Cerebellar Degenerations

Timothy C. Hain, MD

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Last update: Feb 20, 2000

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.

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.

Reference:

Bushara K, Goebel S, Shill H, Goldfarb L, Hallet M. . Gluten sensitivity in sporadic and hereditary cerebellar ataxia. Ann Neurol 2001:49:540-543

 

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).

 

Fredreich's Ataxia.

Friedreich's ataxia is the most common inherited ataxia. 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 Fredreichs is largely confined to the dorsal root ganglion. Cerebellar neurons are usually normal.

FAMILIAL EPISODIC CEREBELLAR ATAXIA

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.

In 1946, Parker described a familial ataxia characterized by attacks of generalized cerebellar ataxia beginning in the 3rd and 4th decade. Vertigo is infrequent and both the trunk and extremities are ataxic. Diplopia and slurring of speech can occur.   Acetazolamide was found to prevent episodic ataxia by Griggs et al in one family, and this medication has also subsequently been found to be useful in both variants (see following as well as this link)

In a second description, Farmer and Mustian (1963) described a family with recurrent vertigo/imbalance beginning in the 2-4th decade, followed by a slowly progressive truncal ataxia. This vestibulocerebellar syndrome is dominantly inherited. It is characterized by episodic ataxia (of course), rebound nystagmus, saccadic overshoot dysmetria, abnormal pursuit and optokinetic nystagmus, and normal semicircular canal responses. About 50% of patients report migraine symptoms. A subtle aspect of otolith related responses, the bias component of OVAR, is reduced in these patients (Furman et al, 1997).  This disorder is linked to chromosome 19p. The abnormal gene apparently encodes a subunit of the calcium channel, and these patients have a decrease in their calcium channel density. A mutation in this gene is also associated with familial hemiplegic migraine, as well as in SCA-6 (see following), but is not involved in the familial variant of benign recurrent vertigo. This episodic ataxia syndrome responds to acetazolamide like the first variant. Another family with a mutation in the calcium channel gene 19p with progressive ataxia was described by Yue et al (1997).

Brandt and Strupp (1997) discuss a nomenclature of EA-1 and EA-2. EA-1 is without vertigo, while EA-2 has vertigo. EA-1 is due to mutations in a potassium channel gene KCNA1 on 12p13, while EA-2 is caused by mutations of a calcium channel gene CACNL1A4 on 19p, which is highly expressed in the cerebellum. EA1 may begin in early childhood with attacks of ataxia lasting minutes and with interictal myokymia. According to Baloh and others (1997), EA2 is characterized by a progressive ataxia with interictal rebound nystagmus evoked by gaze, as well as downbeating nystagmus. Another calcium channelopathy is hypokalemic periodic paralysis which is coded by mutations in CACNA1S. Yet another is caused by a mutation in CACNA1A. It is characterized by episodic ataxia and weakness or hemiplegia. (Jen et al, 1999) Some kindreds have myotonia in addition (Zasorin et al, 1983). Patients with calcium channelopathies including SCA-6 and EA2 have deficient ocular responses to otolith input. These disorders also can present with positional symptoms closely resembling a common ear condition -- benign paroxysmal positional vertigo (BPPV) (Jen et al, 1998).

Another variant, found largely in North Carolina is "periodic vestibulocerebellar ataxia", an autosomal dominant ataxia with defective smooth pursuit. This disorder is genetically distinct from SCA 1,2,3,4,5 as well as episodic ataxia with myokymia (12p), nystagmus (19p), acetazolamide responsive (19p), and DRPLA (12p), according to Damji et al (1996). The acronym "EA3" has been suggested for this syndrome (Steckley et al, 2001). This syndrome does not respond to acetazolamide, has no interictal myokymia, and also have abnormal eye movements.

A fourth variant distinct from EA1 and EA2 has been proposed to be EA4. This disorder includes episodic vestibular ataxia, vertigo, tinnitus, and interictal myokymia. Thus this disorder has symptoms closely resembling Meniere's disease. It is also acetazolamide responsive (Steckley et al, 2001). It was described in a large Canadian kindred of Mennonite heritage. Twelve of 26 individuals had myokymia.

Six other kindreds, representing three distinct syndromes, were described by Gancher and Nutt (1986). One kindred included paroxysmal choreoathetosis.

Several variants of migraine and episodic vertigo have been reported by Baloh. There has recently been a report of a familial vestibulopathy consisting of episodic vertigo and migraine headache. Vestibular testing documents profound bilateral vestibular loss. This syndrome responds to acetazolamide (Baloh et al, 1994). Also reported by Baloh and associates, a form exists with episodic vertigo and essential tremor. This form is also responsive to acetazolamide. (Baloh et al, 1996). Baloh also reported 4 cases of EA2, with classic migraine, linked to chormosome 19p (Baloh et al, 1997). Familial hemiplegic migraine has also been linked to mutations in the calcium channel gene (Ophoff et al, 1996).

Yue et al have speculated that the mechanism for acetazolamide's effect is to decrease pH which inhibits ion permeation through open calcium channels. Acetazolamide might stabilized channels that fail to properly inactivate. Acetazolamide might not work in all cases if the mutation distorted the pore region of the channel, altering the stabilizing effect of H+ ions (Yue et al, 1997).

Familial hemiplegic migraine, is somewhat similar but adds a headache and hemiplegia to the picture. Again dominantly inherited, onset is in childhood or adolescence. Hemiplegia is typically transient but not necessarily. Nystagmus, ataxia and cerebellar atrophy may occur. Impaired P/Q-type calcium channel function is the etiology.

 

SPINOCEREBELLAR ATAXIAS:

All of these disorders exhibit gradually progressive pancerebellar dysfunction, usually beginning in childhood, differentiated by other nervous system involvement. 

SCA Type Oculomotor findings Mutation
SCA-1 (3-15%) Hypermetric saccades, UMN CAG repeat, 6p
SCA2 (6-15%) Diminished velocity saccades, areflexia CAG repeat, 12q
SCA3 (MJD, 30-40%) Gaze-evoked nystagmus, UMN CAG repeat, 14q
SCA-4 (17 families) areflexia Chromosome 16q
SCA-5 Pure cerebellar Chromosome 11
SCA-6 Downbeating nystagmus, positional vertigo CAG repeat, 19p (Calcium channel gene)
SCA-7 Macular degeneration, UMN CAG repeat, 3p
SCA-8 Horizontal nystagmus CTG repeat, 13q
SCA-9    
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

12p CAG expansion
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 A. In trinucleotide repeats, an expansion may increase when passed between an affected parent and his or her affected child -- this is called anticipation.

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 (www.ataxiamjd.org) , see also the OMIM entry. It 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 signs and  progressive external ophthalmoplegia. There is often lid retraction producing a characteristic staring expression, termed bulging eyes. Gaze evoked nystagmus is often present in SCA3 (Rivaud-Pechoux et al, 1998). Restless legs occurs in 45% (Schols, 1998).

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).

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.

 

References

 

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 ell 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.

WHAT CAN YOU DO TO HELP IF YOU HAVE AN SCA ?

  1. Volunteer or otherwise support efforts to do research or disseminate information about SCA
  2. Consider allowing your brain to be autopsied in the event of your death.
  3. See a neurologist yearly to document your clinical course. Keep careful records.

LINKS:

REFERENCES: