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Olivopontocerebellar Atrophy

Sections Olivopontocerebellar Atrophy
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Presentation

History

Dysphagia and dysarthria (and occasionally anarthria) are common manifestations of olivopontocerebellar atrophy (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.^[18]

Physical

Generally, cerebellar signs and extrapyramidal signs are the predominant signs of olivopontocerebellar atrophy (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.

Causes

A unifying etiology of olivopontocerebellar atrophy (OPCA) has not been established.^[19]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^[20]
#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^[21]
%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^{[10, 22, 23]}
#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^[21]
^ 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^[24]
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^{[25, 9]}
%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^{[26, 27]}

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^{[28, 29]}
%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^[30]
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^{[31, 32]}
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^[32]
#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^{[33, 34, 35]}
#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^{[36, 37]}

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^[38]; Waggoner et al, 1938^[39]; Schut, 1950^[40]; Schut and Haymaker, 1951^[24]; Orr et al, 1993^[41] Donato et al. 2012^[42]
#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^[43]; Wadia and Swami, 1971^[44]; Ueyama et al, 1998^[45]
#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^[46]; Kawaguchi et al, 1994^[47]
%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^[48]; Hellenbroich et al, 2003^[49]
#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^[50]
#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^[51]
#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^[52]; Zhuchenko et al, 1997^[53]
#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^[54]; Harding, 1982^[8]
#608768	SCA-8, ADCA-2	KLHL1AS, 13q21	Genetic test available	Onset 20s to 70s; ataxia, dysarthria, nystagmus, impaired smooth pursuit	Koob et al, 1999^[55]; Ikeda et al, 2000^[56]; Factor et al, 2005^[57](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^[58]; Zu et al, 1999^[59]; Grewal et al, 2002^[60]
%604432	SCA-11	SCA11, 15q14-q21.3	Tau-tubulin kinase 2	Onset at 20-40 years; ataxia, dysarthria, nystagmus	Worth et al, 1999^[61]
#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^[62]; Fujigasaki et al, 2001^[63]
#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^[64]
#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^[65]; Brkanac, Bylenok et al 2002^[66]; Chen, Brkanac et al 2003^[67]; Yabe et al 2003^[68]
%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^[69]; Knight et al, 2003^[70]; Hara et al, 2004^[71]
%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^[72]
#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^[73]; Rolfs et al, 2003^[74]; Maltecca et al, 2003^[75]
%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^[76]
%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^[77]; Verbeek et al, 2002^[78]; Chung et al, 2003^[79]; Schelhaas et al, 2004^[80]
%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^[81]
%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^[82]; Vuillaume et al, 2002^[83]
%607346	SCA-22	1p21-q21		Now believed to be identical to SCA-19 (Schelhaas et al, 2004^[80]) though Chung et al (2004)^[79]dispute this	Schelhaas et al, 2001^[77]; Verbeek et al, 2002^[78]; Chung et al, 2004^[79]; Schelhaas et al, 2004^[80]
%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^[84]
%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^[85]
%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^[86]
#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^[87]
%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^[88]
#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^[89]; Koide et al, 1994^[90]
#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^[91]; Hanson et al, 1977^[92]; Gancher and Nutt, 1986^[93]; Browne et al, 1994^[94]; Brandt and Strupp, 1997^[95]; Eunson et al, 2000^[96]
#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^[97]; White, 1969^[98]; Subramony et al, 2003^[99]; Spacey et al, 2005^[100]; Imbrici et al, 2005^[101]
%606554	Episodic ataxia type 3, EA-3	1q42	Unknown	Onset at 1-42 years; vestibular ataxia, vertigo, tinnitus, interictal myokymia	Steckley et al, 2001^[102]; Cader et al, 2005^[103]
%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^[104]; Vance et al, 1984^[105]; Damji et al, 1996^[106]
+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^[107]; Escayg et al, 2000^[108]; Herrmann et al, 2005^[109]
%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^[110]; Müller et al, 1998^[111]
%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^[112]; Gayle and Williams, 1933^[113]; Mahloudji, 1963^[114]; Meijer et al, 2002^[115]; Grewal et al, 2004^[116]

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 ataxia^ll, 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.

Complications

Falls are the primary complications in the early stages of olivopontocerebellar atrophy (OPCA).

Aspiration pneumonia is more common in later stages of OPCA.

