What causes olivopontocerebellar atrophy (OPCA)?

Updated: Dec 17, 2018
  • Author: Sombat Muengtaweepongsa, MD, MSc; Chief Editor: Selim R Benbadis, MD  more...
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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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