Olivopontocerebellar Atrophy

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Background

Olivopontocerebellar atrophy (OPCA) is a neurodegenerative syndrome characterized by prominent cerebellar and extrapyramidal signs, dysarthria, and dysphagia. Those who study OPCA quickly learn that it is not a single entity, and that its nosology can be confusing. The umbrella term of OPCA includes common sporadic forms and uncommon genetic forms. In the genetic subgroup, all 3 major inheritance patterns (autosomal dominant, autosomal recessive, and X-linked) have been described. The classification scheme for autosomal dominant OPCA overlaps with that of autosomal dominant spinocerebellar atrophies (SCAs) and autosomal dominant cerebellar atrophies (ADCAs). In the sporadic type of OPCA, at least some of the cases are a subset of multiple system atrophy (MSA).

While the classification is seemingly convoluted, there is good reasoning behind the complexity. The study of neurodegenerative ataxias draws from the interplay between clinical observations, neuropathological analysis, and biochemistry and molecular genetics. Historically, however, one had to rely solely on the combination of clinical observation and neuropathology to describe the disorders. Because of this, the recognition of the OPCA as its own entity has evolved over time.

The first named ataxia to emerge as a clinical entity was not an OPCA, but Friedreich ataxia, which Nicolaus Friedreich (1825-1882) managed to separate from numerous other conditions, the most prominent being multiple sclerosis (then called disseminated sclerosis) and neurosyphilis.[1, 2] Thirty years later, Pierre Marie described another grouping of hereditary cerebellar ataxias.[3] Essentially, he proposed a classification to include all the non-Friedreich ataxia cases and suggested the name heredoataxia cerebelleuse. Some of these cases would now be termed OPCAs.

In 1907, Holmes described a family with a purely cerebellar form of ataxia, and the terms Holmes ataxia and ataxia of Holmes stuck to this category for decades. In 1922, Marie, Foix, and Alajouanine reported a similar family that probably had the same disease.[4] Thus, both Holmes ataxia and the ataxia of Marie, Foix, and Alajouanine (sometimes called Marie ataxia) are purely cerebellar ataxias. Neither would be considered a type of OPCA.

In 1900, Dejerine and Thomas identified cases that combined purely cerebellar problems with evidence of brainstem pathology.[5] They coined the term olivopontocerebellar atrophy. The neurologic community accepted this name and collected many cases under this rubric. Gradually, researchers realized that both sporadic and hereditary (mostly autosomal dominant) cases comprised this group, and that, broadly speaking, these cases all had similar neuropathologic features that are described later in this article. Menzel (1890) also had described a similar case. Throughout the years, both Dejerine-Thomas ataxia and Menzel ataxia have been used as terms for certain cases of either hereditary or sporadic OPCA.

Disputes in the clinic, on paper, and in conferences have occurred about the usage of these terms, such as fine distinctions between Menzel ataxia and ataxia of Dejerine-Thomas, but they are mainly now of historical interest only. OPCA type 1 (OPCA-I) is synonymous with SCA type 1 (SCA-1) and is sometimes referred to as Menzel-type ataxia. Dejerine-Thomas ataxia might be used for any of the 6 major phenotypic OPCAs, which are better defined below. However, the authors recommend against applying either of these terms to any new case of ataxia. These terms are mentioned here only so the reader may understand where they came from if they are encountered in other literature.

In 1954, Greenfield proposed a new clinicopathological classification of OPCA.[6] This was revised by Harding in 1982, based on anatomical, pathological, and biochemical features.[7] As applied to the purely autosomal dominant ataxias, the classification is as follows:

In the ADCA grouping, the OPCAs are found in ADCA-1 and ADCA-2.

Harding was well aware that this was essentially a phenotypic grouping that lumped a number of different genetic diseases into 3 classes. However, the system was valuable for further genetic and other scientific work, in which Harding herself has been a significant contributor.

Working on a somewhat separate but related track, in 1970, Konigsmark and Weiner attempted to bring some order to the heterogeneity found among the OPCAs.[8] The proposed classification was based on clinical, genetic, and anatomic factors, as follows:

These are detailed in Table 1 in Causes.

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

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

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

Finally, the sporadic OPCAs are considered. According to current knowledge, sporadic cases can be classified into the 3 following categories, which may be modified later based on further research findings:

A separate but related question is whether the sporadic diseases are simply multigenetic, with the genetics being presently too complex to recognize as such.