Differential Diagnoses

Olivopontocerebellar Atrophy. National Institute of Neurological Disorders and Stroke. Available at https://www.ninds.nih.gov/health-information/disorders/olivopontocerebellar-atrophy. Accessed: September 15, 2002.
Friedreich N. Ueber degenerative atrophie der spinalen Hinterstrange. Virchow Arch Path Anat. 1863. 26:391-419.
Friedreich N. Ueber degenerative atrophie der spinalen Hinterstrange. Virchow Arch Path Anat. 1863. 27:1-26.
Marie P. Sur l'heredo-ataxie cerebelleuse.Clinique des maladies nerveuses. Semaine Med, Paris. 1893. 13:444-7.
Marie P, Foix C, Alajouanine T. De l'atrophie cerebelleuse tardive a predominance corticale. Revue Neurologique, Paris. 1922. 38:849-85; 1082-111.
Dejerine J, Thomas A. L'atrophie olivo-ponto-cerebelleuse. Nouv Icon de la Salpet. 1900. 13:330-70.
Greenfield JG. The Spino-cerebellar Degenerations. Springfield, Ill: Charles C. Thomas; 1954.
Harding AE. The clinical features and classification of the late onset autosomal dominant cerebellar ataxias. A study of 11 families, including descendants of the 'the Drew family of Walworth'. Brain. 1982 Mar. 105(Pt 1):1-28. [QxMD MEDLINE Link].
Konigsmark BW, Weiner LP. The olivopontocerebellar atrophies: a review. Medicine (Baltimore). 1970 May. 49(3):227-41. [QxMD MEDLINE Link].
Skre H, Berg K. Cerebellar ataxia and total albinism: a kindred suggesting pleitotropism or linkage. Clin Genet. 1974. 5(3):196-204. [QxMD MEDLINE Link].
Paulson H, Ammache Z. Ataxia and hereditary disorders. Neurol Clin. 2001. Aug;19(3):759-82, viii. [QxMD MEDLINE Link].
Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015 Jan 15. 372 (3):249-63. [QxMD MEDLINE Link]. [Full Text].
Gilman S, Little R, Johanns J, et al. Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy. Neurology. 2000 Aug 22. 55(4):527-32. [QxMD MEDLINE Link].
Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord. 2003 Sep. 18 Suppl 6:S2-12. [QxMD MEDLINE Link].
Kuzdas-Wood D, Stefanova N, Jellinger KA, Seppi K, Schlossmacher MG, Poewe W, et al. Towards translational therapies for multiple system atrophy. Prog Neurobiol. 2014 Jul. 118:19-35. [QxMD MEDLINE Link]. [Full Text].
Stefanova N, Kaufmann WA, Humpel C, Poewe W, Wenning GK. Systemic proteasome inhibition triggers neurodegeneration in a transgenic mouse model expressing human a-synuclein under oligodendrocyte promoter: implications for multiple system atrophy. Acta Neuropathol. 2012 Apr 11. [QxMD MEDLINE Link].
Pikkarainen M, Hartikainen P, Soininen H, Alafuzoff I. Distribution and pattern of pathology in subjects with familial or sporadic late-onset cerebellar ataxia as assessed by p62/sequestosome immunohistochemistry. Cerebellum. 2011 Dec. 10(4):720-31. [QxMD MEDLINE Link].
Meissner WG, Flabeau O, Perez P, Taillard J, Marquant F, Dupouy S, et al. Accuracy of portable polygraphy for the diagnosis of sleep apnea in multiple system atrophy. Sleep Med. 2014 Apr. 15(4):476-9. [QxMD MEDLINE Link].
Jellinger KA. Neuropathology of multiple system atrophy: New thoughts about pathogenesis. Mov Disord. 2014 Oct 9. [QxMD MEDLINE Link].
Banfi S, Servadio A, Chung MY, et al. Identification and characterization of the gene causing type 1 spinocerebellar ataxia. Nat Genet. 1994 Aug. 7(4):513-20. [QxMD MEDLINE Link].
Burk K, Abele M, Fetter M, Dichgans J, Skalej M, Laccone F, et al. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3. Brain. 1996 Oct. 119 ( Pt 5):1497-505. [QxMD MEDLINE Link].
Fickler A. Klinische und pathologisch-anatomische Beitraege zu den Erkrankungen des Kleinhirns. Dtsch Z Nervenheilk. 1911. 41:306-75.
