Timothy C. Hain, MD Page last modified: April 29, 2019
|Figure 1: Sagittal MRI of person with an inherited cerebellar degeneration (of unknown origin). This MRI shows prominent atrophy (shrinkage) of the midline (called the vermis).|
The main goal of this page is to serve as a repository for recent information about inherited cerebellar degenerations. It is not comprehensive, but we hope that it might be of some use to individuals searching for information about these rare conditions on the web. We highly recommend also using the OMIM database, which can be accessed on the web. A large number of the genetic ataxias can be tested for using contemporary methodology. An example of a lab that does this is Athena.
Most of the information here concerns inherited conditions, as there is considerable new data derived from researchers using a nearly complete map of the human genome (your tax dollar is doing some good !), and improvements in the technology of molecular biology. It seems quite feasible that within the next decade, we may be able to determine the gene that is damaged in most inherited cerebellar degenerations. As these data become known, it may also be possible to target specific therapies, probably over the next 2 decades. In other words, stay tuned, but we aren't there yet.
There are numerous non-genetic causes of cerebellar disease. which are not covered here.
A recent review on molecular genetic testing for hereditary ataxia is that of Wallace and Bird, 2018.
If you have a SCA -- we suggest that you do the following:
Pages on this site outside of this main SCA page. Generally these pages exist to host more specific information (often containing videos) of patients with this diagnosis.
According to Wallace and Bird (2018), there are more than 300 hereditary disorders associated with ataxia, and 100 genetic disorders associated with slow progressive incoordination of gait. The most common are expansions nucleotide repeats of 7 genes (ATXN1, 2. 3. 8. 9. CACN1A. amd FXN). They suggest that the first step should be to determine nucleotide repeat lengths.
Interestingly, there are many other neurologic disease cause by nucleotide repeats, not all of which are cerebellar degenerations. These include Huntington disease, several myotonic dystrophies, and Spinal and bulbar muscular atrophy. The human genome also contains many trinucleotide repeats that seem to be benign. Only a small percentage causes disease.
All of these disorders exhibit gradually progressive pancerebellar dysfunction, usually beginning in childhood, differentiated by other nervous system involvement. These disorders were previously known as autosomal dominant cerebellar ataxias. The prevalence of SCA's is estimated to be about 1-4/100,000, but it can be much higher in some regions because of the founder effect. SCA's are all autosomal dominant.
|SCA Type||findings and comments||Mutation|
|SCA-1 (3-15%)||Hypermetric saccades, slow saccades, UMN||CAG repeat, 6p, ATXN1|
Diminished velocity saccades, areflexia
Common in Cuba.
|CAG repeat, 12q, ATXN2|
|SCA3 (MJD, 30-40%)||
Gaze-evoked nystagmus, UMN, slow saccades.
Common in the Azores and Portugal.
|CAG repeat, 14q (ATXN3)|
|SCA-4 (17 families)||areflexia||Chromosome 16q|
|SCA-5||Pure cerebellar||Chromosome 11|
Downbeating nystagmus, positional vertigo
Symptoms can appear for the first time as late as 65 years old.
|CAG repeat, 19p (Calcium channel gene), CACN1A|
|SCA-7||Macular degeneration, UMN, slow saccades||CAG repeat, 3p, ATXN7|
|SCA-8||Horizontal nystagmus||CTG repeat, 13q, ATXN8OS, ATXN8. Both repeats of CTG and CAG.|
|SCA-10 (Zu et al, 5 families)||ataxia, seizures, primarily in Mexicans||Chromosome 22q linked, pentanucleotide repeat, ATXN10, repeats of ATTCT|
|SCA-12 (rare, OHearn et al)||Head and hand tremor, akinseia||5q CAG, PPP2R2B|
|SCA-13 (rare)||Mental retardation||19q|
|SCA-15/16/29||Head and hand tremor||8q|
|SCA17||Age of onset 20-60, dystonia, chorea, spasticity, dementia||TBP, CAG or CAA repeat|
|SCA18||Age of onset 12-25, neuropathy, muscle weakness, atrophy, fasculations, pyramidal signs.|
|SCA 19/22||Mild cerebellar syndrome, dysarthria|
|SCA20||Age of onset 30-40, presents with dysarthria, palatal tremor|
|SCA21||Age of onset 6-30, mild cognitive, tremor, akinesia, rigidity|
|SCA22 -- see sca19|
|SCA23||40-60, pyramidal tract, sensory loss|
|SCA24 -- not listed.|
|SCA 25||ataxia with sensory neuropathy, vomiting and gastrointestinal pain.||2p|
|SCA31||Bean1, TGGAA repeat|
|SCA34||Oculomotor, resembles PSP||ELOVL4|
|SCA35||Age of onset 40-48, pyramidal signs, sensory loss, spasmodic torticollus|
|SCA36||Age of onset 40-60, tongue and skeletal muscle atrophy and fasiculation, hearing loss.||20p13-12.2/NOP56, GGCCTG repeat|
|SCA37||Pure cerebellar syndrome|
|SCA38||Age of onset 40-50, axonal neuropathy, vermal atrophy|
Chorea, seizures, primarily found in Japan
|12p CAG expansion|
The most common autosomal dominant hereditary ataxias are SCA1,2,3,6 and 7. All of these are due to trinucleotide repeats (Wallace and Bird, 2018). Many of these CAG repeats have slow saccades. This seems a little peculiar in that presumably the CAG repeat is in different genes.