A large percentage of the sporadic OPCAs are a subset of MSA, known as cerebellar subtype (MSA-C). Some authorities have claimed that all sporadic OPCAs will progress to include significant autonomic and parkinsonian features and thus evolve into full-blown MSA if the patient lives long enough. According to this view, MSA typically starts as an ataxic OPCA form, an autonomic form (Shy-Drager syndrome), or a parkinsonian form (striatonigral degeneration). Motor neuron degeneration with spasticity and pyramidal weakness, and dementia also eventually occur.[11]

However, a large and careful study by Gilman et al published in 2000 showed that of the cases they selected for analysis, only 25% of the sporadic OPCAs converted to full-blown MSA within 5 years.[12] Nevertheless, all the sporadic OPCAs, Shy-Drager syndrome, striatonigral degeneration, and full-blown MSAs appear on the molecular level to be alpha-synucleinopathies; that is, they involve abnormalities of the protein alpha-synuclein. In addition, Jellinger reports in 2003 that the molecular pathology involves alpha-synuclein–positive glial (and less abundant neuronal) cytoplasmic inclusions in MSA and in all the purported subtypes.[13] These inclusions are also different from the alpha-synucleinopathic inclusions (eg, Lewey bodies), which are seen in other diseases.

The genetic OPCAs are all more pure in the sense that they do not evolve to an MSA picture. Many of the genetic forms are considered SCAs. Some genetic forms have additional characteristics such as retinal involvement, extrapyramidal degeneration, spinal cord degeneration, dystonia, dementia, and other neurological abnormalities dependent mainly on the genetic subtype but even showing variability within the same subtype. The genetic OPCAs are generally not alpha-synucleinopathies.

Clinical distinction of these entities is based on the dominant feature, which may be cerebellar ataxia (observed in OPCAs, SCAs, and MSA), parkinsonism (observed in MSA, striatonigral degeneration, and Shy-Drager syndrome), or autonomic failure (observed in MSA and Shy-Drager syndrome). Whatever the subtype, the term OPCA indicates a form of progressive ataxia distinguished by pontine flattening and cerebellar atrophy on brain imaging studies and at autopsy.

When faced with an adult having progressive ataxia suggestive of OPCA, the role of the clinician includes (1) excluding readily treatable alternative diagnoses, (2) discussing the value of genetic testing with patients in whom such testing is informative, (3) managing symptoms, and (4) advising the patient and family regarding the natural history and the need to plan for the future. No definitive therapy exists for OPCA.[14]

Pathophysiology

The OPCAs are progressive neurodegenerative conditions. Genetic and pathological evidence suggest that abnormalities of alpha-synuclein (αSYN) are important in the pathogenesis of these disorders. Many specific genes have been identified for the genetic forms, although how the genetic abnormalities lead to the specific αSYN abnormalities or to the specific clinical findings remains uncertain. Recently developed models using transgenic mice possessing the genes for human αSYN suggest that MSA involves dysfunction of the ubiquitin-proteasome system causing proteolytic stress that disrupts the oligodendroglial/myelintrophic support. Oligodendroglia in such models, as well as in pathological specimens of the human disease, have cytoplasmic inclusions of fibrillar αSYN.[15] There is also evidence for involvement of the ubiquitin-binding protein p62/sequestosome-1 in some cases of OPCA.[16]

On the gross level, brains show some common characteristics in all cases of OPCA. The pons is diminutive, especially in the area of the basis pontis. Degeneration of the cerebellum occurs, especially in the white matter. This white matter loss is probably due to the dying back of axons from degenerating neurons rather than a primary attack on the myelinated tracts. Loss of Purkinje cells is common. Major neuronal loss occurs in the inferior olivary, arcuate, and pontine nuclei. Dentate nuclei are well preserved. The middle cerebellar peduncles are also atrophic, possibly secondary to degeneration of the basal pontine gray matter. The substantia nigra of the midbrain shows evidence of tissue loss. Cellularly, one sees neuronal degeneration in the arcuate, pontine, inferior olivary, pontobulbar nuclei, and the cerebellar cortex.

Additional areas of degeneration probably account for the difference in subtypes. In sporadic OPCA, oligodendroglial and neuronal intracytoplasmic and intranuclear inclusions characteristic of MSA are frequently seen. Many of these are accumulations of alpha-synuclein. In autosomal dominant OPCA, spinal cord lesions, especially in the posterior columns, spinocerebellar tracts, and anterior gray horn cells, are more common. The cerebellar features may be less prominent. However, so many variations of both the sporadic and genetic forms are described that one can find cases that appear to be exceptions to these generalizations.

Epidemiology

Frequency

The prevalence of OPCA is 3–5 cases per 100,000 individuals; this may represent approximately 5–6% of patients diagnosed with atypical Parkinson disease.

Mortality/Morbidity

The OPCAs are progressive neurodegenerative disorders that have no definitive treatment. Eventually, many patients become wheelchair bound. Severe dysarthria, anarthria, and dysphagia are not uncommon as the disease progresses.

Race-, sex-, and age-related demographics

No apparent racial preference is observed in OPCA. This is unlike Machado-Joseph disease, which has a predominance in certain Azorean, Indian, and Italian families.

A male preponderance is observed in familial cases of OPCA, with a male-to-female ratio of 2:1. However, no such distinction is seen in sporadic cases.

The mean age of onset of sporadic OPCA is 53 years. The mean age of onset of familial OPCA is 28 years (excluding the infantile forms in Table 2 in Causes).