Winkler C. A case of olivo-pontine cerebellar atrophy and our conceptions of neo- and palaio-cerebellum. Schweiz Arch Neurol Psychiat. 1923. 13:684-702.
Schut JW, Haymaker W. Hereditary ataxia: pathologic study of 5 cases of common ancestry. J Neuropath Clin Neurol. 1951. 1:183-213.
Carter HR, Sukavajana C. Familial cerebello-olivary degeneration with late development of rigidity and dementia. Neurology. 1956 Dec. 6(12):876-84. [QxMD MEDLINE Link].
Illarioshkin SN, Tanaka H, Markova ED, et al. X-linked nonprogressive congenital cerebellar hypoplasia: clinical description and mapping to chromosome Xq. Ann Neurol. 1996 Jul. 40(1):75-83. [QxMD MEDLINE Link].
Bertini E, des Portes V, Zanni G, et al. X-linked congenital ataxia: a clinical and genetic study. Am J Med Genet. 2000 May 1. 92(1):53-6. [QxMD MEDLINE Link].
Chou SM, Gilbert EF, Chun RW, et al. Infantile olivopontocerebellar atrophy with spinal muscular atrophy (infantile OPCA + SMA). Clin Neuropathol. 1990 Jan-Feb. 9(1):21-32. [QxMD MEDLINE Link].
Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 1993 Nov-Dec. 15(6):411-22. [QxMD MEDLINE Link].
Rajab A, Mochida GH, Hill A, et al. A novel form of pontocerebellar hypoplasia maps to chromosome 7q11-21. Neurology. 2003 May 27. 60(10):1664-7. [QxMD MEDLINE Link].
Albrecht S, Schneider MC, Belmont J, Armstrong DL. Fatal infantile encephalopathy with olivopontocerebellar hypoplasia and micrencephaly. Report of three siblings. Acta Neuropathol (Berl). 1993. 85(4):394-9. [QxMD MEDLINE Link].
Patel MS, Becker LE, Toi A, et al. Severe, fetal-onset form of olivopontocerebellar hypoplasia in three sibs: PCH type 5?. Am J Med Genet A. 2006 Mar 15. 140(6):594-603. [QxMD MEDLINE Link].
Colella S, Nardo T, Botta E, et al. Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. Hum Mol Genet. 2000 May 1. 9(8):1171-5. [QxMD MEDLINE Link].
Kanda T, Oda M, Yonezawa M, et al. Peripheral neuropathy in xeroderma pigmentosum. Brain. 1990 Aug. 113 (Pt 4):1025-44. [QxMD MEDLINE Link].
De Sanctis C, Cacchione A. L'idiozia xerodermica [xerodermic idiocy]. Rivista Sperimentale di Freniatria e Medicina Legale delle Alienazioni Mentali. 1932. 56:269-92.
Agamanolis DP, Potter JL, Naito HK, et al. Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings. Neurology. 1986 May. 36(5):674-81. [QxMD MEDLINE Link].
Harding BN, Dunger DB, Grant DB, Erdohazi M. Familial olivopontocerebellar atrophy with neonatal onset: a recessively inherited syndrome with systemic and biochemical abnormalities. J Neurol Neurosurg Psychiatry. 1988 Mar. 51(3):385-90. [QxMD MEDLINE Link].
Menzel P. Beitrage zur Kenntnis der hereditaren Ataxie und Kleinhirnatrophie. Archiv fur Psychiatrie und Nervenkrankheiten, Berlin. 1891. 22:160-90.
Waggoner RW, Lowenberg K, Speicher KG. Hereditary cerebellar ataxia: report of a case and genetic study. Arch Neurol Psychiat. 1938. 39:570-86.
Schut JW. Hereditary ataxia: clinical study through six generations. Arch Neurol Psychiat. 1950. 63:535-68.
Orr HT, Chung MY, Banfi S, et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet. 1993 Jul. 4(3):221-6. [QxMD MEDLINE Link].
Donato SD, Mariotti C, Taroni F. Spinocerebellar ataxia type 1. Handb Clin Neurol. 2012. 103:399-421. [QxMD MEDLINE Link].
Boller F, Segarra JM. Spino-pontine degeneration. Eur Neurol. 1969. 2(6):356-73. [QxMD MEDLINE Link].
Wadia NH, Swami RK. A new form of heredo-familial spinocerebellar degeneration with slow eye movements (nine families). Brain. 1971. 94(2):359-74. [QxMD MEDLINE Link].
