA-11

SCA11, 15q14-q21.3

Tau-tubulin kinase 2

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

Worth et al, 1999 [56]

#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 [57] ; Fujigasaki et al, 2001 [58]

#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 [59]

#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 [60] ; Brkanac, Bylenok et al 2002 [61] ; Chen, Brkanac et al 2003 [62] ; Yabe et al 2003 [63]

%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 [64] ; Knight et al, 2003 [65] ; Hara et al, 2004 [66]

%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 [67]

#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 [68] ; Rolfs et al, 2003 [69] ; Maltecca et al, 2003 [70]

%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 [71]

%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 [72] ; Verbeek et al, 2002 [73] ; Chung et al, 2003 [74] ; Schelhaas et al, 2004 [75]

%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 [76]

%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 [77] ; Vuillaume et al, 2002 [78]

%607346

SCA-22

1p21-q21

 

Now believed to be identical to SCA-19 (Schelhaas et al, 2004 [75] ) though Chung et al (2004) [74] dispute this

Schelhaas et al, 2001 [72] ; Verbeek et al, 2002 [73] ; Chung et al, 2004 [74] ; Schelhaas et al, 2004 [75]

%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 [79]

%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 [80]

%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 [81]

#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 [82]

%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 [83]

#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 [84] ; Koide et al, 1994 [85]

#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 [86] ; Hanson et al, 1977 [87] ; Gancher and Nutt, 1986 [88] ; Browne et al, 1994 [89] ; Brandt and Strupp, 1997 [90] ; Eunson et al, 2000 [91]

#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 [92] ; White, 1969 [93] ; Subramony et al, 2003 [94] ; Spacey et al, 2005 [95] ; Imbrici et al, 2005 [96]

%606554

Episodic ataxia type 3, EA-3

1q42

Unknown

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

Steckley et al, 2001 [97] ; Cader et al, 2005 [98]

%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 [99] ; Vance et al, 1984 [100] ; Damji et al, 1996 [101]

+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 [102] ; Escayg et al, 2000 [103] ; Herrmann et al, 2005 [104]

%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 [105] ; Müller et al, 1998 [106]

%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 [107] ; Gayle and Williams, 1933 [108] ; Mahloudji, 1963 [109] ; Meijer et al, 2002 [110] ; Grewal et al, 2004 [111]

Finally, the question of how the OPCAs and SCAs fit with the 2 other systems of terminology is addressed: (1) the ADCAs and (2) the individual eponyms that honor the various physicians from the past who described the conditions that are now better (though still imperfectly) understood today.

Table 4 shows these correspondences. The first row consists of the SCAs because these represent the most accurate and finely divided category. The reader can then go down each column and find the ADCA number, the OPCAs, and the individual eponyms that are essentially equivalent.

In using this table, realize that all of these terms have been used inconsistently through the years. The SCAs are most closely linked to the actual genes involved. Although the ADCAs, with only 3 categories, represent a rather coarse division of these conditions, their phenotypic descriptions are rather simple and they have generally been used consistently in those cases in which they have been used. The use of the OPCA terms for diagnosis has been less consistent and it has been common to use the designation OPCA somewhat loosely. Finally, the eponyms have not been used very consistently, with the exception of Machado-Joseph disease (SCA-3) (which is not an OPCA). Thus, as one moves down the columns in the table, the names become less reliable.

The authors recommend against using the eponyms for fresh diagnoses. The ADCA and OPCA categories may be helpful for formulating ideas about the diagnosis, but one should try to think in terms of the SCA system in order to more readily connect the patient to a proper genetic diagnosis.

Table 4. Dominant Ataxia Nomenclature (Open Table in a new window)

SCAs

SCA-1

SCA-2

SCA-3

SCA types 8, 12, 17, 25, 27, 28, (13)

SCA-7

SCAs 4, 5, 6, 10, 11, 14, 15, 22, 26, (13)

OPCAs

OPCA-1, OPCA-IV

OPCA-2

No OPCA matching SCA-3

No OPCA matching above SCAs

OPCA-III

No OPCA matching above SCAs

ADCAs

ADCA-1

ADCA-1

ADCA-1

ADCA-1

ADCA-2

ADCA-3

Eponyms

Menzel type OPCA (or Menzel ataxia), Schut- Haymaker type OPCA, Dejerine-Thomas ataxia

Holguin type ataxia, Wadia-Swami syndrome, Dejerine-Thomas ataxia

Machado-Joseph disease, Dejerine-Thomas ataxia

Dejerine-Thomas ataxia

Sanger-Brown ataxia§, Dejerine-Thomas ataxia

Holmes 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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