History

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

Respiratory stridor from vocal cord paralysis has been reported.

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

Urinary incontinence occurs late in the course of the disease.

Sleep disturbances are common in persons with OPCA.[17]

Physical

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

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

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

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

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

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

Position sense and vibratory function are reduced secondary to neuropathy.

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

Postural hypotension may predominate among the clinical features.

Causes

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



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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



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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



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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



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Laboratory Studies

Anti-Purkinje cell antibodies

Paraneoplastic cerebellar degeneration is an important entity in the differential diagnosis. Ovarian cancer is one of the malignancies associated with this syndrome, and the paraneoplastic syndrome may manifest in the early and curable stage of cancer. Anti-Purkinje cell antibodies are the diagnostic marker for this entity, and an assay for these antibodies is commercially available. If the patient is a female who has not had oophorectomy and if the degenerative disorder is sporadic rather than clearly familial, additional screening for ovarian cancer is appropriate. Small cell cancer of the lung is also associated with this syndrome.

Vitamin E level

Although isolated vitamin E deficiency is exceedingly rare, the serum vitamin E level should be measured as part of the diagnostic workup.

Imaging Studies

MRI is the imaging study of choice in patients with olivopontocerebellar atrophy (OPCA) because CT scanning does not provide adequate resolution of the pons and cerebellum. MRI typically shows (1) pancerebellar and brainstem atrophy, with flattening of the pons; (2) an enlarged fourth ventricle and cerebellopontine angle; and (3) demyelination of the transverse pontine fibers. This demyelination of the transverse pontine fibers is responsible for the "hot cross bun" sign in a T2 weighted scan, which is thought to be highly specific for multiple system atrophy. Putaminal hyposignal intensity with hypersignal intensity rim in a T2 weighted scan represents putaminal atrophy also suggestive of a diagnosis of multiple system atrophy.[116, 117]



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Axial T2 brain shows hyperintensity signals within pons ("hot cross bun" sign).

 



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Axial T2 weighed shows putaminal hyposignal intensity with hypersinal intensity rim.

In the first year after the onset of cerebellar symptoms in patients with OPCA, MRIs may be normal; therefore, serial MRI examinations are necessary for detecting infratentorial atrophy.

Brain MRI is also useful in patients presenting with spinocerebellar syndromes to exclude the diagnoses of multiple sclerosis, cerebrovascular disease, and malignancy.

MRI also permits visualization of pontine atrophy, which distinguishes OPCA from other forms of genetic ataxias, and presentations of multiple system atrophy that do not yet heavily involve the pons. MRI findings in old patients with some late-onset genetic ataxias, such as spinocerebellar ataxia type 36 (SCA-36), may show similar pattern of OPCA.[118]

MR SPECT has been used in case reports and shows a decreased NAA/Cr ratio consistent with atrophy. The clinical use of this is not yet defined.[119]

Positron emission tomography (PET) scanning shows reduced metabolism in the brain stem and cerebellum. While this finding is of academic interest, PET scanning is not necessary for the diagnostic workup of a patient with OPCA, and the results do not distinguish subtypes of OPCA.

Other Tests

Table 3 in Causes lists whether genetic tests are available for the particular SCA. At present, commercial tests are available for SCA-1 (OPCA-I and OPCA-IV), SCA-2 (OPCA-2), SCA-3 (Machado-Joseph disease, not an OPCA), SCA-7 (OPCA-III), SCA-8 (an ADCA-1 but not an OPCA), SCA-10 (an ADCA-3, not an OPCA), SCA-12 (not an OPCA), SCA-14 (not an OPCA), SCA-17 (may be OPCA-V), and DRPLA (not an OPCA). In addition, a research test may be available for some others, such as episodic ataxia type 1, which is a dominant ataxia that is not an OPCA. Table 3 also provides the relevant chromosome and literature reference to the gene involved.

Sleep studies reveal lack of rapid eye movement and stage IV sleep in patients with OPCA. Apneic periods have also been observed.

Nerve conduction studies reveal a sensory neuropathy greater than motor neuropathy.

Evoked potentials may be delayed, especially visual evoked potentials.

EEG may show diffuse slowing and background disorganization.

None of the studies mentioned is necessary for the diagnostic workup of every patient with a progressive spinocerebellar syndrome.

Histologic Findings

Histologic findings vary among the subtypes of OPCA. The cerebellum shows predominant Purkinje cell loss. Sometimes, Purkinje cells are completely obliterated. Purkinje cell axon torpedoes are variably present. The molecular and granular layers are usually thin. The cerebellar white matter is depleted. The pons exhibits loss of transverse pontine fibers and pontine nuclei. Fibrous gliosis exists in the spaces created by the loss of fibers. Preolivary medullary fibers are reduced, and the arcuate nuclei may be so atrophic that they cannot be found. Some patients demonstrate olivary hypertrophy.