Ueyama H, Kumamoto T, Nagao S, et al. Clinical and genetic studies of spinocerebellar ataxia type 2 in Japanese kindreds. Acta Neurol Scand. 1998 Dec. 98(6):427-32. [QxMD MEDLINE Link].
Nakano KK, Dawson DM, Spence A. Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts. Neurology. 1972 Jan. 22(1):49-55. [QxMD MEDLINE Link].
Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov. 8(3):221-8. [QxMD MEDLINE Link].
Gardner K, Alderson K, Galster B. Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. Neurology. 1994. 44:A361 only.
Hellenbroich Y, Bubel S, Pawlack H, et al. Refinement of the spinocerebellar ataxia type 4 locus in a large German family and exclusion of CAG repeat expansions in this region. J Neurol. 2003 Jun. 250(6):668-71. [QxMD MEDLINE Link].
Ishikawa K, Toru S, Tsunemi T, et al. An autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 is associated with a single-nucleotide substitution in the 5' untranslated region of the gene encoding a protein. Am J Hum Genet. 2005 Aug. 77(2):280-96. [QxMD MEDLINE Link].
Ikeda Y, Dick KA, Weatherspoon MR, et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006 Feb. 38(2):184-90. [QxMD MEDLINE Link].
Subramony SH, Fratkin JD, Manyam BV, Currier RD. Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus. Mov Disord. 1996 Mar. 11(2):174-80. [QxMD MEDLINE Link].
Zhuchenko O, Bailey J, Bonnen P, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997 Jan. 15(1):62-9. [QxMD MEDLINE Link].
David G, Abbas N, Stevanin G, et al. Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat Genet. 1997 Sep. 17(1):65-70. [QxMD MEDLINE Link].
Koob MD, Moseley ML, Schut LJ, et al. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nat Genet. 1999 Apr. 21(4):379-84. [QxMD MEDLINE Link].
Ikeda Y, Shizuka M, Watanabe M, et al. Molecular and clinical analyses of spinocerebellar ataxia type 8 in Japan. Neurology. 2000 Feb 22. 54(4):950-5. [QxMD MEDLINE Link].
Factor SA, Qian J, Lava NS, et al. False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. Ann Neurol. 2005 Mar. 57(3):462-3. [QxMD MEDLINE Link].
Grewal RP, Tayag E, Figueroa KP, et al. Clinical and genetic analysis of a distinct autosomal dominant spinocerebellar ataxia. Neurology. 1998 Nov. 51(5):1423-6. [QxMD MEDLINE Link].
Zu L, Figueroa KP, Grewal R, Pulst SM. Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22. Am J Hum Genet. 1999 Feb. 64(2):594-9. [QxMD MEDLINE Link].
Grewal RP, Achari M, Matsuura T, et al. Clinical features and ATTCT repeat expansion in spinocerebellar ataxia type 10. Arch Neurol. 2002 Aug. 59(8):1285-90. [QxMD MEDLINE Link].
Worth PF, Giunti P, Gardner-Thorpe C, et al. Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3. Am J Hum Genet. 1999 Aug. 65(2):420-6. [QxMD MEDLINE Link].
Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, et al. Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12. Nat Genet. 1999 Dec. 23(4):391-2. [QxMD MEDLINE Link].
Fujigasaki H, Verma IC, Camuzat A, et al. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann Neurol. 2001 Jan. 49(1):117-21. [QxMD MEDLINE Link].
Waters MF, Minassian NA, Stevanin G, et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006 Apr. 38(4):447-51. [QxMD MEDLINE Link].
Yamashita I, Sasaki H, Yabe I, et al. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter. Ann Neurol. 2000 Aug. 48(2):156-63. [QxMD MEDLINE Link].
Brkanac Z, Bylenok L, Fernandez M, et al. A new dominant spinocerebellar ataxia linked to chromosome 19q13.4-qter. Arch Neurol. 2002 Aug. 59(8):1291-5. [QxMD MEDLINE Link].
