What causes olivopontocerebellar atrophy (OPCA)?

Answer

A unifying etiology of OPCA has not been established.^[18]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^[19]
#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^[20]
%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, 21, 22]}
#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^[20]
^ 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^[23]
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^{[24, 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^{[25, 26]}

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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

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^[19]
#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^[20]
%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, 21, 22]}
#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^[20]
^ 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^[23]
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^{[24, 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^{[25, 26]}

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Author

Sombat Muengtaweepongsa, MD, MSc Associate Professor, 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: Nothing to disclose.

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: Ceribell, Eisai, Greenwich, Growhealthy, LivaNova, Neuropace, SK biopharmaceuticals, Sunovion<br/>Serve(d) as a speaker or a member of a speakers bureau for: Eisai, Greenwich, LivaNova, Sunovion<br/>Received research grant from: Cavion, LivaNova, Greenwich, Sunovion, SK biopharmaceuticals, Takeda, UCB.

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.

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