Degeneration of the dorsal columns and neuronal loss in the Clarke columns are present. In addition, dorsal root ganglia and anterior horn cells may be reduced.

Argyrophilic oligodendroglial cytoplasmic inclusions, which under light microscopy may resemble neurofibrillary tangles, are present in sporadic forms of OPCA. These typically contain alpha-synuclein.

Medical Care

Care of olivopontocerebellar atrophy (OPCA) is directed to the treatment of symptoms.

Surgical Care

At times, patients may require enteral feeding to decrease the risk of aspiration.

Percutaneous endoscopic gastrostomy and jejunostomy tube (J-tube) placement may be necessary.

Consultations

Consultations with physical and occupational therapists are helpful to increase mobility; the use of assistive devices can significantly increase functional ability. A recent case study using progressively more challenging static and dynamic balance tasks over a 12-week period produced significant improvement in balance in a patient with proven olivopontocerebellar atrophy.[129] A swallowing evaluation can be a very important part of the early consultation.

Now that genetic testing is available, it can be performed to confirm the diagnosis of autosomal dominant OPCAs. These patients may not develop symptoms until after the onset of their reproductive years; therefore, family members must be evaluated early if a diagnosis of autosomal dominant OPCA is made. Referral for genetic counseling is advisable in these individuals. Not all patients wish to learn of their risks in the absence of an available treatment, while some individuals may use the information for family planning and other types of planning for the future.

Diet

As dysphagia progresses with the disease, a pureed diet or enteral feeding may be required.

Activity

Activity should be allowed ad libitum; however, appropriate measures should be used to minimize falls.

Medication Summary

As previously stated, to date, medical therapy has provided only minimal benefits for OPCA. No medications are actually approved by the FDA for use in this condition. The medications mentioned here may be helpful in certain patients. Physicians should not prescribe these for OPCA unless they are familiar with the contraindications, interactions, precautions, and other potential problems and unless they discuss these with their patients. Brief summaries are listed, but more detail is provided in the package insert and in the literature.

Levodopa/carbidopa (Sinemet)

Clinical Context:  Direct dopaminergic agent. Carbidopa prevents peripheral decarboxylation of levodopa, thus facilitating entry into CNS. Comes in different strengths of 25/100 mg, 25/250 mg, and 10/100 mg.

Amantadine (Symmetrel)

Clinical Context:  Unknown mechanism of action; may release dopamine from remaining dopaminergic terminals in Parkinson patients or from other central sites. Less effective than levodopa in treating Parkinson disease; slightly more effective than anticholinergic agents.

Class Summary

Used to improve parkinsonian and tremor-related symptoms.

Propranolol (Inderal, Betachron E-R)

Clinical Context:  Nonselective beta-adrenergic agonist; mechanism of action for tremor suppression not fully known.

Class Summary

For OPCA, propranolol is used to help reduce the tremor. As with all medication, this pharmacologic therapy should be individualized based on a patient's age, race, known pathophysiologic variables, and concurrent conditions. The usual use of propranolol is to lower blood pressure and help ameliorate left ventricular hypertrophy. It can precipitate congestive heart failure, cause or worsen hyperlipidemia, worsen or precipitate asthma/COPD attacks, and mask hypoglycemia in diabetes. See the package insert for other precautions, interactions, and contraindications.

Bupropion (Wellbutrin, Zyban)

Clinical Context:  Bupropion inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake.

Class Summary

A modest improvement in ataxia has been observed in a few small clinical trials. One study showed no benefits. Another study showed benefits that were not sustained beyond 3 months.

Complications

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

Aspiration pneumonia is more common in later stages of OPCA.

Prognosis

Currently, no effective therapy is available for the neurodegenerative processes that constitute OPCA. Clinically, only supportive care can be given to patients with this progressive disease.