SCA1-3, SCA6-7m 12 and 16, are genetically associated with unstable CAG trinucleotide repeats. Trinucleotide repeats are abnormal "nonsense" areas in human DNA, that tend to get bigger with time. In successive generations, the size of the CAG repeat tends to get bigger causing a decrease in age at onset (called anticipation). Other CAG repeat diseases include Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinal and bulbar muscular atrophy. Surprisingly, the CAG repeats in the SCA1-3 are found on different chromosomes. Other trinucleotide repeat diseases include myotonic dystrophy and fragile X syndrome. In trinucleotide repeats, an expansion may increase when passed between an affected parent and his or her affected child -- this is called anticipation. The premutation carrier state of Fragile-X is also associated with cerebellar findings (Berry-Kravis et al, 2003). This mutation has a frequency of 1/250 in women and 1/813 men.
In SCA1 there is atrophy of Purkinje cells as well as loss of many afferent projections to cerebellar cortex, atrophy of dentatorubral pathways, the dorsal columns and certain cranial nerve nuclei.. SCA1 maps to chromosome 6p. Saccade amplitude is reportedly increased in SCA1, resulting in hypermetria (Rivaud-Pechoux et al, 1998). In dominant kindreds, Moseley et al (1998) found SCA1 in 5.6%. The 10-year survival rate for SCA1 was reported to be 57% (Diallo et al, 2018)
SCA2 is associated with marked loss or slowing of saccadic eye movements (Rivaud-Pechoux et al, 1998; Federighi et al, 2011). Unlike the situation in disorders like PSP, all saccades are affected rather than vertical saccades alone. Federighi and associated suggested that there was damage to the pontine burst cells. There is olivopontocerebellar atrophy in SCA2. SCA2 maps to chromosome 12q. SCA2 may be the most common of the CAG repeat type autosomal dominant cerebellar ataxias. In dominant kindreds, Mosely et al found SCA2 in 15.2% (1998). The 10-year survival rate for SCA2 was reported to be 74% (Diallo et al, 2018)
SCA3, which is dominantly inherited, is also known as Machado-Joseph disease. We have some case examples of this disorder here. The 10-year survival rate for SCA3 was reported to be 73% (Diallo et al, 2018)
SCA6 is an autosomal dominant ataxia associated with small expansions of a trinucleotide repeat (CAG) in the gene CACNL1A4, which encodes a voltage-gated calcium channel. Zoghbi (1997) reviews the genetics of this disorder. The 10-year survival rate for SCA6 was reported to be 87% (Diallo et al, 2018)
Patients with SCA6 can have at least three different syndromes: episodic ataxia, cerebellar ataxia plus brainstem or long tract degeneration, or pure cerebellar ataxia. Calcium channels are identified in Purkinje and granule neurons. Clinically they have a coarse gaze-evoked nystagmus, downbeat nystagmus on lateral gaze, and poor visual suppression (Gomez et al, 1997). SCA6 accounts for about 30% of dominant ataxias in Japan, and between 5-15% of dominantly inherited ataxia in the United States (Geshwind et al, 1997; Mosely et al, 1998). Imaging studies reveal cerebellar atrophy with relative sparing of the brainstem. In Japan, ataxia is the most common initial symptom. Patients with prolonged courses exhibit dystonic postures, involuntary movements and abnormalities in tendon reflexes (Ikeuchi et al, 1997). Takeichi et al (2000) reported that while ocular smooth pursuit is diminished, vestibular cancellation is normal. This may be a distinctive finding of this condition. As mentioned above, patients with calcium channelopathies including SCA-6 and EA2 have deficient ocular responses to otolith input.
SCA7, also dominantly inherited, is associated with retinopathy or blindness. It is also a CAG repeat disorder. Mosely et al (1998) found SCA7 in about 5% of dominantly inherited ataxias. We illustrate a case of this here. SCA7, like SCA2 and 3, has slow saccades.
SCA8 was described in 2000 by Ikeda and others. It is a CAG/CTG repeat disorder. It is characterized by incoordination, ataxic dysarthria, impaired smooth pursuit, horizontal nystagmus, and atrophy of the cerebellar vermis and hemispheres. Myotonic dystrophy is another CTG repeat disorder. Both show maternal anticipation. Average age of onset is 53.8 years.
According to Matsuura et al, SCA 9 is reserved for disorders yet to be described in the literature, and SCA10 (Zu et al, 1998), designates another autosomal dominant ataxia, with occasional seizures.
SCA-10 is rare in populations other than Mexicans (Matsuura and others, 2002).
SCA-17 is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the TATA-box binding protein gene. The clinical features include ataxia, dementia, hyperreflexia, parkinsonism manifestations such as bradykinesia, and postural reflex disturbances.