Chen DH, Brkanac Z, Verlinde CL, et al. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia. Am J Hum Genet. 2003 Apr. 72(4):839-49. [QxMD MEDLINE Link].
Yabe I, Sasaki H, Chen DH, et al. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma. Arch Neurol. 2003 Dec. 60(12):1749-51. [QxMD MEDLINE Link].
Storey E, Gardner RJ, Knight MA, et al. A new autosomal dominant pure cerebellar ataxia. Neurology. 2001 Nov 27. 57(10):1913-5. [QxMD MEDLINE Link].
Knight MA, Kennerson ML, Anney RJ, et al. Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant. Neurobiol Dis. 2003 Jul. 13(2):147-57. [QxMD MEDLINE Link].
Hara K, Fukushima T, Suzuki T, et al. Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus. Neurology. 2004 Feb 24. 62(4):648-51. [QxMD MEDLINE Link].
Miyoshi Y, Yamada T, Tanimura M, et al. A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1-24.1. Neurology. 2001 Jul 10. 57(1):96-100. [QxMD MEDLINE Link].
Nakamura K, Jeong SY, Uchihara T, et al. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet. 2001 Jul 1. 10(14):1441-8. [QxMD MEDLINE Link].
Rolfs A, Koeppen AH, Bauer I, et al. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17). Ann Neurol. 2003 Sep. 54(3):367-75. [QxMD MEDLINE Link].
Maltecca F, Filla A, Castaldo I, et al. Intergenerational instability and marked anticipation in SCA-17. Neurology. 2003 Nov 25. 61(10):1441-3. [QxMD MEDLINE Link].
Brkanac Z, Fernandez M, Matsushita M, et al. Autosomal dominant sensory/motor neuropathy with Ataxia (SMNA): Linkage to chromosome 7q22-q32. Am J Med Genet. 2002 May 8. 114(4):450-7. [QxMD MEDLINE Link].
Schelhaas HJ, Ippel PF, Hageman G, et al. Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia. J Neurol. 2001 Feb. 248(2):113-20. [QxMD MEDLINE Link].
Verbeek DS, Schelhaas JH, Ippel EF, et al. Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet. 2002 Oct. 111(4-5):388-93. [QxMD MEDLINE Link].
Chung MY, Lu YC, Cheng NC, Soong BW. A novel autosomal dominant spinocerebellar ataxia (SCA22) linked to chromosome 1p21-q23. Brain. 2003. June; 126(Pt 6):1293-9. [QxMD MEDLINE Link].
Schelhaas HJ, Verbeek DS, Van de Warrenburg BP, Sinke RJ. SCA19 and SCA22: evidence for one locus with a worldwide distribution. Brain. 2004 Jan. 127(Pt 1):E6; author reply E7. [QxMD MEDLINE Link].
Knight MA, Gardner RJ, Bahlo M, et al. Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20. Brain. 2004 May. 127(Pt 5):1172-81. [QxMD MEDLINE Link].
Devos D, Schraen-Maschke S, Vuillaume I, et al. Clinical features and genetic analysis of a new form of spinocerebellar ataxia. Neurology. 2001 Jan 23. 56(2):234-8. [QxMD MEDLINE Link].
Vuillaume I, Devos D, Schraen-Maschke S, et al. A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1. Ann Neurol. 2002 Nov. 52(5):666-70. [QxMD MEDLINE Link].
Verbeek DS, van de Warrenburg BP, Wesseling P, et al. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3. Brain. 2004 Nov. 127(Pt 11):2551-7. [QxMD MEDLINE Link].
Stevanin G, Bouslam N, Thobois S, et al. Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p. Ann Neurol. 2004 Jan. 55(1):97-104. [QxMD MEDLINE Link].
Yu GY, Howell MJ, Roller MJ, et al. Spinocerebellar ataxia type 26 maps to chromosome 19p13.3 adjacent to SCA6. Ann Neurol. 2005 Mar. 57(3):349-54. [QxMD MEDLINE Link].
van Swieten JC, Brusse E, de Graaf BM, et al. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia [corrected]. Am J Hum Genet. 2003 Jan. 72(1):191-9. [QxMD MEDLINE Link].
Cagnoli C, Mariotti C, Taroni F, et al. SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2. Brain. 2006 Jan. 129(Pt 1):235-42. [QxMD MEDLINE Link].