What is olivopontocerebellar atrophy (OPCA)?What is the Greenfield classification of olivopontocerebellar atrophy (OPCA)?What is the Konigsmark and Weiner classification of olivopontocerebellar atrophy (OPCA)?Which spinocerebellar ataxias (SCAs) are considered olivopontocerebellar atrophies (OPCAs)?How is sporadic olivopontocerebellar atrophy (OPCA) classified?How is genetic olivopontocerebellar atrophy (OPCA) classified?What is the pathophysiology of olivopontocerebellar atrophy (OPCA)?What is the prevalence of olivopontocerebellar atrophy (OPCA)?What is the mortality and morbidity associated with olivopontocerebellar atrophy (OPCA)?Which patient groups have the highest prevalence of olivopontocerebellar atrophy (OPCA)?Which clinical history findings are characteristic of olivopontocerebellar atrophy (OPCA)?What are the signs and symptoms of olivopontocerebellar atrophy (OPCA)?How does the clinical presentation of olivopontocerebellar atrophy (OPCA) vary among subtypes?What causes olivopontocerebellar atrophy (OPCA)?What causes infantile olivopontocerebellar atrophy (OPCA)?What are the spinocerebellar ataxia (SCA) equivalents for olivopontocerebellar atrophy (OPCA)?What are the autosomal dominant cerebellar atrophy (ADCA) equivalents for olivopontocerebellar atrophy (OPCA)?What are the differential diagnoses for Olivopontocerebellar Atrophy?How is paraneoplastic cerebellar degeneration differentiated from olivopontocerebellar atrophy (OPCA)?What is the role of vitamin E measurement in the workup of olivopontocerebellar atrophy (OPCA)?What is the role of MRI in the workup of olivopontocerebellar atrophy (OPCA)?What is the role of genetic testing in the workup of olivopontocerebellar atrophy (OPCA)?What is the role of sleep studies in the workup of olivopontocerebellar atrophy (OPCA)?What is the role of nerve conduction studies and evoked potentials in the workup of olivopontocerebellar atrophy (OPCA)?What is the role of EEG in the workup of olivopontocerebellar atrophy (OPCA)?Which histologic findings are characteristic of olivopontocerebellar atrophy (OPCA)?How is olivopontocerebellar atrophy (OPCA) treated?What is the role of surgery in the treatment of olivopontocerebellar atrophy (OPCA)?Which specialist consultations are beneficial to patients with olivopontocerebellar atrophy (OPCA)?Which dietary modifications are used in the treatment of olivopontocerebellar atrophy (OPCA)?Which activity modifications are used in the treatment of olivopontocerebellar atrophy (OPCA)?What is the role of medications in the treatment of olivopontocerebellar atrophy (OPCA)?Which medications in the drug class Antianxiety Agent are used in the treatment of Olivopontocerebellar Atrophy?Which medications in the drug class Antihypertensive agents are used in the treatment of Olivopontocerebellar Atrophy?Which medications in the drug class Dopaminergic agents are used in the treatment of Olivopontocerebellar Atrophy?What are the possible complications of olivopontocerebellar atrophy (OPCA)?What is the prognosis of olivopontocerebellar atrophy (OPCA)?

Author

Sombat Muengtaweepongsa, MD, MSc, Associate Professor, Department of Neurology, Faculty of Medicine, Thammasat University, Thailand

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Boehringer Ingelheim.

Coauthor(s)

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

Disclosure: Nothing to disclose.

Specialty Editors

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

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

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

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

Disclosure: Nothing to disclose.

Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine

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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Axial T2 brain shows hyperintensity signals within pons ("hot cross bun" sign).

Axial T2 weighed shows putaminal hyposignal intensity with hypersinal intensity rim.

Axial T2 brain shows hyperintensity signals within pons ("hot cross bun" sign).

Axial T2 weighed shows putaminal hyposignal intensity with hypersinal intensity rim.