SCA-34 is autosomal dominant cerebellar ataxia due to an ELOVL4 mutation. Mutations of ELOV4 have been reported in 2 Japanese kindreds and a French-Canadian family. In the Japanese variant, the disorder resembles PSP including the "hot cross bun" sign in some and pontine linear hyperdensities in others. (Ozaki et al, 2015).
SCA-38 is due to a missense mutation of ELOVL5. ELOV5 is involved in fatty acid synthesis. (Di Gregorio et al, 2014).
There are many other ataxias which are not included in the "SCA#" nomenclature.
Grewal and others (1998) described an autosomal dominant spinocerebellar disorder in individuals of mexican-american heritage. The clinical picture included cerebellar ataxia, gaze and rebound nystagmus.
Matsuura et al (1999) mapped an autosomal dominant spinocerebellar ataxia with seizures, also in a hispanic family.
Swartz and others (2003) described an autosomal recessive ataxia with progressive ataxia, corticospinal signs, axonal sensorimotor neuropathy, and disruption of visual fixation by saccadic intrusions. This disorder was mapped to a mutation on 1p36.
Unverricht-Lundborg disease is autosomal recessive, and is due to the CSTB gene.
Dentatorubral and pallidoluysian atrophy (DRPLA)
DRPLA maps to chromosome 12p, and a gene designated "atrophin-1". It was first described by Smith in 1958 (Neurology 1958:8:205-209), and remains rare outside of Asia. Young adults and children display progressive chorea, cerebellar ataxia, oculomotor function and dementia. This disorder has an unstable CAG repeat. Purkinje cells are intact, unlike SCA1, but there is degeneration of the cerebellar dentate nucleus.
Autosomal dominant cerebellar ataxia associated with pigmentary macular dystrophy maps to chromosome 3p.
This obscure autosomal recessive spastic ataxia is caused by mutations in the SACS gene. It was first described in Quebec. French Canadians, like other inbred populations, have more autosomal recessive disorders than the rest of the world. It is characterized by a triad of slowly progressive cerebellar ataxia, lower limb pyramidal tract features, and a sensorimotor neuropathy. There may also be retinal changes, urinary symptoms, progressive cerebellar atrophy, and linear hypointensities in the pons on MRI, considered the hallmark of the disease. (Pilliod et al, 2015)
Gagnon et al (2018) reported on 19 patients with this disorder, of mean age of 38.3. Over just 2 years there was a distressingly large deterioration in several functional measures (that require cooperation). This study is an observational type study, and does not have the predictive value of a blinded or controlled study.
Medicine has advanced greatly in the past 10 years, but treatment of cerebellar disorders has advanced little to nothing. This means that right now, finding out which mutation your family has, is unlikely to result in anything meaningful right now. So why do it ? Well, sometimes it is helpful when one is planning a family. It advances the field, which is important. Finally, "gene editing" is on the horizen now, and if you can identify that you have a specific genetic disorder, you might be one of the early ones to benefit from these powerful new techniques.
There are many genetic testing labs, that offer to test for these disorders, usually as an "out of pocket" price. These labs might ask for $2000 for genetic testing to find out that someone has an untreatable disorder. The cost is $2000, the personal benefit is close to 0. In the United States, these labs seem to have evolved from government funded research projects, where large and expensive sequencing machines were purchased for research endeavors, and made part of a shared facility at a University. Our tax dollars at work ! We are not criticizing the effort to explore the human genome, but we are wondering how these commercial laboratories can make ends meet, given that the equipment is so expensive. Puzzling.
According to Wallace and Bird (2018), the most common type of genetic testing for cerebellar degenerations, commercial exome sequencing, will not identify trinucleotide repeats. They note that there are ten (yes 10) reference laboratories that offer multigene panels. One laboratory in the US (Wallace and Bird do not name this lab), offers a multigene panel that can detect nucleotide repeats in the most common genes.
In general, main stream medicine has very little to offer in treatment for cerebellar disorders. In the overwhelming majority of cases, cerebellar disorders are caused by death of cerebellar neurons. Medicine has no method of regrowing dead neurons. Normally, only a few subpopulations of neurons (such as related to smell) regenerate. There are a few instances where genes have been traced that allow regeneration to occur (i.e. for hair cells in birds). Pursuit of this direction seem promising to us. Stem cell transplants, at the present writing (2010) are wishful thinking.
According to Wallace and Bird (2018), specific treatments are available for only a few of the hereditary ataxias, including vit-E deficiency, REfsum disease, cerebrotendinous xanthomatosis, and CoQ10. This is not much considering the 100-300 disorders that these authors discuss as of 2018.
Some medications are helpful in suppressing overactive neuronal circuits that cause tremor - examples are the benzodiazepines and baclofen.
Some medications are helpful in reducing or increasing motor symptoms -- examples are dopamine agonists (such as L-dopa), and antagonists (such as haloperidol).
The alternative medicine community (AMC ?) offers a multitude of treatments for incurable disorders. We don't especially recommend any of these ourselves, but a few interesting ones suggested by patients are below: