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Timothy
C. Hain, MD 
Page last modified:
May 22, 2008
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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.
If you have a SCA -- we suggest that you do the following:
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Figure 2: High signal seen in both middle cerebellar peduncles in person with Fragile X associated tremor ataxia. |
FXTAS is a very common tremor/ataxia syndrome, which is newly described (as of 2001). It is a late-onset disorder, typically beginning in the 60's or 70's, with involvement of multiple systems -- gait ataxia, intention tremor, peripheral neuropathy, autonomic dysturbance, and sometimes dementia. MRI shows atrophy, white matter changes, and distinctive T2 hyperintensities in the middle cerebellar peduncles. FXTAS may affect as many as 1/3000 men over the age of 50. (Hall et al, 2005). About 3% of persons being tested for hereditary cerebellar disorders are positive for FXTAS. There is no treatment, but genetic counseling may be helpful.
Males transmit this gene to all daughters. Thus the inheritance pattern of the disease itself goes from father->daughter->male children. Female carriers (the daughters) have a 50% chance of transmitting the gene to each child (male or female).
Proposed criteria for genetic testing (FMR1) are:
References:
Friedreich's ataxia was thought to be the most common inherited ataxia, before FXTAS was discovered. It is transmitted with autosomal recessive inheritance. It's estimated prevalence in European populations is 1 in 50,000. It is associated with a mutation that consists of unstable expansion of GAA repeats on chromosome 9. FA alleles are found in about 11.4% of apparently recessive and 5.2% of apparently sporadic patients (Moseley et al, 1998).
Onset of symptoms is usually before 20 years of age (15 +- 8). There is ataxia of all four limbs associated with cerebellar dysarthria, absent reflexes in the lower limbs, sensory loss and pyramidal signs. Hypertrophic concentric cardiomyopathy is found in a majority of patients. Skeletal deformities and abnormalities in glucose metabolism are common. Other associated findings may be facial dysmorphia, myoclonus, dystonia, postural tremor, supranuclear gaze paresis, and mental retardation. Abnormal auditory evoked responses are found in about 50% of patients, and the auditory neuropathy syndrome has been reported in this disease. Sensorineural hearing loss may occur. Temporal bones from patients with Freidreichs have shown spiral ganglion and Scarpa's ganglion cell degeneration (Merchant et al, 2001). In patients homozygous for GAA expansion, the mean time to wheelchair confinement averages 10.8 years, and the mean disease duration is 15+-9 years. (Cosee et al, 1999).
The pathology of Friedreichs is largely confined to the dorsal root ganglion. Cerebellar neurons are usually normal.
Little treatment is available other than supportive care. A recent trial of Idebenone, a free radical scavenger, resulted in modest reductions in cardiac hypertrophy (Mariotti et al, 2003).
These conditions have two main features -- intermittent imbalance and a familial inheritance pattern.
There are two common variants of episodic ataxia syndrome, called EA1 and EA2, as well as a number of other miscellaneous conditions that have episodic ataxia as a common feature. Many of these syndromes also have other associated neurologic symptoms such as movement disorders, muscular problems, or headache.
See this link for much more detail.
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 Type | findings and comments | Mutation |
| SCA-1 (3-15%) | Hypermetric saccades, slow saccades, UMN | CAG repeat, 6p |
| SCA2 (6-15%) | Diminished velocity saccades, areflexia Common in Cuba. |
CAG repeat, 12q |
| SCA3 (MJD, 30-40%) | Gaze-evoked nystagmus, UMN, slow saccades. Common in the Azores. |
CAG repeat, 14q |
| SCA-4 (17 families) | areflexia | Chromosome 16q |
| SCA-5 | Pure cerebellar | Chromosome 11 |
| SCA-6 | Downbeating nystagmus, positional vertigo Symptoms can appear for the first time as late as 65 years old. |
CAG repeat, 19p (Calcium channel gene) |
| SCA-7 | Macular degeneration, UMN, slow saccades | CAG repeat, 3p |
| SCA-8 | Horizontal nystagmus | CTG repeat, 13q |
| SCA-9 |
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| SCA-10 (Zu et al, 5 families) | ataxia, seizures, primarily in Mexicans | Chromosome 22q linked, pentanucleotide repeat |
| SCA-11 | 15q | |
| SCA-12 (rare, OHearn et al) | Head and hand tremor, akinseia | 5q CAG |
| SCA-13 (rare) | Mental retardation | 19q |
| SCA-14 (rare) | Myoclonus | 19q |
| SCA-16 | Head and hand tremor | 8q |
| DRPLA |
Chorea, seizures, primarily found in Japan |
12p CAG expansion |
| SCA 19, 22 ? | Mild cerebellar syndrome, dysarthria | |
| SCA 25 | ataxia with sensory neuropathy, vomiting and gastrointestinal pain. | 2p |
| Mexican-american pedigree of Grewal et al. | Pure cerebellar | Unknown |
| Mexican family of Matsuura et al | Gaze-evoked nystagmus, seizures | Autosomal dominant, chromosome 22q13-qter |
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%.