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 availableOnset 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-2SCA-2, ADCA-IGene map locus 12q24 expanded (CAG)n trinucleotide repeat in the gene encoding ataxin-2 (ATXN2; 601517); autosomal dominant; genetic test availableOnset 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 OPCAFickler-Winkler SyndromeGene/biochemistry not known; autosomal recessiveAdult-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 degenerationADCA-II, SCA-7, OPCA with macular degeneration and external ophthalmoplegiaGene locus 3p21.1-p12; expanded trinucleotide repeat in the gene encoding ataxin-7 (ATXN7; 607640); autosomal dominant; genetic test availableOnset 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 signsThis may be the same as SCA-17Autosomal dominant; genetic test available for SCA-17, but unclear if this is the sameCerebellar ataxia, rigidity, dementia; neuronal loss in cerebellum, basal ganglia, substantia nigra, olivary nuclei, cerebral cortex[24, 8]
%302500 OPCA-X, OPCA X-linked-1SCA-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 knownOnset 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]
OMIM # OPCA Names Other Names Genetic Pattern Description
%607596 Pontocerebellar hypoplasia type 1, PCH-1Pontocerebellar hypoplasia with infantile spinal muscular atrophy, pontocerebellar hypoplasia with anterior horn cell diseaseAutosomal recessiveCerebellar hypoplasia plus motor neuron loss; sometimes called a combination of olivopontocerebellar degeneration plus spinal muscular atrophy; present from birth; patients usually die in infancy[27, 28]
%277470 Pontocerebellar hypoplasia type 2, PCH-2Pontocerebellar hypoplasia with progressive cerebral atrophy, Volendam neurodegenerative diseaseAutosomal recessiveCongenital 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 atrophyCerebellar atrophy with progressive microcephaly, CLAMAutosomal recessive; gene map locus 7q11-q21Gene map locus 7q11-q21Onset in infancy or childhood, cerebellar atrophy with progressive microcephaly; on MRI of small brainstem, small cerebellar vermis and atrophy of the cerebellum and cerebrum; ataxia, truncal hypotonia, and exaggerated deep tendon reflexes; one patient had optic atrophy; seizures common[29]
225753 Pontocerebellar hypoplasia type 4, PCH-4Fatal infantile encephalopathy with olivopontocerebellar hypoplasiaProbably autosomal recessive, possibly autosomal dominant or maternal transmission; biochemical defect and gene locus not knownPatients die in infancy; severe olivopontocerebellar hypoplasia on autopsy[30, 31]
610204 Pontocerebellar hypoplasia type 5, PCH-5Olivopontocerebellar hypoplasia, fetal onsetGenetics not clearPontocerebellar hypoplasia is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem with significant hypoplasia of the olivae, the pons, and the cerebellum; patients typically die in infancy[31]
#278800 De Sanctis-Cacchione syndrome Gene map locus 10q11; an excision repair gene named variously ERCC6, CKN2, COFS, and CSB causing Cockayne syndrome type B (CSB; 133540) or genes of xeroderma pigmentosum, usually XPA (ie, complementation group A); 278700 9q22.3 or more rarely, other genes associated with xeroderma pigmentosum; autosomal recessiveXeroderma pigmentosum (severe sun sensitivity), mental retardation, dwarfism, and progressive neurological deterioration; overlaps with known types of xeroderma pigmentosum and Cockayne syndrome, especially XPA and CSB, apparently as allelic variants but other unknown factors may bring out the olivopontocerebellar (and cerebral) atrophy[32, 33, 34]
#212065 Congenital disorder of glycosylation, type Ia Phosphomannomutase-2 (PMM2; 601785); autosomal recessiveSevere congenital psychomotor retardation, generalized hypotonia, hyporeflexia, and trunk ataxia, neonatal-onset OPCA, peripheral neuropathy, retinitis pigmentosa; defects in other systems include heart and musculoskeletal systems; severe neonatal neurodegenerative disease; some patients have olivopontocerebellar phenotype; usually death in infancy or childhood[35, 36]
Disease OMIM # Disease Names Locus GeneProduct (OMIM #) Description References
#164400 SCA-1, OPCA-I, OPCA-IV (OPCA-IV same as OPCA-I), ADCA-1ATXN1, 6p23CAG expansion repeat in N-terminal coding region of Ataxin-1 (*601556);Onset 30-40 years; ataxia, spasticity, dysarthria, ophthalmoplegia, slow saccades, nystagmus, optic atrophy, pyramidal tract signs; rare extrapyramidal; signs; some have dementia; neuropathy occurs late. Expansion repeat causes toxic gain of function via abnormally long ataxin-1. This worsens in subsequent generations.Menzel, 1891[37] ; Waggoner et al, 1938[38] ; Schut, 1950[39] ; Schut and Haymaker, 1951[23] ; Orr et al, 1993[40]



Donato et al. 2012[41]