Naito H, Oyanagi S. Familial myoclonus epilepsy and choreoathetosis: hereditary dentatorubral-pallidoluysian atrophy. Neurology. 1982 Aug. 32(8):798-807. [QxMD MEDLINE Link].
Koide R, Ikeuchi T, Onodera O, et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994 Jan. 6(1):9-13. [QxMD MEDLINE Link].
VanDyke DH, Griggs RC, Murphy MJ, Goldstein MN. Hereditary myokymia and periodic ataxia. J Neurol Sci. 1975 May. 25(1):109-18. [QxMD MEDLINE Link].
Hanson PA, Martinez LB, Cassidy R. Contractures, continuous muscle discharges, and titubation. Ann Neurol. 1977 Feb. 1(2):120-4. [QxMD MEDLINE Link].
Gancher ST, Nutt JG. Autosomal dominant episodic ataxia: a heterogeneous syndrome. Mov Disord. 1986. 1(4):239-53. [QxMD MEDLINE Link].
Browne DL, Gancher ST, Nutt JG, et al. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994 Oct. 8(2):136-40. [QxMD MEDLINE Link].
Brandt T, Strupp M. Episodic ataxia type 1 and 2 (familial periodic ataxia/vertigo). Audiol Neurootol. 1997 Nov-Dec. 2(6):373-83. [QxMD MEDLINE Link].
Eunson LH, Rea R, Zuberi SM, et al. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Ann Neurol. 2000 Oct. 48(4):647-56. [QxMD MEDLINE Link].
Parker HL. Periodic ataxia. Collected Papers of the Mayo Clinic. 1946. 642-5.
White JC. Familial periodic nystagmus, vertigo, and ataxia. Arch Neurol. 1969 Mar. 20(3):276-80. [QxMD MEDLINE Link].
Subramony SH, Schott K, Raike RS, et al. Novel CACNA1A mutation causes febrile episodic ataxia with interictal cerebellar deficits. Ann Neurol. 2003 Dec. 54(6):725-31. [QxMD MEDLINE Link].
Spacey SD, Materek LA, Szczygielski BI, Bird TD. Two novel CACNA1A gene mutations associated with episodic ataxia type 2 and interictal dystonia. Arch Neurol. 2005 Feb. 62(2):314-6. [QxMD MEDLINE Link].
Imbrici P, Eunson LH, Graves TD, et al. Late-onset episodic ataxia type 2 due to an in-frame insertion in CACNA1A. Neurology. 2005 Sep 27. 65(6):944-6. [QxMD MEDLINE Link].
Steckley JL, Ebers GC, Cader MZ, McLachlan RS. An autosomal dominant disorder with episodic ataxia, vertigo, and tinnitus. Neurology. 2001 Oct 23. 57(8):1499-502. [QxMD MEDLINE Link].
Cader MZ, Steckley JL, Dyment DA, et al. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia. Neurology. 2005 Jul 12. 65(1):156-8. [QxMD MEDLINE Link].
Farmer TW, Mustain VM. Vestibulocerebellar ataxia. A newly defined hereditary syndrome with periodic manifestations. Arch Neurol. 1963 May. 8:471-80. [QxMD MEDLINE Link].
Vance JM, Pericak-Vance MA, Payne CS. Linkage and genetic analysis in adult onset periodic vestibulo-cerebellar ataxia: report of a new family. Am J Hum Genet. 1984. 36:78S.
Damji KF, Allingham RR, Pollock SC, et al. Periodic vestibulocerebellar ataxia, an autosomal dominant ataxia with defective smooth pursuit, is genetically distinct from other autosomal dominant ataxias. Arch Neurol. 1996 Apr. 53(4):338-44. [QxMD MEDLINE Link].
Escayg A, Jones JM, Kearney JA, et al. Calcium channel beta 4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics. 1998 May 15. 50(1):14-22. [QxMD MEDLINE Link].
Escayg A, De Waard M, Lee DD, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000 May. 66(5):1531-9. [QxMD MEDLINE Link].
Herrmann A, Braathen GJ, Russell MB. [Episodic ataxias]. Tidsskr Nor Laegeforen. 2005 Aug 11. 125(15):2005-7. [QxMD MEDLINE Link].
Auburger G, Ratzlaff T, Lunkes A, et al. A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. Genomics. 1996 Jan 1. 31(1):90-4. [QxMD MEDLINE Link].
Müller U, Steinberger D, Németh AH. Clinical and molecular genetics of primary dystonias. Neurogenetics. 1998 Mar. 1(3):165-77. [QxMD MEDLINE Link].
Ferguson FR, Critchley M. A clinical study of an heredo-familial disease resembling disseminated sclerosis. Brain. 1929. 52:203-25.
Gayle Jr RF, Williams JP. A familial disease of the central nervous system resembling multiple sclerosis. Sth Med J. 1933. 26:242-6.
Mahloudji M. Hereditary spastic ataxia simulating disseminated sclerosis. J Neurol Neurosurg Psychiatry. 1963 Dec. 26:511-3. [QxMD MEDLINE Link].
Meijer IA, Hand CK, Grewal KK, et al. A locus for autosomal dominant hereditary spastic ataxia, SAX1, maps to chromosome 12p13. Am J Hum Genet. 2002 Mar. 70(3):763-9. [QxMD MEDLINE Link].
Grewal KK, Stefanelli MG, Meijer IA, et al. A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy. Am J Med Genet A. 2004. Dec 15;131(3):249-54. [QxMD MEDLINE Link].
Brooks DJ, Seppi K, Neuroimaging Working Group on MSA. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord. 2009 May 15. 24 (7):949-64. [QxMD MEDLINE Link].
Kim HJ, Jeon B, Fung VSC. Role of Magnetic Resonance Imaging in the Diagnosis of Multiple System Atrophy. Mov Disord Clin Pract. 2017 Jan-Feb. 4 (1):12-20. [QxMD MEDLINE Link].
Aguiar P, Pardo J, Arias M, Quintáns B, Fernández-Prieto M, Martínez-Regueiro R, et al. PET and MRI detection of early and progressive neurodegeneration in spinocerebellar ataxia type 36. Mov Disord. 2017 Feb. 32 (2):264-273. [QxMD MEDLINE Link]. [Full Text].
Ochrynik T, Bulski T, Modzelewski M, Szatkowski M. Olivopontocerebellar atrophy in MRI spectroscopy- case report. Pol J Radiol. 2007. 72(pt 1):100-2.
Takei A, Hamada T, Yabe I, Sasaki H. Treatment of cerebellar ataxia with 5-HT1A agonist. Cerebellum. 2005. 4(3):211-5. [QxMD MEDLINE Link].
Ogawa M. Pharmacological treatments of cerebellar ataxia. Cerebellum. 2004. 3(2):107-11. [QxMD MEDLINE Link].
Assadi M, Campellone JV, Janson CG, Veloski JJ, Schwartzman RJ, Leone P. Treatment of spinocerebellar ataxia with buspirone. J Neurol Sci. 2007 Sep 15. 260(1-2):143-6. [QxMD MEDLINE Link].
Dluzen DE, McDermott JL, Liu B. Estrogen as a neuroprotectant against MPTP-induced neurotoxicity in C57/B1 mice. Neurotoxicol Teratol. 1996 Sep-Oct. 18(5):603-6. [QxMD MEDLINE Link].
Al Sweidi S, Sánchez MG, Bourque M, Morissette M, Dluzen D, Di Paolo T. Oestrogen receptors and signalling pathways: implications for neuroprotective effects of sex steroids in Parkinson's disease. J Neuroendocrinol. 2012 Jan. 24(1):48-61. [QxMD MEDLINE Link].
D'Astous M, Morissette M, Di Paolo T. Effect of estrogen receptor agonists treatment in MPTP mice: evidence of neuroprotection by an ER alpha agonist. Neuropharmacology. 2004 Dec. 47(8):1180-8. [QxMD MEDLINE Link].
Gardiner SA, Morrison MF, Mozley PD, Mozley LH, Brensinger C, Bilker W, et al. Pilot study on the effect of estrogen replacement therapy on brain dopamine transporter availability in healthy, postmenopausal women. Am J Geriatr Psychiatry. 2004 Nov-Dec. 12(6):621-30. [QxMD MEDLINE Link].
Heo JH, Lee ST, Chu K, Kim M. The efficacy of combined estrogen and buspirone treatment in olivopontocerebellar atrophy. J Neurol Sci. 2008 Aug 15. 271(1-2):87-90. [QxMD MEDLINE Link].
Ristori G, Romano S, Visconti A, Cannoni S, Spadaro M, Frontali M, et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010 Mar 9. 74(10):839-45. [QxMD MEDLINE Link].
Landers M, Adams M, Acosta K, Fox A. Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: a case study. J Neurol Phys Ther. 2009 Sep. 33(3):160-8. [QxMD MEDLINE Link].