SCA2 is associated with marked loss or slowing of saccadic eye movements. There is olivopontocerebellar atrophy. SCA2 maps to chromosome 12q. SCA2 may be the most common of the CAG repeat type autosomal dominant cerebellar ataxias. Saccadic velocity (rapid eye movement velocity) is decreased in SCA2 (Rivaud-Pechoux et al, 1998). In dominant kindreds, Mosely et al found SCA2 in 15.2%.
SCA3, which is dominantly inherited, is also known as Machado-Joseph disease, see also the OMIM entry.
SCA3 is characterized pathologically by spinopontine atrophy, degeneration of the dentate nuclei, vestibular nuclei, extrapyramidal structures, motor cranial nerves, anterior horn cells, and posterior root ganglion, but sparing of the cerebellar cortex. Clinically, it is characterized by cerebellar ataxia, pyramidal tract signs and progressive external ophthalmoplegia. There is often lid retraction producing a characteristic staring expression, termed bulging eyes. (Although this is reported in the literature, we have never encountered this finding in our own clinic population -- and we don't think that this is required). Gaze evoked nystagmus is often present in SCA3 (Rivaud-Pechoux et al, 1998). Restless legs occurs in 45% (Schols, 1998). Fascial and tongue fasciculations are also sometimes present.
MJD was first described in families of Portuguese origin, but it has been documented in many families not of Portuguese ancestry. Several large studies have demonstrated that MJD accounts for about 84% of autosomal dominant SCA in Portuguese, 50% in Germans, and 11 to 29% in other non-Portuguese ethnic populations. The MJD locus has been mapped to chromosome 14q31.1, and the mutation has been demonstrated to be an expansion of a CAG repeat. (Soong et al, 1997). Atrophy of the brainstem and vermis in MJD is closely correlated with both the size of the CAG repeat as well as patient age (Onodera et al, 1998).
Genetic testing is the usual way that MJD is diagnosed. Clinical testing can be suggestive but there is overlap between many other SCAs. VEMP testing (neck) may be reduced in MJD (SCA-3). We illustrate a case of this here.
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.
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.
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).
There are other ataxias which have not been given an "SCA#" nomenclature. Grewal and others (1998) described a new 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 a new autosomal ressive 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.
SCA-17 is an autosomal dominant cerebellar ataxia caused by CAG repeat expansion in the TATA-box binding protein gein. The clinical features include ataxia, dementia, hyperreflexia, parkinsonism manifestations such as bradykinesia, and postural reflex disturbances.
Dentatorubral and pallidoluysian atrophy (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.
Von Hippel-Lindau disease (VHL) manifests by angiomas of the retina and hemangioblastomas of the cerebelum. The gene was mapped to the short arm of Cr3 in 1988 by Seizinger et al (Nature 1988:332:268-269), and isolated in 1993 by Latif (Science 1993:260:1317-1320). Life time risk for renal clear cell carcinoma is 70% and this is the most frequent cause of death. Pheochromocytomas affect 7-20% of cases and can be bilateral or malignant. Non-secretory pancreatic cell tumors also occur. Endolymphatic sac tumors affect about 10% of cases, and VHL should be considered in persons with bilateral endolymphatic sac tumors.
Recently, there has been a peculiar overlapping disorder. Gluten sensitivity (gluten is found in bread) was found in a very high number of patients with genetic cerebellar ataxias as described below (Bushara et al, 2001). If this strange association is confirmed by others, it may become common practice to advise screening for gluten sensitivity in all persons with genetic and idiopathic acquired cerebellar ataxia.
Bushara K, Goebel S, Shill H, Goldfarb L, Hallet M. . Gluten sensitivity in sporadic and hereditary cerebellar ataxia. Ann Neurol 2001:49:540-543
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