#183090 SCA-2, OPCA-2, ADCA-1ATXN2, 12q24Ataxin-2 (601517); genetic test availableOnset in 30s; ataxia, dysarthria, muscle cramps; slow saccades/ophthalmoplegia; peripheral neuropathy, hyporeflexia, dementia in some; no pyramidal or extrapyramidal featuresBoller and Segarra, 1969[42] ; Wadia and Swami, 1971[43] ; Ueyama et al, 1998[44]
#109150 SCA-3 or Machado-Joseph disease, ADCA-1ATXN3, 14q24.3-q31Machado-Joseph disease protein 1(ATXN3). (607047); genetic test availableAll have ataxia, dysarthria, ophthalmoplegia; type I onset in mid 20s with facial-lingual myokymia, pyramidal and extrapyramidal features; type II onset in 40s; type III onset in mid 40s with peripheral neuropathy (weakness and atrophy)Nakano et al, 1972[45] ; Kawaguchi et al, 1994[46]
%600223 SCA-4, ADCA-1Gene 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 someGardner et al, 1994[47] ; Hellenbroich et al, 2003[48]
#117210 SCA, 16q22-linked ADCA-3PLEKHG4, 16q22.1Puratrophin-1 (609526)Typically pure cerebellar ataxia with gait ataxia, cerebellar dysarthria, limb ataxia, decreased muscle tone, horizontal-gaze nystagmus; lacks other feature seen in SCA-4, ADCA-1 (but sometimes called SCA-4)Ishikawa et al, 2005[49]
#600224 SCA-5, ADCA-3SPTBN2, 11p13Spectrin 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 expectancyIkeda et al, 2006[50]
#183086 SCA-6, ADCA-1 ADCA-3CACNA1A, 19p13Voltage-dependent P/Q-type Ca+2 channel alpha-1a subunit (601011); genetic test availableOnset 20-40 years; ataxia, dysarthria, nystagmus, distal sensory loss, normal life expectancySubramony et al, 1996[51] ; Zhuchenko et al, 1997[52]
#164500 SCA-7, OPCA-3 ADCA-2ATXN7, 3p21.1-p12Ataxin-7 (607640); genetic test availableOnset mid 20s; pigmentary retinal degeneration, ataxia, dysarthria, ophthalmoplegia, slow saccades, pyramidal tract signsDavid et al, 1997[53] ; Harding, 1982[7]
#608768 SCA-8, ADCA-2KLHL1AS, 13q21Genetic test availableOnset 20s to 70s; ataxia, dysarthria, nystagmus, impaired smooth pursuitKoob et al, 1999[54] ; Ikeda et al, 2000[55] ; Factor et al, 2005[56] (Factor et al case was actually consistent with MSA)
 SCA-9Unassigned category Unassigned categoryUnassigned category
+603516 SCA-10 ADCA-3ATXN10, 22q13Ataxin-10; genetic test availableOnset in 20s; ataxia, dysarthria, nystagmus, epileptic seizures; to date only found in Mexican familiesGrewal et al, 1998[57] ; Zu et al, 1999[58] ; Grewal et al, 2002[59]
%604432 SCA-11SCA11, 15q14-q21.3Tau-tubulin kinase 2Onset at 20-40 years; ataxia, dysarthria, nystagmusWorth et al, 1999[60]
#604326 SCA-12PPP2R2B, 5q31-q33Serine/threonine protein phosphatase 2A, 55-kd regulatory subunit B, beta isoform; genetic test availableOnset at 8-55 years, commonly 30s; upper extremity and head tremor, gait ataxia, ophthalmoplegia, hyperreflexia, bradykinesia, dementiaHolmes et al, 1999[61] ; Fujigasaki et al, 2001[62]
#605259 SCA-13KCNC3, 19q13.3-q13.4Voltage-gated K+ channel, subfamily C member 3Onset in childhood; ataxia, dysarthria, mental retardation; slow progressionWaters et al, 2006[63]
#605361 SCA-14PRKCG, 19q13.4Kinase C, gamma type; genetic test availableOnset mostly in most those older than 39 years; ataxia, dysarthria, nystagmus; younger patients (< 27 y) also had intermittent axial myoclonus prior to ataxiaYamashita et al 2000[64] ; Brkanac, Bylenok et al 2002[65] ; Chen, Brkanac et al 2003[66] ; Yabe et al 2003[67]
%606658 SCA-15Gene unknown, 3p26.1-p25.3Inositol 1,4,5-triphosphate receptor type 1Similar to SCA-6 and SCA-8; MRI-proven cerebellar atrophy; onset at 10-50 years; slowly progressive pure cerebellar ataxia, ataxic dysarthria, tremor; may have head titubation, nystagmus, oculovestibular reflex abnormalities, mild hyperreflexia (no spasticity or Babinski signs)Storey et al, 2001[68] ; Knight et al, 2003[69] ; Hara et al, 2004[70]
%606364 SCA-16SCA16, 8q22.1-q24.1Contactin-4MRI-proven cerebellar atrophy without brainstem involvement; onset at 20-66 years; pure cerebellar ataxia, some with head tremor, slow progressionMiyoshi et al, 2001[71]
#607136 SCA-17, may be OPCA-5TBP, 6q27TATA-box–binding protein; genetic test availableOnset 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 cerebellumNakamura et al, 2001[72] ; Rolfs et al, 2003[73] ; Maltecca et al, 2003[74]
%607458 SCA-18SCA18 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 senseBrkanac et al, 2002[75]
%607346 SCA-191p21-q21 Onset at 12-40 years; gait and limb ataxia, hyporeflexia, dysphagia, dysarthria, and gaze-evoked horizontal nystagmus; cerebellar atrophy on MRIsSchelhaas et al, 2001[76] ; Verbeek et al, 2002[77] ; Chung et al, 2003[78] ; Schelhaas et al, 2004[79]
%608687 SCA-20SCA20, 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 calcificationKnight et al, 2004[80]
%607454 SCA-21SCA21, 7p21-15 Onset at 6-30 years; cerebellar ataxia, limb ataxia and akinesia, dysarthria, dysgraphia, hyporeflexia, postural tremor, resting tremor, rigidity, cognitive impairment, cerebellar atrophyDevos et al, 2001[81] ; Vuillaume et al, 2002[82]