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Axial T2 brain shows hyperintensity signals within pons ("hot cross bun" sign).
Axial T2 weighed shows putaminal hyposignal intensity with hypersinal intensity rim.

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Table 1. Most Common OPCAs With Alternative Names

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^[20]
#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^[21]
%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^{[10, 22, 23]}
#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^[21]
^ 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^[24]
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^{[25, 9]}
%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^{[26, 27]}

Table 2. Extremely Rare Types of OPCAs

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^{[28, 29]}
%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^[30]
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^{[31, 32]}
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^[32]
#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^{[33, 34, 35]}
#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^{[36, 37]}

Table 3. Dominant SCAs with OPCAs Identified

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^[38]; Waggoner et al, 1938^[39]; Schut, 1950^[40]; Schut and Haymaker, 1951^[24]; Orr et al, 1993^[41] Donato et al. 2012^[42]
#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^[43]; Wadia and Swami, 1971^[44]; Ueyama et al, 1998^[45]
#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^[46]; Kawaguchi et al, 1994^[47]
%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^[48]; Hellenbroich et al, 2003^[49]
#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^[50]
#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^[51]
#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^[52]; Zhuchenko et al, 1997^[53]
#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^[54]; Harding, 1982^[8]
#608768	SCA-8, ADCA-2	KLHL1AS, 13q21	Genetic test available	Onset 20s to 70s; ataxia, dysarthria, nystagmus, impaired smooth pursuit	Koob et al, 1999^[55]; Ikeda et al, 2000^[56]; Factor et al, 2005^[57](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^[58]; Zu et al, 1999^[59]; Grewal et al, 2002^[60]
%604432	SCA-11	SCA11, 15q14-q21.3	Tau-tubulin kinase 2	Onset at 20-40 years; ataxia, dysarthria, nystagmus	Worth et al, 1999^[61]
#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^[62]; Fujigasaki et al, 2001^[63]
#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^[64]
#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^[65]; Brkanac, Bylenok et al 2002^[66]; Chen, Brkanac et al 2003^[67]; Yabe et al 2003^[68]
%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^[69]; Knight et al, 2003^[70]; Hara et al, 2004^[71]
%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^[72]
#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^[73]; Rolfs et al, 2003^[74]; Maltecca et al, 2003^[75]
%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^[76]
%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^[77]; Verbeek et al, 2002^[78]; Chung et al, 2003^[79]; Schelhaas et al, 2004^[80]
%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^[81]
%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^[82]; Vuillaume et al, 2002^[83]
%607346	SCA-22	1p21-q21		Now believed to be identical to SCA-19 (Schelhaas et al, 2004^[80]) though Chung et al (2004)^[79]dispute this	Schelhaas et al, 2001^[77]; Verbeek et al, 2002^[78]; Chung et al, 2004^[79]; Schelhaas et al, 2004^[80]
%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^[84]
%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^[85]
%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^[86]
#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^[87]
%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^[88]
#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^[89]; Koide et al, 1994^[90]
#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^[91]; Hanson et al, 1977^[92]; Gancher and Nutt, 1986^[93]; Browne et al, 1994^[94]; Brandt and Strupp, 1997^[95]; Eunson et al, 2000^[96]
#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^[97]; White, 1969^[98]; Subramony et al, 2003^[99]; Spacey et al, 2005^[100]; Imbrici et al, 2005^[101]
%606554	Episodic ataxia type 3, EA-3	1q42	Unknown	Onset at 1-42 years; vestibular ataxia, vertigo, tinnitus, interictal myokymia	Steckley et al, 2001^[102]; Cader et al, 2005^[103]
%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^[104]; Vance et al, 1984^[105]; Damji et al, 1996^[106]
+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^[107]; Escayg et al, 2000^[108]; Herrmann et al, 2005^[109]
%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^[110]; Müller et al, 1998^[111]
%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^[112]; Gayle and Williams, 1933^[113]; Mahloudji, 1963^[114]; Meijer et al, 2002^[115]; Grewal et al, 2004^[116]

Table 4. Dominant Ataxia Nomenclature

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 ataxia^ll, 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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Author

Sombat Muengtaweepongsa, MD, MSc Professor, Center of Excellence in Stroke, Associate Dean for Research and Innovations, Department of Neurology, Faculty of Medicine, Thammasat University, Thailand

Sombat Muengtaweepongsa, MD, MSc is a member of the following medical societies: American Academy of Neurology, Royal College of Physicians of Thailand

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Boehringer Ingelheim; Astra Zeneca; Novo Nordisk; Daiichi Sankyo; Bayer<br/>Received research grant from: Faculty of Medicine, Thammasat University.

Coauthor(s)

Praween Lolekha, MD, MSc Assistant Professor of Medicine, Division of Neurology, Department of Medicine, Faculty of Medicine, Thammasat University, Thailand

Praween Lolekha, MD, MSc is a member of the following medical societies: International Parkinson and Movement Disorder Society, Medical Association of Thailand, Medical Council of Thailand, Movement Disorder Society, Neurological Society of Thailand, Royal College of Physicians of Thailand, Thai Parkinson Disease - Movement Disorders Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Nestor Galvez-Jimenez, MD, MSc, MHA The Pauline M Braathen Endowed Chair in Neurology, 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, International Parkinson and Movement Disorder Society

Disclosure: Nothing to disclose.

Chief Editor

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

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, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK life science, Sunovion, Takeda, UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Aquestive, Bioserenity, Eisai, Jazz, LivaNova, Neurelis, SK life science, Stratus, Sunovion, UCB<br/>Received research grant from: Cerevel Therapeutics, Ovid Therapeutics, Neuropace, Greenwich Jazz, SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Neuroelectrics Corporation, Longboard, Janssen, Equilibre Biopharmaceuticals.

Additional Contributors

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, Phi Beta Kappa

Disclosure: Nothing to disclose.

Christina J Azevedo, MD Assistant Professor of Clinical Neurology, Department of Neurology, Keck School of Medicine of the University of Southern California

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

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Kalpana Kari, MD; Syed T Arshad, MD; and Yash Mehndiratta, MD to the development and writing of this article.