%607346 SCA-221p21-q21 Now believed to be identical to SCA-19 (Schelhaas et al, 2004[79] ) though Chung et al (2004)[78] dispute thisSchelhaas et al, 2001[76] ; Verbeek et al, 2002[77] ; Chung et al, 2004[78] ; Schelhaas et al, 2004[79]
%610245 SCA-2320p13-12.3 Onset at 40s and 50s; slow progression; gait and limb ataxia, dysarthria (varies), slow saccades and ocular dysmetria, decreased vibratory sense; severe cerebellar atrophyVerbeek, et al, 2004[83]
%608703 SCA-25SCA25, 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 symptomsStevanin et al, 2004[84]
%609306 SCA-2619p13.3 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 medullaYu et al, 2005[85]
#609307 SCA-27FGF14, 13q34Fibroblast 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 gangliavan Swieten et al, 2003[86]
%610246 SCA-2818p11.22-q11.2AFG3-like protein 2Onset 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 hyporeflexiaCagnoli et al, 2006[87]
#125370 Dentatorubral-pallidoluysian atrophy (DRPLA)DRPLA, 12p13.31Atropin-1–related protein (607462); genetic test availableOnset in 20s to 30s; myoclonic epilepsy, dementia, ataxia, choreoathetosis, degeneration of dentatorubral and pallidoluysian systemsNaito and Oyanagi, 1982[88] ; Koide et al, 1994[89]
#160120 Episodic ataxia type 1, EA-1KCNA1, 12p13K+1 voltage-gated channel (A1) (600111); genetic test available on research basisOnset usually in childhood; continuous muscle movement (myokymia) and periodic ataxiaVan Dyke et al, 1975[90] ; Hanson et al, 1977[91] ; Gancher and Nutt, 1986[92] ; Browne et al, 1994[93] ; Brandt and Strupp, 1997[94] ; Eunson et al, 2000[95]
#108500 Episodic ataxia type 2, EA-2CACNA 1A, 19p13Voltage-dependent P/Q-type Ca+2 channel alpha-1A subunit (601011); genetic test available on research basisOnset in childhood; ataxia, downbeating nystagmus dizziness treated with acetazolamide; no progression after childhood; cerebellar atrophyParker, 1946[96] ; White, 1969[97] ; Subramony et al, 2003[98] ; Spacey et al, 2005[99] ; Imbrici et al, 2005[100]
%606554 Episodic ataxia type 3, EA-31q42UnknownOnset at 1-42 years; vestibular ataxia, vertigo, tinnitus, interictal myokymiaSteckley et al, 2001[101] ; Cader et al, 2005[102]
%606552 Episodic ataxia type 4, EA-4UnknownUnknownOnset 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, vertigoFarmer and Mustian, 1963[103] ; Vance et al, 1984[104] ; Damji et al, 1996[105]
+601949 Episodic ataxia type 5, EA-5CACNB 4, 2q22-q23Voltage-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); seizuresEscayg et al, 1998[106] ; Escayg et al, 2000[107] ; Herrmann et al, 2005[108]
%601042 Choreoathetosis spasticity, episodic, CSE12p13 (close to potassium channel gene KCNA1 but not the same)UnknownOnset at 2-15 years; paroxysmal choreoathetosis with episodic ataxia and spasticityAuburger et al, 1996[109] ; Müller et al, 1998[110]
%108600 Hereditary (autosomal dominant) spastic ataxiaSAX1, 12p13UnknownOnset 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 lossFerguson and Critchley, 1929[111] ; Gayle and Williams, 1933[112] ; Mahloudji, 1963[113] ; Meijer et al, 2002[114] ; Grewal et al, 2004[115]
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)
OPCAsOPCA-1†, OPCA-IV†OPCA-2No OPCA matching SCA-3No OPCA matching above SCAsOPCA-IIINo OPCA matching above SCAs
ADCAsADCA-1ADCA-1ADCA-1ADCA-1ADCA-2ADCA-3
EponymsMenzel type OPCA (or Menzel ataxia)‡, Schut- Haymaker type OPCA†, Dejerine-Thomas ataxiaHolguin type ataxia, Wadia-Swami syndrome, Dejerine-Thomas ataxiaMachado-Joseph disease, Dejerine-Thomas ataxiaDejerine-Thomas ataxiaSanger-Brown ataxia§, Dejerine-Thomas ataxiaHolmes ataxiall, ataxia of Marie, Foix, and Alajouanine, Marie ataxia, Nonne syndrome#
*SCA-13 is often said to not be part of ADCA classification. It is mainly a childhood mental retardation/ataxia syndrome. The ataxia is not accompanied by significant brainstem pathology, similar to ADCA-3. The mental retardation can be interpreted as a dementia, putting it in ADCA-1.



† OPCA-IV (Schut-Haymaker OPCA) is now thought to be an SCA-1, which makes it OPCA-I (ie, strictly speaking, OPCA-IV no longer exists).



‡ Menzel OPCA is sometimes taken much more broadly as virtually any OPCA except perhaps OPCA-III. Alternatively, it is taken as essentially the same as ADCA-1. In addition, it is sometimes applied to sporadic OPCAs that have similar presentations to any of the syndromes under ADCA-1.



§ Sanger-Brown ataxia is sometimes taken more broadly. As expansively defined, the term could be used for virtually any of these.



ll Holmes ataxia is sometimes applied to pure sporadic cerebellar ataxia of late onset.



This is sometimes used for most any of these syndromes, which seems to be the sense in which it was used in the original 1893 paper by Marie.



# This is a very obscure term. It is most commonly used for conditions fitting ADCA-3.



**The authors found no papers calling SCA-3 Dejerine-Thomas ataxia, but Dejerine-Thomas ataxia is so broadly defined, the term could possibly be applied to SCA-3.